METAL MICROELECTRODES
MULTICHANNEL ARRAY
PERIPHERAL ELECTRODES
OTHERS
MONOPOLARCONCENTRICSBIPOLARVIBRATING PROBE
Synaptic phospholipids as a new target for cortical hyperexcitability and E/I balance in psychiatric disorders
Author(s): Thalman, C; Horta, G; Qiao, L; Endle, H; Tegeder, I; Cheng, H; Laube, G; Sigrudsson, T; Hauser, MJ; Tenzer, S; Distler, U; Aoki, J; Morris, AJ; Geisslinger, G; Röper, J; Kirischuk, S; Luhmann, HJ; Radyushkin, K; Nitsch, R; Vogt, J
View details
Hide details
Lysophosphatidic acid (LPA) is a synaptic phospholipid, which regulates cortical excitation/inhibition (E/I) balance and controls sensory information processing in mice and man. Altered synaptic LPA signaling was shown to be associated with psychiatric disorders. Here, we show that the LPA-synthesizing enzyme autotaxin (ATX) is expressed in the astrocytic compartment of excitatory synapses and modulates glutamatergic transmission. In astrocytes, ATX is sorted toward fine astrocytic processes and transported to excitatory but not inhibitory synapses. This ATX sorting, as well as the enzymatic activity of astrocyte-derived ATX are dynamically regulated by neuronal activity via astrocytic glutamate receptors. Pharmacological and genetic ATX inhibition both rescued schizophrenia-related hyperexcitability syndromes caused by altered bioactive lipid signaling in two genetic mouse models for psychiatric disorders. Interestingly, ATX inhibition did not affect naive animals. However, as our data suggested that pharmacological ATX inhibition is a general method to reverse cortical excitability, we applied ATX inhibition in a ketamine model of schizophrenia and rescued thereby the electrophysiological and behavioral schizophrenia-like phenotype. Our data show that astrocytic ATX is a novel modulator of glutamatergic transmission and that targeting ATX might be a versatile strategy for a novel drug therapy to treat cortical hyperexcitability in psychiatric disorders.
Non-rectangular waveforms are more charge-efficient than rectangular one in eliciting network-mediated responses of ON type retinal ganglion cells
Author(s): Lee, J; Im, M
View details
Hide details
Objective. For individuals blinded by outer retinal degenerative diseases, retinal prostheses would be a promising option to restore sight. Unfortunately, however, the best performance of existing devices is still far removed from normal vision. One possible reason for the shortcoming is thought to be suboptimal stimulation conditions such as the waveform shape of electric stimulus. In this study, we explored the effects of varying waveforms on network-mediated responses arising in retinal ganglion cells (RGCs). Approach. We used a cell-attached patch clamp technique to record RGC spiking activities in the isolated mouse retina. ON alpha RGCs were targeted by soma size and their light responses to stationary spot flashes. Spiking in targeted RGCs was measured in response to an epiretinally-delivered cathodal current pulse in four waveforms: rectangular, center triangular, increasing and decreasing ramp shapes. Each waveform was tested at three durations (20, 10, and 5 ms) with adjusted amplitude for a range of total charges (50–400 nC). Main results. ON alpha RGCs always generated two bursts of spikes in responses to all stimuli conditions we tested. However, at a given charge, effects of differing waveforms were distinct in the two bursts.
Ovine model of neuropathic pain for assessing mechanisms of spinal cord stimulation therapy via dorsal horn recordings, von Frey filaments, and gait analysis
Author(s): Reddy, CG; Miller, JW; Abode-Iyamah, KO; Safayi, S; Wilson, S; Dalm, BD; Fredericks, DC; Gillies, GT; Howard, MA; Brennan, TJ
View details
Hide details
It is becoming increasingly important to understand the mechanisms of spinal cord stimulation (SCS) in alleviating neuropathic pain as novel stimulation paradigms arise. Additionally, the small anatomic scale of current SCS animal models is a barrier to more translational research. Using chronic constriction injury (CCI) of the common peroneal nerve (CPN) in sheep (ovine), we have created a chronic model of neuropathic pain that avoids motor deficits present in prior large animal models. This large animal model has allowed us to implant clinical grade SCS hardware, which enables both acute and chronic testing using von Frey filament thresholds and gait analysis. Furthermore, the larger anatomic scale of the sheep allows for simultaneous single-unit recordings from the dorsal horn and SCS with minimal electrical artifact. etectable tactile hypersensitivity occurred 21 days after nerve injury, with preliminary indications that chronic SCS may reverse it in the painful limb. Gait analysis revealed no hoof drop in the CCI model. Single neurons were identified and discriminated in the dorsal horn, and their activity was modulated via SCS. Unlike previous large animal models that employed a complete transection of the nerve, no motor deficit was observed in the sheep with CCI. To our knowledge, this is the first reported large animal model of chronic neuropathic pain which facilitates the study of both acute and chronic SCS using complementary behavioral and electrophysiologic measures. As demonstrated by our successful establishment of these techniques, an ovine model of neuropathic pain is suitable for testing the mechanisms of SCS.
Synaptic phospholipids as a new target for cortical hyperexcitability and E/I balance in psychiatric disorders
Author(s): Thalman, C; Horta, G; Qiao, L; Endle, H; Tegeder, I; Cheng, H; Laube, G; Sigrudsson, T; Hauser, MJ; Tenzer, S; Distler, U; Aoki, J; Morris, AJ; Geisslinger, G; Röper, J; Kirischuk, S; Luhmann, HJ; Radyushkin, K; Nitsch, R; Vogt, J
View details
Hide details
Lysophosphatidic acid (LPA) is a synaptic phospholipid, which regulates cortical excitation/inhibition (E/I) balance and controls sensory information processing in mice and man. Altered synaptic LPA signaling was shown to be associated with psychiatric disorders. Here, we show that the LPA-synthesizing enzyme autotaxin (ATX) is expressed in the astrocytic compartment of excitatory synapses and modulates glutamatergic transmission. In astrocytes, ATX is sorted toward fine astrocytic processes and transported to excitatory but not inhibitory synapses. This ATX sorting, as well as the enzymatic activity of astrocyte-derived ATX are dynamically regulated by neuronal activity via astrocytic glutamate receptors. Pharmacological and genetic ATX inhibition both rescued schizophrenia-related hyperexcitability syndromes caused by altered bioactive lipid signaling in two genetic mouse models for psychiatric disorders. Interestingly, ATX inhibition did not affect naive animals. However, as our data suggested that pharmacological ATX inhibition is a general method to reverse cortical excitability, we applied ATX inhibition in a ketamine model of schizophrenia and rescued thereby the electrophysiological and behavioral schizophrenia-like phenotype. Our data show that astrocytic ATX is a novel modulator of glutamatergic transmission and that targeting ATX might be a versatile strategy for a novel drug therapy to treat cortical hyperexcitability in psychiatric disorders.
Corrosion protection properties of inhibitor containing hybrid PEO-epoxy coating on magnesium
Author(s): Yang, J; Blawert, C; Lamaka, S; Snihirova, D; Lu, X; Di, S; Zheludkevich, M
View details
Hide details
A hybrid PEO-epoxy coating was developed for magnesium. A highly-efficient corrosion inhibitor (3-methysalicylate) was impregnated into the anodized layer, which was sealed by an epoxy layer through dip-coating process. Influence of dip-coating parameters on coating properties was investigated. The corrosion performance was evaluated through general and localized electrochemical techniques. As a result, the epoxy layers registered superior resistance, whereas the anodized layer suppressed corrosion expansion. Longer immersion and triple-dipping favored the production of better sealed epoxy layer. The active protection mechanism was achieved by suppression the re-deposition of detrimental impurity and/or adsorption upon the exposed surface from incorporated inhibitor.
Corrosion behaviour of galvanized steel studied by electrochemical microprobes applied on low-angle cross sections
Author(s): Manhabosco, S; Manhabosco, T; Geoffroy, N; Vignal, V; Dick, L
View details
Hide details
The combined use of the microcapillary cell (MEC) and scanning vibrating electrode technique (SVET) and low-angle cross sections was employed to elucidate the role of each coating region on the protection of the cut-edge corrosion of galvanized steels. Different compounds are involved in the blocking action of the corrosion products: Zincite (ZnO) on the steel substrate, hydrozincite (Zn5(OH)6(CO3)2) at the coating/steel interface, and Simonkolleite (Zn5(OH)8Cl2) and ZnO on the different coating regions in different proportions. The coating surface is also active at the initial stage and during long-term protection and thus, must be considered in experimental simulation of the cut-edge corrosion.
Non-rectangular waveforms are more charge-efficient than rectangular one in eliciting network-mediated responses of ON type retinal ganglion cells
Author(s): Lee, J; Im, M
View details
Hide details
Objective. For individuals blinded by outer retinal degenerative diseases, retinal prostheses would be a promising option to restore sight. Unfortunately, however, the best performance of existing devices is still far removed from normal vision. One possible reason for the shortcoming is thought to be suboptimal stimulation conditions such as the waveform shape of electric stimulus. In this study, we explored the effects of varying waveforms on network-mediated responses arising in retinal ganglion cells (RGCs). Approach. We used a cell-attached patch clamp technique to record RGC spiking activities in the isolated mouse retina. ON alpha RGCs were targeted by soma size and their light responses to stationary spot flashes. Spiking in targeted RGCs was measured in response to an epiretinally-delivered cathodal current pulse in four waveforms: rectangular, center triangular, increasing and decreasing ramp shapes. Each waveform was tested at three durations (20, 10, and 5 ms) with adjusted amplitude for a range of total charges (50–400 nC). Main results. ON alpha RGCs always generated two bursts of spikes in responses to all stimuli conditions we tested. However, at a given charge, effects of differing waveforms were distinct in the two bursts. For the first burst, the increasing ramp was most effective among the four waveforms (p
Effect of twins on the corrosion behavior of Mg–5Y–7Gd–1Nd–0.5Zr Mg alloy
Author(s): Liu, J; Han, E; Song, Y; Shan, D
View details
Hide details
Deformation treatment is an efficient method to improve the mechanical properties of Mg alloys. However, twins inevitably arise during the deformation treatment due to the hexagonal closed–packed crystal structure of Mg. The role of twins in the corrosion behavior of Mg–5Y–7Gd–1Nd–0.5Zr (EW75) Mg alloy was studied by scanning electron microscopy (SEM) observations, scanning Kelvin probe force microscopy (SKPFM), zero–resistance ammeter (ZRA) measurements, scanning vibrating electrode technique (SVET), electrochemical tests and weight loss measurements. It is found that the micro–galvanic corrosion between twins and matrix plays the dual roles: accelerate the dissolution reaction of Mg substrate and promote the formation of surface film. The formation of compact surface film dominates the reactions in the EW75 alloy with twins. As a result, the twins in EW75 alloy can improve the corrosion resistance.
Ovine model of neuropathic pain for assessing mechanisms of spinal cord stimulation therapy via dorsal horn recordings, von Frey filaments, and gait analysis
Author(s): Reddy, CG; Miller, JW; Abode-Iyamah, KO; Safayi, S; Wilson, S; Dalm, BD; Fredericks, DC; Gillies, GT; Howard, MA; Brennan, TJ
View details
Hide details
It is becoming increasingly important to understand the mechanisms of spinal cord stimulation (SCS) in alleviating neuropathic pain as novel stimulation paradigms arise. Additionally, the small anatomic scale of current SCS animal models is a barrier to more translational research. Using chronic constriction injury (CCI) of the common peroneal nerve (CPN) in sheep (ovine), we have created a chronic model of neuropathic pain that avoids motor deficits present in prior large animal models. This large animal model has allowed us to implant clinical grade SCS hardware, which enables both acute and chronic testing using von Frey filament thresholds and gait analysis. Furthermore, the larger anatomic scale of the sheep allows for simultaneous single-unit recordings from the dorsal horn and SCS with minimal electrical artifact. Detectable tactile hypersensitivity occurred 21 days after nerve injury, with preliminary indications that chronic SCS may reverse it in the painful limb. Gait analysis revealed no hoof drop in the CCI model. Single neurons were identified and discriminated in the dorsal horn, and their activity was modulated via SCS. Unlike previous large animal models that employed a complete transection of the nerve, no motor deficit was observed in the sheep with CCI. To our knowledge, this is the first reported large animal model of chronic neuropathic pain which facilitates the study of both acute and chronic SCS using complementary behavioral and electrophysiologic measures. As demonstrated by our successful establishment of these techniques, an ovine model of neuropathic pain is suitable for testing the mechanisms of SCS.
Selective Silencing of Hippocampal Parvalbumin Interneurons Induces Development of Recurrent Spontaneous Limbic Seizures in Mice
Author(s): Drexel, M; Romanov, RA; Wood, J; Weger, S; Heilbronn, R; Wulff, P; Tasan, RO; Harkany, T; Sperk, G
View details
Hide details
Temporal lobe epilepsy (TLE) is the most frequent form of focal epilepsies and is generally associated with malfunctioning of the hippocampal formation. Recently, a preferential loss of parvalbumin (PV) neurons has been observed in the subiculum of TLE patients and in animal models of TLE. To demonstrate a possible causative role of defunct PV neurons in the generation of TLE, we permanently inhibited GABA release selectively from PV neurons of the ventral subiculum by injecting a viral vector expressing tetanus toxin light chain in male mice. Subsequently, mice were subjected to telemetric EEG recording and video monitoring. Eighty-eight percent of the mice presented clusters of spike-wave discharges (C-SWDs; 40.0 ± 9.07/month), and 64% showed spontaneous recurrent seizures (SRSs; 5.3 ± 0.83/month). Mice injected with a control vector presented with neither C-SWDs nor SRSs. No neurodegeneration was observed due to vector injection or SRS. Interestingly, mice that presented with only C-SWDs but no SRSs, developed SRSs upon injection of a subconvulsive dose of pentylenetetrazole after 6 weeks. The initial frequency of SRSs declined by ∼30% after 5 weeks. In contrast to permanent silencing of PV neurons, transient inhibition of GABA release from PV neurons through the designer receptor hM4Di selectively expressed in PV-containing neurons transiently reduced the seizure threshold of the mice but induced neither acute nor recurrent seizures. Our data demonstrate a critical role for perisomatic inhibition mediated by PV-containing interneurons, suggesting that their sustained silencing could be causally involved in the development of TLE.SIGNIFICANCE STATEMENT Development of temporal lobe epilepsy (TLE) generally takes years after an initial insult during which maladaptation of hippocampal circuitries takes place. In human TLE and in animal models of TLE, parvalbumin neurons are selectively lost in the subiculum, the major output area of the hippocampus. The present experiments demonstrate that specific and sustained inhibition of GABA release from parvalbumin-expressing interneurons (mostly basket cells) in sector CA1/subiculum is sufficient to induce hyperexcitability and spontaneous recurrent seizures in mice. As in patients with nonlesional TLE, these mice developed epilepsy without signs of neurodegeneration. The experiments highlight the importance of the potent inhibitory action mediated by parvalbumin cells in the hippocampus and identify a potential mechanism in the development of TLE.
Resistance to action potential depression of a rat axon terminal in vivo
Author(s): Martijn C. Sierksma and J. Gerard G. Borst
View details
Hide details
The shape of the presynaptic action potential (AP) has a strong impact on neurotransmitter release. Because of the small size of most terminals in the central nervous system, little is known about the regulation of their AP shape during natural firing patterns in vivo. The calyx of Held is a giant axosomatic terminal in the auditory brainstem, whose biophysical properties have been well studied in slices. Here, we made whole-cell recordings from calyceal terminals in newborn rat pups. The calyx showed a characteristic burst firing pattern, which has previously been shown to originate from the cochlea. Surprisingly, even for frequencies over 200 Hz, the AP showed little or no depression. Current injections showed that the rate of rise of the AP depended strongly on its onset potential, and that the membrane potential after the AP (Vafter) was close to the value at which no depression would occur during high-frequency activity. Immunolabeling revealed that Nav1.6 is already present at the calyx shortly after its formation, which was in line with the fast recovery from AP depression that we observed in slice recordings. Our findings thus indicate that fast recovery from depression and an inter-AP membrane potential that minimizes changes on the next AP in vivo, together enable high timing precision of the calyx of Held already shortly after its formation.
Altered Expression of Reorganized Inputs as They Ascend From the Cuneate Nucleus to Cortical Area 3b in Monkeys With Long-Term Spinal Cord Injuries.
Author(s): Halder, P; Kambi, N; Chand, P; Jain, N
View details
Hide details
Chronic deafferentations in adult mammals result in reorganization of the brain. Lesions of the dorsal columns of the spinal cord at cervical levels in monkeys result in expansion of the intact chin inputs into the deafferented hand representation in area 3b, second somatosensory (S2) and parietal ventral (PV) areas of the somatosensory cortex, ventroposterior lateral nucleus (VPL) of the thalamus, and cuneate nucleus of the brainstem. Here, we describe the extent and nature of reorganization of the cuneate and gracile nuclei of adult macaque monkeys with chronic unilateral lesions of the dorsal columns, and compare it with the reorganization of area 3b in the same monkeys. In both, area 3b and the cuneate nucleus chin inputs expand to reactivate the deafferented neurons. However, unlike area 3b, neurons in the cuneate nucleus also acquire receptive fields on the shoulder, neck, and occiput. A comparison with the previously published results shows that reorganization in the cuneate nucleus is similar to that in VPL. Thus, the emergent topography following deafferentations by spinal cord injuries undergoes transformation as the reorganized inputs ascend from subcortical nuclei to area 3b. The results help us understand mechanisms of the brain plasticity following spinal cord injuries.
Giant modulation of the electronic band gap of carbon nanotubes by dielectric screening.
Author(s): Aspitarte, L; McCulley, DR; Bertoni, A; Island, JO; Ostermann, M; Rontani, M; Steele, GA; Minot, ED
View details
Hide details
Carbon nanotubes (CNTs) are a promising material for high-performance electronics beyond silicon. But unlike silicon, the nature of the transport band gap in CNTs is not fully understood. The transport gap in CNTs is predicted to be strongly driven by electron-electron (e-e) interactions and correlations, even at room temperature. Here, we use dielectric liquids to screen e-e interactions in individual suspended ultra-clean CNTs. Using multiple techniques, the transport gap is measured as dielectric screening is increased. Changing the dielectric environment from air to isopropanol, we observe a 25% reduction in the transport gap of semiconducting CNTs, and a 32% reduction in the band gap of narrow-gap CNTs. Additional measurements are reported in dielectric oils. Our results elucidate the nature of the transport gap in CNTs, and show that dielectric environment offers a mechanism for significant control over the transport band gap.
Application of SVET/SIET Techniques to Study Healing Processes in Coated Metal Substrates
Author(s): Bastos, A
View details
Hide details
Self-healing has become a hot topic in the field of protective coatings where an intense effort is being carried out to find ways to prolong the service life of both coating and metal substrate. This chapter reviews the use of two localized electrochemical techniques, the Scanning Vibrating Electrode Technique (SVET) and the Scanning Ion-Selective Electrode Technique (SIET) for studying the performance, degradation, and healing processes of coated metals. First, a brief outline of corrosion and corrosion protection, with emphasis on organic coatings, is given to provide the context of the work. This is followed by the concept of self-healing coatings. The principles of SVET and SIET are then presented, together with selected examples of their use. The chapter closes with a discussion on the strategies to probe healing processes and a review of published work.
Influence of the Polyethyleneglycol Plasticizer on the on the Mechanical and Electrochemical Properties of Siloxane Hybrid Films Applied on Tinplate
Author(s): Marcolin, P; Beltrami, L; de Souza, JM; Boniatti, R; Menezes, T; Correa, C; Quevedo, M; Bastos, A; Ferreira, M; Oliveira, C; Moura, A; Führ, LT; Schneider, EL; Kunst, CM
View details
Hide details
The coatings developed by s ol - gel process have been proven to be an efficient alternative for corrosion protection of metal surfaces, especially to replace the chromate technique. The sol - gel processes have several advantages, such as their high purity and an excellent distribution of the components. The objective of this work is to characterize the hybrid films morphologically and electrochemically with different plasticizer concentrations, obtained by sol - gel process applied on tinplate. The film was prepared with two alkoxide pre cursor, 3 - trimethoxysilylpropyl methacrylate (TMSPMA) and tetraethoxysilane (TEOS) with addition of cerium nitrate. The polyethyleneglycol (PEG) was added in four different concentrations and their effect on the film was evaluated. The morphological charac terization was performed by scanning electron microscopy and profilometry. The electrochemical characterization was performed using the electrochemical impedance spectroscopy (EIS) and the scanning vibrating electrode technique (SVET). The results showed t hat the enhanced performance was obtained with the coating containing PEG 20 g.L - 1 because the corrosion of the system, which was detected after 120 hours, showed only two small points of corrosion and only one active. The lowest amount of PEG improved the plasticity and the barrier properties of the hybrid film.
Vision Recovery and Connectivity by Fetal Retinal Sheet Transplantation in an Immunodeficient Retinal Degenerate Rat Model
Author(s): Seiler, MJ; Lin, RE; McLelland, BT; Mathur, A; Lin, B; Sigman, J; De Guzman, AT; Kitzes, LM; Aramant, RB; Thomas, BB
View details
Hide details
Purpose: To characterize a recently developed model, the retinal degenerate immunodeficient S334ter line-3 rat (SD-Foxn1 Tg(S334ter)3Lav) (RD nude rat), and to test whether transplanted rat fetal retinal sheets can elicit lost responses to light. Methods: National Institutes of Health nude rats (SD-Foxn1 Tg) with normal retina were compared to RD nude rats with and without transplant for morphology and visual function. Retinal sheets from transgenic rats expressing human placental alkaline phosphatase (hPAP) were transplanted into the subretinal space of RD nude rats between postnatal day (P) 26 and P38. Transplant morphology was examined in vivo using optical coherence tomography (OCT). Visual function was assessed by optokinetic (OKN) testing, electroretinogram (ERG), and superior colliculus (SC) electrophysiology. Cryostat sections were analyzed for various retinal/synaptic markers and for the expression of donor hPAP. Results: Optical coherence tomography scans showed the placement and laminar development of retinal sheet transplants in the subretinal space. Optokinetic testing demonstrated a deficit in visual acuity in RD nude rats that was improved after retinal sheet transplantation. No ERG responses were detected in the RD nude rats with or without transplantation. Superior colliculus responses were absent in age-matched control and sham surgery RD nude rats; however, robust light-evoked responses were observed in a specific location in the SC of transplanted RD nude rats. Responsive regions corresponded to the area of transplant placement in the eye. The quality of visual responses correlated with transplant organization and placement. Conclusions: The data suggest that retinal sheet transplants integrate into the host retina of RD nude rats and recover significant visual function.
SVET Study of Galvanic Corrosion of Al/Mg2Si Couple in Aqueous Solutions at Different pH
Author(s): Lia, LL; b, ; Zhanga, B; z, ; Tianb, B; Zhoua, Y; Wanga, JQ; Hana, EH; Ke, W
View details
Hide details
The galvanic corrosion behavior between pure Al and synthesized bulk Mg2Si in 0.01 M NaCl solution at different pH values has been investigated by the scanning vibrating electrode technique (SVET). At pH 2, bulk Mg2Si actively dissolves and it acts as an anode. With the increase of exposure time, the anodic activity of Mg2Si decreases drastically and eventually anodic activity appears on Al surface. In alkaline solution, Mg2Si phase always acts as the cathode. The preferential dissolution of Mg and enrichment of Si found by energy dispersive X-ray spectroscopy are responsible for the observed anodic activity decay of Mg2Si in acidic solution. At pH 6, the galvanic corrosion current of Al/Mg2Si couple is much less than those at pH 2 and pH 13, and Mg2Si mainly undergoes self-dissolution. These results indicate that the dealloying of binary Mg2Si phase depends on the solution pH value and corrosion time, which subsequently have a great influence on the galvanic corrosion current of Al/Mg2Si couple.
The BET/BRD inhibitor JQ1 improves brain plasticity in WT and APP mice
Author(s): Benito, E; Ramachandran, B; Schroeder, H; Schmidt, G; Urbanke, H; Burkhardt, S; Capece, V; Dean, C; Fischer, A
View details
Hide details
Histone acetylation is essential for memory formation and its deregulation contributes to the pathogenesis of Alzheimer's disease. Thus, targeting histone acetylation is discussed as a novel approach to treat dementia. The histone acetylation landscape is shaped by chromatin writer and eraser proteins, while readers link chromatin state to cellular function. Chromatin readers emerged novel drug targets in cancer research but little is known about the manipulation of readers in the adult brain. Here we tested the effect of JQ1-a small-molecule inhibitor of the chromatin readers BRD2, BRD3, BRD4 and BRDT-on brain function and show that JQ1 is able to enhance cognitive performance and long-term potentiation in wild-type animals and in a mouse model for Alzheimer's disease. Systemic administration of JQ1 elicited a hippocampal gene expression program that is associated with ion channel activity, transcription and DNA repair. Our findings suggest that JQ1 could be used as a therapy against dementia and should be further tested in the context of learning and memory.
Ablation of neuropsin-neuregulin 1 signaling imbalances ErbB4 inhibitory networks and disrupts hippocampal gamma oscillation
Author(s): Kawata, M; Morikawa, S; Shiosaka, S; Tamura, H
View details
Hide details
Parvalbumin-expressing interneurons are pivotal for the processing of information in healthy brain, whereas the coordination of these functions is seriously disrupted in diseased brain. How these interneurons in the hippocampus participate in pathological functions remains unclear. We previously reported that neuregulin 1 (NRG1)-ErbB4 signaling, which is actuated by neuropsin, is important for coordinating brain plasticity. Neuropsin cleaves mature NRG1 (bound to extracellular glycosaminoglycans) in response to long-term potentiation or depression, liberating a soluble ligand that activates its receptor, ErbB4. Here, we show in mice that kainate-induced status epilepticus transiently elevates the proteolytic activity of neuropsin and stimulates cFos expression with a time course suggesting that activation of ErbB4- and parvalbumin-expressing interneurons follows the excitation and subsequent silencing of pyramidal neurons. In neuropsin-deficient mice, kainate administration impaired signaling and disrupted the neuronal excitation-inhibition balance (E/I balance) in hippocampal networks, by decreasing the activity of parvalbumin-positive interneurons while increasing that of pyramidal neurons, resulting in the progression of status epilepticus. Slow, but not fast, gamma oscillations in neuropsin-deficient mice showed reduced power. Intracerebroventricular infusion of the soluble NRG1 ligand moiety restored the E/I balance, status epilepticus and gamma oscillations to normal levels. These results suggest that the neuropsin-NRG1 signaling system has a role in pathological processes underlying temporal lobe epilepsy by regulating the activity of parvalbumin-expressing interneurons, and that neuropsin regulates E/I balance and gamma oscillations through NRG1-ErbB4 signaling toward parvalbumin-expressing interneurons. This neuronal system may be a useful target of pharmacological therapies against cognitive disorders.
An Integrated Circuit for Simultaneous Extracellular Electrophysiology Recording and Optogenetic Neural Manipulation
Author(s): Chen, CH; McCullagh, EA; Pun, SH; Mak, PU; Vai, MI; Mak, PI; Klug, A; Lei, TC
View details
Hide details
The ability to record and to control action potential firing in neuronal circuits is critical to understand how the brain functions. The objective of this study is to develop a monolithic integrated circuit (IC) to record action potentials and simultaneously control action potential firing using optogenetics. A low-noise and high input impedance (or low input capacitance) neural recording amplifier is combined with a high current laser/light-emitting diode (LED) driver in a single IC. The low input capacitance of the amplifier (9.7 pF) was achieved by adding a dedicated unity gain stage optimized for high impedance metal electrodes. The input referred noise of the amplifier is [Formula: see text], which is lower than the estimated thermal noise of the metal electrode. Thus, the action potentials originating from a single neuron can be recorded with a signal-to-noise ratio of at least 6.6. The LED/laser current driver delivers a maximum current of 330 mA, which is adequate for optogenetic control. The functionality of the IC was tested with an anesthetized Mongolian gerbil and auditory stimulated action potentials were recorded from the inferior colliculus. Spontaneous firings of fifth (trigeminal) nerve fibers were also inhibited using the optogenetic protein Halorhodopsin. Moreover, a noise model of the system was derived to guide the design. A single IC to measure and control action potentials using optogenetic proteins is realized so that more complicated behavioral neuroscience research and the translational neural disorder treatments become possible in the future.
julius seizure, a Drosophila Mutant, Defines a Neuronal Population Underlying Epileptogenesis
Author(s): Horne, M; Krebushevski, K; Wells, A; Tunio, N; Jarvis, C; Francisco, G; Geiss, J; Recknagel, A; Deitcher, DL
View details
Hide details
Epilepsy is a neural disorder characterized by recurrent seizures. Bang-sensitive Drosophila represent an important model for studying epilepsy and neuronal excitability. Previous work identified the bang-sensitive gene slamdance (sda) as an allele of the aminopeptidase N gene. Here we show through extensive genetic analysis, including recombination frequency, deficiency mapping, transposon insertion complementation testing, RNA interference (RNAi), and genetic rescue that the gene responsible for the seizure sensitivity is julius seizure (jus), formerly CG14509, which encodes a novel transmembrane domain protein. We also describe more severe genetic alleles of jus RNAi-mediated knockdown of jus revealed that it is required only in neurons and not glia, and that partial bang-sensitivity is caused by knockdown in GABAergic or cholinergic but not glutamatergic neurons. RNAi knockdown of jus at the early pupal stages leads to strong seizures in adult animals, implicating that stage as critical for epileptogenesis. A C-terminal-tagged version of Jus was generated from a fosmid genomic clone. This fosmid fusion rescued the bang-sensitive phenotype and was expressed in the optic lobes and the subesophageal and thoracic abdominal ganglia. The protein was primarily localized in axons, especially in the neck connectives, extending into the thoracic abdominal ganglion.
Water diffusion closely reveals neural activity status in rat brain loci affected by anesthesia
Author(s): Abe, Y; Tsurugizawa, T; Le Bihan, D
View details
Hide details
Diffusion functional MRI (DfMRI) reveals neuronal activation even when neurovascular coupling is abolished, contrary to blood oxygenation level-dependent (BOLD) functional MRI (fMRI). Here, we show that the water apparent diffusion coefficient (ADC) derived from DfMRI increased in specific rat brain regions under anesthetic conditions, reflecting the decreased neuronal activity observed with local field potentials (LFPs), especially in regions involved in wakefulness. In contrast, BOLD signals showed nonspecific changes, reflecting systemic effects of the anesthesia on overall brain hemodynamics status. Electrical stimulation of the central medial thalamus nucleus (CM) exhibiting this anesthesia-induced ADC increase led the animals to transiently wake up. Infusion in the CM of furosemide, a specific neuronal swelling blocker, led the ADC to increase further locally, although LFP activity remained unchanged, and increased the current threshold awakening the animals under CM electrical stimulation. Oppositely, induction of cell swelling in the CM through infusion of a hypotonic solution (-80 milliosmole [mOsm] artificial cerebrospinal fluid [aCSF]) led to a local ADC decrease and a lower current threshold to wake up the animals. Strikingly, the local ADC changes produced by blocking or enhancing cell swelling in the CM were also mirrored remotely in areas functionally connected to the CM, such as the cingulate and somatosensory cortex. Together, those results strongly suggest that neuronal swelling is a significant mechanism underlying DfMRI.
Microprofiling real time nitric oxide flux for field studies using a stratified nanohybrid carbon–metal electrode
Author(s): Chaturvedi, P; Vanegas, DC; Hauser, BA; Foster, JS; Sepúlveda, MS; McLamore, ES
View details
Hide details
Nitric oxide (NO) is an important signaling molecule that is involved in stress response, homeostasis, host defense, and cell development. In most cells, NO levels are in the femtomolar to micromolar range, with extracellular concentrations being much lower. Thus, real time measurement of spatiotemporal NO dynamics near the surface of living cells/tissues is a major challenge. Here, we report the development, application, and validation of a self referencing (i.e., oscillating) NO microelectrode for field studies of biological cells and tissues. The durable microelectrode is based on a hybrid nanomaterial composed of nanoceria, reduced graphene oxide and nanoplatinum and is intended for field use. One of the main focuses was to address the common pitfall of high overpotential through use of hydrophobic, and size/charge-selective materials in a thin film coated on top of the nanocatalyst sensor. The sensitivity (0.95 ± 0.03 pA nM−1), response time (1.1 ± 0.1 s), operating potential (+720 mV), and selectivity of the nanomaterial-modified microelectrode are similar to laboratory microelectrode designs, enabling studies of NO flux in field studies. NO efflux was first measured from chitosan and alginate polymers in abiotic studies, and a deterministic model used to determine the effective diffusion coefficient for each polymer composite. To demonstrate the practicality of the sensor, NO flux was quantified in three model organisms with known NO pathways, including: bacteria, plant, and an invertebrate animal. For each organism, an established hypothesis was validated based on NO flux measurement and the results confirm data collected using standard analytical techniques. The sensor can be used to expand our fundamental knowledge of NO transport by facilitating field experiments which are not possible with standard techniques.
Sniff invariant odor coding
Author(s): Shusterman, R; Sirotin, YB; Smear, MC; Ahmadian, VO; Rinberg, VO
View details
Hide details
Sampling regulates stimulus intensity and temporal dynamics at the sense organ. Despite variations in sampling behavior, animals must make veridical perceptual judgments about external stimuli. In olfaction, odor sampling varies with respiration, which influences neural responses at the olfactory periphery. Nevertheless, rats were able to perform fine odor intensity judgments despite variations in sniff kinetics. To identify the features of neural activity supporting stable intensity perception, in awake mice we measured responses of Mitral/Tufted (MT) cells to different odors and concentrations across a range of sniff frequencies. Amplitude and latency of the MT cells' responses vary with sniff duration. A fluid dynamics (FD) model based on odor concentration kinetics in the intranasal cavity can account for this variability. Eliminating sniff waveform dependence of MT cell responses using the FD model significantly improves concentration decoding. This suggests potential schemes for sniff waveform invariant odor concentration coding.
A CMOS Current Steering Neurostimulation Array With Integrated DAC Calibration and Charge Balancing.
Author(s): Greenwald, E; Maier, C; Wang, Q; Beaulieu, R; Etienne-Cummings, R; Cauwenberghs, G; Thakor, N
View details
Hide details
An 8-channel current steerable, multi-phasic neural stimulator with on-chip current DAC calibration and residue nulling for precise charge balancing is presented. Each channel consists of two sub-binary radix DACs followed by wide-swing, high output impedance current buffers providing time-multiplexed source and sink outputs for anodic and cathodic stimulation. A single integrator is shared among channels and serves to calibrate DAC coefficients and to closely match the anodic and cathodic stimulation phases. Following calibration, the differential non-linearity is within ±0.3 LSB at 8-bit resolution, and the two stimulation phases are matched within 0.3%. Individual control in digital programming of stimulation coefficients across the array allows altering the spatial profile of current stimulation for selection of stimulation targets by current steering. Combined with the self-calibration and current matching functions, the current steering capabilities integrated on-chip support use in fully implanted neural interfaces with autonomous operation for and adaptive stimulation under variations in electrode and tissue conditions. As a proof-of-concept we applied current steering stimulation through a multi-channel cuff electrode on the sciatic nerve of a rat.
Sensitivity of neurons in the middle temporal area of marmoset monkeys to random dot motion
Author(s): Chaplin, TA; Allitt, BJ; Hagan, MA; Price, NSC; Rajan, R; Rosa, MGP; Lui, LL
View details
Hide details
Neurons in the middle temporal area (MT) of the primate cerebral cortex respond to moving visual stimuli. The sensitivity of MT neurons to motion signals can be characterized by using random-dot stimuli, in which the strength of the motion signal is manipulated by adding different levels of noise (elements that move in random directions). In macaques, this has allowed the calculation of neurometric thresholds. We characterized the responses of MT neurons in sufentanil/nitrous oxide-anesthetized marmoset monkeys, a species that has attracted considerable recent interest as an animal model for vision research. We found that MT neurons show a wide range of neurometric thresholds and that the responses of the most sensitive neurons could account for the behavioral performance of macaques and humans. We also investigated factors that contributed to the wide range of observed thresholds. The difference in firing rate between responses to motion in the preferred and null directions was the most effective predictor of neurometric threshold, whereas the direction tuning bandwidth had no correlation with the threshold. We also showed that it is possible to obtain reliable estimates of neurometric thresholds using stimuli that were not highly optimized for each neuron, as is often necessary when recording from large populations of neurons with different receptive field concurrently, as was the case in this study. These results demonstrate that marmoset MT shows an essential physiological similarity to macaque MT and suggest that its neurons are capable of representing motion signals that allow for comparable motion-in-noise judgments.NEW & NOTEWORTHY We report the activity of neurons in marmoset MT in response to random-dot motion stimuli of varying coherence. The information carried by individual MT neurons was comparable to that of the macaque, and the maximum firing rates were a strong predictor of sensitivity. Our study provides key information regarding the neural basis of motion perception in the marmoset, a small primate species that is becoming increasingly popular as an experimental model.
Representation of egomotion in rat's trident and E-row whisker cortices
Author(s): Chorev, E; Preston-Ferrer, P; Brecht, M
View details
Hide details
The whisker trident, a three-whisker array on the rat's chin, has been implicated in egomotion sensing and might function as a tactile speedometer. Here we study the cortical representation of trident whiskers and E-row whiskers in barrel cortex. Neurons identified in trident cortex of anesthetized animals showed sustained velocity-sensitive responses to ground motion. In freely moving animals, about two-thirds of the units in the trident and E-row whisker cortices were tuned to locomotion speed, a larger fraction of speed-tuned cells than in the somatosensory dysgranular zone. Similarly, more units were tuned to acceleration and showed sensitivity to turning in trident and E-row whisker cortices than in the dysgranular zone. Microstimulation in locomoting animals evoked small but significant speed changes, and such changes were larger in the trident and E-row whisker representations than in the dysgranular zone. Thus, activity in trident and E-row cortices represents egomotion information and influences locomotion behavior.
Spatiotemporal trajectories of reactivation of somatosensory cortex by direct and secondary pathways after dorsal column lesions in squirrel monkeys
Author(s): Qi, HX; Wang, F; Liao, CC; Friedman, RM; Tang, C; Kaas, JH; Avison, MJ
View details
Hide details
After lesions of the somatosensory dorsal column (DC) pathway, the cortical hand representation can become unresponsive to tactile stimuli, but considerable responsiveness returns over weeks of post-lesion recovery. The reactivation suggests that preserved subthreshold sensory inputs become potentiated and axon sprouting occurs over time to mediate recovery. Here, we studied the recovery process in 3 squirrel monkeys, using high-resolution cerebral blood volume-based functional magnetic resonance imaging (CBV-fMRI) mapping of contralateral somatosensory cortex responsiveness to stimulation of distal finger pads with low and high level electrocutaneous stimulation (ES) before and 2, 4, and 6weeks after a mid-cervical level contralateral DC lesion. Both low and high intensity ES of digits revealed the expected somatotopy of the area 3b hand representation in pre-lesion monkeys, while in areas 1 and 3a, high intensity stimulation was more effective in activating somatotopic patterns. Six weeks post-lesion, and irrespective of the severity of loss of direct DC inputs (98%, 79%, 40%), somatosensory cortical area 3b of all three animals showed near complete recovery in terms of somatotopy and responsiveness to low and high intensity ES. However there was significant variability in the patterns and amplitudes of reactivation of individual digit territories within and between animals, reflecting differences in the degree of permanent and/or transient silencing of primary DC and secondary inputs 2weeks post-lesion, and their spatio-temporal trajectories of recovery between 2 and 6weeks. Similar variations in the silencing and recovery of somatotopy and responsiveness to high intensity ES in areas 3a and 1 are consistent with individual differences in damage to and recovery of DC and spinocuneate pathways, and possibly the potentiation of spinothalamic pathways. Thus, cortical deactivation and subsequent reactivation depends not only on the degree of DC lesion, but also on the severity and duration of loss of secondary as well as primary inputs revealed by low and high intensity ES.
Parabrachial complex links pain transmission to descending pain modulation
Author(s): Roeder, Z; Chen, Q; Davis, S; Carlson, JD; Tupone, D; Heinricher, MM
View details
Hide details
The rostral ventromedial medulla (RVM) has a well-documented role in pain modulation and exerts antinociceptive and pronociceptive influences mediated by 2 distinct classes of neurons, OFF-cells and ON-cells. OFF-cells are defined by a sudden pause in firing in response to nociceptive inputs, whereas ON-cells are characterized by a burst of activity. Although these reflex-related changes in ON- and OFF-cell firing are critical to their pain-modulating function, the pathways mediating these responses have not been identified. The present experiments were designed to test the hypothesis that nociceptive input to the RVM is relayed through the parabrachial complex (PB). In electrophysiological studies, ON- and OFF-cells were recorded in the RVM of lightly anesthetized male rats before and after an infusion of lidocaine or muscimol into PB. The ON-cell burst and OFF-cell pause evoked by noxious heat or mechanical probing were substantially attenuated by inactivation of the lateral, but not medial, parabrachial area. Retrograde tracing studies showed that neurons projecting to the RVM were scattered throughout PB. Few of these neurons expressed calcitonin gene-related peptide, suggesting that the RVM projection from PB is distinct from that to the amygdala. These data show that a substantial component of bottom-up nociceptive drive to RVM pain-modulating neurons is relayed through the PB. While the PB is well known as an important relay for ascending nociceptive information, its functional connection with the RVM allows the spinoparabrachial pathway to access descending control systems as part of a recurrent circuit.
Active corrosion protection coating for a ZE41 magnesium alloy created by combining PEO and sol–gel techniques
Author(s): logo, DK; logo, KA; Kallip, S; Lisenkov, AD; logo, MS; Lamakac, SV; Ferreira, MG; Zheludkevich, ML
View details
Hide details
An active protective coating for ZE41 magnesium alloy was produced by sealing an anodic layer, loaded with 1,2,4-triazole, with a sol–gel film. An anodic oxide layer was formed using PEO in a silicate–fluoride alkaline solution. This thin (1.8 μm) porous PEO layer was impregnated with corrosion inhibitor 1,2,4-triazole and sealed with a silica-based sol–gel film modified with titanium oxide. For the first time it was demonstrated that this relatively thin PEO-based composite coating revealed high barrier properties and provided superior protection against corrosion attack during 1 month of continuous exposure to 3% NaCl. A scanning vibrating electrode technique showed a sharp decrease (100 times) of corrosion activity in micro defects formed in the 1,2,4-triazole doped composite coating, when compared to blank samples.
Ipsilateral cortical inputs to the rostral and caudal motor areas in rats
Author(s): Mohammed, H; Jain, N
View details
Hide details
Rats have a complete body representation in the primary motor cortex (M1). Rostrally there are additional representations of the forelimb and whiskers, called the rostral forelimb area (RFA) and the rostral whisker area (RWA). Recently we showed that sources of thalamic inputs to RFA and RWA are similar, but they are different from those for the caudal forelimb area (CFA) and the caudal whisker area (CWA) of M1 (Mohammed and Jain [2014] J Comp Neurol 522:528-545). We proposed that RWA and RFA are part of a second motor area, the rostral motor area (RMA). Here we report ipsilateral cortical connections of whisker representation in RMA, and compare them with connections of CWA. Connections of RFA, CFA, and the caudally located hindlimb area (CHA), which is a part of M1, were determined for comparison. The most distinctive features of cortical inputs to RWA compared with CWA include lack of inputs from the face region of the primary somatosensory cortex (S1), and only about half as much inputs from S1 compared with the lateral somatosensory areas S2 (second somatosensory area) and the parietal ventral area (PV). A similar pattern of inputs is seen for CFA and RFA, with RFA receiving smaller proportion of inputs from the forepaw region of S1 compared with CFA, and receiving fewer inputs from S1 compared with those from S2. These and other features of the cortical input pattern suggest that RMA has a distinct, and more of integrative functional role compared with M1. J. Comp. Neurol. 524:3104-3123, 2016. © 2016 Wiley Periodicals, Inc.
Temporal properties of network-mediated responses to repetitive stimuli are dependent upon retinal ganglion cell type.
Author(s): Im, M; Fried, SI
View details
Hide details
To provide artificially-elicited vision that is temporally dynamic, retinal prosthetic devices will need to repeatedly stimulate retinal neurons. However, given the diversity of physiological types of retinal ganglion cells (RGCs) as well as the heterogeneity of their responses to electric stimulation, temporal properties of RGC responses have not been adequately investigated. Here, we explored the cell type dependence of network-mediated RGC responses to repetitive electric stimulation at various stimulation rates.
A role for acoustic distortion in novel rapid frequency modulation behaviour in free-flying male mosquitoes
Author(s): Simões, PM; Ingham, RA; Gibson, G; Russell, IJ
View details
Hide details
We describe a new stereotypical acoustic behaviour by male mosquitoes in response to the fundamental frequency of female flight tones during mating sequences. This male-specific free-flight behaviour consists of phonotactic flight beginning with a steep increase in wing-beat frequency (WBF) followed by rapid frequency modulation (RFM) of WBF in the lead up to copula formation. Male RFM behaviour involves remarkably fast changes in WBF and can be elicited without acoustic feedback or physical presence of the female. RFM features are highly consistent, even in response to artificial tones that do not carry the multi-harmonic components of natural female flight tones. Comparison between audiograms of the robust RFM behaviour and the electrical responses of the auditory Johnston's organ (JO) reveals that the male JO is tuned not to the female WBF per se but, remarkably, to the difference between the male and female WBFs. This difference is generated in the JO responses as a result of intermodulation distortion products (DPs) caused by non-linear interaction between male-female flight tones in the vibrations of the antenna. We propose that male mosquitoes rely on their own flight tones in making use of DPs to acoustically detect, locate and orientate towards flying females. We argue that the previously documented flight-tone harmonic convergence of flying male and female mosquitoes could be a consequence of WBF adjustments so that DPs generated through flight-tone interaction fall within the optimal frequency ranges for JO detection.
Neural correlates of behavioral amplitude modulation sensitivity in the budgerigar midbrain
Author(s): Henry, KS; Neilans, EG; Abrams, KS; Idrobo, F; Carney, LH
View details
Hide details
Amplitude modulation (AM) is a crucial feature of many communication signals, including speech. Whereas average discharge rates in the auditory midbrain correlate with behavioral AM sensitivity in rabbits, the neural bases of AM sensitivity in species with human-like behavioral acuity are unexplored. Here, we used parallel behavioral and neurophysiological experiments to explore the neural (midbrain) bases of AM perception in an avian speech mimic, the budgerigar (Melopsittacus undulatus). Behavioral AM sensitivity was quantified using operant conditioning procedures. Neural AM sensitivity was studied using chronically implanted microelectrodes in awake, unrestrained birds. Average discharge rates of multiunit recording sites in the budgerigar midbrain were insufficient to explain behavioral sensitivity to modulation frequencies < 100 Hz for both tone- and noise-carrier stimuli, even with optimal pooling of information across recording sites. Neural envelope synchrony, in contrast, could explain behavioral performance for both carrier types across the full range of modulation frequencies studied (16-512 Hz). The results suggest that envelope synchrony in the budgerigar midbrain may underlie behavioral sensitivity to AM. Behavioral AM sensitivity based on synchrony in the budgerigar, which contrasts with rate-correlated behavioral performance in rabbits, raises the possibility that envelope synchrony, rather than average discharge rate, might also underlie AM perception in other species with sensitive AM detection abilities, including humans. These results highlight the importance of synchrony coding of envelope structure in the inferior colliculus. Furthermore, they underscore potential benefits of devices (e.g., midbrain implants) that evoke robust neural synchrony.
Social context differentially modulates activity of two interneuron populations in an avian basal ganglia nucleus
Author(s): Woolley, SC
View details
Hide details
Basal ganglia circuits are critical for the modulation of motor performance across behavioral states. In zebra finches, a cortical-basal ganglia circuit dedicated to singing is necessary for males to adjust their song performance and transition between spontaneous singing, when they are alone (undirected song), and a performance state, when they sing to a female (female-directed song). However, we know little about the role of different basal ganglia cell types in this behavioral transition or the degree to which behavioral context modulates the activity of different neuron classes. To investigate whether interneurons in the songbird basal ganglia encode information about behavioral state, I recorded from two interneuron types, fast-spiking interneurons (FSI) and external pallidal (GPe) neurons, in the songbird basal ganglia nucleus area X during both female-directed and undirected singing. Both cell types exhibited higher firing rates, more frequent bursting, and greater trial-by-trial variability in firing when male zebra finches produced undirected songs compared with when they produced female-directed songs. However, the magnitude and direction of changes to the firing rate, bursting, and variability of spiking between when birds sat silently and when they sang undirected and female-directed song varied between FSI and GPe neurons. These data indicate that social modulation of activity important for eliciting changes in behavioral state is present in multiple cell types within area X and suggests that social interactions may adjust circuit dynamics during singing at multiple points within the circuit.
Development of semi-chronic microdrive system for large-scale circuit mapping in macaque mesolimbic and basal ganglia systems
Author(s): Shaoyu Qiao, ; Brown, KA; Orsborn, AL; Ferrentino, B; Pesaran, B
View details
Hide details
The development of novel neurotechnologies for treating refractory neuropsychiatry disorders depends on understanding and manipulating the dynamics of neural circuits across large-scale brain networks. The mesolimbic pathway plays an essential role in reward processing and mood regulation and disorders of this pathway underlie many neuropsychiatric disorders. Here, we present the design of a customized semi-chronic microdrive array that precisely targets the anatomical structures of non-human primate (NHP) mesolimbic and basal ganglia systems. We present an integrated experimental paradigm that uses this device to map and manipulate large-scale neural circuits. The system combines electrophysiology, spatiotemporal multisite patterned intracortical microstimulation (ICMS), and diffusion tractography. We propose that this system provides a flexible platform for exploring and identifying neural signatures which can serve as novel targets for closed-loop stimulation in the clinical treatment of neuropsychiatric disorders.
Median nerve stimulation reduces ventricular arrhythmias induced by dorsomedial hypothalamic stimulation
Author(s): Zhao, S; Tang, M; Yuan, K; Gu, J; Yu, J; Long, X; Liu, M; Cao, JM; Zhang, S
View details
Hide details
This study tested the hypothesis that median nerve stimulation (MNS) prevents ventricular arrhythmias (VAs) induced by dorsomedial hypothalamus stimulation (DMHS) and investigated the electrophysiological mechanisms underlying the anti-arrhythmic effects of MNS by recording left stellate ganglion activity (LSGA). Eighteen rabbits were anesthetized, the median nerve was anchored by stimulating electrodes, and a bipolar electrode was implanted into the LSG to record nerve activity. The DMH was stimulated to induce arrhythmia. All animals underwent six repetitions of DMHS (30 s). The 18 rabbits were divided into the following 3 groups: a control group, which underwent only DMHS (n = 6); an MNS group, which underwent MNS during both the third and fourth DMHS repetitions (n = 6); and an LSGA-recording group, for which LSGA was recorded at baseline, immediately following DMHS and again immediately following MNS and DMHS (n = 6). Repeated DMHS-induced multiple VAs, in the rabbits. Compared with the DMHS-only group, the concurrent administration of MNS during DMHS significantly reduced the incidence of VAs (7 ± 3 and 9 ± 2 beats for the third and fourth DMHS + MNS repetitions vs. 29 ± 8 and 27 ± 9 beats for the first two DMHS repetitions, p < 0.05). The total duration of the abnormal discharges of the LSG (ADLSG) following MNS and DMHS was significantly reduced compared with that of the DMHS-only group (40 ± 18 vs. 14 ± 6 s, p < 0.05). MNS reduced VAs induced by DMHS, which is thought to be mediated through suppressing of ADLSG. Median nerve electrical stimulation prevented ventricular arrhythmias induced by DMHS through the mechanism of suppressing abnormal discharges of left stellate ganglion.
Fabrication and Microassembly of a mm-Sized Floating Probe for a Distributed Wireless Neural Interface
Author(s): Yeon, P; Mirbozorgi, SA; Ash, B; Eckhardt, H; Ghovanloo, M
View details
Hide details
A new class of wireless neural interfaces is under development in the form of tens to hundreds of mm-sized untethered implants, distributed across the target brain region(s). Unlike traditional interfaces that are tethered to a centralized control unit and suffer from micromotions that may damage the surrounding neural tissue, the new free-floating wireless implantable neural recording (FF-WINeR) probes will be stand-alone, directly communicating with an external interrogator. Towards development of the FF-WINeR, in this paper we describe the micromachining, microassembly, and hermetic packaging of 1-mm3 passive probes, each of which consists of a thinned micromachined silicon die with a centered Ø(diameter) 130 μm through-hole, an Ø81 μm sharpened tungsten electrode, a 7-turn gold wire-wound coil wrapped around the die, two 0201 surface mount capacitors on the die, and parylene-C/Polydimethylsiloxane (PDMS) coating. The fabricated passive probe is tested under a 3-coil inductive link to evaluate power transfer efficiency (PTE) and power delivered to a load (PDL) for feasibility assessment. The minimum PTE/PDL at 137 MHz were 0.76%/240 μW and 0.6%/191 μW in the air and lamb head medium, respectively, with coil separation of 2.8 cm and 9 kΩ receiver (Rx) loading. Six hermetically sealed probes went through wireless hermeticity testing, using a 2-coil inductive link under accelerated lifetime testing condition of 85 °C, 1 atm, and 100%RH. The mean-time-to-failure (MTTF) of the probes at 37 °C is extrapolated to be 28.7 years, which is over their lifetime.
Rebuilding motor function of the spinal cord based on functional electrical stimulation
Author(s): Shen, XY; Du, W; Huang, W; Chen, Y
View details
Hide details
Rebuilding the damaged motor function caused by spinal cord injury is one of the most serious challenges in clinical neuroscience. The function of the neural pathway under the damaged sites can be rebuilt using functional electrical stimulation technology. In this study, the locations of motor function sites in the lumbosacral spinal cord were determined with functional electrical stimulation technology. A three-dimensional map of the lumbosacral spinal cord comprising the relationship between the motor function sites and the corresponding muscle was drawn. Based on the individual experimental parameters and normalized coordinates of the motor function sites, the motor function sites that control a certain muscle were calculated. Phasing pulse sequences were delivered to the determined motor function sites in the spinal cord and hip extension, hip flexion, ankle plantarflexion, and ankle dorsiflexion movements were successfully achieved. The results show that the map of the spinal cord motor function sites was valid. This map can provide guidance for the selection of electrical stimulation sites during the rebuilding of motor function after spinal cord injury.
Information Accumulation over Time in Monkey Inferior Temporal Cortex Neurons Explains Pattern Recognition Reaction Time under Visual Noise
Author(s): Kuboki, R; Sugase-Miyamoto, Y; Matsumoto, N; Richmond, BJ; Shidara, M
View details
Hide details
We recognize objects even when they are partially degraded by visual noise. We studied the relation between the amount of visual noise (5, 10, 15, 20, or 25%) degrading 8 black-and-white stimuli and stimulus identification in 2 monkeys performing a sequential delayed match-to-sample task. We measured the accuracy and speed with which matching stimuli were identified. The performance decreased slightly (errors increased) as the amount of visual noise increased for both monkeys. The performance remained above 80% correct, even with 25% noise. However, the reaction times markedly increased as the noise increased, indicating that the monkeys took progressively longer to decide what the correct response would be as the amount of visual noise increased, showing that the monkeys trade time to maintain accuracy. Thus, as time unfolds the monkeys act as if they are accumulating the information and/or testing hypotheses about whether the test stimulus is likely to be a match for the sample being held in short-term memory. We recorded responses from 13 single neurons in area TE of the 2 monkeys. We found that stimulus-selective information in the neuronal responses began accumulating when the match stimulus appeared. We found that the greater the amount of noise obscuring the test stimulus, the more slowly stimulus-related information by the 13 neurons accumulated. The noise induced slowing was about the same for both behavior and information. These data are consistent with the hypothesis that area TE neuron population carries information about stimulus identity that accumulates over time in such a manner that it progressively overcomes the signal degradation imposed by adding visual noise.
Implantable microcoils for intracortical magnetic stimulation
Author(s): Lee, SW; Fallegger, F; Casse, BD; Fried, SI
View details
Hide details
Neural prostheses that stimulate the neocortex have the potential to treat a wide range of neurological disorders. However, the efficacy of electrode-based implants remains limited, with persistent challenges that include an inability to create precise patterns of neural activity as well as difficulties in maintaining response consistency over time. These problems arise from fundamental limitations of electrodes as well as their susceptibility to implantation and have proven difficult to overcome. Magnetic stimulation can address many of these limitations, but coils small enough to be implanted into the cortex were not thought strong enough to activate neurons. We describe a new microcoil design and demonstrate its effectiveness for both activating cortical neurons and driving behavioral responses. The stimulation of cortical pyramidal neurons in brain slices in vitro was reliable and could be confined to spatially narrow regions ( < 60 μm). The spatially asymmetric fields arising from the coil helped to avoid the simultaneous activation of passing axons. In vivo implantation was safe and resulted in consistent and predictable behavioral responses. The high permeability of magnetic fields to biological substances may yield another important advantage because it suggests that encapsulation and other adverse effects of implantation will not diminish coil performance over time, as happens to electrodes. These findings suggest that a coil-based implant might be a useful alternative to existing electrode-based devices. The enhanced selectivity of microcoil-based magnetic stimulation will be especially useful for visual prostheses as well as for many brain-computer interface applications that require precise activation of the cortex.
Corticotropin releasing factor receptor type 1 signaling in epilepsy and traumatic brain injury
Author(s): Narla, VV
View details
Hide details
A platinum-iridium electrode (Microprobes, Inc., MD, USA) with a tip diameter of 200- 300 micrometers was used to stimulate the lateral olfactory tract of the piriform cortex. The stimulation of each slice was in the range of 160-200 µA, each square pulse was 2.0 ms in length.
Suppression of piriform cortex activity in rat by corticotropin-releasing factor 1 and serotonin 2A/C receptors
Author(s): Narla, C; Dunn, HA; Ferguson, SS; Poulter, MO
View details
Hide details
The piriform cortex (PC) is richly innervated by corticotropin-releasing factor (CRF) and serotonin (5-HT) containing axons arising from central amygdala and Raphe nucleus. CRFR1 and 5-HT2A/2CRs have been shown to interact in manner where CRFR activation subsequently potentiates the activity of 5-HT2A/2CRs. The purpose of this study was to determine how the activation of CRFR1 and/or 5-HT2Rs modulates PC activity at both the circuit and cellular level. Voltage sensitive dye imaging showed that CRF acting through CRFR1 dampened activation of the Layer II of PC and interneurons of endopiriform nucleus. Application of the selective 5-HT2A/CR agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) following CRFR1 activation potentiated this effect. Blocking the interaction between CRFR1 and 5-HT2R with a Tat-CRFR1-CT peptide abolished this potentiation. Application of forskolin did not mimic CRFR1 activity but instead blocked it, while a protein kinase A antagonist had no effect. However, activation and antagonism of protein kinase C (PKC) either mimicked or blocked CRF modulation, respectively. DOI had no effect when applied alone indicating that the prior activation of CRFR1 receptors was critical for DOI to show significant effects similar to CRF. Patch clamp recordings showed that both CRF and DOI reduced the synaptic responsiveness of Layer II pyramidal neurons. CRF had highly variable effects on interneurons within Layer III, both increasing and decreasing their excitability, but DOI had no effect on the excitability of this group of neurons. These data show that CRF and 5-HT, acting through both CRFR1 and 5-HT2A/CRs, reduce the activation of the PC. This modulation may be an important blunting mechanism of stressor behaviors mediated through the olfactory cortex.
The influence of vibration and probe movement on SVET measurements
Author(s): Bastos, AC; Quevedo, MC; Ferreira, MGS
View details
Hide details
This communication describes a set of experiments performed to evaluate the influence of SVET vibration and movement of the probe on the obtained results. Both vibration and movement during scanning stir the solution with the risk of enhancing the oxygen transport to the surface thus increasing the measured currents and accelerating the corrosion process. It is shown that, for the SVET system used, due to its small probe, the effect of the vibration is negligible in normal operation. On the contrary, the movement of the probe during scanning increases the cathodic reaction and smaller excursions or slower movements just marginally reduce this effect. It is also shown that only the region of the sample under the probe is affect and for just brief instants. The overall corrosion in the long run is not influenced and the measured maps only scarcely show any evidences of artifacts introduced by the probe movement.
Evaluation of poly(3,4-ethylenedioxythiophene)/carbon nanotube neural electrode coatings for stimulation in the dorsal root ganglion.
Author(s): Kolarcik, CL; Catt, K; Rost, E; Albrecht, IN; Bourbeau, D; Du, Z; Kozai, TD; Luo, X; Weber, DJ; Cui, XT
View details
Hide details
The dorsal root ganglion is an attractive target for implanting neural electrode arrays that restore sensory function or provide therapy via stimulation. However, penetrating microelectrodes designed for these applications are small and deliver low currents. For long-term performance of microstimulation devices, novel coating materials are needed in part to decrease impedance values at the electrode-tissue interface and to increase charge storage capacity.
Subthalamic deep brain stimulation reduces pathological information transmission to the thalamus in a rat model of parkinsonism
Author(s): Anderson, CJ; Sheppard, DT; Huynh, R; Anderson, DN; Polar, CA; Dorval, AD
View details
Hide details
The degeneration of dopaminergic neurons in the substantia nigra pars compacta leads to parkinsonian motor symptoms via changes in electrophysiological activity throughout the basal ganglia. High-frequency deep brain stimulation (DBS) partially treats these symptoms, but the mechanisms are unclear. We hypothesize that motor symptoms of Parkinson's disease (PD) are associated with increased information transmission from basal ganglia output neurons to motor thalamus input neurons and that therapeutic DBS of the subthalamic nucleus (STN) treats these symptoms by reducing this extraneous information transmission. We tested these hypotheses in a unilateral, 6-hydroxydopamine-lesioned rodent model of hemiparkinsonism. Information transfer between basal ganglia output neurons and motor thalamus input neurons increased in both the orthodromic and antidromic directions with hemiparkinsonian (hPD) onset, and these changes were reversed by behaviorally therapeutic STN-DBS. Omnidirectional information increases in the parkinsonian state underscore the detrimental nature of that pathological information and suggest a loss of information channel independence. Therapeutic STN-DBS reduced that pathological information, suggesting an effective increase in the number of independent information channels. We interpret these data with a model in which pathological information and fewer information channels diminishes the scope of possible motor activities, driving parkinsonian symptoms. In this model, STN-DBS restores information-channel independence by eliminating or masking the parkinsonism-associated information, and thus enlarges the scope of possible motor activities, alleviating parkinsonian symptoms.
Guard cell SLAC1-type anion channels mediate flagellin-induced stomatal closure
Author(s): Guzel Deger, A; Scherzer, S; Nuhkat, M; Kedzierska, J; Kollist, H; Brosché, M; Unyayar, S; Boudsocq, M; Hedrich, R; Roelfsema, MR
View details
Hide details
During infection plants recognize microbe-associated molecular patterns (MAMPs), and this leads to stomatal closure. This study analyzes the molecular mechanisms underlying this MAMP response and its interrelation with ABA signaling. Stomata in intact Arabidopsis thaliana plants were stimulated with the bacterial MAMP flg22, or the stress hormone ABA, by using the noninvasive nanoinfusion technique. Intracellular double-barreled microelectrodes were applied to measure the activity of plasma membrane ion channels. Flg22 induced rapid stomatal closure and stimulated the SLAC1 and SLAH3 anion channels in guard cells. Loss of both channels resulted in cells that lacked flg22-induced anion channel activity and stomata that did not close in response to flg22 or ABA. Rapid flg22-dependent stomatal closure was impaired in plants that were flagellin receptor (FLS2)-deficient, as well as in the ost1-2 (Open Stomata 1) mutant, which lacks a key ABA-signaling protein kinase. By contrast, stomata of the ABA protein phosphatase mutant abi1-1 (ABscisic acid Insensitive 1) remained flg22-responsive. These data suggest that the initial steps in flg22 and ABA signaling are different, but that the pathways merge at the level of OST1 and lead to activation of SLAC1 and SLAH3 anion channels.
Spatial properties of network-mediated response of retinal ganglion cells to electric stimulation
Author(s): Im, M; Fried, SI
View details
Hide details
Retinal prosthetics consistently demonstrate the ability to restore limited visual perception to those blinded from outer retinal degenerative diseases. However, the performance of retinal implants is highly inconsistent and high-density arrays have proven only marginally better than much sparser ones suggesting that improving the overall quality of elicited vision may require more than just a high density electrode array. Existing devices are also implanted subretinally and epiretinally raising the possibility that electrode location also contributes to percept quality. Here, we compared the responses to stimulation from subretinal and epiretinal electrodes in the same cell. Use of a 4×4 subretinal electrode array allowed us to also compare responses to different numbers of electrodes activated simultaneously. Surprisingly, responses showed minimal dependence of both the electrode position (epiretinal vs. subretinal) as well as on electrode size (one vs. up to nine electrodes). However, when charge density considerations are implemented, such as those that are necessary during clinical use, the responses arising from smaller electrodes were less effective. This finding may help to explain the inconsistency between theoretical visual acuity and achievement in clinical testing with the high density implanted arrays.
Conjunctive input processing drives feature selectivity in hippocampal CA1 neurons
Author(s): Bittner, KC; Grienberger, C; Vaidya, SP; Milstein, AD; Macklin, JJ; Suh, J; Tonegawa, S; Magee, JC
View details
Hide details
Feature-selective firing allows networks to produce representations of the external and internal environments. Despite its importance, the mechanisms generating neuronal feature selectivity are incompletely understood. In many cortical microcircuits the integration of two functionally distinct inputs occurs nonlinearly through generation of active dendritic signals that drive burst firing and robust plasticity. To examine the role of this processing in feature selectivity, we recorded CA1 pyramidal neuron membrane potential and local field potential in mice running on a linear treadmill. We found that dendritic plateau potentials were produced by an interaction between properly timed input from entorhinal cortex and hippocampal CA3. These conjunctive signals positively modulated the firing of previously established place fields and rapidly induced new place field formation to produce feature selectivity in CA1 that is a function of both entorhinal cortex and CA3 input. Such selectivity could allow mixed network level representations that support context-dependent spatial maps.
Reward modulates the effect of visual cortical microstimulation on perceptual decisions
Author(s): Cicmil, N; Cumming, BG; Parker, AJ; Krug, K
View details
Hide details
Effective perceptual decisions rely upon combining sensory information with knowledge of the rewards available for different choices. However, it is not known where reward signals interact with the multiple stages of the perceptual decision-making pathway and by what mechanisms this may occur. We combined electrical microstimulation of functionally specific groups of neurons in visual area V5/MT with performance-contingent reward manipulation, while monkeys performed a visual discrimination task. Microstimulation was less effective in shifting perceptual choices towards the stimulus preferences of the stimulated neurons when available reward was larger. Psychophysical control experiments showed this result was not explained by a selective change in response strategy on microstimulated trials. A bounded accumulation decision model, applied to analyse behavioural performance, revealed that the interaction of expected reward with microstimulation can be explained if expected reward modulates a sensory representation stage of perceptual decision-making, in addition to the better-known effects at the integration stage.
Genetic dissection of the Down syndrome critical region
Author(s): Jiang, X; Liu, C; Yu, T; Zhang, L; Meng, K; Xing, Z; Belichenko, PV; Kleschevnikov, AM; Pao, A; Peresie, J; Wie, S; Mobley, WC; Yu, YE
View details
Hide details
Down syndrome (DS), caused by trisomy 21, is the most common chromosomal disorder associated with developmental cognitive deficits. Despite intensive efforts, the genetic mechanisms underlying developmental cognitive deficits remain poorly understood, and no treatment has been proven effective. The previous mouse-based experiments suggest that the so-called Down syndrome critical region of human chromosome 21 is an important region for this phenotype, which is demarcated by Setd4/Cbr1 and Fam3b/Mx2. We first confirmed the importance of the Cbr1-Fam3b region using compound mutant mice, which carry a duplication spanning the entire human chromosome 21 orthologous region on mouse chromosome 16 [Dp(16)1Yey] and Ms1Rhr. By dividing the Setd4-Mx2 region into complementary Setd4-Kcnj6 and Kcnj15-Mx2 intervals, we started an unbiased dissection through generating and analyzing Dp(16)1Yey/Df(16Setd4-Kcnj6)Yey and Dp(16)1Yey/Df(16Kcnj15-Mx2)Yey mice. Surprisingly, the Dp(16)1Yey-associated cognitive phenotypes were not rescued by either deletion in the compound mutants, suggesting the possible presence of at least one causative gene in each of the two regions. The partial rescue by a Dyrk1a mutation in a compound mutant carrying Dp(16)1Yey and the Dyrk1a mutation confirmed the causative role of Dyrk1a, whereas the absence of a similar rescue by Df(16Dyrk1a-Kcnj6)Yey in Dp(16)1Yey/Df(16Dyrk1a-Kcnj6)Yey mice demonstrated the importance of Kcnj6. Our results revealed the high levels of complexities of gene actions and interactions associated with the Setd4/Cbr1-Fam3b/Mx2 region as well as their relationship with developmental cognitive deficits in DS.
Indirect activation elicits strong correlations between light and electrical responses in ON but not OFF retinal ganglion cells
Author(s): Im, M; Fried, SI
View details
Hide details
To improve the quality of vision elicited by retinal prosthetics, elicited neural activity should resemble physiological signalling patterns; here, we hypothesized that electric stimulation that activates the synaptic circuitry of the retina would lead to closer matches than that which activates ganglion cells directly. We evaluated this hypothesis by comparing light and electrical responses in different types of ganglion cells. In contrast to the similarity in their light responses, electrical responses in ON and OFF cells of the same type were quite distinct. Further, electrical and light responses in the same cell were much better correlated in ON vs. OFF ganglion cells. Stimuli that activated photoreceptors yielded better correlations than those which activated bipolar cells. Our results suggest that the closer match to physiology in the ON signal transmitted to the brain may help to explain preferential reports of 'bright' phosphenes during earlier clinical trials. To improve the efficacy of microelectronic retinal prosthetics it will be necessary to better understand the response of retinal neurons to electric stimulation. While stimulation that directly activates ganglion cells generally has the lowest threshold, the similarity in responsiveness across cells makes it extremely difficult for such an approach to re-create cell-type specific patterns of neural activity that arise normally in the healthy retina. In contrast, stimulation that activates neurons presynaptic to ganglion cells utilizes at least some of the existing retinal circuitry and therefore is thought to produce neural activity that better matches physiological signalling. Surprisingly, the actual benefit(s) of this approach remain unsubstantiated. Here, we recorded from ganglion cells in the rabbit retinal explant in response to electrical stimuli that activated the network. Targeted cells were first classified into known types via light responses so that the consistency of electrical responses within individual types could be evaluated. Both transient and sustained ON ganglion cells exhibited highly consistent electrical response patterns which were distinct from one another. Further, properties of the response (interspike interval, latency, peak firing rate, and spike count) in a given cell were well correlated to the corresponding properties of the light response for that same cell. Electric responses in OFF ganglion cells formed two groups, distinct from ON groups, and the correlation levels between electric and light responses were much weaker. The closer match in ON pathway responses may help to explain some preferential reporting of bright stimuli during psychophysical testing.
Deep brain stimulation of the subthalamic nucleus reestablishes neuronal information transmission in the 6-OHDA rat model of parkinsonism
Author(s): Dorval, AD; Grill, WM
View details
Hide details
Pathophysiological activity of basal ganglia neurons accompanies the motor symptoms of Parkinson's disease. High-frequency (>90 Hz) deep brain stimulation (DBS) reduces parkinsonian symptoms, but the mechanisms remain unclear. We hypothesize that parkinsonism-associated electrophysiological changes constitute an increase in neuronal firing pattern disorder and a concomitant decrease in information transmission through the ventral basal ganglia, and that effective DBS alleviates symptoms by decreasing neuronal disorder while simultaneously increasing information transfer through the same regions. We tested these hypotheses in the freely behaving, 6-hydroxydopamine-lesioned rat model of hemiparkinsonism. Following the onset of parkinsonism, mean neuronal firing rates were unchanged, despite a significant increase in firing pattern disorder (i.e., neuronal entropy), in both the globus pallidus and substantia nigra pars reticulata. This increase in neuronal entropy was reversed by symptom-alleviating DBS. Whereas increases in signal entropy are most commonly indicative of similar increases in information transmission, directed information through both regions was substantially reduced (>70%) following the onset of parkinsonism. Again, this decrease in information transmission was partially reversed by DBS. Together, these results suggest that the parkinsonian basal ganglia are rife with entropic activity and incapable of functional information transmission. Furthermore, they indicate that symptom-alleviating DBS works by lowering the entropic noise floor, enabling more information-rich signal propagation. In this view, the symptoms of parkinsonism may be more a default mode, normally overridden by healthy basal ganglia information. When that information is abolished by parkinsonian pathophysiology, hypokinetic symptoms emerge
Ultra-low power neural stimulator for electrode interfaces
Author(s): Nag, S; Sharma, D; Thakor, NV
View details
Hide details
Power loss at the output stage of conventional constant current neural stimulators is notably high. This is particularly disadvantageous for applications in implantable systems where power budget is limited. We present a novel electrical stimulator architecture for significantly reduced power loss and low noise operation. The system generates a calibrated output voltage profile for driving electrode impedance with an approximate biphasic current stimulation. The stimulator utilizes switched-capacitor output driver stage and low speed operations for substantial reduction in power loss. The hardware is capable of generating on-demand clock signals for appropriate switching events through a feedback mechanism. The self-clocking ultra-low power stimulator front-end and its controller exhibits quasi-stable quiescent power consumption of 3.75 μW and raw efficiency up to 98%. The low power stimulator architecture consumes nearly 70% less power than conventional linear mode stimulators and half of the reported state-of-the art design. Output peak-to-peak noise down to 20 mV is achieved through this design. Demonstrations are shown with RC impedance, platinum-iridium electrode in saline solution and in-vivo somatosensory cortex stimulation.
A graphene oxide nanocomposite for neural interfacing applications
Author(s): Weaver, CL
View details
Hide details
… GO/PEDOT films were electrodeposited onto platinum/iridium (Pt/Ir) microelectrodes (standard tip, diameter: 2-3 m, MicroProbes, Gaithersburg, MD) for electrochemical characterization or gold sputtered plastic microscope coverslips (macroelectrode area: 0.38 cm2) for surface …
Tunable, spatially addressable functionalization strategies for micro/nano scale, multi-analyte biosensors
Author(s): Madangopal, R
View details
Hide details
… Platinum/Iridium (Pt/Ir) microelectrodes (PI20033.0A10, Microprobes Inc., Gaithersburg, MD) with 256 m diameter shaft, 3 m parylene C insulation, 13 m exposed tip diameter and, 3.0M impedance were used for the design and characterization of the three-layer functionalization …
Large-scale reorganization of the somatosensory cortex following spinal cord injuries is due to brainstem plasticity
Author(s): Kambi, N; Halder, P; Rajan, R; Arora, V; Chand, P; Arora, M; Jain, N
View details
Hide details
Adult mammalian brains undergo reorganization following deafferentations due to peripheral nerve, cortical or spinal cord injuries. The largest extent of cortical reorganization is seen in area 3b of the somatosensory cortex of monkeys with chronic transection of the dorsal roots or dorsal columns of the spinal cord. These injuries cause expansion of intact face inputs into the deafferented hand cortex, resulting in a change of representational boundaries by more than 7 mm. Here we show that large-scale reorganization in area 3b following spinal cord injuries is due to changes at the level of the brainstem nuclei and not due to cortical mechanisms. Selective inactivation of the reorganized cuneate nucleus of the brainstem eliminates observed face expansion in area 3b. Thus, the substrate for the observed expanded face representation in area 3b lies in the cuneate nucleus.
The degradation of glial scar and enhancement of chronic intracortical recording electrode performance through the local delivery of dexamethasone and chondroitinase
Author(s): Alba, NA
View details
Hide details
… (a and d Microprobes for Life Science, Inc … Simple electrode/cannula implants were hand-fabricated by adhering two tungsten microwire electrodes (Microprobes for Life Science, Gaithersburg MD) to opposite sides of CMA cannulae using UV-activated cement (Fig. 2.4) …
Novel flexible Parylene neural probe with 3D sheath structure for enhancing tissue integration
Author(s): Kuo, JT; Kim, BJ; Hara, SA; Lee, CD; Gutierrez, CA; Hoang, TQ; Meng, E
View details
Hide details
A Parylene C neural probe with a three dimensional sheath structure was designed, fabricated, and characterized. Multiple platinum (Pt) electrodes for recording neural signals were fabricated on both inner and outer surfaces of the sheath structure. Thermoforming of Parylene was used to create the three dimensional sheath structures from flat surface micromachined microchannels using solid microwires as molds. Benchtop electrochemical characterization was performed on the thin film Pt electrodes using cyclic voltammetry and electrochemical impedance spectroscopy and showed that electrodes possessed low impedances suitable for neuronal recordings. A procedure for implantation of the neural probe was developed and successfully demonstrated in vitro into an agarose brain tissue model. The electrode-lined sheath will be decorated with eluting neurotrophic factors to promote in vivo neural tissue ingrowth post-implantation. These features will enhance tissue integration and improve recording quality towards realizing reliable chronic neural interfaces.
Midbrain raphe stimulation improves behavioral and anatomical recovery from fluid-percussion brain injury
Author(s): Carballosa Gonzalez, MM; Blaya, MO; Alonso, OF; Bramlett, HM; Hentall, ID
View details
Hide details
The midbrain median raphe (MR) and dorsal raphe (DR) nuclei were tested for their capacity to regulate recovery from traumatic brain injury (TBI). An implanted, wireless self-powered stimulator delivered intermittent 8-Hz pulse trains for 7 days to the rat's MR or DR, beginning 4-6 h after a moderate parasagittal (right) fluid-percussion injury. MR stimulation was also examined with a higher frequency (24 Hz) or a delayed start (7 days after injury). Controls had sham injuries, inactive stimulators, or both. The stimulation caused no apparent acute responses or adverse long-term changes. In water-maze trials conducted 5 weeks post-injury, early 8-Hz MR and DR stimulation restored the rate of acquisition of reference memory for a hidden platform of fixed location. Short-term spatial working memory, for a variably located hidden platform, was restored only by early 8-Hz MR stimulation. All stimulation protocols reversed injury-induced asymmetry of spontaneous forelimb reaching movements tested 6 weeks post-injury. Post-mortem histological measurement at 8 weeks post-injury revealed volume losses in parietal-occipital cortex and decussating white matter (corpus callosum plus external capsule), but not hippocampus. The cortical losses were significantly reversed by early 8-Hz MR and DR stimulation, the white matter losses by all forms of MR stimulation. The generally most effective protocol, 8-Hz MR stimulation, was tested 3 days post-injury for its acute effect on forebrain cyclic adenosine monophosphate (cAMP), a key trophic signaling molecule. This procedure reversed injury-induced declines of cAMP levels in both cortex and hippocampus. In conclusion, midbrain raphe nuclei can enduringly enhance recovery from early disseminated TBI, possibly in part through increased signaling by cAMP in efferent targets. A neurosurgical treatment for TBI using interim electrical stimulation in raphe repair centers is suggested.
The inferior colliculus encodes the Franssen auditory spatial illusion
Author(s): Rajala, AZ; Yan, Y; Dent, ML; Populin, LC
View details
Hide details
Illusions are effective tools for the study of the neural mechanisms underlying perception because neural responses can be correlated to the physical properties of stimuli and the subject's perceptions. The Franssen illusion (FI) is an auditory spatial illusion evoked by presenting a transient, abrupt tone and a slowly rising, sustained tone of the same frequency simultaneously on opposite sides of the subject. Perception of the FI consists of hearing a single sound, the sustained tone, on the side that the transient was presented. Both subcortical and cortical mechanisms for the FI have been proposed, but, to date, there is no direct evidence for either. The data show that humans and rhesus monkeys perceive the FI similarly. Recordings were taken from single units of the inferior colliculus in the monkey while they indicated the perceived location of sound sources with their gaze. The results show that the transient component of the Franssen stimulus, with a shorter first spike latency and higher discharge rate than the sustained tone, encodes the perception of sound location. Furthermore, the persistent erroneous perception of the sustained stimulus location is due to continued excitation of the same neurons, first activated by the transient, by the sustained stimulus without location information. These results demonstrate for the first time, on a trial-by-trial basis, a correlation between perception of an auditory spatial illusion and a subcortical physiological substrate.
Gain control of γ frequency activation by a novel feed forward disinhibitory loop: implications for normal and epileptic neural activity
Author(s): Birjandian, Z; Narla, C; Poulter, MO
View details
Hide details
The inhibition of excitatory (pyramidal) neurons directly dampens their activity resulting in a suppression of neural network output. The inhibition of inhibitory cells is more complex. Inhibitory drive is known to gate neural network synchrony, but there is also a widely held view that it may augment excitability by reducing inhibitory cell activity, a process termed disinhibition. Surprisingly, however, disinhibition has never been demonstrated to be an important mechanism that augments or drives the activity of excitatory neurons in a functioning neural circuit. Using voltage sensitive dye imaging (VSDI) we show that 20-80 Hz stimulus trains, β-γ activation, of the olfactory cortex pyramidal cells in layer II leads to a subsequent reduction in inhibitory interneuron activity that augments the efficacy of the initial stimulus. This disinhibition occurs with a lag of about 150-250 ms after the initial excitation of the layer 2 pyramidal cell layer. In addition, activation of the endopiriform nucleus also arises just before the disinhibitory phase with a lag of about 40-80 ms. Preventing the spread of action potentials from layer II stopped the excitation of the endopiriform nucleus, abolished the disinhibitory activity, and reduced the excitation of layer II cells. After the induction of experimental epilepsy the disinhibition was more intense with a concomitant increase in excitatory cell activity. Our observations provide the first evidence of feed forward disinhibition loop that augments excitatory neurotransmission, a mechanism that could play an important role in the development of epileptic seizures.
Pure Graphene Oxide Doped Conducting Polymer Nanocomposite for Bio-interfacing
Author(s): Luo, X; Weaver, CL; Tan, S; Cui, XT
View details
Hide details
Advanced materials that are highly biocompatible and easily modifiable with biomolecules are of great importance for bio-interfacing and the development of biodevices. Here, a biocompatible conducting polymer based nanocomposite was electrochemically synthesized through the electropolymerization of poly(3, 4-ethylene dioxythiophene) (PEDOT) in the presence of graphene oxide (GO) as the only dopant. GO contains many negatively charged carboxyl functional groups and is highly dispersible in aqueous solutions, enabling its facile incorporation and even distribution throughout the conducting polymer. PEDOT/GO films exhibited minimal cytotoxicity after 24 h and supported neuron growth with significantly longer neurites than a control PEDOT/PSS film, indicating that the PEDOT/GO film provides a positive growth signal to developing neurons. While some of the negatively charged functional carboxyl groups of GO dope the PEDOT, others are exposed freely on the surface of the nanocomposite allowing easy functionalization of the PEDOT/GO composite with biomolecules. Functional laminin peptide, RNIAEIIKDI (p20), was covalently bound to the surface of the PEDOT/GO film and maintained its bioactivity, as evidenced by an increased neurite outgrowth from neurons cultured on the functionalized composite surface. The ease of biomolecule functionalization of the PEDOT/GO nanocomposite, along with its low electrochemical impedance, minimal toxicity and permissiveness to neuron growth, underlines its potential as a material for widespread biosensing, neural interfacing and tissue engineering applications.
Effect of hypothermia on cortical and thalamic signals in anesthetized rats
Author(s): Chen, C; Maybhate, A; Thakor, NV; Jia, X
View details
Hide details
Beneficial effects of hypothermia on subjects with neuro-pathologies have been well demonstrated in both animal studies and clinical trials. Although it is known that temperature significantly impacts neurological injuries, the underlying mechanism remains unclear. We studied the effect of temperature modulation on neural signals in the cortex and the thalamus in uninjured brains of anesthetized rats. Six rats were divided into a hypothermic (32 to 34 °C, n=3) and a hyperthermic group (38.5 to 39.5 °C, n=3). EEG, and extracellular signals from somatosensory cortex and the ventral posterolateral nucleus of thalamus were recorded at different temperature phases (normothermia (36.5 to 37.5 °C) and hypothermia or hyperthermia). During hypothermia, similar burst suppression (BS) patterns were observed in cortical and thalamic signals as in EEG, but thalamic activity was not completely under suppression when both EEG and cortical signals were electrically silent. In addition, our results showed that hypothermia significantly increased the burst suppression ratio (BSR) in EEG, cortical and thalamic signals by 3.42, 3.25, 7.29 times respectively (P<0.01), and prolonged the latency of neuronal response in cortex to median nerve stimulation from 9 ms to 16 ms (P<0.01). Furthermore, during normothermia, the correlation coefficient between thalamic and cortical signals was 0.35±0.02 while during hypothermia, it decreased to 0.16±0.03 with statistical significance (P<0.01). These results can potentially assist in better understanding the effects of hypothermia.
A long-lasting wireless stimulator for small mammals
Author(s): Hentall, ID
View details
Hide details
The chronic effects of electrical stimulation in unrestrained awake rodents are best studied with a wireless neural stimulator that can operate unsupervised for several weeks or more. A robust, inexpensive, easily built, cranially implantable stimulator was developed to explore the restorative effects of brainstem stimulation after neurotrauma. Its connectorless electrodes directly protrude from a cuboid epoxy capsule containing all circuitry and power sources. This physical arrangement prevents fluid leaks or wire breakage and also simplifies and speeds implantation. Constant-current pulses of high compliance (34 volts) are delivered from a step-up voltage regulator under microprocessor control. A slowly pulsed magnetic field controls activation state and stimulation parameters. Program status is signaled to a remote reader by interval-modulated infrared pulses. Capsule size is limited by the two batteries. Silver oxide batteries rated at 8 mA-h were used routinely in 8 mm wide, 15 mm long and 4 mm high capsules. Devices of smaller contact area (5 by 12 mm) but taller (6 mm) were created for mice. Microstimulation of the rat's raphe nuclei with intermittent 5-min (50% duty cycle) trains of 30 μA, 1 ms pulses at 8 or 24 Hz frequency during 12 daylight hours lasted 21.1 days ±0.8 (mean ± standard error, Kaplan-Meir censored estimate, n = 128). Extended lifetimes (>6 weeks, no failures, n = 16) were achieved with larger batteries (44 mA-h) in longer (18 mm), taller (6 mm) capsules. The circuit and electrode design are versatile; simple modifications allowed durable constant-voltage stimulation of the rat's sciatic nerve through a cylindrical cathode from a subcutaneous pelvic capsule. Devices with these general features can address in small mammals many of the biological and technical questions arising neurosurgically with prolonged peripheral or deep brain stimulation.
Blink perturbation effects on saccades evoked by microstimulation of the superior colliculus
Author(s): Katnani, HA; Van Opstal, AJ; Gandhi, NJ
View details
Hide details
Current knowledge of saccade-blink interactions suggests that blinks have paradoxical effects on saccade generation. Blinks suppress saccade generation by attenuating the oculomotor drive command in structures like the superior colliculus (SC), but they also disinhibit the saccadic system by removing the potent inhibition of pontine omnipause neurons (OPNs). To better characterize these effects, we evoked the trigeminal blink reflex by delivering an air puff to one eye as saccades were evoked by sub-optimal stimulation of the SC. For every stimulation site, the peak and average velocities of stimulation with blink movements (SwBMs) were lower than stimulation-only saccades (SoMs), supporting the notion that the oculomotor drive is weakened in the presence of a blink. In contrast, the duration of the SwBMs was longer, consistent with the hypothesis that the blink-induced inhibition of the OPNs could prolong the window of time available for oculomotor commands to drive an eye movement. The amplitude of the SwBM could also be larger than the SoM amplitude obtained from the same site, particularly for cases in which blink-associated eye movements exhibited the slowest kinematics. The results are interpreted in terms of neural signatures of saccade-blink interactions.
A test of spatial temporal decoding mechanisms in the superior colliculus.
Author(s): Katnani, HA; Van Opstal, AJ; Gandhi, NJ
View details
Hide details
Population coding is a ubiquitous principle in the nervous system for the proper control of motor behavior. A significant amount of research is dedicated to studying population activity in the superior colliculus (SC) to investigate the motor control of saccadic eye movements. Vector summation with saturation (VSS) has been proposed as a mechanism for how population activity in the SC can be decoded to generate saccades. Interestingly, the model produces different predictions when decoding two simultaneous populations at high vs. low levels of activity. We tested these predictions by generating two simultaneous populations in the SC with high or low levels of dual microstimulation. We also combined varying levels of stimulation with visually induced activity. We found that our results did not perfectly conform to the predictions of the VSS scheme and conclude that the simplest implementation of the model is incomplete. We propose that additional parameters to the model might account for the results of this investigation.
The relative impact of microstimulation parameters on movement generation
Author(s): Katnani, HA; Gandhi, NJ
View details
Hide details
Microstimulation is widely used in neurophysiology to characterize brain areas with behavior and in clinical therapeutics to treat neurological disorder. Current intensity and frequency, which respectively influence activation patterns in spatial and temporal domains, are typically selected to elicit a desired response, but their effective influence on behavior has not been thoroughly examined. We delivered microstimulation to the primate superior colliculus while systematically varying each parameter to capture effects of a large range of parameter space. We found that frequency was more effective in driving output properties, whereas properties changed gradually with intensity. Interestingly, when different parameter combinations were matched for total charge, effects on behavioral properties became seemingly equivalent. This study provides a first level resource for choosing desired parameter ranges to effectively manipulate behavior. It also provides insights into interchangeability of parameters, which can assist clinical microstimulation that looks to appropriately control behavior within designated constraints, such as power consumption.
Spatial manipulation of cells and organelles using single electrode dielectrophoresis
Author(s): Graham, DM; Messerli, MA; Pethig, R
View details
Hide details
The selection, isolation, and accurate positioning of single cells in three dimensions are increasingly desirable in many areas of cell biology and tissue engineering. We describe the application of a simple and low cost dielectrophoretic device for picking out and relocating single target cells. The device consists of a single metal electrode and an AC signal generator. It does not require microfabrication technologies or sophisticated electronics. The dielectrophoretic manipulator also discriminates between live and dead cells and is capable of redistributing intracellular organelles.
Mineral fine structure of the American lobster cuticle
Author(s): Kunkel, JG; Nagel, W; Jercinovic, MJ
View details
Hide details
A major role of lobster integument is protection from microbes. Calcite and amorphous calcium carbonate are the most abundant and most acid vulnerable of the cuticle minerals. We propose that calcite is invested in neutralizing an acidifying environment modulated by the epicuticle. A minor cuticle component is carbonate apatite (CAP), proposed to play critical roles in the integument's structural protective function. The CAP of lobster exhibits a flexible composition; its least soluble forms line the cuticular canals most exposed to the environment. A trabecular CAP structure illustrates efficient use of a sparse phosphate resource, cooperating in the hardness of the inner exocuticle. A schematic model of the cuticle emphasizes structural and chemical diversity. A thin outer calcite layer provides a dense microbial barrier that dissolves slowly through the epicuticle, providing an external, alkaline, unstirred layer that would be inhibitory to bacterial movement and metabolism. Injury to the epicuticle covering this mineralized surface unleashes an immediate efflux of carbonate, accentuating the normal alkalinity of an antimicrobial unstirred layer. The trabecular CAP inner exocuticle provides rigidity to prevent bending and cracking of the calcite outer exocuticle. The combined mineral fine structure of lobster cuticle supports antimicrobial function as well as plays a structural protective role.
Subspace matching thalamic microstimulation to tactile evoked potentials in rat somatosensory cortex
Author(s): Brockmeier, AJ; Choi, JS; Emigh, MS; Li, L; Francis, JT; Principe, JC
View details
Hide details
We show experimental results that the evoked local field potentials of the rat somatosensory cortex from natural tactile touch of forepaw digits and matched thalamic microstimulation can be qualitatively and quantitively similar. In ongoing efforts to optimize the microstimulation settings (e.g., location, amplitude, etc.) to match the natural response, we investigate whether subspace projection methods, specifically the eigenface approach proposed in the computer vision community (Turk and Pentland 1991 [1]), can be used to choose the parameters of microstimulation such that the response matches a single tactile touch realization. Since the evoked potentials from multiple electrodes are high dimensional spatio-temporal data, the subspace projections improve computational efficiency and can reduce the effect of noisy realizations. In computing the PCA projections we use the peristimulus averages instead of the realizations. The dataset is pruned of unreliable stimulation types. A new subspace is computed for the pruned stimulation type, and is used to estimate a sequence of microstimulations to best match the natural responses. This microstimulation sequence is applied in vivo and quantitative analysis shows that per realization matching does statistically better than choosing randomly from the pruned subset.
Characterization of the auditory system responses to infrared neural stimulation of the cochlear nucleus
Author(s): Guex, A
View details
Hide details
… Systems, Carlsborg WA). Current pulses were delivered to the exposed CN using a parylene-insulated platinum-iridium twisted electrode (51mm length, impedance = 0.1-0.5 MΩ) (Microprobe Inc., Gaithersburg, MD). Bipolar stimuli …
System level assessment of motor control through patterned microstimulation in the superior colliculus
Author(s): Katnani, HA
View details
Hide details
… liquid reward. As the animal performed this task, a platinum iridium microelectrode (1.0-1.5 M; MicroProbes for Life Science, Inc., Gaithesburg, MD) was advanced with a hydraulic microdrive (Narashigie, Tokyo, Japan). The …
Bursts and oscillations as independent properties of neural activity in the parkinsonian globus pallidus internus
Author(s): Chan, V; Starr, PA; Turner, RS
View details
Hide details
Bursts and oscillatory modulations in firing rate are hallmark features of abnormal neuronal activity in the parkinsonian Globus Pallidus internus (GPi). Although often implicated together in the pathophysiology of parkinsonian signs, little is known about how burst discharges and oscillatory firing (OF) relate to each other. To investigate this question, extracellular single-unit neuronal activity was recorded from 132 GPi cells in 14 Parkinson's disease patients. We found that burst firing was equally prevalent in OF and non-oscillatory firing (NOF) cells (p>0.5). More than half of the cells were characterized by either aperiodic bursty activity or OF, but not both. OF and NOF cells had statistically-indistinguishable levels of mean burstiness (p=0.8). Even when bursting and OF co-existed in individual cells, levels of burstiness and oscillatory power were seldom correlated across time. Interestingly, however, the few OF cells with spectral peaks between 8-13 Hz (α-range) were substantially burstier than other cells (p < 0.01) and showed an unique burst morphology and stronger temporal correlations between oscillatory power and burstiness. We conclude that independent mechanisms may underlie the burst discharges and OF typical of most neurons in the parkinsonian GPi.
Optogenetic manipulation of cerebellar Purkinje cell activity in vivo
Author(s): Tsubota, T; Ohashi, Y; Tamura, K; Sato, A; Miyashita, Y
View details
Hide details
Purkinje cells (PCs) are the sole output neurons of the cerebellar cortex. Although their anatomical connections and physiological response properties have been extensively studied, the causal role of their activity in behavioral, cognitive and autonomic functions is still unclear because PC activity cannot be selectively controlled. Here we developed a novel technique using optogenetics for selective and rapidly reversible manipulation of PC activity in vivo. We injected into rat cerebellar cortex lentiviruses expressing either the light-activated cationic channel channelrhodopsin-2 (ChR2) or light-driven chloride pump halorhodopsin (eNpHR) under the control of the PC-specific L7 promoter. Transgene expression was observed in most PCs (ChR2, 92.6%; eNpHR, 95.3%), as determined by immunohistochemical analysis. In vivo electrophysiological recordings showed that all light-responsive PCs in ChR2-transduced rats increased frequency of simple spike in response to blue laser illumination. Similarly, most light-responsive PCs (93.8%) in eNpHR-transduced rats decreased frequency of simple spike in response to orange laser illumination. We then applied these techniques to characterize the roles of rat cerebellar uvula, one of the cardiovascular regulatory regions in the cerebellum, in resting blood pressure (BP) regulation in anesthetized rats. ChR2-mediated photostimulation and eNpHR-mediated photoinhibition of the uvula had opposite effects on resting BP, inducing depressor and pressor responses, respectively. In contrast, manipulation of PC activity within the neighboring lobule VIII had no effect on BP. Blue and orange laser illumination onto PBS-injected lobule IX didn't affect BP, indicating the observed effects on BP were actually due to PC activation and inhibition. These results clearly demonstrate that the optogenetic method we developed here will provide a powerful way to elucidate a causal relationship between local PC activity and functions of the cerebellum.
Order of operations for decoding superior colliculus activity for saccade generation.
Author(s): Katnani, HA; Gandhi, NJ
View details
Hide details
To help understand the order of events that occurs when generating saccades, we simulated and tested two commonly stated decoding models that are believed to occur in the oculomotor system: vector averaging (VA) and center-of-mass. To generate accurate saccades, each model incorporates two required criteria: 1) a decoding mechanism that deciphers a population response of the superior colliculus (SC) and 2) an exponential transformation that converts the saccade vector into visual coordinates. The order of these two criteria is used differently within each model, yet the significance of the sequence has not been quantified. To distinguish between each decoding sequence and hence, to determine the order of events necessary to generate accurate saccades, we simulated the two models. Distinguishable predictions were obtained when two simultaneous motor commands are processed by each model. Experimental tests of the models were performed by observing the distribution of endpoints of saccades evoked by weighted, simultaneous microstimulation of two SC sites. The data were consistent with the predictions of the VA model, in which exponential transformation precedes the decoding computation.
Stimulation of the nucleus accumbens as behavioral reward in awake behaving monkeys
Author(s): Bichot, NP; Heard, MT; Desimone, R
View details
Hide details
It has been known that monkeys will repeatedly press a bar for electrical stimulation in several different brain structures. We explored the possibility of using electrical stimulation in one such structure, the nucleus accumbens, as a substitute for liquid reward in animals performing a complex task, namely visual search. The animals had full access to water in the cage at all times on days when stimulation was used to motivate them. Electrical stimulation was delivered bilaterally at mirror locations in and around the accumbens, and the animals' motivation to work for electrical stimulation was quantified by the number of trials they performed correctly per unit of time. Acute mapping revealed that stimulation over a large area successfully supported behavioral performance during the task. Performance improved with increasing currents until it reached an asymptotic, theoretically maximal level. Moreover, stimulation with chronically implanted electrodes showed that an animal's motivation to work for electrical stimulation was at least equivalent to, and often better than, when it worked for liquid reward while on water control. These results suggest that electrical stimulation in the accumbens is a viable method of reward in complex tasks. Because this method of reward does not necessitate control over water or food intake, it may offer an alternative to the traditional liquid or food rewards in monkeys, depending on the goals and requirements of the particular research project.
Applications of noninvasive physiological sensing to measure indole acetic acid transport
Author(s): Diggs, AR
View details
Hide details
… Briefly platinum iridium microelectrodes from Micro MicroProbes(Gaithersburg MD), tapered and insulated all the way to a 2-4 M tip was platinized for forty seconds and exposed to 3-(mercaptopropyl) trimethoxysilane for 6 hours …
Ventral root or dorsal root ganglion microstimulation to evoke hindlimb motor responses
Author(s): Bourbeau, DJ
View details
Hide details
… potassium chloride. 2.2.2 Stimulation and data acquisition. Using a micromanipulator, we implanted a single wire electrode (MicroProbes, Gaithersburg, MD) for electrical microstimulation into the exposed DRG. These parylene …
FLOATING MICROELECTRODE ARRAYLINEAR MICROELECTRODE ARRAYMICROELECTRODE ARRAYMICROWIRE ARRAY
In-Vivo Tests of a 16-Channel Implantable Wireless Neural Stimulator
Author(s): Philip Troyk, Samuel Bredeson, Stuart Cogan, Mario Romero-Ortega, Sungjae Suh, Zhe Hu, Aswini Kanneganti, Rafael Granja-Vazquez, Jennifer Seifert, Martin Bak
View details
Hide details
Wireless stimulation of neural tissue could enable many emerging neural prosthesis designs, and eliminate problems associated with percutaneous wires and connectors. Our laboratory has developed a 16-channel wireless floating microelectrode array (WFMA) for chronic implantation. Here, we report on its first use within in-vivo experiments, using a rat sciatic nerve model. Stimulus currents and associated muscular movements were determined for electrodes of two WFMA devices implanted into four animal subjects.
Long-term stability of neural signals from microwire arrays implanted in common marmoset motor cortex and striatum
Author(s): Debnath, S; Prins, N; Pohlmeyer, E; Mylavarapu, R; Geng, S; Sanchez, J; Prasad, A
View details
Hide details
Current neuroprosthetics rely on stable, high quality recordings from chronically implanted microelectrode arrays (MEAs) in neural tissue. While chronic electrophysiological recordings and electrode failure modes have been reported from rodent and larger non-human primate (NHP) models, chronic recordings from the marmoset model have not been previously described. The common marmoset is a New World primate that is easier to breed and handle compared to larger NHPs and has a similarly organized brain, making it a potentially useful smaller NHP model for neuroscience studies. This study reports recording stability and signal quality of MEAs chronically implanted in behaving marmosets. Six adult male marmosets, trained for reaching tasks, were implanted with either a 16-channel tungsten microwire array (five animals) or a Pt-Ir floating MEA (one animal) in the hand-arm region of the primary motor cortex (M1) and another MEA in the striatum targeting the nucleus accumbens (NAcc). Signal stability and quality was quantified as a function of array yield (active electrodes that recorded action potentials), neuronal yield (isolated single units during a recording session), and signal-to-noise ratio (SNR). Out of 11 implanted MEAs, nine provided functional recordings for at least three months, with two arrays functional for 10 months. In general, implants had high yield, which remained stable for up to several months. However, mechanical failure attributed to MEA connector was the most common failure mode. In the longest implants, signal degradation occurred, which was characterized by gradual decline in array yield, reduced number of isolated single units, and changes in waveform shape of action potentials. This work demonstrates the feasibility of long-term recordings from MEAs implanted in cortical and deep brain structures in the marmoset model. The ability to chronically record cortical signals for neural prosthetics applications in the common marmoset extends the potential of this model in neural interface research.
Neural dynamics of variable grasp movement preparation in the macaque fronto-parietal network
Author(s): Michaels, JA; Dann, B; Intveld, RW; Scherberger, H
View details
Hide details
Our voluntary grasping actions lie on a continuum between immediate action and waiting for the right moment, depending on the context. Therefore, studying grasping requires investigating how preparation time affects this process. Two macaque monkeys (Macaca mulatta) performed a grasping task with a short instruction followed by an immediate or delayed go cue (0-1300 ms) while we recorded in parallel from neurons in the hand area (F5) of the ventral premotor cortex and the anterior intraparietal area (AIP). Initial population dynamics followed a fixed trajectory in the neural state space unique to each grip type, reflecting unavoidable preparation, then diverged depending on the delay. Although similar types of single unit responses were present in both areas, population activity in AIP stabilized within a unique memory state while F5 activity continued to evolve, tracking subjective anticipation of the go cue. Intriguingly, activity during movement initiation clustered into two trajectory clusters, corresponding to movements that were either 'as fast as possible' or withheld movements, demonstrating a widespread state shift in the frontoparietal grasping network when movements must be withheld. Our results reveal how dissociation between static and dynamic components of movement preparation as well as differentiation between cortical areas is possible through population level analysis.
Mixed selectivity morphs population codes in prefrontal cortex
Author(s): Parthasarathy, Aw; Herikstad, R; Bong, JH; Medina, FS; Libedinsky, C; n, SY
View details
Hide details
The prefrontal cortex maintains working memory information in the presence of distracting stimuli. It has long been thought that sustained activity in individual neurons or groups of neurons was responsible for maintaining information in the form of a persistent, stable code. Here we show that, upon the presentation of a distractor, information in the lateral prefrontal cortex was reorganized into a different pattern of activity to create a morphed stable code without losing information. In contrast, the code in the frontal eye fields persisted across different delay periods but exhibited substantial instability and information loss after the presentation of a distractor. We found that neurons with mixed-selective responses were necessary and sufficient for the morphing of code and that these neurons were more abundant in the lateral prefrontal cortex than the frontal eye fields. This suggests that mixed selectivity provides populations with code-morphing capability, a property that may underlie cognitive flexibility.
Rodent model for assessing the long term safety and performance of peripheral nerve recording electrodes.
Author(s): Vasudevan, S; Patel, K; Welle, C
View details
Hide details
In the US alone, there are approximately 185 000 cases of limb amputation annually, which can reduce the quality of life for those individuals. Current prosthesis technology could be improved by access to signals from the nervous system for intuitive prosthesis control. After amputation, residual peripheral nerves continue to convey motor signals and electrical stimulation of these nerves can elicit sensory percepts. However, current technology for extracting information directly from peripheral nerves has limited chronic reliability, and novel approaches must be vetted to ensure safe long-term use. The present study aims to optimize methods to establish a test platform using rodent model to assess the long term safety and performance of electrode interfaces implanted in the peripheral nerves.
METHODOLOGICAL CONSIDERATIONS FOR A CHRONIC NEURAL INTERFACE WITH THE CUNEATE NUCLEUS OF MACAQUES
Author(s): Suresh, AK; Winberry, J; Versteeg, C; Chowdhury, RH; Tomlinson, T; Rosenow, JM; Miller, LE; Bensmaia, SJ
View details
Hide details
While the response properties of neurons in the somatosensory nerves and anterior parietal cortex have been extensively studied, little is known about the encoding of tactile and proprioceptive information in the cuneate nucleus (CN) or external cuneate nucleus (ECN), the first recipients of upper limb somatosensory afferent signals. The major challenge in characterizing neural coding in CN/ECN has been to record from these tiny, difficult to access brainstem structures. Most previous investigations of CN response properties have been carried out in decerebrate or anesthetized animals, thereby eliminating the well-documented top-down signals from cortex, which likely exert a strong influence on CN responses. Seeking to fill this gap in our understanding of somatosensory processing, we describe an approach to chronically implant arrays of electrodes in the upper limb representation in the brain stem in primates. First, we describe the topography of CN/ECN in Rhesus macaques, including its somatotopic organization and the layout of its submodalities (touch and proprioception). Second, we describe the design of electrode arrays and the implantation strategy to obtain stable recordings. Third, we show sample responses of CN/ECN neurons in brainstem obtained from awake, behaving monkeys. With this method, we are in a position to characterize, for the first time, somatosensory representations in CN and ECN of primates.
Independent Mobility Achieved through a Wireless Brain-Machine Interface
Author(s): Libedinsky, C; So, R; Xu, Z; Kyar, TK; Ho, D; Lim, C; Chan, L; Chua, Y; Yao, L; Cheong, JH; Lee, JH; Vishal, KV; Guo, Y; Chen, ZN; Lim, LK; Li, P; Liu, L; Zou, X; Ang, KK; Gao, Y; Ng, WH; Han, BS; Chng, K; Guan, C; Je, M; Yen, SC
View details
Hide details
Individuals with tetraplegia lack independent mobility, making them highly dependent on others to move from one place to another. Here, we describe how two macaques were able to use a wireless integrated system to control a robotic platform, over which they were sitting, to achieve independent mobility using the neuronal activity in their motor cortices. The activity of populations of single neurons was recorded using multiple electrode arrays implanted in the arm region of primary motor cortex, and decoded to achieve brain control of the platform. We found that free-running brain control of the platform (which was not equipped with any machine intelligence) was fast and accurate, resembling the performance achieved using joystick control. The decoding algorithms can be trained in the absence of joystick movements, as would be required for use by tetraplegic individuals, demonstrating that the non-human primate model is a good pre-clinical model for developing such a cortically-controlled movement prosthetic. Interestingly, we found that the response properties of some neurons differed greatly depending on the mode of control (joystick or brain control), suggesting different roles for these neurons in encoding movement intention and movement execution. These results demonstrate that independent mobility can be achieved without first training on prescribed motor movements, opening the door for the implementation of this technology in persons with tetraplegia.
A four-dimensional virtual hand brain-machine interface using active dimension selection.
Author(s): Rouse, AG
View details
Hide details
Brain-machine interfaces (BMI) traditionally rely on a fixed, linear transformation from neural signals to an output state-space. In this study, the assumption that a BMI must control a fixed, orthogonal basis set was challenged and a novel active dimension selection (ADS) decoder was explored.
Parallel electrochemical measurements of implanted neural recording microelectrodes
Author(s): Hu, Z; Troyk, P; DeMichele, G
View details
Hide details
An electrochemical instrument capable of parallel measurement of 16 microelectrodes was used, for the first time, for evaluating 32 implanted microelectrodes in-vivo. The result reveals the inadequacy of traditional single-frequency impedance measurements as an assessment of microelectrodes. The combinational measurements of cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) provide more comprehensive information of the “health” of implanted microelectrodes. Parallel measurements allow investigators to gather this information for a large number of electrodes at much faster speed than have been traditionally available.
A bidirectional peripheral neural interface for restoring sensorimotor function of non-human primates
Author(s): Zhang, P; Ma, X; He, J
View details
Hide details
Upper limb loss is a big disaster and markedly affects the quality of life. Bidirectional peripheral neural interface (PNI) is a feasible way to restore the sensorimotor functions of amputees. Bidirectional interface includes motor commands decoding and sensory feedback restoring. In this paper, we presented two neurobehavioral platforms for studying bidirectional PNI in the monkey. In the first platform, the monkey was guided to do reaching and grasping tasks meanwhile cortical and peripheral neural signals were recorded, motor commands can be decoded. In the other platform, the monkey was guided to express tactile sensation into motor action; sensory feedback restoring can be seen from the action of the monkey. We designed a bidirectional PNI and tried to achieve it, many substantial challenges still remains.
Brain-computer interface control with small motor cortex ensembles
Author(s): Law, AJ
View details
Hide details
… 10. Using general anesthesia and aseptic technique, two male rhesus macaques, monkey M and monkey V, were implanted with four floating microelectrode arrays (FMAs, MicroProbes, Gaithersburg, MD) in the primary motor cortex (M1) of the left hemisphere …
Regenerative Peripheral Nerve Interfacing Of Sensory Modalities
Author(s): Dutta, NT
View details
Hide details
Figure 2.1: Shows (A) Arrangement of 18 electrodes with dimensions of the Floating Multielectrode array as in REMI design (Array dimensions 2.5mmX1.95mm)(Courtesy Microprobes Inc., MD)
Object vision to hand action in macaque parietal, premotor, and motor cortices
Author(s): Schaffelhofer, S; Scherberger, H
View details
Hide details
Grasping requires translating object geometries into appropriate hand shapes. How the brain computes these transformations is currently unclear. We investigated three key areas of the macaque cortical grasping circuit with microelectrode arrays and found cooperative but anatomically separated visual and motor processes. The parietal area AIP operated primarily in a visual mode. Its neuronal population revealed a specialization for shape processing, even for abstract geometries, and processed object features ultimately important for grasping. Premotor area F5 acted as a hub that shared the visual coding of AIP only temporarily and switched to highly dominant motor signals towards movement planning and execution. We visualize these non-discrete premotor signals that drive the primary motor cortex M1 to reflect the movement of the grasping hand. Our results reveal visual and motor features encoded in the grasping circuit and their communication to achieve transformation for grasping.
A chronic neural interface to the macaque dorsal column nuclei
Author(s): Richardson, AG; Weigand, PK; Sritharan, SY; Lucas, TH
View details
Hide details
The dorsal column nuclei (DCN) of the brain stem contain secondary afferent neurons, which process ascending somatosensory information. Most of the known physiology of the DCN in primates has been acquired in acute experiments with anesthetized animals. Here, we developed a technique to implant a multielectrode array (MEA) chronically in the DCN of macaque monkeys to enable experiments with the animals awake. Two monkeys were implanted with brain-stem MEAs for 2-5 mo with no major adverse effects. Responses of the cuneate and gracile nuclei were quantified at the level of both field potentials and single units. Tactile receptive fields (RFs) were identified for 315 single units. A subset of these units had very regular spiking patterns with spike frequencies predominantly in the alpha band (8-14 Hz). The stability of the neuronal recordings was assessed with a novel analysis that identified units by their mean spike waveform and by the spike-triggered average of activity on all other electrodes in the array. Fifty-six identified neurons were observed over two or more sessions and in a few cases for as long as 1 mo. RFs of stable neurons were largely consistent across days. The results demonstrate that a chronic DCN implant in a macaque can be safe and effective, yielding high-quality unit recording for several months. The unprecedented access to these nuclei in awake primates should lead to a better understanding of their role in sensorimotor behavior.
Somatosensory encoding with cuneate nucleus microstimulation: Detection of artificial stimuli
Author(s): Sritharan, SY; Richardson, AG; Weigand, PK; Planell-Mendez, I; Xilin Liu, ; Hongjie Zhu, ; Milin Zhang, ; Van der Spiegel, J; Lucas, TH
View details
Hide details
The sense of touch and proprioception are critical to movement control. After spinal cord injury, these senses may be restored with direct, electrical microstimulation of the brain as part of a complete sensorimotor neuroprosthesis. The present study was designed to test, in part, the hypothesis that the cuneate nucleus (CN) of the brainstem is a suitable site to encode somatosensory information. Two rhesus macaques were implanted with microelectrode arrays providing chronic access to the CN. The monkeys were trained on an active touch oddity task to detect vibrotactile stimuli. When the vibrotactile stimuli were replaced with electrical stimuli delivered to the CN, initial detection probabilities were near chance. Detection performance improved over time, reaching a plateau after about 10 daily sessions. At plateau performance, the monkeys exhibited detection probabilities that were 68-80% higher than the chance probability. Finally, detection probability was quantified as a function of stimulus amplitude. The resulting psychometric curve showed a detection threshold of 45 μA for 100-Hz stimulus trains. These behavioral data are the first to show that artificial CN activation is sufficient for perception. The results are consistent with our hypothesis and motivate future tests of the CN as a somatosensory encoding site.
Implantation and testing of WFMA stimulators in macaque
Author(s): Trovk, PR; Frim, D; Roitberg, B; Towle, VL; Takahashi, K; Suh, S; Bak, M; Bredeson, S; Zhe Hu
View details
Hide details
Our on-going work to develop an intracortical visual prosthesis has motivated the design, fabrication, and testing of a Wireless Floating Microelectrode Array (WFMA) stimulator. This implantable device can be used for an electrical stimulation interface in the peripheral and the central nervous system. Previously, its use in a sciatic nerve rodent model was described. Here implantation of two WFMAs in motor cortex of two NHP (macaque - two devices/animal) is presented. Preliminary functional tests show the implanted devices to be fully functional with stimulation-induced motor movements obtained. Functional testing is on-going.
Decoding a wide range of hand configurations from macaque motor, premotor, and parietal cortices
Author(s): Schaffelhofer, S; Agudelo-Toro, A; Scherberger, H
View details
Hide details
Despite recent advances in decoding cortical activity for motor control, the development of hand prosthetics remains a major challenge. To reduce the complexity of such applications, higher cortical areas that also represent motor plans rather than just the individual movements might be advantageous. We investigated the decoding of many grip types using spiking activity from the anterior intraparietal (AIP), ventral premotor (F5), and primary motor (M1) cortices. Two rhesus monkeys were trained to grasp 50 objects in a delayed task while hand kinematics and spiking activity from six implanted electrode arrays (total of 192 electrodes) were recorded. Offline, we determined 20 grip types from the kinematic data and decoded these hand configurations and the grasped objects with a simple Bayesian classifier. When decoding from AIP, F5, and M1 combined, the mean accuracy was 50% (using planning activity) and 62% (during motor execution) for predicting the 50 objects (chance level, 2%) and substantially larger when predicting the 20 grip types (planning, 74%; execution, 86%; chance level, 5%). When decoding from individual arrays, objects and grip types could be predicted well during movement planning from AIP (medial array) and F5 (lateral array), whereas M1 predictions were poor. In contrast, predictions during movement execution were best from M1, whereas F5 performed only slightly worse. These results demonstrate for the first time that a large number of grip types can be decoded from higher cortical areas during movement preparation and execution, which could be relevant for future neuroprosthetic devices that decode motor plans.
Representation of continuous hand and arm movements in macaque areas M1, F5, and AIP: a comparative decoding study.
Author(s): Menz, VK; Schaffelhofer, S; Scherberger, H
View details
Hide details
In the last decade, multiple brain areas have been investigated with respect to their decoding capability of continuous arm or hand movements. So far, these studies have mainly focused on motor or premotor areas like M1 and F5. However, there is accumulating evidence that anterior intraparietal area (AIP) in the parietal cortex also contains information about continuous movement.
Smoothness as a failure mode of Bayesian mixture models in brain-machine interfaces
Author(s): Yousefi, S; Wein, A; Kowalski, KC; Richardson, AG; Srinivasan, L
View details
Hide details
Various recursive Bayesian filters based on reach state equations (RSE) have been proposed to convert neural signals into reaching movements in brain-machine interfaces. When the target is known, RSE produce exquisitely smooth trajectories relative to the random walk prior in the basic Kalman filter. More realistically, the target is unknown, and gaze analysis or other side information is expected to provide a discrete set of potential targets. In anticipation of this scenario, various groups have implemented RSE-based mixture (hybrid) models, which define a discrete random variable to represent target identity. While principled, this approach sacrifices the smoothness of RSE with known targets. This paper combines empirical spiking data from primary motor cortex and mathematical analysis to explain this loss in performance. We focus on angular velocity as a meaningful and convenient measure of smoothness. Our results demonstrate that angular velocity in the trajectory is approximately proportional to change in target probability. The constant of proportionality equals the difference in heading between parallel filters from the two most probable targets, suggesting a smoothness benefit to more narrowly spaced targets. Simulation confirms that measures to smooth the data likelihood also improve the smoothness of hybrid trajectories, including increased ensemble size and uniformity in preferred directions. We speculate that closed-loop training or neuronal subset selection could be used to shape the user's tuning curves towards this end.
Chronic and low charge injection wireless intraneural stimulation in vivo
Author(s): Romero-Ortega, M; Kanneganti, A; Bendale, G; Seifert, J; Bredeson, S; Troyk, P; Deku, F; Cogan, S
View details
Hide details
Functional stability and in-vivo reliability are significant factors determining the longevity of a neural interface. In this ongoing study, we test the performance of a wireless floating microelectrode array (WFMA) over a period of 143 days. The topography of the microelectrodes has allowed for selective stimulation of different fascicles of the rat sciatic nerve. We confirmed that motor evoked thresholds remain stable over time and that the nerve stimulation charges were within tissue safety limits. Importantly, motor evoked responses were elicited at threshold currents in fully awake animals without causing pain or discomfort. These data validate the use of the WFMA system for intraneural interfacing of peripheral nerves for neuroprosthetic and bioelectronics medical applications.
In Vivo Electrochemical Analysis of a PEDOT/MWCNT Neural Electrode Coating
Author(s): Alba, NA; Du, ZJ; Catt, KA; Kozai, TD; Cui, XT
View details
Hide details
Neural electrodes hold tremendous potential for improving understanding of brain function and restoring lost neurological functions. Multi-walled carbon nanotube (MWCNT) and dexamethasone (Dex)-doped poly(3,4-ethylenedioxythiophene) (PEDOT) coatings have shown promise to improve chronic neural electrode performance. Here, we employ electrochemical techniques to characterize the coating in vivo. Coated and uncoated electrode arrays were implanted into rat visual cortex and subjected to daily cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) for 11 days. Coated electrodes experienced a significant decrease in 1 kHz impedance within the first two days of implantation followed by an increase between days 4 and 7. Equivalent circuit analysis showed that the impedance increase is the result of surface capacitance reduction, likely due to protein and cellular processes encapsulating the porous coating. Coating's charge storage capacity remained consistently higher than uncoated electrodes, demonstrating its in vivo electrochemical stability. To decouple the PEDOT/MWCNT material property changes from the tissue response, in vitro characterization was conducted by soaking the coated electrodes in PBS for 11 days. Some coated electrodes exhibited steady impedance while others exhibiting large increases associated with large decreases in charge storage capacity suggesting delamination in PBS. This was not observed in vivo, as scanning electron microscopy of explants verified the integrity of the coating with no sign of delamination or cracking. Despite the impedance increase, coated electrodes successfully recorded neural activity throughout the implantation period.
Sensitivity to microstimulation of somatosensory cortex distributed over multiple electrodes
Author(s): Kim, S; Callier, T; Tabot, GA; Tenore, FV; Bensmaia, SJ
View details
Hide details
Meaningful and repeatable tactile sensations can be evoked by electrically stimulating primary somatosensory cortex. Intracortical microstimulation (ICMS) may thus be a viable approach to restore the sense of touch in individuals who have lost it, for example tetraplegic patients. One of the potential limitations of this approach, however, is that high levels of current can damage the neuronal tissue if the resulting current densities are too high. The limited range of safe ICMS amplitudes thus limits the dynamic range of ICMS-evoked sensations. One way to get around this limitation would be to distribute the ICMS over multiple electrodes in the hopes of intensifying the resulting percept without increasing the current density experienced by the neuronal tissue. Here, we test whether stimulating through multiple electrodes is a viable solution to increase the dynamic range of ICMS-elicited sensations without increasing the peak current density. To this end, we compare the ability of non-human primates to detect ICMS delivered through one vs. multiple electrodes. We also compare their ability to discriminate pulse trains differing in amplitude when these are delivered through one or more electrodes. We find that increasing the number of electrodes through which ICMS is delivered only has a marginal effect on detectability or discriminability despite the fact that 2-4 times more current is delivered overall. Furthermore, the impact of multielectrode stimulation (or lack thereof) is found whether pulses are delivered synchronously or asynchronously, whether the leading phase of the pulses is cathodic or anodic, and regardless of the spatial configuration of the electrode groups.
Experimental validation of a primary afferent based somatosensory neuroprosthesis
Author(s): Ayers, CA
View details
Hide details
… Floating microelectrode arrays. 38. (Microprobes for Life Science, Gaithersburg, MD, USA) were implanted chronically in the L6 and L7 DRG of four cats and the stability and selectivity of the response to stimulation was monitored for up to six months after implantation …
Predicting Reaction Time from the Neural State Space of the Premotor and Parietal Grasping Network
Author(s): Michaels, JA; Dann, B; Intveld, RW; Scherberger, H
View details
Hide details
Neural networks of the brain involved in the planning and execution of grasping movements are not fully understood. The network formed by macaque anterior intraparietal area (AIP) and hand area (F5) of the ventral premotor cortex is implicated strongly in the generation of grasping movements. However, the differential role of each area in this frontoparietal network is unclear. We recorded spiking activity from many electrodes in parallel in AIP and F5 while three macaque monkeys (Macaca mulatta) performed a delayed grasping task. By analyzing neural population activity during action preparation, we found that state space analysis of simultaneously recorded units is significantly more predictive of subsequent reaction times (RTs) than traditional methods. Furthermore, because we observed a wide variety of individual unit characteristics, we developed the sign-corrected average rate (SCAR) method of neural population averaging. The SCAR method was able to explain at least as much variance in RT overall as state space methods. Overall, F5 activity predicted RT (18% variance explained) significantly better than AIP (6%). The SCAR methods provides a straightforward interpretation of population activity, although other state space methods could provide richer descriptions of population dynamics. Together, these results lend support to the differential role of the parietal and frontal cortices in preparation for grasping, suggesting that variability in preparatory activity in F5 has a more potent effect on trial-to-trial RT variability than AIP. Grasping movements are planned before they are executed, but how is the preparatory activity in a population of neurons related to the subsequent reaction time (RT)? A population analysis of the activity of many neurons recorded in parallel in macaque premotor (F5) and parietal (AIP) cortices during a delayed grasping task revealed that preparatory activity in F5 could explain a threefold larger fraction of variability in trial-to-trial RT than AIP. These striking differences lend additional support to a differential role of the parietal and premotor cortices in grasp movement preparation, suggesting that F5 has a more direct influence on trial-to-trial variability and movement timing, whereas AIP might be more closely linked to overall movement intentions.
Behavioral assessment of sensitivity to intracortical microstimulation of primate somatosensory cortex
Author(s): Kim, S; Callier, T; Tabot, GA; Gaunt, RA; Tenore, FV; Bensmaia, SJ
View details
Hide details
Intracortical microstimulation (ICMS) is a powerful tool to investigate the functional role of neural circuits and may provide a means to restore sensation for patients for whom peripheral stimulation is not an option. In a series of psychophysical experiments with nonhuman primates, we investigate how stimulation parameters affect behavioral sensitivity to ICMS. Specifically, we deliver ICMS to primary somatosensory cortex through chronically implanted electrode arrays across a wide range of stimulation regimes. First, we investigate how the detectability of ICMS depends on stimulation parameters, including pulse width, frequency, amplitude, and pulse train duration. Then, we characterize the degree to which ICMS pulse trains that differ in amplitude lead to discriminable percepts across the range of perceptible and safe amplitudes. We also investigate how discriminability of pulse amplitude is modulated by other stimulation parameters-namely, frequency and duration. Perceptual judgments obtained across these various conditions will inform the design of stimulation regimes for neuroscience and neuroengineering applications.
Generalized analog thresholding for spike acquisition at ultralow sampling rates
Author(s): He, BD; Wein, A; Varshney, LR; Kusuma, J; Richardson, AG; Srinivasan, L
View details
Hide details
Efficient spike acquisition techniques are needed to bridge the divide from creating large multielectrode arrays (MEA) to achieving whole-cortex electrophysiology. In this paper, we introduce generalized analog thresholding (gAT), which achieves millisecond temporal resolution with sampling rates as low as 10 Hz. Consider the torrent of data from a single 1,000-channel MEA, which would generate more than 3 GB/min using standard 30-kHz Nyquist sampling. Recent neural signal processing methods based on compressive sensing still require Nyquist sampling as a first step and use iterative methods to reconstruct spikes. Analog thresholding (AT) remains the best existing alternative, where spike waveforms are passed through an analog comparator and sampled at 1 kHz, with instant spike reconstruction. By generalizing AT, the new method reduces sampling rates another order of magnitude, detects more than one spike per interval, and reconstructs spike width. Unlike compressive sensing, the new method reveals a simple closed-form solution to achieve instant (noniterative) spike reconstruction. The base method is already robust to hardware nonidealities, including realistic quantization error and integration noise. Because it achieves these considerable specifications using hardware-friendly components like integrators and comparators, generalized AT could translate large-scale MEAs into implantable devices for scientific investigation and medical technology.
Chronic recruitment of primary afferent neurons by microstimulation in the feline dorsal root ganglia.
Author(s): Fisher, LE; Ayers, CA; Ciollaro, M; Ventura, V; Weber, DJ; Gaunt, RA
View details
Hide details
This study describes results of primary afferent neural microstimulation experiments using microelectrode arrays implanted chronically in the lumbar dorsal root ganglia (DRG) of four cats. The goal was to test the stability and selectivity of these microelectrode arrays as a potential interface for restoration of somatosensory feedback after damage to the nervous system such as amputation.
Principal components of hand kinematics and neurophysiological signals in motor cortex during reach to grasp movements
Author(s): Mollazadeh, M; Aggarwal, V; Thakor, NV; Schieber, MH
View details
Hide details
A few kinematic synergies identified by principal component analysis (PCA) account for most of the variance in the coordinated joint rotations of the fingers and wrist used for a wide variety of hand movements. To examine the possibility that motor cortex might control the hand through such synergies, we collected simultaneous kinematic and neurophysiological data from monkeys performing a reach-to-grasp task. We used PCA, jPCA and isomap to extract kinematic synergies from 18 joint angles in the fingers and wrist and analyzed the relationships of both single-unit and multiunit spike recordings, as well as local field potentials (LFPs), to these synergies. For most spike recordings, the maximal absolute cross-correlations of firing rates were somewhat stronger with an individual joint angle than with any principal component (PC), any jPC or any isomap dimension. In decoding analyses, where spikes and LFP power in the 100- to 170-Hz band each provided better decoding than other LFP-based signals, the first PC was decoded as well as the best decoded joint angle. But the remaining PCs and jPCs were predicted with lower accuracy than individual joint angles. Although PCs, jPCs or isomap dimensions might provide a more parsimonious description of kinematics, our findings indicate that the kinematic synergies identified with these techniques are not represented in motor cortex more strongly than the original joint angles. We suggest that the motor cortex might act to sculpt the synergies generated by subcortical centers, superimposing an ability to individuate finger movements and adapt the hand to grasp a wide variety of objects.
Rapid acquisition of novel interface control by small ensembles of arbitrarily selected primary motor cortex neurons
Author(s): Law, AJ; Rivlis, G; Schieber, MH
View details
Hide details
Pioneering studies demonstrated that novel degrees of freedom could be controlled individually by directly encoding the firing rate of single motor cortex neurons, without regard to each neuron's role in controlling movement of the native limb. In contrast, recent brain-computer interface work has emphasized decoding outputs from large ensembles that include substantially more neurons than the number of degrees of freedom being controlled. To bridge the gap between direct encoding by single neurons and decoding output from large ensembles, we studied monkeys controlling one degree of freedom by comodulating up to four arbitrarily selected motor cortex neurons. Performance typically exceeded random quite early in single sessions and then continued to improve to different degrees in different sessions. We therefore examined factors that might affect performance. Performance improved with larger ensembles. In contrast, other factors that might have reflected preexisting synaptic architecture-such as the similarity of preferred directions-had little if any effect on performance. Patterns of comodulation among ensemble neurons became more consistent across trials as performance improved over single sessions. Compared with the ensemble neurons, other simultaneously recorded neurons showed less modulation. Patterns of voluntarily comodulated firing among small numbers of arbitrarily selected primary motor cortex (M1) neurons thus can be found and improved rapidly, with little constraint based on the normal relationships of the individual neurons to native limb movement. This rapid flexibility in relationships among M1 neurons may in part underlie our ability to learn new movements and improve motor skill.
Predicting hand orientation in reach-to-grasp tasks using neural activities from primary motor cortex
Author(s): Zhang, P; Ma, X; Huang, H; He, J
View details
Hide details
Hand orientation is an important control parameter during reach-to-grasp task. In this paper, we presented a study for predicting hand orientation of non-human primate by decoding neural activities from primary motor cortex (M1). A non-human primate subject was guided to do reaching and grasping tasks meanwhile neural activities were acquired by chronically implanted microelectrode arrays. A Support Vector Machines (SVMs) classifier has been trained for predicting three different hand orientations using these M1 neural activities. Different number of neurons were selected and analyzed; the classifying accuracy was 94.1% with 2 neurons and was 100% with 8 neurons. Data from highly event related neuron units contribute a lot to the accuracy of hand orientation prediction. These results indicate that three different hand orientations can be predicted accurately and effectively before the actual movements occurring with a small number of related neurons in M1.
On the asynchronously continuous control of mobile robot movement by motor cortical spiking activity
Author(s): Xu, Z; So, RQ; Toe, KK; Ang, KK; Guan, C
View details
Hide details
This paper presents an asynchronously intracortical brain-computer interface (BCI) which allows the subject to continuously drive a mobile robot. This system has a great implication for disabled patients to move around. By carefully designing a multiclass support vector machine (SVM), the subject's self-paced instantaneous movement intents are continuously decoded to control the mobile robot. In particular, we studied the stability of the neural representation of the movement directions. Experimental results on the nonhuman primate showed that the overt movement directions were stably represented in ensemble of recorded units, and our SVM classifier could successfully decode such movements continuously along the desired movement path. However, the neural representation of the stop state for the self-paced control was not stably represented and could drift.
A study of predicting movement intentions in various spatial reaching tasks from M1 neural activities
Author(s): Ma, X; Zhang, P; Huang, H; He, J
View details
Hide details
Understanding how M1 neurons innervate flexible coordinated upper limb reaching and grasping is important for BMI systems that attempt to reproduce the same actions. In this paper, we presented a study for exploring M1 neuronal activities while a non-human primate subject was guided to finish different visual cued spatial reaching and grasping tasks. By applying various configurations of target objects in the experiment paradigm, we can make thorough investigations on how neural ensemble activities represented subjects' intentions in different task-related time stages when target objects' properties, including shape, position, orientation, varied. Extracted neuron units were categorized according to their event related attributes. The prediction of subjects' movement intentions was completed with a support vector machine (SVM) based method and a simulated on-line test was performed to illustrate the validation of the proposed method. The results showed that, by M1 neural ensemble spike train signals, correct prediction of subject's intentions can be generated in certain time intervals before the movements were actually executed.
Chronic sensory-motor activity in behaving animals using regenerative multi-electrode interfaces
Author(s): Desai, VH; Anand, S; Tran, M; Kanneganti, A; Vasudevan, S; Seifert, JL; Cheng, J; Keefer, EW; Romero-Ortega, MI
View details
Hide details
Regenerative peripheral nerve interfaces have been proposed as viable alternatives for the natural control and feel of robotic prosthetic limbs. We have developed a Regenerative Multi-electrode Interface (REMI) that guides re-growing axons through an electrode array deployed in the lumen of a nerve guide. While acute studies have shown the use of the REMI in the rat sciatic nerve, the quality of chronic signal recording has not been reported. Here we show that implantation of this interface in the sciatic nerve is stable with high quality recordings up to 120 days and failures mainly attributable to abiotic factors related to pedestal detachment and wire breakage. We further tested the interfacing of REMI with fascicles of the sciatic nerve that primarily innervate muscles (tibial) and skin (sural). When implanted into the tibial nerve, bursting activity was observed synchronous to stepping. However, implantation of REMI into the sural nerve failed due to its small size. While fascicles smaller than 300 μm are a challenge for regenerative interfacing, we show that a modified REMI can be used in an insertion mode to record sensory signals from skin. In summary, the REMI represents an effective tool for recording firing patterns of specific axon types during voluntary movement, which may be used to improve the motor control and sensory feedback in closed loop control systems for robotic prosthesis.
Abiotic-biotic characterization of Pt/Ir microelectrode arrays in chronic implants
Author(s): Prasad, A; Xue, QS; Dieme, R; Sankar, V; Mayrand, RC; Nishida, T; Streit, WJ; Sanchez, JC
View details
Hide details
Pt/Ir electrodes have been extensively used in neurophysiology research in recent years as they provide a more inert recording surface as compared to tungsten or stainless steel. While floating microelectrode arrays (FMA) consisting of Pt/Ir electrodes are an option for neuroprosthetic applications, long-term in vivo functional performance characterization of these FMAs is lacking. In this study, we have performed comprehensive abiotic-biotic characterization of Pt/Ir arrays in 12 rats with implant periods ranging from 1 week up to 6 months. Each of the FMAs consisted of 16-channel, 1.5 mm long, and 75 μm diameter microwires with tapered tips that were implanted into the somatosensory cortex. Abiotic characterization included (1) pre-implant and post-explant scanning electron microscopy (SEM) to study recording site changes, insulation delamination and cracking, and (2) chronic in vivo electrode impedance spectroscopy. Biotic characterization included study of microglial responses using a panel of antibodies, such as Iba1, ED1, and anti-ferritin, the latter being indicative of blood-brain barrier (BBB) disruption. Significant structural variation was observed pre-implantation among the arrays in the form of irregular insulation, cracks in insulation/recording surface, and insulation delamination. We observed delamination and cracking of insulation in almost all electrodes post-implantation. These changes altered the electrochemical surface area of the electrodes and resulted in declining impedance over the long-term due to formation of electrical leakage pathways. In general, the decline in impedance corresponded with poor electrode functional performance, which was quantified via electrode yield. Our abiotic results suggest that manufacturing variability and insulation material as an important factor contributing to electrode failure. Biotic results show that electrode performance was not correlated with microglial activation (neuroinflammation) as we were able to observe poor performance in the absence of neuroinflammation, as well as good performance in the presence of neuroinflammation. One biotic change that correlated well with poor electrode performance was intraparenchymal bleeding, which was evident macroscopically in some rats and presented microscopically by intense ferritin immunoreactivity in microglia/macrophages. Thus, we currently consider intraparenchymal bleeding, suboptimal electrode fabrication, and insulation delamination as the major factors contributing toward electrode failure.
Microelectrode array recordings from the ventral roots in chronically implanted cats
Author(s): Debnath, S; Bauman, MJ; Fisher, LE; Weber, DJ; Gaunt, RA
View details
Hide details
The ventral spinal roots contain the axons of spinal motoneurons and provide the only location in the peripheral nervous system where recorded neural activity can be assured to be motor rather than sensory. This study demonstrates recordings of single unit activity from these ventral root axons using floating microelectrode arrays (FMAs). Ventral root recordings were characterized by examining single unit yield and signal-to-noise ratios (SNR) with 32-channel FMAs implanted chronically in the L6 and L7 spinal roots of nine cats. Single unit recordings were performed for implant periods of up to 12 weeks. Motor units were identified based on active discharge during locomotion and inactivity under anesthesia. Motor unit yield and SNR were calculated for each electrode, and results were grouped by electrode site size, which were varied systematically between 25 and 160 μm to determine effects on signal quality. The unit yields and SNR did not differ significantly across this wide range of electrode sizes. Both SNR and yield decayed over time, but electrodes were able to record spikes with SNR > 2 up to 12 weeks post-implant. These results demonstrate that it is feasible to record single unit activity from multiple isolated motor units with penetrating microelectrode arrays implanted chronically in the ventral spinal roots. This approach could be useful for creating a spinal nerve interface for advanced neural prostheses, and results of this study will be used to improve design of microelectrodes for chronic neural recording in the ventral spinal roots.
Mathematical and Experimental Models for Studying Somatosensory Feedback via Primary Afferent Microstimulation
Author(s): Hokanson, JA
View details
Hide details
For cat 2, both L6 and L7 were implanted with 32-channel floating microelectrode arrays (FMA, Microprobes Inc., Gaithersburg , MD).
Evaluation and use of regenerative multi electrode interfaces in peripheral nerves
Author(s): Desai, V
View details
Hide details
… (a) Ceramic Base holding 18 Platinum electrodes of FMA. (b) REMI consisting of 18 pin Floating Micro-electrode Array (FMA) in a polyurethane conduit; Image source- Microprobes Inc. (c) (d) Utah Slanted Electrode Array (USEA) Scale Bar = 1mm …
Evaluation Of Tissue Response From The Regenerative Multielectrode Array (REMI) Implant Using ATF-3 And cJun
Author(s): Bhetawal, S
View details
Hide details
FMA were cust om made having the dimension of 2.45mm X 1.95 mm X 0.45 mm (Microprobes Inc. MD) and each FMA consists of 18 Platinum / Iridium (70 / 30 %) electrodes separated by 400 μm and height range from 0.7 mm to 1 mm to maximize the neuronal contacts at different p lanes.
Restoring the sense of touch with a prosthetic hand through a brain interface
Author(s): Tabot, GA; Dammann, JF; Berg, JA; Tenore, FV; Boback, JL; Vogelstein, RJ; Bensmaia, SJ
View details
Hide details
Our ability to manipulate objects dexterously relies fundamentally on sensory signals originating from the hand. To restore motor function with upper-limb neuroprostheses requires that somatosensory feedback be provided to the tetraplegic patient or amputee. Given the complexity of state-of-the-art prosthetic limbs and, thus, the huge state space they can traverse, it is desirable to minimize the need for the patient to learn associations between events impinging on the limb and arbitrary sensations. Accordingly, we have developed approaches to intuitively convey sensory information that is critical for object manipulation--information about contact location, pressure, and timing--through intracortical microstimulation of primary somatosensory cortex. In experiments with nonhuman primates, we show that we can elicit percepts that are projected to a localized patch of skin and that track the pressure exerted on the skin. In a real-time application, we demonstrate that animals can perform a tactile discrimination task equally well whether mechanical stimuli are delivered to their native fingers or to a prosthetic one. Finally, we propose that the timing of contact events can be signaled through phasic intracortical microstimulation at the onset and offset of object contact that mimics the ubiquitous on and off responses observed in primary somatosensory cortex to complement slowly varying pressure-related feedback. We anticipate that the proposed biomimetic feedback will considerably increase the dexterity and embodiment of upper-limb neuroprostheses and will constitute an important step in restoring touch to individuals who have lost it.
State-based decoding of hand and finger kinematics using neuronal ensemble and LFP activity during dexterous reach-to-grasp movements.
Author(s): Aggarwal, V; Mollazadeh, M; Davidson, AG; Schieber, MH; Thakor, NV
View details
Hide details
The performance of brain-machine interfaces (BMIs) that continuously control upper limb neuroprostheses may benefit from distinguishing periods of posture and movement so as to prevent inappropriate movement of the prosthesis. Few studies, however, have investigated how decoding behavioral states and detecting the transitions between posture and movement could be used autonomously to trigger a kinematic decoder. We recorded simultaneous neuronal ensemble and local field potential (LFP) activity from microelectrode arrays in primary motor cortex (M1) and dorsal (PMd) and ventral (PMv) premotor areas of two male rhesus monkeys performing a center-out reach-and-grasp task, while upper limb kinematics were tracked with a motion capture system with markers on the dorsal aspect of the forearm, hand, and fingers. A state decoder was trained to distinguish four behavioral states (baseline, reaction, movement, hold), while a kinematic decoder was trained to continuously decode hand end point position and 18 joint angles of the wrist and fingers. LFP amplitude most accurately predicted transition into the reaction (62%) and movement (73%) states, while spikes most accurately decoded arm, hand, and finger kinematics during movement. Using an LFP-based state decoder to trigger a spike-based kinematic decoder [r = 0.72, root mean squared error (RMSE) = 0.15] significantly improved decoding of reach-to-grasp movements from baseline to final hold, compared with either a spike-based state decoder combined with a spike-based kinematic decoder (r = 0.70, RMSE = 0.17) or a spike-based kinematic decoder alone (r = 0.67, RMSE = 0.17). Combining LFP-based state decoding with spike-based kinematic decoding may be a valuable step toward the realization of BMI control of a multifingered neuroprosthesis performing dexterous manipulation.
Neuroprosthetic technology for individuals with spinal cord injury
Author(s): Collinger, JL; Foldes, S; Bruns, TM; Wodlinger, B; Gaunt, R; Weber, DJ
View details
Hide details
Spinal cord injury (SCI) results in a loss of function and sensation below the level of the lesion. Neuroprosthetic technology has been developed to help restore motor and autonomic functions as well as to provide sensory feedback. This paper provides an overview of neuroprosthetic technology that aims to address the priorities for functional restoration as defined by individuals with SCI. We describe neuroprostheses that are in various stages of preclinical development, clinical testing, and commercialization including functional electrical stimulators, epidural and intraspinal microstimulation, bladder neuroprosthesis, and cortical stimulation for restoring sensation. We also discuss neural recording technologies that may provide command or feedback signals for neuroprosthetic devices. Neuroprostheses have begun to address the priorities of individuals with SCI, although there remains room for improvement. In addition to continued technological improvements, closing the loop between the technology and the user may help provide intuitive device control with high levels of performance.
Comparison of Abiotic-Biotic Responses of Tungsten Microwires, Pt/Ir Floating Arrays, and Utah Arrays in Chronic Neural Implants
Author(s): Nishida, T; Shaw, G; Streit, W; Sanchez, JC
View details
Hide details
Chronically implanted electrodes in the nervous syst em undergo temporal degradation in signal quality o ver time as they can be affected by both biotic and abiotic factors ultimately resulting in electrode failure [1]. An i nterplay of these time varying factors affect the functional performance o f implanted electrodes on different time scales ran ging from hours and days following implantation surgery [2, 3]. We have been studying this time-varying relationship of th e various electrode failure modes for three electrode types commonly us ed in humans, primates and rodents in a well -contro lled surgical and testing environment designed for chronic electrode evaluation [4, 5]. In this study, we provide a comp rehensive comparison between the electrodes to serve as an aid for choos ing electrode types and materials in neuroprostheti c research. In this work, we focused on detailed abiotic and biotic character ization of tungsten microwires (Tucker Davis Techno logies, Alachua FL) in 25 rats, Pt/Ir floating microelectrode arrays (Mic roProbe, Gaithersburg MD) in 15 rats, and silicon sh ank arrays (Blackroc k Microsystems, UT) in 10 rats. Abiotic characterizat ion was performed via evaluation of pre-implant and post-explant scanning electron microscope (SEM) images of electr ode recording sites to evaluate morphological chang es at the electrode recording sites, corrosion, and insulation delamina tion for all electrodes. Electrical characterization was performed through daily electrode impedance spectroscopy before each recording session to provide insights into the dyna mic nature of the electrode-tissue interface. Biotic characterization was performed via post-mortem histopathology to as sess blood brain barrier (BBB) disruption, and microglial activation and deg eneration. Finally, we coupled the chronic electrod e functional performance (array yield, signal-to-noise ratio) wi th the abiotic and biotic responses to provide a mo re complete understanding of these interactions during the chro nic lifetime of an electrode in the neural tissue. Comprehensive electrode characterization suggested that electrode recording characteristics are related to changes in impedanc e spectra and future electrode performance can be predicted using given impedance values. Abiotic analysis indicated progres sive increases in electrode impedance in the first 2-3 weeks followin g implant where large changes in complex impedance spectra corresponded with poor electrode performance during this period. The Pt/Ir arrays exhibited greater dai ly variation in electrode impedance as compared to both the Utah ar rays and the tungsten microwires. Post-explant SEM i maging indicated tungsten microwires were more prone to corrosion an d insulation damage even on short-time scales of fe w weeks as compared to Pt/Ir arrays which indicated reduced cor rosion and insulation damage even for the longest-t erm animals (6- months). Histopathology indicated that in general, there was reduced expression of microglial markers (Iba1, ED1) and ferritin (marker for BBB disruption) for the Pt/Ir a rrays as compared to the tungsten microwire arrays. Functional performance for the Utah arrays was poor (70% yield) and compar able among animals for both tungsten microwires and Pt/Ir arrays .
A new method of accurate hand- and arm-tracking for small primates.
Author(s): Schaffelhofer, S; Scherberger, H
View details
Hide details
The investigation of grasping movements in cortical motor areas depends heavily on the measurement of hand kinematics. Currently used methods for small primates need either a large number of sensors or provide insufficient accuracy. Here, we present both a novel glove based on electromagnetic tracking sensors that can operate at a rate of 100 Hz and a new modeling method that allows to monitor 27 degrees of freedom (DOF) of the hand and arm using only seven sensors. A rhesus macaque was trained to wear the glove while performing precision and power grips during a delayed grasping task in the dark without noticeable hindrance. During five recording sessions all 27 joint angles and their positions could be tracked reliably. Furthermore, the field generator did not interfere with electrophysiological recordings below 1 kHz and did not affect single-cell separation. Measurements with the glove proved to be accurate during static and dynamic testing (mean absolute error below 2° and 3°, respectively). This makes the glove a suitable solution for characterizing electrophysiological signals with respect to hand grasping and in particular for brain-machine interface applications.
Activity of the same motor cortex neurons during repeated experience with perturbed movement dynamics.
Author(s): Richardson, AG; Borghi, T; Bizzi, E
View details
Hide details
Neurons in the primary motor cortex (M1) have been shown to have persistent, memory-like activity following adaptation to altered movement dynamics. However, the techniques used to study these memory traces limited recordings to only single sessions lasting no more than a few hours. Here, chronically implanted microelectrode arrays were used to study the long-term neuronal responses to repeated experience with perturbing, velocity-dependent force fields. Force-field-related neuronal activity within each session was similar to that found previously. That is, the directional tuning curves of the M1 neurons shifted in a manner appropriate to compensate for the forces. Next, the across-session behavior was examined. Long-term learning was evident in the performance improvements across multiple force-field sessions. Correlated with this change, the neuronal population had smaller within-session spike rate changes as experience with the force field increased. The smaller within-session changes were a result of persistent across-session shifts in directional tuning. The results extend the observation of memory traces of newly learned dynamics and provide further evidence for the role of M1 in early motor memory formation.
Normal molecular repair mechanisms in regenerative peripheral nerve interfaces allow recording of early spike activity despite immature myelination
Author(s): Seifert, JL; Desai, V; Watson, RC; Musa, T; Kim, YT; Keefer, EW; Romero, MI
View details
Hide details
Clinical use of neurally controlled prosthetics has advanced in recent years, but limitations still remain, including lacking fine motor control and sensory feedback. Indwelling multi-electrode arrays, cuff electrodes, and regenerative sieve electrodes have been reported to serve as peripheral neural interfaces, though long-term stability of the nerve-electrode interface has remained a formidable challenge. We recently developed a regenerative multi-electrode interface (REMI) that is able to record neural activity as early as seven days post-implantation. While this activity might represent normal neural depolarization during axonal regrowth, it can also be the result of altered nerve regeneration around the REMI. This study evaluated high-throughput expression levels of 84 genes involved in nerve injury and repair, and the histological changes that occur in parallel to this early neural activity. Animals exhibiting spike activity increased from 29% to 57% from 7 to 14 days following REMI implantation with a corresponding increase in firing rate of 113%. Two weeks after implantation, numbers of neurofilament-positive axons in the control and REMI implanted nerves were comparable, and in both cases the number of myelinated axons was low. During this time, expression levels of genes related to nerve injury and repair were similar in regenerated nerves, both in the presence or absence of the electrode array. Together, these results indicate that the early neural activity is intrinsic to the regenerating axons, and not induced by the REMI neurointerface.
A real time brain machine interface for hand grasping via signals from higher order cortical areas
Author(s): SubaÅ, E
View details
Hide details
After recovery from this procedure, and subsequent training of the task in the head-fixed condition, each animal was implanted with floating microelectrode arrays (FMAs, Microprobe Inc, Gaithersburg, MD, USA) in a separate procedure.
Cortical control of intraspinal microstimulation to restore motor function after paralysis
Author(s): Zimmermann, JB
View details
Hide details
Additionally, a Ęoating microelectrode array (FMA; MicroProbes, Gaithersburg, MD, USA) – consisting of platinum/iridium electrodes, im- pedance ∼ kΩ, array size . × . mm , electrode length – mm, diameter μm – was implanted into the cords of monkeys Ti and X (cf. section ..). ISMS was delivered ac- cording to three stimulation sequences:
A floating 3D silicon microprobe array for neural drug delivery compatible with electrical recording
Author(s): Spieth, S; Brett, O; Seidl, K; Aarts, AA; Erismis, MA; Herwik, S; Trenkle, F; Tätzner, S; Auber, J; Daub, M
View details
Hide details
This paper reports on the design, fabrication, assembly and characterization of a three-dimensional silicon-based floating microprobe array for localized drug delivery to be applied in neuroscience research. The microprobe array is composed of a silicon platform into which up to four silicon probe combs with needle-like probe shafts can be inserted. Two dedicated positions in the array allow the integration of combs for drug delivery. The implemented comb variants feature 8 mm long probe shafts with two individually addressable microchannels incorporated in a single shaft or distributed to two shafts. Liquid supply to the array is realized by a highly flexible 250 µm thick multi-lumen microfluidic cable made from polydimethylsiloxane (PDMS). The specific design concept of the slim-base platform enables floating implantation of the array in the small space between brain and skull. In turn, the flexible cable mechanically decouples the array from any microfluidic interface rigidly fixed to the skull. After assembly of the array, full functionality is demonstrated and characterized at infusion rates from 1 to 5 µL min−1. Further, the effect of a parylene-C coating on the water vapour and osmotic liquid water transport through the PDMS cable walls is experimentally evaluated by determining the respective transmission rates including the water vapour permeability of the used PDMS type.
Integrated neural systems and algorithms for analysis of population activity during dexterous hand movements
Author(s): Mollazadeh, M
View details
Hide details
… 2.2.2 Microelectrode Array Implantation. Using sterile technique and isoflorane anesthesia, each monkey was implanted withmultiple floating microelectrode arrays (FMAs, MicroProbes, Gaithersburg, MD) in corti¬cal motor areas of the left hemisphere …
An information transmission measure for the analysis of effective connectivity among cortical neurons
Author(s): Law, AJ; Sharma, G; Schieber, MH
View details
Hide details
We present a methodology for detecting effective connections between simultaneously recorded neurons using an information transmission measure to identify the presence and direction of information flow from one neuron to another. Using simulated and experimentally-measured data, we evaluate the performance of our proposed method and compare it to the traditional transfer entropy approach. In simulations, our measure of information transmission outperforms transfer entropy in identifying the effective connectivity structure of a neuron ensemble. For experimentally recorded data, where ground truth is unavailable, the proposed method also yields a more plausible effective connectivity structure than transfer entropy.
In search of more robust decoding algorithms for neural prostheses, a data driven approach
Author(s): Subasi, E; Townsend, B; Scherberger, H
View details
Hide details
In the past decade the field of neural interface systems has enjoyed an increase in attention from the scientific community and the general public, in part due to the enormous potential that such systems have to increase the quality of life for paralyzed patients. While significant progress has been made, serious challenges remain to be addressed from both biological and engineering perspectives. A key issue is how to optimize the decoding of neural information, such that neural signals are correctly mapped to effectors that interact with the outside world - like robotic hands and limbs or the patient's own muscles. Here we present some recent progress on tackling this problem by applying the latest developments in machine learning. Neural data was collected from macaque monkeys performing a real-time hand grasp decoding task. Signals were recorded via chronically implanted electrodes in the anterior intraparietal cortex (AIP) and ventral premotor cortex (F5), brain areas that are known to be involved in the transformation of visual signals into hand grasping instructions. We present a comparative study of different classical machine learning methods with an application of decoding of hand postures, as well as a new approach for more robust decoding. Results suggests that combining data-driven algorithmic approaches with well-known parametric methods could lead to better performing and more robust learners, which may have direct implications for future clinical devices.
Quantification of Chronic Microelectrode Signal Quality over Time
Author(s): Sleight, TW
View details
Hide details
… obtained from microelectrode arrays (16-channel, NeuroNexus, Inc, 16-channel, MicroProbes for Life Science) implanted chronically in the barrel cortex of adult rats. Signal to noise ratio of unit … (A) Floating Microelectrode Array (MicroProbes for Life Science, Gaithersburg, MD) …
NERVE CUFF
Electrical stimulation of renal nerves for modulating urine glucose excretion in rats
Author(s): Jiman, A; Chhabra, K; Lewis, A; Cederna, P; Seeley, R; Low, M; Bruns, T
View details
Hide details
Background The role of the kidney in glucose homeostasis has gained global interest. Kidneys are innervated by renal nerves, and renal denervation animal models have shown improved glucose regulation. We hypothesized that stimulation of renal nerves at kilohertz frequencies, which can block propagation of action potentials, would increase urine glucose excretion. Conversely, we hypothesized that low frequency stimulation, which has been shown to increase renal nerve activity, would decrease urine glucose excretion. Methods We performed non-survival experiments on male rats under thiobutabarbital anesthesia. A cuff electrode was placed around the left renal artery, encircling the renal nerves. Ureters were cannulated bilaterally to obtain urine samples from each kidney independently for comparison. Renal nerves were stimulated at kilohertz frequencies (1–50 kHz) or low frequencies (2–5 Hz), with intravenous administration of a glucose bolus shortly into the 25–40-min stimulation period. Urine samples were collected at 5–10-min intervals, and colorimetric assays were used to quantify glucose excretion and concentration between stimulated and non-stimulated kidneys. A Kruskal-Wallis test was performed across all stimulation frequencies (α = 0.05), followed by a post-hoc Wilcoxon rank sum test with Bonferroni correction (α = 0.005). Results For kilohertz frequency trials, the stimulated kidney yielded a higher average total urine glucose excretion at 33 kHz (+ 24.5%; n = 9) than 1 kHz (− 5.9%; n = 6) and 50 kHz (+ 2.3%; n = 14). In low frequency stimulation trials, 5 Hz stimulation led to a lower average total urine glucose excretion (− 40.4%; n = 6) than 2 Hz (− 27.2%; n = 5). The average total urine glucose excretion between 33 kHz and 5 Hz was statistically significant (p
Spinal interneuronal mechanisms underlying pudendal and tibial neuromodulation of bladder function in cats
Author(s): Yecies, T; Li, S; Zhang, Y; Cai, H; Shen, B; Wang, J; Roppolo, J; de Groat, W; Tai, C
View details
Hide details
This study examined the mechanisms underlying pudendal and tibial neuromodulation of bladder function at the single neuron level in the spinal cord. A microelectrode was inserted into the S2 spinal cord of anesthetized cats to record single neuron activity induced by bladder distention over a range of constant intravesical pressures (10-40 cmH2O). Pudendal nerve stimulation (PNS) or tibial nerve stimulation (TNS) was applied at 5 Hz frequency and 0.2 ms pulse width and at multiples of the threshold (T) intensities for inducing anal or toe twitches. A total of 14 spinal neurons from 11 cats were investigated. Both PNS and TNS at 2 T intensity significantly (p < .05) reduced by 40-50% the frequency of firing induced by bladder distention at 20-40 cmH2O in the same spinal neurons. This reduction was not changed by blocking opioid receptors with naloxone (1 mg/kg, i.v.). Activation of pudendal afferents by repeatedly stroking (3-5 times per second) the genital skin using a cotton swab also inhibited the neuron activity induced by bladder distention. Prolonged (30 min) TNS at 4 T intensity produced a short lasting (10-18 min) post-stimulation inhibition that reduced by 40-50% bladder-related neuron activity at different bladder pressures. These results indicate that PNS and TNS inhibition of reflex bladder activity may be mediated in part by convergence of inhibitory inputs onto the same population of bladder-related interneurons in laminae V-VII of the S2 spinal cord and that an opioid receptor mechanism is not involved in the inhibition. Copyright © 2018 Elsevier Inc. All rights reserved.
Frequency Dependent Tibial Neuromodulation of Bladder Underactivity and Overactivity in Cats
Author(s): Theisen, K; Browning, J; Li, X; Li, S; Shen, B; Wang, J; Roppolo, JR; de Groat, WC; Tai, C
View details
Hide details
This study is aimed at determining if tibial nerve stimulation (TNS) can modulate both bladder underactivity and overactivity. In α-chloralose anesthetized cats, tripolar cuff electrodes were implanted on both tibial nerves and TNS threshold (T) for inducing toe twitching was determined for each nerve. Normal bladder activity was elicited by slow intravesical infusion of saline; while bladder overactivity was induced by infusion of 0.25% acetic acid to irritate the bladder. Bladder underactivity was induced during saline infusion by repeated application (2-6 times) of 30-min TNS (5 Hz, 4-8T, 0.2 msec) to the left tibial nerve, while TNS (1 Hz, 4T, 0.2 msec) was applied to the right tibial nerve to reverse the bladder underactivity. Prolonged 5-Hz TNS induced bladder underactivity by significantly increasing bladder capacity to 173.8% ± 10.4% of control and reducing the contraction amplitude to 40.1% ± 15.3% of control, while 1 Hz TNS normalized the contraction amplitude and significantly reduced the bladder capacity to 130%-140% of control. TNS at 1 Hz in normal bladders did not change contraction amplitude and only slightly changed the capacity, but in both normal and underactive bladders significantly increased contraction duration. The effects of 1 Hz TNS did not persist following stimulation. Under isovolumetric conditions when the bladder was underactive, TNS (0.5-3 Hz; 1-4T) induced large amplitude and sustained bladder contractions. In overactive bladders, TNS during cystometry inhibited bladder overactivity at 5 Hz but not at 1 Hz. This study indicates that TNS at different frequencies might be used to treat bladder underactivity and overactivity. © 2018 International Neuromodulation Society.
Constitutive Vagus Nerve Activation Modulates Immune Suppression in Sepsis Survivors
Author(s): Rana, M; Fei-Bloom, Y; Son, M; La Bella, A; Ochani, M; Levine, YA; Chiu, PY; Wang, P; Chavan, SS; Volpe, BT; Sherry, B; Diamond, B
View details
Hide details
Patients surviving a septic episode exhibit persistent immune impairment and increased mortality due to enhanced vulnerability to infections. In the present study, using the cecal ligation and puncture (CLP) model of polymicrobial sepsis, we addressed the hypothesis that altered vagus nerve activity contributes to immune impairment in sepsis survivors. CLP-surviving mice exhibited less TNFα in serum following administration of LPS, a surrogate for an infectious challenge, than control-operated (control) mice. To evaluate the role of the vagus nerve in the diminished response to LPS, mice were subjected to bilateral subdiaphragmatic vagotomy at 2 weeks post-CLP. CLP-surviving vagotomized mice exhibited increased serum and tissue TNFα levels in response to LPS-challenge compared to CLP-surviving, non-vagotomized mice. Moreover, vagus nerve stimulation in control mice diminished the LPS-induced TNFα responses while having no effect in CLP mice, suggesting constitutive activation of vagus nerve signaling in CLP-survivors. The percentage of splenic CD4+ ChAT-EGFP+ T cells that relay vagus signals to macrophages was increased in CLP-survivors compared to control mice, and vagotomy in CLP-survivors resulted in a reduced percentage of ChAT-EGFP+ cells. Moreover, CD4 knockout CLP-surviving mice exhibited an enhanced LPS-induced TNFα response compared to wild-type mice, supporting a functional role for CD4+ ChAT+ T cells in mediating inhibition of LPS-induced TNFα responses in CLP-survivors. Blockade of the cholinergic anti-inflammatory pathway with methyllcaconitine, an α7 nicotinic acetylcholine receptor antagonist, restored LPS-induced TNFα responses in CLP-survivors. Our study demonstrates that the vagus nerve is constitutively active in CLP-survivors and contributes to the immune impairment.
Sciatic nerve stimulation and its effects on upper airway resistance in the anesthetized rabbit model relevant to sleep apnea
Author(s): Schiefer, M; Gamble, J; Strohl, KP
View details
Hide details
Obstructive sleep apnea (OSA) is a disorder characterized by collapse of the velopharynx and/or oropharynx during sleep when drive to the upper airway is reduced. Here, we explore an indirect approach for activation of upper airway muscles that might affect airway dynamics, namely, unilateral electrical stimulation of the afferent fibers of the sciatic nerve, in an anesthetized rabbit model. A nerve cuff electrode was placed around the sciatic and hypoglossal nerves to deliver stimulus while airflow, air pressure, and alae nasi electromyogram (EMG) were monitored both before and after sciatic transection. Sciatic nerve stimulation increased respiratory effort, rate, and alae nasi EMG, which persisted for seconds after stimulation; however, upper airway resistance was unchanged. Hypoglossal stimulation reduced resistance without altering drive. Although sciatic nerve stimulation is not ideal for treating OSA, it remains a target for altering respiratory drive. NEW & NOTEWORTHY Previously, sciatic nerve stimulation has been shown to activate upper airway and chest wall muscles. The supposition that resistance through the upper airway would be reduced with this afferent reflex was disproven. Findings were in contrast with the effect of hypoglossal nerve stimulation, which was shown to decrease resistance without changing muscle activation or ventilatory drive.
A wrappable microwire electrode for awake, chronic interfacing with small diameter autonomic peripheral nerves
Author(s): Falcone, JD; Liu, T; Goldman, L; Pogue, DD; Straka, M
View details
Hide details
Bioelectronic medicine requires the ability to monitor and modulate nerve activity in awake patients over time. The vagus nerve is a promising stimulation target, and preclinical models often use mice. However, an awake, chronic mouse vagus nerve interface has yet to be demonstrated. Here, we developed a functional wrappable microwire electrode to chronically interface with the small diameter mouse cervical vagus nerve (~100 μm). In an acute setting, the wrappable microwire had similar recording performance to commercially available electrodes. A chronic, awake mouse model was then developed to record spontaneous compound action potentials (CAPs). Viable signal-to-noise ratios (SNRs) were obtained from the wrappable microwires between 30 and 60 days (n = 8). Weekly impedance measurements showed no correlation between SNR or time. The wrappable microwires successfully interfaced with small diameter nerves and has been validated in a chronic, awake preclinical model, which can better facilitate clinical translation for bioelectronic medicine.
Reversible temporally-specific inhibition of muscle using a light-activated chloride channel
Author(s): Gorini, C; Iyer, S; Vyas, S; Ramakrishnan, C; Deisseroth, K; Delp, S
View details
Hide details
Achieving reversible, temporally specific inhibition of motor neurons has the potential to revolutionize treatment of disorders marked by muscle hyperactivity. Current treatment strategies are inadequate – surgical interventions are irreversible and pharmaceutical interventions have off-target effects. Optogenetic strategies for inhibiting muscle activity have theoretical promise; however, trafficking and expression problems have prevented translatable optogenetic suppression of muscle activity. Here, we exploit recent innovations in opsin engineering to demonstrate virally mediated, temporally specific optogenetic inhibition of motor neurons and muscle activity in vivo. We show that intra-muscular injection of adeno-associated virus serotype 6 can drive expression of the inhibitory channelrhodopsin mutant iC++ in both immunodeficient and wild-type mice. Illumination of the sciatic nerve in wild-type mice resulted in 64.8% inhibition of evoked twitch force. Optical excitation during tetanic stimulation in wild-type mice resulted in 59.1% inhibition at 10 Hz and 55.4% at 25 Hz. The extent of optogenetic inhibition was titratable, and ranged from 0% to 78.4% as illumination intensity was changed from 1 mW to 20 mW/mm2. These results could have therapeutic applicability to disorders such as spasticity, hypertonia and urinary incontinence, and provide a new tool to neuroscientists and muscle physiologists wishing to reversibly inhibit motor neuron activity in vivo.
Positioning the Nerve Cuff Distally on the Sciatic Nerve Improves the Classification of Ankle-Movement Proprioceptive ENG Signals
Author(s): Silveira, C; Brunton, E; Spendiff, S; Nazarpour, K
View details
Hide details
Recording of neural signals from intact peripheral nerves in patients with spinal cord injury or stroke survivors offers the possibility for the development of closed-loop sensorimotor prostheses. However, questions remain over the positioning of neural interfaces such that the separability of neural data recorded from the peripheral nerves is improved. Afferent electroneurographic signals were recorded with nerve cuffs placed on the sciatic nerve of rats in response to various mechanical stimuli to the hindpaw. The mean absolute value of the signal was extracted and fed into classifiers. The performance of the classifier was evaluated when information was available from a single cuff placed either distally or proximally on the sciatic nerve. Results confirmed earlier findings that proprioceptive ENG signals, elicited by the movement of the ankle, can be identified and separated in neural recordings made with a cuff electrode. In addition, classification scores improved when the nerve cuff was placed distally on the nerve rather than proximally, taking advantage of the nerve's underlying anatomy.
Adaptive myoelectric pattern recognition toward improved multifunctional prosthesis control
Author(s): Liu, J
View details
Hide details
The non-stationary property of electromyography (EMG) signals in real life settings usually hinders the clinical application of the myoelectric pattern recognition for prosthesis control. The classical EMG pattern recognition approach consists of two separate steps: training and testing, without considering the changes between training and testing data induced by electrode shift, fatigue, impedance changes and psychological factors, and often results in performance degradation. The aim of this study was to develop an adaptive myoelectric pattern recognition system, aiming to retrain the classifier online with the testing data without supervision, providing a self-correction mechanism for suppressing misclassifications. This paper presents an adaptive unsupervised classifier based on support vector machine (SVM) to improve the classification performance. Experimental data from 15 healthy subjects were used to evaluate performance. Preliminary study on intra-session and inter-session EMG data was conducted to verify the performance of the unsupervised adaptive SVM classifier. The unsupervised adaptive SVM classifier outperformed the conventional SVM by 3.3% and 8.0% for the combination of time-domain and autoregressive features in the intra-session and inter-session tests, respectively. The proposed approach is capable of incorporating the useful information in testing data to the classification model by taking into account the overtime changes in the testing data with respect to the training data to retrain the original classifier, therefore providing a self-correction mechanism for suppressing misclassifications. Copyright © 2015 IPEM. Published by Elsevier Ltd. All rights reserved.
Separability of neural responses to standardised mechanical stimulation of limbs
Author(s): Brunton, E; Blau, CW; Nazarpour, K
View details
Hide details
Considerable scientific and technological efforts are currently being made towards the development of neural prostheses. Understanding how the peripheral nervous system responds to electro-mechanical stimulation of the limb, will help to inform the design of prostheses that can restore function or accelerate recovery from injury to the sensory motor system. However, due to differences in experimental protocols, it is difficult, if not impossible, to make meaningful comparisons between different peripheral nerve interfaces. Therefore, we developed a low-cost electronic system to standardise the mechanical stimulation of a rat's hindpaw. Three types of mechanical stimulations, namely, proprioception, touch and nociception were delivered to the limb and the electroneurogram signals were recorded simultaneously from the sciatic nerve with a 16-contact cuff electrode. For the first time, results indicate separability of neural responses according to stimulus type as well as intensity. Statistical analysis reveal that cuff contacts placed circumferentially, rather than longitudinally, are more likely to lead to higher classification rates. This flexible setup may be readily adapted for systematic comparison of various electrodes and mechanical stimuli in rodents. Hence, we have made its electro-mechanical design and computer programme available online.
Glutamatergic Mechanisms Involved in Bladder Overactivity and Pudendal Neuromodulation in Cats
Author(s): Uy, J; Yu, M; Jiang, X; Jones, C; Shen, B; Wang, J; Roppolo, JR; de Groat, WC; Tai, C
View details
Hide details
The involvement of ionotropic glutamate receptors in bladder overactivity and pudendal neuromodulation was determined in α-chloralose anesthetized cats by intravenously administering MK801 (a NMDA receptor antagonist) or CP465022 (an AMPA receptor antagonist). Infusion of 0.5% acetic acid (AA) into the bladder produced bladder overactivity. In the first group of 5 cats, bladder capacity was significantly (P < 0.05) reduced to 55.3±10.0% of saline control by AA irritation. Pudendal nerve stimulation (PNS) significantly (P < 0.05) increased bladder capacity to 106.8 ± 15.0% and 106.7 ± 13.3% of saline control at 2T and 4T intensity, respectively. T is threshold intensity for inducing anal twitching. MK801 at 0.3 mg/kg prevented the increase in capacity by 2T or 4T PNS. In the second group of 5 cats, bladder capacity was significantly (P < 0.05) reduced to 49.0 ± 7.5% of saline control by AA irritation. It was then significantly (P < 0.05) increased to 80.8±13.5% and 79.0±14.0% of saline control by 2T and 4T PNS, respectively. CP465022 at 0.03-1 mg/kg prevented the increase in capacity by 2T PNS and at 0.3-1 mg/kg prevented the increase in capacity by 4T PNS. In both groups, MK801 at 0.3 mg/kg and CP465022 at 1 mg/kg significantly (P < 0.05) increased the prestimulation bladder capacity (about 80% and 20%, respectively) and reduced the amplitude of bladder contractions (about 30 and 20 cmH2O, respectively). These results indicate that NMDA and AMPA glutamate receptors are important for PNS to inhibit bladder overactivity and that tonic activation of these receptors also contributes to the bladder overactivity induced by AA irritation.
Sacral Neuromodulation Blocks Pudendal Inhibition of Reflex Bladder Activity in Cats: Insight into the Efficacy of Sacral Neuromodulation in Fowler's Syndrome
Author(s): Li, X; Uy, J; Yu, M; Li, S; Theisen, K; Browning, J; Shen, B; Wang, J; Roppolo, JR; de Groat, WC; Tai, C
View details
Hide details
This study tested the hypothesis that sacral neuromodulation, i.e. electrical stimulation of afferent axons in sacral spinal root, can block pudendal afferent inhibition of the micturition reflex. In α-chloralose anesthetized cats, pudendal nerve stimulation (PNS) at 3-5 Hz was used to inhibit bladder reflex activity while the sacral S1 or S2 dorsal root was stimulated at 15-30 Hz to mimic sacral neuromodulation and to block the bladder inhibition induced by PNS. The intensity threshold (T) for PNS or S1/S2 dorsal root stimulation (DRS) to induce muscle twitch of anal sphincter or toe was determined. PNS at 1.5-2T intensity inhibited the micturition reflex by significantly (p < 0.01) increasing bladder capacity to 150-170% of control capacity. S1 DRS alone at 1-1.5T intensity did not inhibit bladder activity, but completely blocked PNS inhibition and restored bladder capacity to control level. At higher intensity (1.5-2T), S1 DRS alone inhibited the micturition reflex and significantly increased bladder capacity to 135.8±6.6% of control capacity. However, the same higher intensity S1 DRS applied simultaneously with PNS, suppressed PNS inhibition and significantly (p < 0.01) reduced bladder capacity to 126.8±9.7% of control capacity. S2 DRS at both low (1T) and high (1.5-2T) intensity failed to significantly reduce PNS inhibition. PNS and S1 DRS did not change the amplitude and duration of micturition reflex contractions, but S2 DRS at 1.5-2T intensity doubled the duration of the contraction and increased bladder capacity. These results are important for understanding the mechanisms underlying sacral neuromodulation of non-obstructive urinary retention in Fowler's syndrome.
Sex difference in the contribution of GABAB receptors to tibial neuromodulation of bladder overactivity in cats
Author(s): Fuller, TW; Jiang, X; Bansal, U; Lamm, V; Shen, B; Wang, J; Roppolo, JR; de Groat, WC; Tai, C
View details
Hide details
This study investigated the role of γ-aminobutyric acid subtype B (GABAB) receptors in tibial and pudendal neuromodulation of bladder overactivity induced by intravesical administration of dilute (0.5%) acetic acid (AA) in α-chloralose-anesthetized cats. To inhibit bladder overactivity, tibial or pudendal nerve stimulation (TNS or PNS) was applied at 5 Hz and two or four times threshold (T) intensity for inducing toe or anal sphincter twitch. TNS at 2T or 4T intensity significantly (P < 0.05) increased the bladder capacity to 173.8 ± 16.2 or 198.5 ± 24.1%, respectively, of control capacity. Meanwhile, PNS at 2T or 4T intensity significantly (P < 0.05) increased the bladder capacity to 217 ± 18.8 and 221.3 ± 22.3% of control capacity, respectively. CGP52432 (a GABAB receptor antagonist) at intravenous dosages of 0.1-1 mg/kg completely removed the TNS inhibition in female cats but had no effect in male cats. CGP52432 administered intravenously also had no effect on control bladder capacity or the pudendal inhibition of bladder overactivity. These results reveal a sex difference in the role of GABAB receptors in tibial neuromodulation of bladder overactivity in cats and that GABAB receptors are not involved in either pudendal neuromodulation or irritation-induced bladder overactivity.
A micro-scale printable nanoclip for electrical stimulation and recording in small nerves.
Author(s): Lissandrello, CA; Gillis, WF; Shen, J; Pearre, BW; Vitale, F; Pasquali, M; Holinski, BJ; Chew, DJ; White, AE; Gardner, TJ
View details
Hide details
The vision of bioelectronic medicine is to treat disease by modulating the signaling of visceral nerves near various end organs. In small animal models, the nerves of interest can have small diameters and limited surgical access. New high-resolution methods for building nerve interfaces are desirable. In this study, we present a novel nerve interface and demonstrate its use for stimulation and recording in small nerves.
A benchtop biorobotic platform for in vitro observation of muscle-tendon dynamics with parallel mechanical assistance from an elastic exoskeleton
Author(s): Robertson, BD; Vadakkeveedu, S; Sawicki, GS
View details
Hide details
We present a novel biorobotic framework comprised of a biological muscle-tendon unit (MTU) mechanically coupled to a feedback controlled robotic environment simulation that mimics in vivo inertial/gravitational loading and mechanical assistance from a parallel elastic exoskeleton. Using this system, we applied select combinations of biological muscle activation (modulated with rate-coded direct neural stimulation) and parallel elastic assistance (applied via closed-loop mechanical environment simulation) hypothesized to mimic human behavior based on previously published modeling studies. These conditions resulted in constant system-level force-length dynamics (i.e., stiffness), reduced biological loads, increased muscle excursion, and constant muscle average positive power output-all consistent with laboratory experiments on intact humans during exoskeleton assisted hopping. Mechanical assistance led to reduced estimated metabolic cost and MTU apparent efficiency, but increased apparent efficiency for the MTU+Exo system as a whole. Findings from this study suggest that the increased natural resonant frequency of the artificially stiffened MTU+Exo system, along with invariant movement frequencies, may underlie observed limits on the benefits of exoskeleton assistance. Our novel approach demonstrates that it is possible to capture the salient features of human locomotion with exoskeleton assistance in an isolated muscle-tendon preparation, and introduces a powerful new tool for detailed, direct examination of how assistive devices affect muscle-level neuromechanics and energetics.
Lumbosacral spinal segmental contributions to tibial and pudendal neuromodulation of bladder overactivity in cats
Author(s): Bansal, U; Fuller, TW; Jiang, X; Bandari, J; Zhang, Z; Shen, B; Wang, J; Roppolo, JR; de Groat, WC; Tai, C
View details
Hide details
To determine the spinal segmental afferent contributions to tibial and pudendal inhibition of bladder overactivity. Intravesical infusion of 0.5% acetic acid was used to irritate the bladder and induce bladder overactivity in anesthetized cats. Tibial or pudendal nerve stimulation was used to suppress the bladder overactivity and increase bladder capacity during cystometry. L5-S3 dorsal roots ipsilateral to the stimulation were exposed by a laminectomy and transected sequentially during the experiments to determine the role of individual dorsal roots in tibial or pudendal neuromodulation. Transection of L5 dorsal root had no effect. Transection of L6 dorsal root in four cats produced an average 18% reduction in tibial inhibition, which is not a significant change when averaged in the group of 10 cats. Transection of L7 dorsal root completely removed the tibial inhibition without changing reflex bladder activity or pudendal inhibition. Transection of S1 dorsal root reduced the pudendal inhibition, after which transection of S2 dorsal root completely removed the pudendal inhibition. Transection of S3 dorsal root had no effect. The control bladder capacity was increased only by transection of S2 dorsal root. This study in cats revealed that tibial and pudendal neuromodulation of reflex bladder overactivity depends on activation of primary afferent pathways that project into different spinal segments. This difference may be related to the recent observation in cats that the two types of neuromodulation have different mechanisms of action.
Post-stimulation block of frog sciatic nerve by high-frequency (kHz) biphasic stimulation
Author(s): Yang, G; Xiao, Z; Wang, J; Shen, B; Roppolo, JR; de Groat, WC; Tai, C
View details
Hide details
This study determined if high-frequency biphasic stimulation can induce nerve conduction block that persists after the stimulation is terminated, i.e., post-stimulation block. The frog sciatic nerve-muscle preparation was used in the study. Muscle contraction force induced by low-frequency (0.5 Hz) nerve stimulation was recorded to indicate the occurrence and recovery of nerve block induced by the high-frequency (5 or 10 kHz) biphasic stimulation. Nerve block was observed during high-frequency stimulation and after termination of the stimulation. The recovery from post-stimulation block occurred in two distinct phases. During the first phase, the complete block induced during high-frequency stimulation was maintained. The average maximal duration for the first phase was 107 ± 50 s. During the second phase, the block gradually or abruptly reversed. The duration of both first and second phases was dependent on stimulation intensity and duration but not frequency. Stimulation of higher intensity (1.4-2 times block threshold) and longer duration (5 min) produced the longest period (249 ± 58 s) for a complete recovery. Post-stimulation block can be induced by high-frequency biphasic stimulation, which is important for future investigations of the blocking mechanisms and for optimizing the stimulation parameters or protocols in clinical applications.
Identification of sensory information in mixed nerves using multi-channel cuff electrodes for closed loop neural prostheses
Author(s): Brunton, E; Blau, C; Silveira, C
View details
Hide details
The addition of sensory feedback is expected to greatly enhance the performance of motor neuroprostheses. In the case of stroke or spinal cord injured patients, sensory information can be obtained from electroneurographic (ENG) signals recorded from intact nerves in the non-functioning limb. Here, we aimed to identify sensory information recorded from mixed nerves using a multi-channel cuff electrode. ENG afferent signals were recorded in response to mechanical stimulation of the foot corresponding to three different functional types of sensory stimuli, namely: nociception, proprioception and touch. Offline digital signal processing was used to extract features for use as inputs for classification. A quadratic support vector machine was used to classify the data and the five fold cross validation error was measured. The results show that classification of nociceptive and proprioceptive stimuli is feasible, with cross validation errors of less than 10%. However, further work is needed to determine whether the touch information can be extracted more reliably from these recordings.
Saphenous Nerve Stimulation Normalizes Bladder Underactivity Induced by Tibial Nerve Stimulation in Cats.
Author(s): Li, S; Li, X; Theisen, K; Browning, J; Shen, B; Wang, J; Roppolo, JR; de Groat, WC; Tai, C
View details
Hide details
This study in α-chloralose anesthetized cats aimed at investigating the bladder responses to saphenous nerve stimulation (SNS). A urethral catheter was used to infuse the bladder with saline and to record changes in bladder pressure. With the bladder fully distended, SNS at 1 Hz frequency and an intensity slightly below the threshold (T) for inducing an observable motor response of the hindlimb muscles induced large amplitude (40-150 cmH2O) bladder contractions. Application of SNS (1 Hz, 2-4T) during cystometrograms (CMGs), when the bladder was slowly (1-3 ml/min) infused with saline, significantly (p<0.05) increased the duration of the micturition contraction to more than 200% of the control without changing bladder capacity or contraction amplitude. Repeated application (1-8 times) of intense (4-8T intensity) 30-minute tibial nerve stimulation (TNS) produced prolonged post-TNS inhibition that significantly (p<0.01) increased bladder capacity to 135.9±7.6% and decreased the contraction amplitude to 44.1±16.5% of the pre-TNS control level. During the period of post-TNS inhibition, SNS (1 Hz, 2-4T) applied during CMGs completely restored the bladder capacity and the contraction amplitude to the pre-TNS control level and almost doubled the duration of the micturition contraction. These results indicate that SNS at 1 Hz can facilitate the normal micturition reflex and normalize the reflex when it is suppressed during post-TNS inhibition. This study provides an opportunity to develop a novel neuromodulation therapy for underactive bladder using SNS.
An Excitatory Reflex from the Superficial Peroneal Nerve to the Bladder in Cats
Author(s): Yu, M; Uy, J; Jiang, X; Li, X; Jones, C; Shen, B; Wang, J; Roppolo, JR; de Groat, WC; Tai, C
View details
Hide details
This study in α-chloralose anesthetized cats discovered an excitatory peroneal nerve-to-bladder reflex. A urethral catheter was used to infuse the bladder with saline and record bladder pressure changes. Electrical stimulation was applied to the superficial peroneal nerve to trigger a reflex bladder activity. With the bladder distended at a volume about 90% of bladder capacity, superficial peroneal nerve stimulation (PNS) at 1-3 Hz and threshold (T) intensity for inducing muscle twitching on the posterior thigh induced large amplitude (40-150 cmH2O) bladder contractions. PNS (1-3 Hz, 1-2T) applied during cystometrograms (CMGs) when the bladder was slowly (1-3 ml/min) infused with saline, significantly (p<0.01) reduced bladder capacity to about 80% of the control capacity and significantly (p<0.05) enhanced reflex bladder contractions. To determine the impact of PNS on tibial nerve stimulation (TNS) induced changes in bladder function, PNS was delivered following TNS. TNS of 30-minute duration produced long-lasting post-stimulation inhibition and significantly (p<0.01) increased bladder capacity to 140.5±7.6% of the control capacity. During the post-TNS inhibition period, PNS (1-3 Hz, 1-4T) applied during CMGs completely restored bladder capacity to the control level and significantly (p<0.05) increased the duration of reflex bladder contractions to about 200% of control. The excitatory peroneal nerve-to-bladder reflex could also be activated by transcutaneous PNS using skin surface electrodes attached to the dorsal surface of the foot. These results raise the possibility of developing novel neuromodulation therapies to treat underactive bladder and non-obstructive urinary retention.
Role of cannabinoid receptor type 1 in tibial and pudendal neuromodulation of bladder overactivity in cats
Author(s): Jiang, X; Yu, M; Uy, J; Fuller, TW; Jones, C; Shen, B; Wang, J; Roppolo, JR; de Groat, WC; Tai, C
View details
Hide details
The role of cannabinoid type 1 (CB1) receptors in tibial and pudendal neuromodulation of bladder overactivity induced by intravesical infusion of 0.5% acetic acid (AA) was determined in α-chloralose anesthetized cats. AA irritation significantly (P < 0.01) reduced bladder capacity to 36.6 ± 4.8% of saline control capacity. Tibial nerve stimulation (TNS) at two or four times threshold (2T or 4T) intensity for inducing toe movement inhibited bladder overactivity and significantly (P < 0.01) increased bladder capacity to 69.2 ± 9.7 and 79.5 ± 7.2% of saline control, respectively. AM 251 (a CB1 receptor antagonist) administered intravenously at 0.03 or 0.1 mg/kg significantly (P < 0.05) reduced the inhibition induced by 2T or 4T TNS, respectively, without changing the prestimulation bladder capacity. However, intrathecal administration of AM 251 (0.03 mg) to L7 spinal segment had no effect on TNS inhibition. Pudendal nerve stimulation (PNS) also inhibited bladder overactivity induced by AA irritation, but AM 251 at 0.01-1 mg/kg iv had no effect on PNS inhibition or the prestimulation bladder capacity. These results indicate that CB1 receptors play an important role in tibial but not pudendal neuromodulation of bladder overactivity and the site of action is not within the lumbar L7 spinal cord. Identification of neurotransmitters involved in TNS or PNS inhibition of bladder overactivity is important for understanding the mechanisms of action underlying clinical application of neuromodulation therapies for bladder disorders.
Selective stimulation and neural recording on peripheral nerves using flexible split ring electrodes
Author(s): Sheshadri, SL; Xiang, Z; Delgado-Martinez, I; Xue, N; Sun, T; Thakor, NV; Yen, S; Lee, C
View details
Hide details
Reliable neural interfaces between peripheral nerves and implantable devices are at the center of advanced neural prosthetics and bioelectronic medicine. In this paper, selective sciatic nerve recording and stimulation were investigated using flexible split ring electrodes. The design enabled easy and reliable implantation of active electrodes on the sciatic nerve with minimal pressure on the nerve, but still provided good electrical contact with the nerve. Selective muscle stimulation was achieved by varying the stimulation configuration of the four active electrodes on the nerve to produce different muscle activation patterns. In addition, partially evoked neural signals were also recorded from the nerve using a transverse differential bipolar configuration, demonstrating differential recording capability. In addition, we showed that the quality of the neural signals recorded by the split ring electrode was higher than recordings from a commercial cuff electrode in terms of signal-to-noise ratio (SNR). Overall, our data shows that this flexible split ring electrode could be effective in neuromodulation in the future.
Pudendal but not tibial nerve stimulation inhibits bladder contractions induced by stimulation of pontine micturition center in cats
Author(s): Lyon, TD; Ferroni, MC; Kadow, BT; Slater, RC; Zhang, Z; Chang, V; Lamm, V; Shen, B; Wang, J; Roppolo, JR; de Groat, WC; Tai, C
View details
Hide details
This study examined the possibility that pudendal nerve stimulation (PNS) or tibial nerve stimulation (TNS) inhibits the excitatory pathway from the pontine micturition center (PMC) to the urinary bladder. In decerebrate cats under α-chloralose anesthesia, electrical stimulation of the PMC (40 Hz frequency, 0.2-ms pulse width, 10-25 s duration) using a microelectrode induced bladder contractions >20 cmH2O amplitude when the bladder was filled to 60-70% capacity. PNS or TNS (5 Hz, 0.2 ms) at two and four times the threshold (2T and 4T) to induce anal or toe twitch was applied to inhibit the PMC stimulation-induced bladder contractions. Propranolol, a nonselective β-adrenergic receptor antagonist, was administered intravenously (1 mg/kg i.v.) to determine the role of sympathetic pathways in PNS/TNS inhibition. PNS at both 2T and 4T significantly (P < 0.05) reduced the amplitude and area under the curve of the bladder contractions induced by PMC stimulation, while TNS at 4T facilitated the bladder contractions. Propranolol completely eliminated PNS inhibition and TNS facilitation. This study indicates that PNS, but not TNS, inhibits PMC stimulation-induced bladder contractions via a β-adrenergic mechanism that may occur in the detrusor muscle as a result of reflex activity in lumbar sympathetic nerves. Neither PNS nor TNS activated a central inhibitory pathway with synaptic connections to the sacral parasympathetic neurons that innervate the bladder. Understanding the site of action involved in bladder neuromodulation is important for developing new therapies for bladder disorders.
A Bidirectional Neural Interface IC With Chopper Stabilized BioADC Array and Charge Balanced Stimulator
Author(s): Greenwald, E; So, E; Wang, Q; Mollazadeh, M; Maier, C; Etienne-Cummings, R; Cauwenberghs, G; Thakor, N
View details
Hide details
We present a bidirectional neural interface with a 4-channel biopotential analog-to-digital converter (bioADC) and a 4-channel current-mode stimulator in 180 nm CMOS. The bioADC directly transduces microvolt biopotentials into a digital representation without a voltage-amplification stage. Each bioADC channel comprises a continuous-time first-order ∆Σ modulator with a chopper-stabilized OTA input and current feedback, followed by a second-order comb-filter decimator with programmable oversampling ratio. Each stimulator channel contains two independent digital-to-analog converters for anodic and cathodic current generation. A shared calibration circuit matches the amplitude of the anodic and cathodic currents for charge balancing. Powered from a 1.5 V supply, the analog and digital circuits in each recording channel draw on average [Formula: see text] and [Formula: see text] of supply current, respectively. The bioADCs achieve an SNR of [Formula: see text] and a SFDR of [Formula: see text] , for better than 9-b ENOB. Intracranial EEG recordings from an anesthetized rat are shown and compared to simultaneous recordings from a commercial reference system to validate performance in-vivo . Additionally, we demonstrate bidirectional operation by recording cardiac modulation induced through vagus nerve stimulation, and closed-loop control of cardiac rhythm. The micropower operation, direct digital readout, and integration of electrical stimulation circuits make this interface ideally suited for closed-loop neuromodulation applications.
Microstimulation of the lumbar DRG recruits primary afferent neurons in localized regions of lower limb
Author(s): Ayers, CA; Fisher, LE; Gaunt, RA; Weber, DJ
View details
Hide details
Patterned microstimulation of the dorsal root ganglion (DRG) has been proposed as a method for delivering tactile and proprioceptive feedback to amputees. Previous studies demonstrated that large- and medium-diameter afferent neurons could be recruited separately, even several months after implantation. However, those studies did not examine the anatomical localization of sensory fibers recruited by microstimulation in the DRG. Achieving precise recruitment with respect to both modality and receptive field locations will likely be crucial to create a viable sensory neuroprosthesis. In this study, penetrating microelectrode arrays were implanted in the L5, L6, and L7 DRG of four isoflurane-anesthetized cats instrumented with nerve cuff electrodes around the proximal and distal branches of the sciatic and femoral nerves. A binary search was used to find the recruitment threshold for evoking a response in each nerve cuff. The selectivity of DRG stimulation was characterized by the ability to recruit individual distal branches to the exclusion of all others at threshold; 84.7% (n = 201) of the stimulation electrodes recruited a single nerve branch, with 9 of the 15 instrumented nerves recruited selectively. The median stimulation threshold was 0.68 nC/phase, and the median dynamic range (increase in charge while stimulation remained selective) was 0.36 nC/phase. These results demonstrate the ability of DRG microstimulation to achieve selective recruitment of the major nerve branches of the hindlimb, suggesting that this approach could be used to drive sensory input from localized regions of the limb. This sensory input might be useful for restoring tactile and proprioceptive feedback to a lower-limb amputee.
Role of glycine in nociceptive and non-nociceptive bladder reflexes and pudendal afferent inhibition of these reflexes in cats
Author(s): Rogers, MJ; Shen, B; Reese, JN; Xiao, Z; Wang, J; Lee, A; Roppolo, JR; de Groat, WC; Tai, C
View details
Hide details
This study examined the role of glycinergic transmission in nociceptive and non-nociceptive bladder reflexes and in inhibition of these reflexes by pudendal nerve stimulation (PNS). Cystometrograms (CMGs) were performed in α-chloralose anesthetized cats by intravesical infusion of saline or 0.25% acetic acid (AA) to trigger, respectively, non-nociceptive or nociceptive bladder reflexes. PNS at 2 or 4 times threshold (T) intensity for inducing anal twitch was used to inhibit the bladder reflexes. Strychnine (a glycine receptor antagonist) was administered in cumulative doses (0.001-0.3 mg/kg, i.v.) at 60-120 min intervals. Strychnine at 0.001-0.3 mg/kg significantly (P < 0.05) increased bladder capacity and reduced contraction amplitude during saline CMGs but did not change these parameters during AA CMGs except at the 0.3 mg/kg dose which increased bladder capacity. Strychnine did not alter PNS inhibition during saline CMGs except at the highest dose at 2T intensity, but significantly (P < 0.05) suppressed PNS inhibition during AA CMGs after 0.001-0.003 mg/kg doses at 2T and 4T intensities. During AA CMGs strychnine (0.3 mg/kg) also unmasked a post-PNS excitatory effect that significantly reduced bladder capacity after termination of PNS. Glycinergic inhibitory neurotransmission in the central nervous system plays an unexpected role to tonically enhance the magnitude and reduce the bladder volume threshold for triggering the non-nociceptive bladder reflex. This is attributable to inhibition by glycine of another inhibitory mechanism. Glycine also has a minor role in PNS inhibition of the nociceptive bladder reflex. Neurourol. Urodynam. 35:798-804, 2016. © 2015 Wiley Periodicals, Inc.
Implantable neurotechnologies: a review of micro- and nanoelectrodes for neural recording
Author(s): Patil, AC; Thakor, NV
View details
Hide details
Electrodes serve as the first critical interface to the biological organ system. In neuroprosthetic applications, for example, electrodes interface to the tissue for either signal recording or tissue stimulation. In this review, we consider electrodes for recording neural activity. Recording electrodes serve as wiretaps into the neural tissues, providing readouts of electrical activity. These signals give us valuable insights into the organization and functioning of the nervous system. The recording interfaces have also shown promise in aiding treatment of motor and sensory disabilities caused by neurological disorders. Recent advances in fabrication technology have generated wide interest in creating tiny, high-density electrode interfaces for neural tissues. An ideal electrode should be small enough and be able to achieve reliable and conformal integration with the structures of the nervous system. As a result, the existing electrode designs are being shrunk and packed to form small form factor interfaces to tissue. Here, an overview of the historic and state-of-the-art electrode technologies for recording neural activity is presented first with a focus on their development road map. The fact that the dimensions of recording electrode sites are being scaled down from micron to submicron scale to enable dense interfaces is appreciated. The current trends in recording electrode technologies are then reviewed. Current and future considerations in electrode design, including the use of inorganic nanostructures and biologically inspired or biocomapatible materials are discussed, along with an overview of the applications of flexible materials and transistor transduction schemes. Finally, we detail the major technical challenges facing chronic use of reliable recording electrode technology.
Sympathetic β-adrenergic mechanism in pudendal inhibition of nociceptive and non-nociceptive reflex bladder activity
Author(s): Kadow, BT; Lyon, TD; Zhang, Z; Lamm, V; Shen, B; Wang, J; Roppolo, JR; de Groat, WC; Tai, C
View details
Hide details
This study investigated the role of the hypogastric nerve and β-adrenergic mechanisms in the inhibition of nociceptive and non-nociceptive reflex bladder activity induced by pudendal nerve stimulation (PNS). In α-chloralose-anesthetized cats, non-nociceptive reflex bladder activity was induced by slowly infusing saline into the bladder, whereas nociceptive reflex bladder activity was induced by replacing saline with 0.25% acetic acid (AA) to irritate the bladder. PNS was applied at multiple threshold (T) intensities for inducing anal sphincter twitching. During saline infusion, PNS at 2T and 4T significantly (P < 0.01) increased bladder capacity to 184.7 ± 12.6% and 214.5 ± 10.4% of the control capacity. Propranolol (3 mg/kg iv) had no effect on PNS inhibition, but 3-[(2-methyl-4-thiazolyl)ethynyl]pyridine (MTEP; 1-3 mg/kg iv) significantly (P < 0.05) reduced the inhibition. During AA irritation, the control bladder capacity was significantly (P < 0.05) reduced to ∼22% of the saline control capacity. PNS at 2T and 4T significantly (P < 0.01) increased bladder capacity to 406.8 ± 47% and 415.8 ± 46% of the AA control capacity. Propranolol significantly (P < 0.05) reduced the bladder capacity to 276.3% ± 53.2% (at 2T PNS) and 266.5 ± 72.4% (at 4T PNS) of the AA control capacity, whereas MTEP (a metabotropic glutamate 5 receptor antagonist) removed the residual PNS inhibition. Bilateral transection of the hypogastric nerves produced an effect similar to that produced by propranolol. This study indicates that hypogastric nerves and a β-adrenergic mechanism in the detrusor play an important role in PNS inhibition of nociceptive but not non-nociceptive reflex bladder activity. In addition to this peripheral mechanism, a central nervous system mechanism involving metabotropic glutamate 5 receptors also has a role in PNS inhibition.
Serial estimation of motor unit numbers using an implantable system following nerve injury and repair in rats
Author(s): Willand, MP; Catapano, J
View details
Hide details
Motor unit number estimation (MUNE) is an established technique to assess recovery following peripheral nerve injury. In rats, where the vast majority of peripheral nerve research is conducted, assessing motor units at various time points requires a terminal procedure due to the invasive nature of current techniques. Here, we present an implanted system that was used to serially assess MUNE after peripheral nerve injury and repair in rats. This system significantly increases the efficiency of peripheral nerve research by negating the need for terminal procedures, allowing for serial MUNE assessment over time in the same rat. Our system utilizes a commercial implantable stimulator, custom designed cuff electrode, and corresponding custom software with automatic M-wave classification to quickly assess functional reinnervation up to 8 weeks following nerve injury and repair. The concepts presented in this paper are applicable to any implanted device with a transcutaneous radio frequency or inductive link that can be used to trigger nerve stimulation. The methodology is also applicable to researchers without access to implantable devices.
Development of battery-free neural interface and modulated control of tibialis anterior muscle via common peroneal nerve based on triboelectric nanogenerators (TENGs)
Author(s): Lee, S; Wang, H; Shi, Q; Dhakar, L; Wang, J; Thakor, NV; Yen, S; Lee, C
View details
Hide details
Flexible and stretchable electronics, also known as e-skin, have been a technology to create diversified sensors and wearable devices. Implantable bioelectronics have recently been recognized as a promising research field to modulate biological signals and treat many diseases and pathological conditions. The marriage of two technologies gives us a new cutting-edge research area, i.e., implantable flexible electronics. While strain sensors, ECG sensors, pH sensors, temperature sensors and LED chips have been integrated together as a novel platform for measuring physiological signals, one of critical challenges for long-term use of such devices is a reliable power source with sound output power. To support operation of the implantable bioelectronics, triboelectric nanogenerators (TENGs) have recently been explored, as a promising technology to harvest energy, as the concept of scavenging human body energy into useful electrical power. In this work, we investigate stacked TENGs with output voltage of 160 Vp-p and a short circuit current of 6.7 µA as a potential power source for neural stimulation using flexible and adjustable neural interfaces. To advance a generic design of flexible neural interfaces which is good at sciatic nerve recording and stimulation, we optimize a new flexible sling electrode and successfully achieve neural signal recording with different amplitudes and latencies. More importantly, successful selective stimulation achieved in this work proves that the flexible sling electrode is a good generic neural interface. We demonstrate direct stimulation of a sciatic nerve and a common peroneal nerve in rats by the TENGs connected with the suggested interface and a pair of Pt/Ir wires, respectively, while monitoring muscle signals. The muscle contraction can be controlled by the operation of the TENGs. This prove-concept result indicates that this technology could be the way of realizing battery-free wearable neuromodulators in the future.
Propranolol, but not naloxone, enhances spinal reflex bladder activity and reduces pudendal inhibition in cats
Author(s): Rogers, MJ; Xiao, Z; Shen, B; Wang, J; Schwen, Z; Roppolo, JR; de Groat, WC; Tai, C
View details
Hide details
This study examined the role of β-adrenergic and opioid receptors in spinal reflex bladder activity and in the inhibition induced by pudendal nerve stimulation (PNS) or tibial nerve stimulation (TNS). Spinal reflex bladder contractions were induced by intravesical infusion of 0.25% acetic acid in α-chloralose-anesthetized cats after an acute spinal cord transection (SCT) at the thoracic T9/T10 level. PNS or TNS at 5 Hz was applied to inhibit these spinal reflex contractions at 2 and 4 times the threshold intensity (T) for inducing anal or toe twitch, respectively. During a cystrometrogram (CMG), PNS at 2T and 4T significantly (P < 0.05) increased bladder capacity from 58.0 ± 4.7% to 85.8 ± 10.3% and 96.5 ± 10.7%, respectively, of saline control capacity, while TNS failed to inhibit spinal reflex bladder contractions. After administering propranolol (3 mg/kg iv, a β₁/β₂-adrenergic receptor antagonist), the effects of 2T and 4T PNS on bladder capacity were significantly (P < 0.05) reduced to 64.5 ± 9.5% and 64.7 ± 7.3%, respectively, of the saline control capacity. However, the residual PNS inhibition (about 10% increase in capacity) was still statistically significant (P < 0.05). Propranolol treatment also significantly (P = 0.0019) increased the amplitude of bladder contractions but did not change the control bladder capacity. Naloxone (1 mg/kg iv, an opioid receptor antagonist) had no effect on either spinal reflex bladder contractions or PNS inhibition. At the end of experiments, hexamethonium (10 mg/kg iv, a ganglionic blocker) significantly (P < 0.05) reduced the amplitude of the reflex bladder contractions. This study indicates an important role of β₁/β₂-adrenergic receptors in pudendal inhibition and spinal reflex bladder activity.
Role of spinal metabotropic glutamate receptor 5 in pudendal inhibition of the nociceptive bladder reflex in cats
Author(s): Reese, JN; Rogers, MJ; Xiao, Z; Shen, B; Wang, J; Schwen, Z; Roppolo, JR; de Groat, WC; Tai, C
View details
Hide details
This study examined the role of spinal metabotropic glutamate receptor 5 (mGluR5) in the nociceptive C-fiber afferent-mediated spinal bladder reflex and in the inhibtion of this reflex by pudendal nerve stimulation (PNS). In α-chloralose-anesthetized cats after spinal cord transection at the T9/T10 level, intravesical infusion of 0.25% acetic acid irritated the bladder, activated nociceptive C-fiber afferents, and induced spinal reflex bladder contractions of low amplitude (
Role of the brain stem in tibial inhibition of the micturition reflex in cats
Author(s): Ferroni, MC; Slater, RC; Shen, B; Xiao, Z; Wang, J; Lee, A; Roppolo, JR; de Groat, WC; Tai, C
View details
Hide details
This study examined the role of the brain stem in inhibition of bladder reflexes induced by tibial nerve stimulation (TNS) in α-chloralose-anesthetized decerebrate cats. Repeated cystometrograms (CMGs) were performed by infusing saline or 0.25% acetic acid (AA) to elicit normal or overactive bladder reflexes, respectively. TNS (5 or 30 Hz) at three times the threshold (3T) intensity for inducing toe movement was applied for 30 min between CMGs to induce post-TNS inhibition or applied during the CMGs to induce acute TNS inhibition. Inhibition was evident as an increase in bladder capacity without a change in amplitude of bladder contractions. TNS applied for 30 min between saline CMGs elicited prolonged (>2 h) poststimulation inhibition that significantly (P < 0.05) increased bladder capacity to 30–60% above control; however, TNS did not produce this effect during AA irritation. TNS applied during CMGs at 5 Hz but not 30 Hz significantly (P < 0.01) increased bladder capacity to 127.3 ± 6.1% of saline control or 187.6 ± 5.0% of AA control. During AA irritation, naloxone (an opioid receptor antagonist) administered intravenously (1 mg/kg) or directly to the surface of the rostral brain stem (300–900 μg) eliminated acute TNS inhibition and significantly (P < 0.05) reduced bladder capacity to 62.8 ± 22.6% (intravenously) or 47.6 ± 25.5% (brain stem application). Results of this and previous studies indicate 1) forebrain circuitry rostral to the pons is not essential for TNS inhibition; and 2) opioid receptors in the brain stem have a critical role in TNS inhibition of overactive bladder reflexes but are not involved in inhibition of normal bladder reflexes.
Single-pulse and unidirectional electrical activation of the cervical vagus nerve reduces tumor necrosis factor in endotoxemia
Author(s): Olofsson, PS; Levine, YA; Caravaca, A; Chavan, SS; Pavlov, VA; Faltys, M; Tracey, KJ
View details
Hide details
The inflammatory reflex is a neural circuit defined by action potentials transmitted in the vagus nerve that regulate cytokine production in the spleen. Detailed mechanistic studies implicate the vagus nerve, the splenic nerve, a T-cell subset that produces acetylcholine under the control of adrenergic signals, and alpha7 nicotinic acetylcholine receptors (α7nAChR). expressed on macrophages. This study defines the vagus nerve fibers that transmit the efferent signal in this pathway, a motor arc of the inflammatory reflex. Mice and rats were subjected to electrical cervical vagus nerve stimulation or sham surgery. Cytokine levels in serum were measured in endotoxemic animals or in endotoxin-exposed blood samples. Evoked potentials were measured in the vagus nerve and a portion of the vagus nerve was anesthetized using local application of lidocaine before stimulation. The lowest threshold subdiaphragmatic fibers in the rat vagus nerve have conduction velocities consistent with that of myelinated B fibers. The stimulation current threshold for significant suppression of serum TNF levels was similar in mice and rats (≤500 μA). Blockade of the fibers caudal to the site of vagus nerve stimulation impaired the inhibition of TNF release. A single suprathreshold pulse stimulation was sufficient to suppress TNF release in endotoxemia. These results indicate that single-pulse and unidirectional electrical activation of the cervical vagus nerve reduce TNF in endotoxemia.
Role of µ, κ, and δ opioid receptors in tibial inhibition of bladder overactivity in cats
Author(s): Zhang, Z; Slater, RC; Ferroni, MC; Kadow, BT; Lyon, TD; Shen, B; Xiao, Z; Wang, J; Kang, A; Roppolo, JR; de Groat, WC; Tai, C
View details
Hide details
In α-chloralose anesthetized cats, we examined the role of opioid receptor (OR) subtypes (µ, κ, and δ) in tibial nerve stimulation (TNS)-induced inhibition of bladder overactivity elicited by intravesical infusion of 0.25% acetic acid (AA). The sensitivity of TNS inhibition to cumulative i.v. doses of selective OR antagonists (cyprodime for µ, nor-binaltorphimine for κ, or naltrindole for δ ORs) was tested. Naloxone (1 mg/kg, i.v., an antagonist for µ, κ, and δ ORs) was administered at the end of each experiment. AA caused bladder overactivity and significantly (P < 0.01) reduced bladder capacity to 21.1% ± 2.6% of the saline control. TNS at 2 or 4 times threshold (T) intensity for inducing toe movement significantly (P < 0.01) restored bladder capacity to 52.9% ± 3.6% or 57.4% ± 4.6% of control, respectively. Cyprodime (0.3-1.0 mg/kg) completely removed TNS inhibition without changing AA control capacity. Nor-binaltorphimine (3-10 mg/kg) also completely reversed TNS inhibition and significantly (P < 0.05) increased AA control capacity. Naltrindole (1-10 mg/kg) reduced (P < 0.05) TNS inhibition but significantly (P < 0.05) increased AA control capacity. Naloxone (1 mg/kg) had no effect in cyprodime pretreated cats, but it reversed the nor-binaltorphimine-induced increase in bladder capacity and eliminated the TNS inhibition remaining in naltrindole pretreated cats. These results indicate a major role of µ and κ ORs in TNS inhibition, whereas δ ORs play a minor role. Meanwhile, κ and δ ORs also have an excitatory role in irritation-induced bladder overactivity.
Unconstrained muscle-tendon workloops indicate resonance tuning as a mechanism for elastic limb behavior during terrestrial locomotion
Author(s): Robertson, BD; Sawicki, GS
View details
Hide details
In terrestrial locomotion, there is a missing link between observed spring-like limb mechanics and the physiological systems driving their emergence. Previous modeling and experimental studies of bouncing gait (e.g., walking, running, hopping) identified muscle-tendon interactions that cycle large amounts of energy in series tendon as a source of elastic limb behavior. The neural, biomechanical, and environmental origins of these tuned mechanics, however, have remained elusive. To examine the dynamic interplay between these factors, we developed an experimental platform comprised of a feedback-controlled servo-motor coupled to a biological muscle-tendon. Our novel motor controller mimicked in vivo inertial/gravitational loading experienced by muscles during terrestrial locomotion, and rhythmic patterns of muscle activation were applied via stimulation of intact nerve. This approach was based on classical workloop studies, but avoided predetermined patterns of muscle strain and activation-constraints not imposed during real-world locomotion. Our unconstrained approach to position control allowed observation of emergent muscle-tendon mechanics resulting from dynamic interaction of neural control, active muscle, and system material/inertial properties. This study demonstrated that, despite the complex nonlinear nature of musculotendon systems, cyclic muscle contractions at the passive natural frequency of the underlying biomechanical system yielded maximal forces and fractions of mechanical work recovered from previously stored elastic energy in series-compliant tissues. By matching movement frequency to the natural frequency of the passive biomechanical system (i.e., resonance tuning), muscle-tendon interactions resulting in spring-like behavior emerged naturally, without closed-loop neural control. This conceptual framework may explain the basis for elastic limb behavior during terrestrial locomotion.
Effects of striatal nitric oxide production on regional cerebral blood flow and seizure development in rats exposed to extreme hyperoxia
Author(s): Gasier, HG; Demchenko, IT; Allen, BW; Piantadosi, CA
View details
Hide details
The endogenous vasodilator and signaling molecule nitric oxide has been implicated in cerebral hyperemia, sympathoexcitation, and seizures induced by hyperbaric oxygen (HBO2) at or above 3 atmospheres absolute (ATA). It is unknown whether these events in the onset of central nervous system oxygen toxicity originate within specific brain structures and whether blood flow is diverted to the brain from peripheral organs with high basal flow, such as the kidney. To explore these questions, total and regional cerebral blood flow (CBF) were measured in brain structures of the central autonomic network in anesthetized rats in HBO2 at 6 ATA. Electroencephalogram (EEG) recordings, cardiovascular hemodynamics, and renal blood flow (RBF) were also monitored. As expected, mean arterial blood pressure and total and regional CBF increased preceding EEG spikes while RBF was unaltered. Of the brain structures examined, the earliest rise in CBF occurred in the striatum, suggesting increased neuronal activation. Continuous unilateral or bilateral striatal infusion of the nitric oxide synthase inhibitor N(ω)-nitro-L-arginine methyl ester attenuated CBF responses in that structure, but global EEG discharges persisted and did not differ from controls. Our novel findings indicate that: 1) cerebral hyperemia in extreme HBO2 in rats does not occur at the expense of renal perfusion, highlighting the remarkable autoregulatory capability of the kidney, and 2) in spite of a sentinel increase in striatal blood flow, additional brain structure(s) likely govern the pathogenesis of HBO2-induced seizures because EEG discharge latency was unchanged by local blockade of striatal nitric oxide production and concomitant hyperemia.
Effects of duloxetine and WAY100635 on pudendal inhibition of bladder overactivity in cats
Author(s): Reese, J; Xiao, Z; Schwen, Z; Matsuta, Y; Shen, B; Wang, J; Roppolo, JR; de Groat, WC; Tai, C
View details
Hide details
This study was aimed at determining the effect of duloxetine (a serotonin-norepinephrine reuptake inhibitor) on pudendal inhibition of bladder overactivity. Cystometrograms were performed on 15 cats under α-chloralose anesthesia by infusing saline and then 0.25% acetic acid (AA) to induce bladder overactivity. To inhibit bladder overactivity, pudendal nerve stimulation (PNS) at 5 Hz was applied to the right pudendal nerve at two and four times the threshold (T) intensity for inducing anal twitch. Duloxetine (0.03-3 mg/kg) was administered intravenously to determine the effect on PNS inhibition. AA irritation significantly (P < 0.01) reduced bladder capacity to 27.9 ± 4.6% of saline control capacity. PNS alone at both 2T and 4T significantly (P < 0.01) inhibited bladder overactivity and increased bladder capacity to 83.6 ± 7.6% and 87.5 ± 7.7% of saline control, respectively. Duloxetine at low doses (0.03-0.3 mg/kg) caused a significant reduction in PNS inhibition without changing bladder capacity. However, at high doses (1-3 mg/kg) duloxetine significantly increased bladder capacity but still failed to enhance PNS inhibition. WAY100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide; a 5-HT1A receptor antagonist, 0.5-1 mg/kg i.v.) reversed the suppressive effect of duloxetine on PNS inhibition and significantly (P < 0.05) increased the inhibitory effect of duloxetine on bladder overactivity but did not enhance the effect of PNS. These results indicate that activation of 5-HT1A autoreceptors on the serotonergic neurons in the raphe nucleus may suppress duloxetine and PNS inhibition, suggesting that the coadministration of a 5-HT1A antagonist drug might be useful in enhancing the efficacy of duloxetine alone and/or the additive effect of PNS-duloxetine combination for the treatment of overactive bladder symptoms.
Pudendal nerve stimulation and block by a wireless-controlled implantable stimulator in cats
Author(s): Yang, G; Wang, J; Shen, B; Roppolo, JR; de Groat, WC; Tai, C
View details
Hide details
The study aims to determine the functionality of a wireless-controlled implantable stimulator designed for stimulation and block of the pudendal nerve. In five cats under α-chloralose anesthesia, the stimulator was implanted underneath the skin on the left side in the lower back along the sacral spine. Two tripolar cuff electrodes were implanted bilaterally on the pudendal nerves in addition to one bipolar cuff electrode that was implanted on the left side central to the tripolar cuff electrode. The stimulator provided high-frequency (5-20 kHz) biphasic stimulation waveforms to the two tripolar electrodes and low-frequency (1-100 Hz) rectangular pulses to the bipolar electrode. Bladder and urethral pressures were measured to determine the effects of pudendal nerve stimulation (PNS) or block. The maximal (70-100 cmH2O) urethral pressure generated by 20-Hz PNS applied via the bipolar electrode was completely eliminated by the pudendal nerve block induced by the high-frequency stimulation (6-15 kHz, 6-10 V) applied via the two tripolar electrodes. In a partially filled bladder, 20-30 Hz PNS (2-8 V, 0.2 ms) but not 5 Hz stimulation applied via the bipolar electrode elicited a large sustained bladder contraction (45.9 ± 13.4 to 52.0 ± 22 cmH2O). During cystometry, the 5 Hz PNS significantly (p < 0.05) increased bladder capacity to 176.5 ± 27.1% of control capacity. The wireless-controlled implantable stimulator successfully generated the required waveforms for stimulation and block of pudendal nerve, which will be useful for restoring bladder functions after spinal cord injury.
Role of spinal GABAA receptors in pudendal inhibition of nociceptive and nonnociceptive bladder reflexes in cats
Author(s): Xiao, Z; Reese, J; Schwen, Z; Shen, B; Wang, J; Roppolo, JR; de Groat, WC; Tai, C
View details
Hide details
Picrotoxin, an antagonist for γ-aminobutyric acid receptor subtype A (GABAA), was used to investigate the role of GABAA receptors in nociceptive and nonnociceptive reflex bladder activities and pudendal inhibition of these activities in cats under α-chloralose anesthesia. Acetic acid (AA; 0.25%) was used to irritate the bladder and induce nociceptive bladder overactivity, while saline was used to distend the bladder and induce nonnociceptive bladder activity. To modulate the bladder reflex, pudendal nerve stimulation (PNS) was applied at multiple threshold (T) intensities for inducing anal sphincter twitching. AA irritation significantly (P < 0.01) reduced bladder capacity to 34.3 ± 7.1% of the saline control capacity, while PNS at 2T and 4T significantly (P < 0.01) increased AA bladder capacity to 84.0 ± 7.8 and 93.2 ± 15.0%, respectively, of the saline control. Picrotoxin (0.4 mg it) did not change AA bladder capacity but completely removed PNS inhibition of AA-induced bladder overactivity. Picrotoxin (iv) only increased AA bladder capacity at a high dose (0.3 mg/kg) but significantly (P < 0.05) reduced 2T PNS inhibition at low doses (0.01-0.1 mg/kg). During saline cystometry, PNS significantly (P < 0.01) increased bladder capacity to 147.0 ± 7.6% at 2T and 172.7 ± 8.9% at 4T of control capacity, and picrotoxin (0.4 mg it or 0.03-0.3 mg/kg iv) also significantly (P < 0.05) increased bladder capacity. However, picrotoxin treatment did not alter PNS inhibition during saline infusion. These results indicate that spinal GABAA receptors have different roles in controlling nociceptive and nonnociceptive reflex bladder activities and in PNS inhibition of these activities.
Somatic modulation of spinal reflex bladder activity mediated by nociceptive bladder afferent nerve fibers in cats
Author(s): Xiao, Z; Rogers, MJ; Shen, B; Wang, J; Schwen, Z; Roppolo, JR; de Groat, WC; Tai, C
View details
Hide details
The goal of the present study was to determine if supraspinal pathways are necessary for inhibition of bladder reflex activity induced by activation of somatic afferents in the pudendal or tibial nerve. Cats anesthetized with α-chloralose were studied after acute spinal cord transection at the thoracic T9/T10 level. Dilute (0.25%) acetic acid was used to irritate the bladder, activate nociceptive afferent C-fibers, and trigger spinal reflex bladder contractions (amplitude: 19.3 ± 2.9 cmH2O). Hexamethonium (a ganglionic blocker, intravenously) significantly (P < 0.01) reduced the amplitude of the reflex bladder contractions to 8.5 ± 1.9 cmH2O. Injection of lidocaine (2%, 1-2 ml) into the sacral spinal cord or transection of the sacral spinal roots and spinal cord further reduced the contraction amplitude to 4.2 ± 1.3 cmH2O. Pudendal nerve stimulation (PNS) at frequencies of 0.5-5 Hz and 40 Hz but not at 10-20 Hz inhibited reflex bladder contractions, whereas tibial nerve stimulation (TNS) failed to inhibit bladder contractions at all tested frequencies (0.5-40 Hz). These results indicate that PNS inhibition of nociceptive afferent C-fiber-mediated spinal reflex bladder contractions can occur at the spinal level in the absence of supraspinal pathways, but TNS inhibition requires supraspinal pathways. In addition, this study shows, for the first time, that after acute spinal cord transection reflex bladder contractions can be triggered by activating nociceptive bladder afferent C-fibers using acetic acid irritation. Understanding the sites of action for PNS or TNS inhibition is important for the clinical application of pudendal or tibial neuromodulation to treat bladder dysfunctions.
An Implantable Neuroprosthetic Device to Normalize Bladder Function after SCI
Author(s): Tai, C
View details
Hide details
… The three cuff electrodes (NCE112/113, MicroProbes Inc., Gaithersburg, MD) as shown in Fig.8A were tunneled underneath the skin from the stimulator to the exposed pudendal nerves and were placed around the left and right pudendal nerves as shown in Fig.8B …
Poststimulation inhibition of the micturition reflex induced by tibial nerve stimulation in rats
Author(s): Matsuta, Y; Roppolo, JR; de Groat, WC; Tai, C
View details
Hide details
The purpose of this study was to determine the effect of tibial nerve stimulation (TNS) on the micturition reflex. Experiments were conducted in 24 rats under urethane anesthesia. A catheter was inserted into the bladder via the bladder dome for saline infusion. A cuff electrode was placed around right tibial nerve for stimulation. TNS (5 Hz, 0.2 msec pulse width) at 2-4 times the threshold (T) intensity for inducing a toe movement was applied either during slow (0.08 mL/min) infusion of the bladder or for 30 min with an empty bladder. TNS had no effect on the micturition reflex when it was applied during slow bladder infusion. However, the 30-min TNS applied with an empty bladder induced poststimulation inhibition and significantly (P < 0.05) increased the bladder capacity to about 140% of prestimulation level in a 50-min period following the termination of stimulation. The bladder compliance was also significantly (P < 0.05) increased after the 30-min TNS. These results suggest that different mechanisms might exist in acute- and post-TNS inhibition of micturition reflex. The animal model developed in this study will be very useful for further investigations of the neurotransmitter mechanisms underlying tibial neuromodulation of bladder function.
A novel Microchannel Electrode Array: towards bioelectronic medical interfacing of small peripheral nerves
Author(s): Kim, YT; Kanneganti, A; Fatemi, S; Nothnagle, C; Wijesundara, M; Romero-Ortega, MI
View details
Hide details
Bioelectronic medicine is an emerging field that relies on electrical signals to modulate complex neuronal circuits, particularly in the peripheral nervous system, as an alternative to drug-enabled therapeutics. Small autonomic nerves are one of the targets in this field, however, interfacing peripheral nerves smaller than 300 μm remains a challenge. Here we report the development of a Microchannel Electrode Array (DCEA) capable of interfacing nerve fascicles as small as 50-300μm. The current μCEA records and stimulates from 28 channels and is designed for easy implantation and removal, bearing promise to enable neural interfacing in BM.
Biomechanical and functional variation in rat sciatic nerve following cuff electrode implantation
Author(s): Restaino, SM; Abliz, E; Wachrathit, K; Krauthamer, V; Shah, SB
View details
Hide details
Nerve cuff electrodes are commonly and successfully used for stimulating peripheral nerves. On the other hand, they occasionally induce functional and morphological changes following chronic implantation, for reasons not always clear. We hypothesize that restriction of nerve mobility due to cuff implantation may alter nerve conduction. We quantified acute changes in nerve-muscle electrophysiology, using electromyography, and nerve kinematics in anesthetized Sprague Dawley rat sciatic nerves during controlled hindlimb joint movement. We compared electrophysiological and biomechanical response in uncuffed nerves and those secured within a cuff electrode using analysis of variance (ANOVA) and regression analysis. Tethering resulting from cuff implantation resulted in altered nerve strain and a complex biomechanical environment during joint movement. Coincident with biomechanical changes, electromyography revealed significantly increased variability in the response of conduction latency and amplitude in cuffed, but not free, nerves following joint movement. Our findings emphasize the importance of the mechanical interface between peripheral nerves and their devices on neurophysiological performance. This work has implications for nerve device design, implantation, and prediction of long-term efficacy.
Effect of methysergide on pudendal inhibition of micturition reflex in cats
Author(s): Matsuta, Y; Schwen, Z; Mally, AD; Shen, B; Wang, J; Roppolo, JR; de Groat, WC; Tai, C
View details
Hide details
The role of 5-HT2 and opioid receptors in pudendal inhibition of bladder activity induced by intravesical infusion of saline or 0.25% acetic acid (AA) was investigated in anesthetized cats using methysergide (a 5-HT2 receptor antagonist) and naloxone (an opioid receptor antagonist). AA irritated the bladder and significantly (P<0.0001) reduced bladder capacity to 27.0 ± 7.4% of saline control capacity. Pudendal nerve stimulation (PNS) at multiples of the threshold (T) intensity for inducing anal sphincter twitching restored bladder capacity to 60.1 ± 8.0% at 1-2T (P<0.0001) and 92.2 ± 14.1% at 3-4T (P=0.001) of the saline control capacity. Methysergide (0.03-1mg/kg, i.v.) suppressed low intensity (1-2T) PNS inhibition but not high intensity (3-4T) inhibition, and also significantly (P<0.05) increased control bladder capacity at the dosage of 0.3-1mg/kg. During saline infusion without AA irritation, PNS significantly increased bladder capacity to 150.8 ± 9.9% at 1-2T (P<0.01) and 180.4 ± 16.6% at 3-4T (P<0.01) of the saline control capacity. Methysergide (0.1-1 mg/kg) significantly (P<0.05) increased saline control bladder capacity and suppressed PNS inhibition at the dosage of 0.03-1mg/kg. After methysergide treatment (1 mg/kg), naloxone significantly (P<0.05) reduced control bladder capacity during AA infusion but had no effect during saline infusion. Naloxone also had no influence on PNS inhibition. These results suggest that 5-HT2 receptors play a role in PNS inhibition of reflex bladder activity and interact with opioid mechanisms in micturition reflex pathway. Understanding neurotransmitter mechanisms underlying pudendal neuromodulation is important for the development of new treatments for bladder disorders.
Effect of high-frequency alternating current on spinal afferent nociceptive transmission
Author(s): Cuellar, JM; Alataris, K; Walker, A; Yeomans, DC; Antognini, JF
View details
Hide details
The study was performed to test the hypothesis that high-frequency alternating current (HFAC) ranging from 2 to 100 kHz delivered to the spinal dorsal roots reduces activity of spinal wide dynamic range (WDR) dorsal horn neurons (DHNs) during noxious peripheral stimulation. This hypothesis was tested in both small and large animal in vivo preparations. Single-unit extracellular spinal DHN recordings were performed in seven adult rats and four adult goats while testing various parameters of HFAC delivered to the nerve roots or dorsal root entry zone using various electrode types. Frequencies tested ranged from 2 to 100 kHz but focused on the 3 to 50 kHz range. This study investigated the ability of HFAC to inhibit WDR neuronal activity evoked by noxious mechanical (pinch), and electrical stimuli was tested but was primarily focused on electrical stimulation. Rat Study: Effects of HFAC were successfully tested on 11 WDR neurons. Suppression or complete blockade of evoked activity was observed in all 11 of these neurons. Complete data sets for neurons systematically tested with 15 baseline and post-HFAC stimulus sweeps were obtained in five neurons, the nociceptive activity of which was suppressed by an average of 69 ± 9.7% (p < 0.0001). Goat Study: HFAC was successfully tested on 15 WDR neurons. Conclusive suppression or complete nociceptive blockade was observed for 12/15 and complete data sets with at least 20 baseline and post-HFAC stimulus sweeps were obtained from eight DHNs. For these neurons the mean activity suppression was 70 ± 10% (p < 0.005). Delivery of HFAC to the region of epidural nerve root or nerve root entry inhibited afferent nociceptive input and therefore may have potential to serve as an alternative to traditional spinal cord stimulation without sensory paresthesia as neuronal activation cannot occur at frequencies in this range.
Contribution of opioid and metabotropic glutamate receptor mechanisms to inhibition of bladder overactivity by tibial nerve stimulation
Author(s): Matsuta, Y; Mally, AD; Zhang, F; Shen, B; Wang, J; Roppolo, JR; de Groat, WC; Tai, C
View details
Hide details
The contribution of metabotropic glutamate receptors (mGluR) and opioid receptors to inhibition of bladder overactivity by tibial nerve stimulation (TNS) was investigated in cats under α-chloralose anesthesia using LY341495 (a group II mGluR antagonist) and naloxone (an opioid receptor antagonist). Slow infusion cystometry was used to measure the volume threshold (i.e., bladder capacity) for inducing a large bladder contraction. After measuring the bladder capacity during saline infusion, 0.25% acetic acid (AA) was infused to irritate the bladder, activate the nociceptive C-fiber bladder afferents, and induce bladder overactivity. AA significantly (P < 0.0001) reduced bladder capacity to 26.6 ± 4.7% of saline control capacity. TNS (5 Hz, 0.2 ms) at 2 and 4 times the threshold (T) intensity for inducing an observable toe movement significantly increased bladder capacity to 62.2 ± 8.3% at 2T (P < 0.01) and 80.8 ± 9.2% at 4T (P = 0.0001) of saline control capacity. LY341495 (0.1-5 mg/kg iv) did not change bladder overactivity, but completely suppressed the inhibition induced by TNS at a low stimulus intensity (2T) and partially suppressed the inhibition at high intensity (4T). Following administration of LY341495, naloxone (0.01 mg/kg iv) completely eliminated the high-intensity TNS-induced inhibition. However, without LY341495 treatment a 10 times higher dose (0.1 mg/kg) of naloxone was required to completely block TNS inhibition. These results indicate that interactions between group II mGluR and opioid receptor mechanisms contribute to TNS inhibition of AA-induced bladder overactivity. Understanding neurotransmitter mechanisms underlying TNS inhibition of bladder overactivity is important for the development of new treatments for bladder disorders.
α7 nicotinic acetylcholine receptor (α7nAChR) expression in bone marrow-derived non-T cells is required for the inflammatory reflex
Author(s): Olofsson, PS; Katz, DA; Rosas-Ballina, M; Levine, YA; Ochani, M; Valdés-Ferrer, SI; Pavlov, VA; Tracey, KJ; Chavan, SS
View details
Hide details
The immune response to infection or injury coordinates host defense and tissue repair, but also has the capacity to damage host tissues. Recent advances in understanding protective mechanisms have found neural circuits that suppress release of damaging cytokines. Stimulation of the vagus nerve protects from excessive cytokine production and ameliorates experimental inflammatory disease. This mechanism, the inflammatory reflex, requires the α7 nicotinic acetylcholine receptor (α7nAChR), a ligand-gated ion channel expressed on macrophages, lymphocytes, neurons and other cells. To investigate cell-specific function of α7nAChR in the inflammatory reflex, we created chimeric mice by cross-transferring bone marrow between wild-type (WT) and α7nAChR-deficient mice. Deficiency of α7nAChR in bone marrow-derived cells significantly impaired vagus nerve-mediated regulation of tumor necrosis factor (TNF), whereas α7nAChR deficiency in neurons and other cells had no significant effect. In agreement with recent work, the inflammatory reflex was not functional in nude mice, because functional T cells are required for the integrity of the pathway. To investigate the role of T-cell α7nAChR, we adoptively transferred α7nAChR-deficient or WT T cells to nude mice. Transfer of WT and α7nAChR-deficient T cells restored function, indicating that α7nAChR expression on T cells is not necessary for this pathway. Together, these results indicate that α7nAChR expression in bone marrow-derived non-T cells is required for the integrity of the inflammatory reflex.
Inhibition of micturition reflex by activation of somatic afferents in posterior femoral cutaneous nerve
Author(s): Tai, C; Shen, B; Mally, AD; Zhang, F; Zhao, S; Wang, J; Roppolo, JR; de Groat, WC
View details
Hide details
This study determined if activation of somatic afferents in posterior femoral cutaneous nerve (PFCN) could modulate the micturition reflex recorded under isovolumetric conditions in α-chloralose anaesthetized cats. PFCN stimulation inhibited reflex bladder activity and significantly (P <0.05) increased bladder capacity during slow infusion of saline or 0.25% acetic acid (AA). The optimal frequency for PFCN stimulation-induced bladder inhibition was between 3 and 10 Hz, and a minimal stimulation intensity of half of the threshold for inducing anal twitching was required. Bilateral pudendal nerve transection eliminated PFCN stimulation-induced anal twitching but did not change the stimulation-induced bladder inhibition, excluding the involvement of pudendal afferent or efferent axons in PFCN afferent inhibition.Mechanical or electrical stimulation on the skin surface in the PFCN dermatome also inhibited bladder activity. Prolonged (2 × 30 min) PFCN stimulation induced a post-stimulation inhibition that persists for at least 2 h. This study revealed a new cutaneous-bladder reflex activated by PFCN afferents. Although the mechanisms and physiological functions of this cutaneous-bladder reflex need to be further studied, our data raise the possibility that stimulation of PFCN afferents might be useful clinically for the treatment of overactive bladder symptoms.
Neuromuscular control of fundamental frequency and glottal posture at phonation onset
Author(s): Chhetri, DK; Neubauer, J; Berry, DA
View details
Hide details
The laryngeal neuromuscular mechanisms for modulating glottal posture and fundamental frequency are of interest in understanding normal laryngeal physiology and treating vocal pathology. The intrinsic laryngeal muscles in an in vivo canine model were electrically activated in a graded fashion to investigate their effects on onset frequency, phonation onset pressure, vocal fold strain, and glottal distance at the vocal processes. Muscle activation plots for these laryngeal parameters were evaluated for the interaction of following pairs of muscle activation conditions: (1) cricothyroid (CT) versus all laryngeal adductors (TA/LCA/IA), (2) CT versus LCA/IA, (3) CT versus thyroarytenoid (TA) and, (4) TA versus LCA/IA (LCA: lateral cricoarytenoid muscle, IA: interarytenoid). Increases in onset frequency and strain were primarily affected by CT activation. Onset pressure correlated with activation of all adductors in activation condition 1, but primarily with CT activation in conditions 2 and 3. TA and CT were antagonistic for strain. LCA/IA activation primarily closed the cartilaginous glottis while TA activation closed the mid-membranous glottis.
Inhibition of bladder overactivity by a combination of tibial neuromodulation and tramadol treatment in cats
Author(s): Zhang, F; Mally, AD; Ogagan, PD; Shen, B; Wang, J; Roppolo, JR; de Groat, WC; Tai, C
View details
Hide details
Our recent study in cats revealed that inhibition of bladder overactivity by tibial nerve stimulation (TNS) depends on the activation of opioid receptors. TNS is a minimally invasive treatment for overactive bladder (OAB), but its efficacy is low. Tramadol (an opioid receptor agonist) is effective in treating OAB but elicits significant adverse effects. This study was to determine if a low dose of tramadol (expected to produce fewer adverse effects) can enhance the TNS inhibition of bladder overactivity. Bladder overactivity was induced in α-chloralose-anesthetized cats by an intravesical infusion of 0.25% acetic acid (AA) during repeated cystometrograms (CMGs). TNS (5 Hz) at two to four times the threshold intensity for inducing toe movement was applied during CMGs before and after tramadol (0.3-7 mg/kg iv) to examine the interaction between the two treatments. AA irritation significantly reduced bladder capacity to 24.8 ± 3.3% of the capacity measured during saline infusion. TNS alone reversibly inhibited bladder overactivity and significantly increased bladder capacity to 50-60% of the saline control capacity. Tramadol administered alone in low doses (0.3-1 mg/kg) did not significantly change bladder capacity, whereas larger doses (3-7 mg/kg) increased bladder capacity (50-60%). TNS in combination with tramadol (3-7 mg/kg) completely reversed the effect of AA. Tramadol also unmasked a prolonged (>2 h) TNS inhibition of bladder overactivity that persisted after termination of the stimulation. The results suggest a novel treatment strategy for OAB by combining tibial neuromodulation with a low dose of tramadol, which is minimally invasive with a potentially high efficacy and fewer adverse effects.
Differential role of opioid receptors in tibial nerve inhibition of nociceptive and nonnociceptive bladder reflexes in cats
Author(s): Tai, C; Larson, JA; Ogagan, PD; Chen, G; Shen, B; Wang, J; Roppolo, JR; de Groat, WC
View details
Hide details
Naloxone (an opioid receptor antagonist) was used to examine the role of opioid mechanisms in bladder reflexes and in somatic afferent inhibition of these reflexes by tibial nerve stimulation (TNS). Experiments were conducted in α-chloralose-anesthetized cats when the bladder was infused with saline or 0.25% acetic acid (AA). The bladder volume was measured at the first large-amplitude (>30 cmH(2)O) contraction during a cystometrogram and termed estimated bladder capacity (EBC). AA irritated the bladder, induced bladder overactivity, and significantly (P < 0.0001) reduced EBC to 14.3 ± 1.9% of the saline control. TNS (5 Hz, 0.2 ms) at 4 and 8 times the threshold (T) intensity for inducing an observable toe movement suppressed AA-induced bladder overactivity and significantly increased EBC to 41.5 ± 9.9% (4T, P < 0.05) and 46.1 ± 7.9% (8T, P < 0.01) of the saline control. Naloxone (1 mg/kg iv) completely eliminated TNS inhibition of bladder overactivity. Naloxone (0.001-1 mg/kg iv) did not change EBC during AA irritation. However, during saline infusion naloxone (1 mg/kg iv) significantly (P < 0.01) reduced EBC to 66.5 ± 8.1% of the control EBC. During saline infusion, TNS induced an acute increase in EBC and an increase that persisted following the stimulation. Naloxone (1 mg/kg) did not alter either type of inhibition. However, naloxone administered during the poststimulation inhibition decreased EBC. These results indicate that opioid receptors have different roles in modulation of nociceptive and nonnociceptive bladder reflexes and in somatic afferent inhibition of these reflexes, raising the possibility that opioid receptors may be a target for pharmacological treatment of lower urinary tract disorders.
Plasticity of urinary bladder reflexes evoked by stimulation of pudendal afferent nerves after chronic spinal cord injury in cats
Author(s): Tai, C; Chen, M; Shen, B; Wang, J; Liu, H; Roppolo, JR; de Groat, WC
View details
Hide details
Bladder reflexes evoked by stimulation of pudendal afferent nerves (PudA-to-Bladder reflex) were studied in normal and chronic spinal cord injured (SCI) adult cats to examine the reflex plasticity. Physiological activation of pudendal afferent nerves by tactile stimulation of the perigenital skin elicits an inhibitory PudA-to-Bladder reflex in normal cats, but activates an excitatory reflex in chronic SCI cats. However, in both normal and chronic SCI cats electrical stimulation applied to the perigenital skin or directly to the pudendal nerve induces either inhibitory or excitatory PudA-to-Bladder reflexes depending on stimulation frequency. An inhibitory response occurs at 3-10 Hz stimulation, but becomes excitatory at 20-30 Hz. The inhibitory reflex activated by electrical stimulation significantly (P<0.05) increases the bladder capacity to about 180% of control capacity in normal and chronic SCI cats. The excitatory reflex significantly (P<0.05) reduces bladder capacity to about 40% of control capacity in chronic SCI cats, but does not change bladder capacity in normal cats. Electrical stimulation of pudendal afferent nerves during slow bladder filling elicits a large amplitude bladder contraction comparable to the contraction induced by distension alone. A bladder volume about 60% of bladder capacity was required to elicit this excitatory reflex in normal cats; however, in chronic SCI cats a volume less than 20% of bladder capacity was sufficient to unmask an excitatory response. This study revealed the co-existence of both inhibitory and excitatory PudA-to-Bladder reflex pathways in cats before and after chronic SCI. However our data combined with published electrophysiological data strongly indicates that the spinal circuitry for both the excitatory and inhibitory PudA-to-Bladder reflexes undergoes a marked reorganization after SCI.
Involvement of metabotropic glutamate receptor 5 in pudendal inhibition of nociceptive bladder activity in cats
Author(s): Larson, JA; Ogagan, PD; Chen, G; Shen, B; Wang, J; Roppolo, JR; de Groat, WC; Tai, C
View details
Hide details
This study used MTEP, a metabotropic glutamate receptor 5 (mGluR5) antagonist, to examine the role of mGluR5 in the neural control of the urinary bladder and in the inhibition of the micturition reflex by pudendal nerve stimulation (PNS). Experiments were conducted in 11 female cats under α-chloralose anaesthesia when the bladder was infused with either saline or 0.25% acetic acid (AA). AA irritated the bladder, induced bladder overactivity and significantly (P < 0.001) reduced bladder capacity to 14.9 ± 10.3% of the saline control capacity. MTEP (0.1-50 mg kg(-1), i.v.) significantly (P < 0.05) increased bladder capacity during saline distension but not during AA irritation. However, MTEP induced a transient inhibition of isovolumetric bladder contractions under both conditions. PNS (5 Hz), which was tested at the threshold (T) intensity for inducing a complete inhibition of isovolumetric bladder contractions and at an intensity of 3-4T, suppressed AA-induced bladder overactivity and significantly increased bladder capacity to 68.0 ± 31.3% at 1T (P < 0.05) and 98.5 ± 55.3% at 3-4T (P < 0.01) of the saline control capacity. MTEP dose dependently (0.1-50 mg kg(-1), i.v.) suppressed PNS inhibition of bladder overactivity at low intensity (1T) but not at high intensity (3-4T). During saline infusion PNS significantly (P < 0.05) increased bladder capacity to 167.7 ± 27.1% at 1T and 196.0 ± 37.4% at 3-4T. These inhibitory effects were not observed after MTEP (0.1-50 mg kg(-1), i.v.) which also increased bladder capacity. These results indicate that glutamic acid has a transmitter function in bladder and somato-bladder reflex mechanisms and raise the possibility that mGluR5 may be a target for pharmacological treatment of lower urinary tract disorders.
A voltage-controlled capacitive discharge method for electrical activation of peripheral nerves
Author(s): Rosellini, WM; Yoo, PB; Engineer, N; Armstrong, S; Weiner, RL; Burress, C; Cauller, L
View details
Hide details
A voltage-controlled capacitive discharge (VCCD) method was investigated as an alternative to rectangular stimulus pulses currently used in peripheral nerve stimulation therapies. In two anesthetized Gottingen mini pigs, the threshold (total charge per phase) for evoking a compound nerve action potential (CNAP) was compared between constant current (CC) and VCCD methods. Electrical pulses were applied to the tibial and posterior cutaneous femoralis nerves using standard and modified versions of the Medtronic 3778 Octad. In contrast to CC stimulation, the combined application of VCCD pulses with a modified Octad resulted in a marked decrease (-73 ± 7.4%) in the stimulation threshold for evoking a CNAP. This was consistent for different myelinated fiber types and locations of stimulation. The VCCD method provides a highly charge-efficient means of activating myelinated fibers that could potentially be used within a wireless peripheral nerve stimulator system.
Prolonged poststimulation inhibition of bladder activity induced by tibial nerve stimulation in cats
Author(s): Tai, C; Shen, B; Chen, M; Wang, J; Roppolo, JR; de Groat, WC
View details
Hide details
Inhibition of bladder activity by tibial nerve stimulation was investigated in α-chloralose-anesthetized cats with an intact spinal cord. Short-duration (3-5 min) tibial nerve stimulation at both low (5 Hz) and high (30 Hz) frequencies applied repeatedly during rhythmic isovolumetric bladder contractions was effective in inhibiting reflex bladder activity. Both frequencies of stimulation were also effective in inducing inhibition that persisted after the termination of the stimulation. The poststimulation inhibitory effect induced by the short-duration stimulation significantly increased bladder capacity to 181.6 ± 24.36% of the control capacity measured before applying the stimulation. Thirty-minute continuous stimulation induced prolonged poststimulation inhibition of bladder activity, which lasted for more than 2 h and significantly increased bladder capacity to 161.1 ± 2.9% of the control capacity. During the poststimulation periods, 5-Hz stimulation applied during the cystometrogram elicited a further increase (~30% on average) in bladder capacity, but 30-Hz stimulation was ineffective. These results in cats support the clinical observation that tibial nerve neuromodulation induces a long-lasting poststimulation inhibitory effect that is useful in treating overactive bladder symptoms.
Influence of naloxone on inhibitory pudendal-to-bladder reflex in cats
Author(s): Chen, ML; Shen, B; Wang, J; Liu, H; Roppolo, JR; de Groat, WC; Tai, C
View details
Hide details
To determine the involvement of opioid receptors in the inhibitory pudendal-to-bladder reflex, the effect of naloxone (0.01-1 mg/kg, i.v.), an opioid receptor antagonist, on the inhibition of bladder activity evoked by pudendal nerve stimulation was investigated in alpha-chloralose anesthetized cats. The inhibition of reflex isovolumetric bladder contractions induced by pudendal nerve stimulation (5-10 Hz) at intensity threshold (T) for producing complete inhibition was significantly suppressed by naloxone at a high dose (0.3 mg/kg). However, the inhibition elicited at higher intensities (1.5-3 T) was not changed. Naloxone (1 mg/kg) did not alter the frequency dependence of the inhibitory effect of pudendal stimulation. During cystometrograms (CMGs) pudendal nerve stimulation significantly increased bladder capacity to 155.1+/-24.5% and 163.4+/-10% of the control at stimulation intensities of 1 T and 1.5-3 T, respectively. After administration of naloxone (1 mg/kg), the bladder capacity during pudendal nerve stimulation at inhibition threshold (1 T) was not significantly different from control, but it was significantly increased at higher intensities (1.5-3 T). Naloxone alone markedly reduced bladder capacity to 43+/-11.1% of the control, and pudendal stimulation completely reversed this facilitatory effect. This study revealed that activation of opioid receptors contributes to or facilitates the inhibitory pudendal-to-bladder reflex. The reduction in bladder capacity after naloxone treatment also indicates that endogenous opioid peptides mediate a tonic inhibition of micturition. Understanding the neurotransmitter mechanisms involved in the inhibitory pudendal-to-bladder reflex could promote the development of new treatments for bladder overactivity and incontinence.
Contributions of Prefrontal Cortex Subsections to Response Inhibition
Author(s): Hardung, S
View details
Hide details
In everyday life altering environmental conditions require flexible adaptation of planned or already initiated actions. Humans and animals are forced to constantly update their behavior to avoid maladaptive actions. Studies linked responseinhibition deficits to several neurological diseases and emphasized the critical role of the PFC for appropriately timed actions (Aron, 2011; Aron et al., 2014a; Chambers et al., 2009). These neuropsychiatric disorders include fronto-temporal dementia (Pompanin et al., 2014), and Parkinson’s disease (Gauggel et al., 2004).
Chronic monitoring of lower urinary tract activity via a sacral dorsal root ganglia interface.
Author(s): Khurram, A; Ross, SE; Sperry, ZJ; Ouyang, A; Stephan, C; Jiman, AA; Bruns, TM
View details
Hide details
Our goal is to develop an interface that integrates chronic monitoring of lower urinary tract (LUT) activity with stimulation of peripheral pathways.
Adjacent regenerative peripheral nerve interfaces produce phase-antagonist signals during voluntary walking in rats
Author(s): Ursu, D; Nedic, A; Urbanchek, M; Cederna, P; Gillespie, RB
View details
Hide details
Regenerative Peripheral Nerve Interfaces (RPNIs) are neurotized muscle grafts intended to produce electromyographic signals suitable for motorized prosthesis control. Two RPNIs producing independent agonist/antagonist signals are required for each control axis; however, it is unknown whether signals from adjacent RPNIs are independent. The purpose of this work was to determine signaling characteristics from two adjacent RPNIs, the first neurotized by a foot dorsi-flexor nerve and the second neurotized by a foot plantar-flexor nerve in a rodent model. Two Control group rats had electrodes implanted onto the soleus (tibial nerve) and extensor digitorum longus (peroneal nerve) muscles in the left hind limb. Two Dual-RPNI group rats had two separate muscles grafted to the left thigh and each implanted with electrodes: the extensor digitorum longus was neurotized with a transected fascicle from the tibial nerve, and the tibialis anterior was implanted with a transected peroneal nerve. Four months post-surgery, rats walked on a treadmill, were videographed, and electromyographic signals were recorded. Amplitude and periodicity of all signals relative to gait period were quantified. To facilitate comparisons across groups, electromyographic signals were expressed as a percent of total stepping cycle activity for each stance and swing gait phase.
Invasive Cortical Microelectrode Array Longitudinal Performance: Temporal Dynamics of Electrical Impedance Spectroscopy and Multiunit Activity
Author(s): Welle, C; Street, MG; Ruda, K; Civillico, E; Takmakov, PA
View details
Hide details
Addition of neural sensing elements to neurostimulation devices can ‘close the loop’ to provide dynamic, patient-specific neuromodulation. Recently approved medical devices, such as the Neuropace RNS System for drug-resistant epilepsy and the Inspire Upper Airway Stimulation device monitor the patient’s electrophysiological activity and titrate stimulation accordingly, improving therapeutic outcomes. Current devices rely on a few, large electrode contacts; however, high-density electrode interfaces will provide greater information content to maximize the therapeutic benefit. High-density neural interfaces have been explored in the context of brain computer interface devices, which utilize microelectrode arrays to detect neural activity used to control prosthetic devices. Although the high-density multielectrode arrays implanted in human cortex can record from hundreds of neurons simultaneously, the device performance gradually declines within six to twelve months post-implantation as the number of recorded neurons dwindles. Preclinical investigations have identified several key factors implicated in this failure, including poor tissue integration resulting in inflammation, blood-brain barrier compromise and electrode material breakdown. To differentiate between tissue-related, biological failure modalities and material-related physical modalities, we performed electrical impedance spectroscopy (EIS) before, during and after the long-term implantation of high-density electrode arrays in the mouse motor cortex. Three different types of commercial research-grade electrodes were sterilized with ethylene oxide and implanted into the neocortex (Blackrock, Neuronexus and Microprobes for Life Science). Implant duration lasted for between 6-12 months, and EIS was collected across the implant duration. EIS was measured over frequencies ranging from 1Hz to 1MHz with 5 frequency points per decade using a Gamry Reference 600 potentiostat (Gamry Instruments). Multi-unit activity was also collected throughout the course of implantation during periods of spontaneous movement in awake, behaving animals using a 16-channel data acquisition system (Neuralynx). As expected, electrode implantation lead to an overall increase in impedance across three device types. However, the largest increase in impedance was not centered around 1kHz (a common frequency for impedance spectroscopy in vivo), but instead centered between 10-100kHz for all array types. Much of this increase was reduced when EIS was measured after the arrays were explanted from the brain, suggesting that changes in the resistive component of the tissue medium is the largest contribution to in vivo impedance dynamics.
The Biocompatibility of Intracortical Microelectrode Recording Arrays for Brain Machine Interfacing
Author(s): Skousen, JL; Tresco, PA
View details
Hide details
The potentia l of brain machine interfaces (BMI ): also called brain computer interfaces, neural interfaces, or neuroprost hetics) provide hope for many suffering from long -term paralysis or amputation.[1] This hope is based on a number of exciting pre -clinical and clinical studies demonstrating that consciously modulated neuronal signaling can be used to control external devi ces and permit paralyzed and locked -in patients to interact with their environment.[2 -6] With expanding efforts from researchers, clinicians, government agencies and patient volunteers to bring these devices to the clinic, one of the primary questions that must be addressed is how to make these types of biomedical devices more biocompatible. Here the term biocompatibility describes “the ability of an [implant] to perform with an appropriate host response in a specific application.”[7, 8] Answering this two -part question is a large component of the broader regulatory requirement that requires developers to provide valid scientific evidence of a device’s safety and efficacy prior to receiving approval to go to market for clinical use.[9] As the first part of t he definition of biocompatility centers on device performance, Section 1 will analyze the types, successes and current functional limitations of intracortical recording microelectrode arrays used in BMI applications. Then to provide insight into the second part of the definition, Section 2 will describe what has been learned over the last 70 years from studies of the brain tissue response to recording microelectrode arrays implanted in brain tissue. Section 3 will discuss the progress that has been made to elucidate the connection between the brain tissue response and recording performance. The chapter concludes in Section 4 where we consider what lies ahead. The primary purpose of this chapter is to present what is known of microelectrode -based BMI biocompa tibility to the wide audience involved in this field. By identifying primary failure modes and describing how the host tissue response likely impacts device function and patient health, we hope to direct the field toward strategies that will improve the bi ocompatibility of existing and next generation intracortical recording devices to extend their usefulness as a basic science tool and in clinical applications.
Differential effects of levodopa and apomorphine on neuronal population oscillations in the cortico-basal ganglia loop circuit in vivo in experimental parkinsonism
Author(s): Kühn, J; Haumesser, JK; Beck, MH; Altschüler, J; Kühn, AA; Nikulin, VV; van Riesen, C
View details
Hide details
The current pharmacotherapy of Parkinson's disease (PD) is primarily based on two classes of drugs: dopamine precursors, namely levodopa, and dopamine receptor agonists, such as apomorphine. Although both types of agents exert their beneficial clinical effects on motor and non-motor symptoms in PD via dopamine receptors, clinical efficiency and side effects differ substantially between levodopa and apomorphine. Levodopa can provide a greater symptomatic relief than dopamine receptor agonists. However, because long-term levodopa use is associated with early debilitating motor fluctuations, dopamine receptor agonists are often recommended in younger patients. The pharmacodynamic basis of these profound differences is incompletely understood. It has been hypothesized that levodopa and dopamine receptor agonists may have diverging effects on beta and gamma oscillations that have been shown to be of importance for the pathophysiology of PD. Here, we used electrophysiological recordings in anesthetized dopamine-intact and dopamine-depleted rats to systemically compare the impact of levodopa or apomorphine on neuronal population oscillations in three nodes of the cortico-basal ganglia loop circuit. Our results showed that levodopa had a higher potency than apomorphine to suppress the abnormal beta oscillations often associated with bradykinesia while simultaneously enhancing the gamma oscillations often associated with increased movement. Our data suggests that the higher clinical efficacy of levodopa as well as some of its side effects, as e.g. dyskinesias may be based on its characteristic ability to modulate beta-/gamma-oscillation dynamics in the cortico-basal ganglia loop circuit.
Ultrasoft microwire neural electrodes improve chronic tissue integration
Author(s): Du, ZJ; Kolarcik, CL; Kozai, TDY; Luebben, SD; Sapp, SA; Zheng, XS; Nabity, JA; Cui, XT
View details
Hide details
Chronically implanted neural multi-electrode arrays (MEA) are an essential technology for recording electrical signals from neurons and/or modulating neural activity through stimulation. However, current MEAs, regardless of the type, elicit an inflammatory response that ultimately leads to device failure. Traditionally, rigid materials like tungsten and silicon have been employed to interface with the relatively soft neural tissue. The large stiffness mismatch is thought to exacerbate the inflammatory response. In order to minimize the disparity between the device and the brain, we fabricated novel ultrasoft electrodes consisting of elastomers and conducting polymers with mechanical properties much more similar to those of brain tissue than previous neural implants. In this study, these ultrasoft microelectrodes were inserted and released using a stainless steel shuttle with polyethyleneglycol (PEG) glue. The implanted microwires showed functionality in acute neural stimulation. When implanted for 1 or 8weeks, the novel soft implants demonstrated significantly reduced inflammatory tissue response at week 8 compared to tungsten wires of similar dimension and surface chemistry.
High channel count single-unit recordings from nonhuman primate frontal cortex
Author(s): Mitz, AR; Bartolo, R; Saunders, RC; Browning, PG; Talbot, T; Averbeck, BB
View details
Hide details
Single unit recording in behaving nonhuman primates is widely used to study the primate central nervous system. However, certain questions cannot be addressed without recording large numbers of neurons simultaneously. Multiple 96-electrode probes can be implanted at one time, but certain problems must be overcome to make this approach practical. We describe a series of innovations and practical guidance for implanting and recording from 8 arrays of 96 electrodes (768 electrodes) in the frontal cortex of Macaca mulatta. The methods include an individualized 3D-printed connector mounting platform, sequencing of assembly and surgical steps to minimize surgery time, and interventions to protect electrical connections of the implant. The methodology is robust and was successful in our hands on the first attempt. On average, we were able to isolate hundreds (535.7 and 806.9 in two animals) of high quality units in each session during one month of recording. To the best of our knowledge, this technique at least doubles the number of Blackrock arrays that have been successfully implanted in single animals. Although each technological component was pre-existing at the time we developed these methods, their amalgamation to solve the problem of high channel count recording is novel. The implantation of large numbers of electrodes opens new research possibilities. Refinements could lead to even greater capacity.
Prototype Deep Brain Stimulation System with Closed-Loop Control Feedback for Modulating Bladder Functions in Traumatic Brain Injured Animals
Author(s): Jen, E; Lin, C; Hsieh, T; Chiu, Y; Chen, TL; Chen, M; Peng, C
View details
Hide details
Traumatic brain injury (TBI) typically causes permanent brain tissue damage, which leads to permanent severe voiding dysfunction. Urinary retention is often refractory to standard therapies, and most patients require self-catheterization, which results in frequent urinary tract infections and reduces quality of life. Deep brain stimulation (DBS) might be a feasible alternative approach for treating bladder disorders in patients with TBI. In this study, we developed a DBS system with a closed-loop control strategy and determined the feasibility of this DBS system for improving bladder voiding function in a TBI animal model. A prototype of the DBS system was designed, fabricated and integrated with a closed-loop control algorithm based on the real-time external urethral sphincter-electromyogram feedback. A series of animal experiments was conducted to determine whether the feedback algorithm accurately detects the bladder status during cystometric measurements. Subsequent animal experiments were conducted to implement this DBS system and determine the performance of the closed-loop strategy for improving bladder functions in the TBI animal model. We successfully implemented a closed-loop algorithm for DBS control, and the accuracy of the bladder voiding phase detection was > 90%. Our system significantly improved the voiding efficiency in TBI rats from 22 to 74%. Although the prototype of the DBS feedback system was fabricated with surface-mounted device components and mounted on a 3D printed circuit board, the design principles and animal experience gathered from this research can serve as a basis for developing a new implantable bladder controller in the future.
Expiratory muscle strength training evaluated with simultaneous high-resolution manometry and electromyography
Author(s): Hutcheson, KA; Hammer, MJ; Rosen, SP; Jones, CA; McCulloch, TM
View details
Hide details
To examine feasibility of a simultaneous high-resolution pharyngeal manometry (HRM) and electromyography (EMG) experimental paradigm to detect swallowing-related patterns of palatal, laryngeal, and pharyngeal muscle activity during expiratory training. Technical report. Simultaneous HRM, surface submental, and intramuscular EMG were acquired in two healthy participants during five tasks: 10-cc water swallow, maximum expiratory pressure (MEP) testing, and expiratory muscle strength training (EMST) at three pressure levels (sham, 50%, and 75% MEP). Experimental conditions were feasible. Velopharyngeal closing pressure, palate EMG activity, and pharyngeal EMG activity increased as expiratory load increased. In contrast, thyroarytenoid EMG activity was low during the expiratory task, consistent with glottic opening during exhalation.
Regenerative Peripheral Nerve Interface for Prostheses Control: Electrode Comparison
Author(s): Sando, IC; Leach, MK; Woo, SL; Moon, JD; Cederna, PS; Langhals, NB; Urbanchek, MG
View details
Hide details
This study compared epimysial patch electrodes with intramuscular hook electrodes using monopolar and bipolar recording configurations. The purpose was to determine which strategy transduced muscle signals with better fidelity for control of myoelectric prostheses. One of the two electrode styles, patch (n = 4) or hook (n = 6) was applied to the left extensor digitorum longus muscle in rats. Electrodes were evaluated at the time of placement and at monthly intervals for 4 months. Evaluations consisted of evoked electromyography signals from stimulation pulses applied to the peroneal and tibial nerves in both monopolar and bipolar recording configurations. Compared with hook electrodes, patch electrodes recorded larger signals of interest and minimized muscle tissue injury. A bipolar electrode configuration significantly reduced signal noise when compared with a monopolar configuration. Epimysial patch electrodes outperform intramuscular hook electrodes during chronic skeletal muscle implantation.
Effect of H 3 BO 3 on corrosion in 0.01 M NaCl solution of the interface between low alloy steel A508 and alloy 52M
Author(s): Wang, S; Ming, H; Ding, J; Zhang, Z; Han, JW; Atrens, A
View details
Hide details
The corrosion of the low alloy steel A508-alloy 52 M interface region in buffered and non-buffered chloride containing solutions was studied by using the scanning vibrating electrode technique (SVET), scanning ion-selective electrode technique (SIET), and time of flight secondary ion mass spectroscopy (ToF-SIMS). The typical pit in low alloy steel A508 formed in NaCl solution was stopped immediately when H3BO3 was added to the NaCl solution, and the pit became cathodic. With increasing immersion time, H3BO3 entered into the pit, and the corrosion of A508 became general corrosion.
Regulation of excitability in tonic firing substantia gelatinosa neurons of the spinal cord by small-conductance Ca(2+)-activated K(+) channels
Author(s): Yang, K
View details
Hide details
The excitability of substantia gelatinosa (SG) neurons in the spinal dorsal horn determines the processing of nociceptive information from the periphery to the central nervous system. Small conductance Ca(2+)-activated K(+) (SK) channels on neurons supply strong negative feedback control on neuronal excitability by affecting afterhyperpolarization (AHP). However, the role of SK channels in regulating tonic-firing SG neuron excitability remains elusive. In the present study, whole-cell recordings were conducted in SG neurons from acute spinal cord slices of adult rats. The SK channel opener 1-ethyl-2-benzimidazolinone (1-EBIO) attenuated spike discharges and increased AHP amplitudes; this effect was mimicked by a high Ca(2+) external solution. Systemic administration of 1-EBIO attenuated the thermal-induced nociception behavior. Conversely, the inhibition of SK channels with apamin, a specific SK channel inhibitor, increased neuronal excitability and decreased the AHP amplitudes; this effect was mimicked by a Ca(2+)-free external solution. Apamin increased excitatory synaptic transmission by increasing the amplitudes of evoked excitatory postsynaptic potentials (eEPSPs). This facilitation depended on N-methyl-d-aspartate (NMDA) receptors, extracellular Mg(2+) and intracellular Ca(2+). Voltage-gated Ca(2+) channels (VGCCs) were also involved in the apamin-induced effects. Strikingly, 1-EBIO action on decreasing excitability persisted in the presence of apamin, indicating that 1-EBIO manipulates SK channels via a pathway rather than via apamin-sensitive SK channels. The data reveal a previously uncharacterized mechanism for manipulating SG neuronal excitability by Ca(2+) conductances via both apamin-sensitive and apamin-insensitive pathways. Because SG neurons in the dorsal horn are involved in regulating nociception, manipulating neuronal excitability via SK channels indicates a potential therapeutic target.
Predicting the activation states of the muscles governing upper esophageal sphincter relaxation and opening
Author(s): Omari, TI; Jones, CA; Hammer, MJ; Cock, C; Dinning, P; Wiklendt, L; Costa, M; McCulloch, TM
View details
Hide details
The swallowing muscles that influence upper esophageal sphincter (UES) opening are centrally controlled and modulated by sensory information. Activation and deactivation of neural inputs to these muscles, including the intrinsic cricopharyngeus (CP) and extrinsic submental (SM) muscles, results in their mechanical activation or deactivation, which changes the diameter of the lumen, alters the intraluminal pressure, and ultimately reduces or promotes flow of content. By measuring the changes in diameter, using intraluminal impedance, and the concurrent changes in intraluminal pressure, it is possible to determine when the muscles are passively or actively relaxing or contracting. From these mechanical states of the muscle, the neural inputs driving the specific motor behaviors of the UES can be inferred. In this study we compared predictions of UES mechanical states directly with the activity measured by electromyography (EMG). In eight subjects, pharyngeal pressure and impedance were recorded in parallel with CP- and SM-EMG activity. UES pressure and impedance swallow profiles correlated with the CP-EMG and SM-EMG recordings, respectively. Eight UES muscle states were determined by using the gradient of pressure and impedance with respect to time. Guided by the level and gradient change of EMG activity, mechanical states successfully predicted the activity of the CP muscle and SM muscle independently. Mechanical state predictions revealed patterns consistent with the known neural inputs activating the different muscles during swallowing. Derivation of activation state maps may allow better physiological and pathophysiological interpretations of UES function.
A multisensor approach to improve manometric analysis of the upper esophageal sphincter
Author(s): Jones, CA; Ciucci, MR; Hammer, MJ; McCulloch, TM
View details
Hide details
High-resolution manometry (HRM) improves on previous manometric systems by including a greater number of sensors that are more densely placed. Due to deglutitive movement of the HRM catheter and upper esophageal sphincter (UES), it is unclear which HRM sensors capture pressure in the UES. To address this issue, we present two complementary studies to describe UES pressure patterns using HRM + videofluoroscopy and HRM + electromyography (EMG). Case series involving a new analysis method. Study 1: Simultaneous HRM + videofluoroscopy were performed in 11 healthy subjects swallowing five 10-mL thin-liquid boluses. HRM catheter and UES movement were tracked to identify UES pressure patterns over multiple HRM sensors. Study 2: Simultaneous HRM + cricopharyngeal EMGs were performed in six healthy subjects swallowing five 10-mL water boluses. HRM and EMG outputs were correlated over individual and multiple HRM sensors. HRM sensors move prior to UES movement (P < .001) and to a lesser extent in rostral and ventral directions (P ≤ .01) than the UES. UES closure pressure is captured with two distinct patterns: 1) a rostral UES pattern with short durations and fast rate of pressure release, depicting UES descent along the catheter as it closes; and 2) a caudal UES pattern with tonic pressures at baseline and a deglutitive nadir. The HRM + EMG multisensor correlation (r = 0.88) was significantly stronger than the single-sensor correlation (r = 0.80; P = .02). During deglutition, the HRM catheter and the UES rise above baseline positions and create a distinctive, multisensor manometric trace. Accurate deglutitive UES pressure evaluation must include multiple manometric sensors. 4 Laryngoscope, 126:657-664, 2016.
Sound frequency-invariant neural coding of a frequency-dependent cue to sound source location
Author(s): Jones, HG; Brown, AD; Koka, K; Thornton, JL; Tollin, DJ
View details
Hide details
The century-old duplex theory of sound localization posits that low- and high-frequency sounds are localized with two different acoustical cues, interaural time and level differences (ITDs and ILDs), respectively. While behavioral studies in humans and behavioral and neurophysiological studies in a variety of animal models have largely supported the duplex theory, behavioral sensitivity to ILD is curiously invariant across the audible spectrum. Here we demonstrate that auditory midbrain neurons in the chinchilla (Chinchilla lanigera) also encode ILDs in a frequency-invariant manner, efficiently representing the full range of acoustical ILDs experienced as a joint function of sound source frequency, azimuth, and distance. We further show, using Fisher information, that nominal low-frequency and high-frequency ILD-sensitive neural populations can discriminate ILD with similar acuity, yielding neural ILD discrimination thresholds for near-midline sources comparable to behavioral discrimination thresholds estimated for chinchillas. These findings thus suggest a revision to the duplex theory and reinforce ecological and efficiency principles that hold that neural systems have evolved to encode the spectrum of biologically relevant sensory signals to which they are naturally exposed.
Salmonella enterica biofilm-mediated dispersal by nitric oxide donors in association with cellulose nanocrystal hydrogels
Author(s): Marvasi, M; Durie, IA; McLamore, ES; Vanegas, DC; Chaturvedi, P
View details
Hide details
Protected by extracellular polymers, microbes within biofilms are significantly more resistant to disinfectants. Current research has been instrumental in identifying nitric oxide donors and hydrogels as potential disinfectant additives. Nitric oxide (NO) donors are considered a very promising molecule as biofilm dispersal agents and hydrogels have recently attracted a lot of interest due to their biocompatible properties and ability to form stable thin films. When the NO donor MAHMA NONOate was dissolved in phosphate saline buffer, it was able to reduce the biomass of well-established biofilms up to 15% for at least 24 h of contact time. Encapsulation of MAHMA NONOate and molsidomine within a hydrogel composed of cellulose nanocrystals (CNC) has shown a synergistic effect in dispersing well-established biofilms: after 2 h of exposure, moderate but significant dispersion was measured. After 6 h of exposure, the number of cells transitioning from the biofilm to the planktonic state was up to 0.6 log higher when compared with non-treated biofilms. To further explore the transport processes of NO donors within hydrogels, we measured the nitric oxide flux from gels, at 25°C for a composite of 0.1 µM MAHMA NONOate-CNC. Nitric oxide diffuses up to 500 µm from the hydrogel surface, with flux decreasing according to Fick's law. 60% of NO was released from the hydrogel composite during the first 23 min. These data suggest that the combined treatments with nitric oxide donor and hydrogels may allow for new sustainable cleaning strategies.
Fault-tolerant hybrid epoxy-silane coating for corrosion protection of magnesium alloy AZ31
Author(s): SVLamak, ; HBXue, ; NNAHMeis, ; ACCEsteves, ; MGSFerreira,
View details
Hide details
In this work, a hybrid epoxy-silane coating was developed for corrosion protection of magnesium alloy AZ31. The average thickness of the film produced by dip-coating procedure was 14 μm. The adhesion strength of the epoxy-silane coating to the Mg substrate was evaluated by pull-off tests and was found to be higher than 16 MPa both in dry and wet conditions. The hybrid epoxy-silane coating showed high corrosion resistance both when intact and when punched through by a needle. The low frequency impedance of intact coating was higher than 1 GΩ cm2 after one month of immersion in 3.5% NaCl solution. Both, artificially induced defects and corrosion sites that appeared on the metal surface did not propagate. Their passivation behavior, that we call fault-tolerance, was observed by EIS, SVET-SIET and SEM-EDS. It was ascribed to the good adhesion, high coating integrity and corrosion inhibiting effect provided by diethylenetriamine used as epoxy hardener.
Vestibular Implants: 8 Years of Experience with Electrical Stimulation of the Vestibular Nerve in 11 Patients with Bilateral Vestibular Loss
Author(s): Guinand, N; van de Berg, R; Cavuscens, S; Stokroos, RJ; Ranieri, M; Pelizzone, M; Kingma, H; Guyot, JP; Perez-Fornos, A
View details
Hide details
The concept of the vestibular implant is primarily to artificially restore the vestibular function in patients with a bilateral vestibular loss (BVL) by providing the central nervous system with motion information using electrical stimulation of the vestibular nerve. Our group initiated human trials about 10 years ago. Between 2007 and 2013, 11 patients with a BVL received a vestibular implant prototype providing electrodes to stimulate the ampullary branches of the vestibular nerve. Eye movements were recorded and analyzed to assess the effects of the electrical stimulation. Perception induced by electrical stimulation was documented. Smooth, controlled eye movements were obtained in all patients showing that electrical stimulation successfully activated the vestibulo-ocular pathway. However, both the electrical dynamic range and the amplitude of the eye movements were variable from patient to patient. The axis of the response was consistent with the stimulated nerve branch in 17 out of the 24 tested electrodes. Furthermore, in at least 1 case, the elicited eye movements showed characteristics similar to those of compensatory eye movements observed during natural activities such as walking. Finally, diverse percepts were reported upon electrical stimulation (i.e., rotatory sensations, sound, tickling or pressure) with intensity increasing as the stimulation current increased. These results demonstrate that electrical stimulation is a safe and effective means to activate the vestibular system, even in a heterogeneous patient population with very different etiologies and disease durations. Successful tuning of this information could turn this vestibular implant prototype into a successful artificial balance organ.
Preparation for the Implantation of an Intracortical Visual Prosthesis in a Human
Author(s): Troyk, PR
View details
Hide details
This project is to perform translational research tasks needed to prepare an intracortical visual prosthesis (ICVP) for testing in a human. No human trialtesting of the prosthesis will occur under the funded work. Preparatory tasks include final maturation of the implantable hardware, pre FDA IDE testing of the ICVP in non-human primates, reliability and biocompatibility testing, development of a human testing protocol, development of a human volunteer selection and assessment protocol, preparation of an investigation device exemption application (IDE) to the FDA. Progress to-date has been somewhat hampered by delayed approval of the psychology testing protocols (human subjects), and the animal testing protocols (non-human primates), by the USARMYMC. However, all protocol approvals have now been obtained. This delay has also slowed the spending of funds for these areas within the first year. The work focused on technology maturation has been highly productive. Sample stimulator units have been subjected to brutal environmental testing with 100 survival. Larger numbers of stimulator units are in the process of being constructed to provide statistical power for the environmental testing. Following the human protocol acceptances, work has commenced at both IIT and Johns Hopkins for the development of the testing and assessment protocols. A graduate student from IIT has initiated work within the laboratory of Dr. Dagnelie at JHU. Analysis of interview data from the earlier Dobelle visual prosthesis recipients has already yielded valuable insight about the volunteer recruitment and participation process. Sixteen publications and presentations have resulted from the funded work, and several publications are in preparation. While the project is projected for a 1-year no-cost extension request, due to the slow start-up, it is anticipated that by the end of the project all parts of the SOW will be complete, with the ICVP ready for clinical testing in a human trial.
Multi-ion transport and reaction model used to improve the understanding of local current density measurements in presence of concentration gradients around a point current source
Author(s): Demeter, A; Dolgikh, O; Bastos, A; Deconinck, D; Lamaka, S; Topa, V; Deconinck, J
View details
Hide details
A departure from the theoretical current density distribution close to a point current source is observed in both Scanning Reference Electrode Technique (SRET) and Scanning Vibrating Electrode Technique (SVET) measurements. Here we report the use of a general multi-ion transport and reaction model, which accounts for micro-convection to point out the origin of the deviations that are experimentally observed. The validity of the model is proven by comparison against both analytical and measured (SRET and SVET) distributions of the current density in a typical calibration setup. Solutions with different conductivities and different impressed currents are considered.
Modulation of neural activity by reward in medial intraparietal cortex is sensitive to temporal sequence of reward
Author(s): Rajalingham, R; Stacey, RG; Tsoulfas, G; Musallam, S
View details
Hide details