Pairing sound with vagus nerve stimulation modulates cortical synchrony and phase coherence in tinnitus: An exploratory retrospective study
Recent research has shown that vagus nerve stimulation (VNS) paired with tones or with rehabilitative training can help patients to achieve reductions in tinnitus perception or to expedite motor rehabilitation after suffering an ischemic stroke. The rationale behind this treatment is that VNS paired with experience can drive neural plasticity in a controlled and therapeutic direction.
Sven Vanneste, Jeffrey Martin, Robert L. Rennaker II, Michael P. Kilgard
The interaction of pulse width and current intensity on the extent of cortical plasticity evoked by vagus nerve stimulation
Repeatedly pairing a tone with a brief burst of vagus nerve stimulation (VNS) results in a reorganization of primary auditory cortex (A1). The plasticity-enhancing and memory-enhancing effects of VNS follow an inverted-U response to stimulation intensity, in which moderate intensity currents yield greater effects than low or high intensity currents. It is not known how other stimulation parameters effect the plasticity-enhancing effects of VNS.
Kristofer W. Loerwald, Michael S. Borland, Robert L . Rennaker II, Seth A. Hays, Michael P. Kilgard
The Interval Between VNS-Tone Pairings Determines the Extent of Cortical Map Plasticity
Repeatedly pairing vagus nerve stimulation (VNS) with a tone or movement drives highly specific and long-lasting plasticity in auditory or motor cortex, respectively. Based on this robust enhancement of plasticity, VNS paired with rehabilitative training has emerged as a potential therapy to improve recovery, even when delivered long after the neurological insult.
Michael S. Borland, Crystal T. Engineer, William A. Vrana, Nicole A. Moreno, Navzer D. Engineer, Sven Vanneste, Pryanka Sharma, Meghan C. Pantalia, Mark C. Lane, Robert L. Rennaker, Michael P. Kilgard
Vagus Nerve Stimulation Paired with Tones for the Treatment of Tinnitus: A Prospective Randomized Double-blind Controlled Pilot Study in Humans
The aim of the pilot study was to evaluate the effect of Vagus Nerve Stimulation (VNS) paired with sounds in chronic tinnitus patients. All participants were implanted and randomized to a paired VNS (n = 16) or control (n = 14) group. After 6 weeks of home therapy, all participants received paired VNS. The device was used on 96% of days with good compliance.
Tyler R, Cacace A, Stocking C, Tarver B, Engineer N, Martin J, Deshpande A, Stecker N, Pereira M, Kilgard M, Burress C, Pierce D, Rennaker R, Vanneste S
Effects of vagus nerve stimulation on extinction of conditioned fear and post-traumatic stress disorder symptoms in rats
Exposure-based therapies help patients with post-traumatic stress disorder (PTSD) to extinguish conditioned fear of trauma reminders. However, controlled laboratory studies indicate that PTSD patients do not extinguish conditioned fear as well as healthy controls, and exposure therapy has high failure and dropout rates.
Noble LJ, Gonzalez IJ, Meruva VB, Callahan KA, Belfort BD, Ramanathan KR, Meyers E, Kilgard MP, Rennaker RL, McIntyre CK
Vagus nerve stimulation as a potential
adjuvant to behavioral therapy for autism
and other neurodevelopmental disorders
Vagus nerve stimulation (VNS) is an FDA approved therapy that is safe and effective in reducing seizurefrequency and duration in individuals with epilepsy. Individuals with neurodevelopmental disorders often exhibitdecreased vagal tone, and studies indicate that VNS can be used to overcome an insufficient vagal response. Multiplestudies have also docum ented si gnifi cant imp rovements in quality of life after VNS therapy in individuals wi thneurodevelop mental diso rders. Moreover, recent f inding s indicate that VNS significantly enhances the b enefitsof rehabilitative training in animal models and patients, leading to greater recovery in a variety of neurological diseases.Here, we review these findings and provide a discussion of how VNS paired with rehabilitation may yield benefits inthe context of neurodevelopmental disorders.
Crystal T. Engineer, Seth A. Hays and Michael P. Kilgard
Traumatic brain injury occludes training-dependent cortical reorganization in the contralesional hemisphere
Rehabilitative training drives plasticity in the ipsilesional (injured) motor cortex that is
believed to support recovery of motor function after either stroke or TBI. In addition,
adaptive plasticity in the contralesional (uninjured) motor cortex has been well‐
characterized in the context of stroke. While similar rehabilitation‐dependent plasticity in
the intact hemisphere may occur after TBI, this has yet to be thoroughly explored. In this
study, we investigated the effects of TBI and forelimb training on reorganization of
movement representations in the intact motor cortex. Rats were trained to proficiency on
the isometric pull task and then received a controlled‐cortical impact (CCI) in the left
motor cortex to impair function of the trained right forelimb. After TBI, animals
underwent forelimb training on the pull task for two months. At the end of training,
intracortical microstimulation (ICMS) was used to document the organization of the intact
motor cortex (the contralesional hemisphere). TBI significantly decreased the cortical area
eliciting movements of the impaired forelimb in untrained animals. In the absence of TBI,
training significantly increased forelimb map area compared to untrained controls.
However, training of the impaired forelimb after TBI was insufficient to increase forelimb
map area. These findings are consistent with other studies showing impaired
rehabilitation‐dependent plasticity after TBI and provide a novel characterization of TBI on
rehabilitation‐dependent plasticity in contralesional motor circuits.
Mr. David Pruitt, Miss Tanya Danaphongse, Ms. Ariel Schmid, Mr. Robert Morrison, Dr. Michael Kilgard, Dr. Robert L Rennaker II, and Dr. Seth Hays.
Median and ulnar nerve injuries reduce volitional forelimb strength in rats
Peripheral nerve injuries (PNI) are among the leading causes of physical disability in the United States. The majority of injuries occur in the upper extremities, and functional recovery is often limited. Robust animal models are critical first steps for developing effective therapies to restore function after PNI.
Eric C. Meyers MS, Rafael Granja MD, Bleyda R. Solorzano BS, Mario Romero-Ortega PhD, Michael P. Kilgard PhD, Robert L. Rennaker II PhD, Seth Hays PhD
Parametric characterization of neural activity in the locus coeruleus in response to vagus nerve stimulation
In this study, we recorded neural activity in the LC and the mesencephalic trigeminal nucleus (Me5) in response to VNS over a broad range of current amplitudes, pulse frequencies, train durations, inter-train intervals, and pulse widths. Brief 0.5 s trains of VNS drive rapid, phasic firing of LC neurons at 0.1 mA. Higher current intensities and longer pulse widths drive greater increases in LC firing rate. Varying the pulse frequency substantially affects the timing, but not the total amount, of phasic LC activity. VNS drives pulse-locked neural activity in the Me5 at current levels above 1.2 mA. These results provide insight into VNS-evoked phasic neural activity in multiple neural structures and may be useful in guiding the selection of VNS parameters to enhance clinical efficacy.
Daniel R. Hulsey, Jonathan R. Riley, Kristofer W. Loerwald, Robert L. Rennaker II, Michael P. Kilgarda, Seth A. Hays
Temporal plasticity in auditory cortex improves neural discrimination of speech sounds
Many individuals with language learning impairments exhibit temporal processing deficits and degraded neural responses to speech sounds. Auditory training can improve both the neural and behavioral deficits, though significant deficits remain. Recent evidence suggests that vagus nerve stimulation (VNS) paired with rehabilitative therapies enhances both cortical plasticity and recovery of normal function.
Crystal T. Engineer, Jai A. Shetake, Navzer D. Engineer, Will A. Vrana, Jordan T. Wolf, Michael P. Kilgard
Patent
Methods, systems, and devices for pairing vagus nerve stimulation with motor therapy in stroke patients
Vagus Nerve Stimulation Enhances Extinction of Conditioned Fear in Rats and Modulates Arc Protein, CaMKII, and GluN2B-Containing NMDA Receptors in the Basolateral Amygdala.
Vagus nerve stimulation (VNS) enhances the consolidation of extinction of conditioned fear. High frequency stimulation of the infralimbic cortex (IL) produces long-term potentiation in the basolateral amygdala (BLA) in rats given VNS-paired extinction training, whereas the same stimulation produces long-term depression in sham-treated rats.
Alvarez-Dieppa AC, Griffin K, Cavalier S, McIntyre CK
Forelimb training drives transient map reorganization in ipsilateral motor cortex
Skilled motor training results in reorganization of contralateral motor cortex movement representations. The ipsilateral motor cortex is believed to play a role in skilled motor control, but little is known about how training influences reorganization of ipsilateral motor representations of the trained limb.
Pruitt DT, Schmid AN, Danaphongse TT, Flanagan KE, Morrison RA, Kilgard MP, Rennaker RL 2nd, Hays SA
Design and demonstration of an intracortical probe technology with tunable modulus
Intracortical probe technology, consisting of arrays of microelectrodes, offers a means of recording the bioelectrical activity from neural tissue. A major limitation of existing intracortical probe technology pertains to limited lifetime of 6 months to a year of recording after implantation. A major contributor to device failure is widely believed to be the interfacial mechanical mismatch of conventional stiff intracortical devices and the surrounding brain tissue. We describe the design, development, and demonstration of a novel functional intracortical probe technology that has a tunable Young's modulus from ∼2 GPa to ∼50 MPa.
Dustin M. Simon, Hamid Charkhkar, Conan St. John, Sakthi Rajendran, Tong Kang, Radu Reit, David Arreaga-Salas, Daniel G. McHail, Gretchen L. Knaack, Andrew Sloan, Dane Grasse, Theodore C. Dumas, Robert L. Rennaker, Joseph J. Pancrazio, Walter E. Voit
Vagus Nerve Stimulation During Rehabilitative Training Improves Forelimb Recovery After Chronic Ischemic Stroke in Rats
Stroke is a leading cause of long-term disability. Currently, there are no consistently effective rehabilitative treatments for chronic stroke patients. Our recent studies demonstrate that vagus nerve stimulation (VNS) paired with rehabilitative training improves recovery of function in multiple models of stroke.
Khodaparast N, Kilgard MP, Casavant R, Ruiz A, Qureshi I, Ganzer PD, Rennaker RL 2nd, Hays SA
Awake behaving electrophysiological correlates of forelimb hyperreflexia, weakness and disrupted muscular synchronization following cervical spinal cord injury in the rat
Spinal cord injury usually occurs at the level of the cervical spine and results in profound impairment of forelimb function. In this study, we recorded awake behaving intramuscular electromyography (EMG) from the biceps and triceps muscles of the impaired forelimb during volitional and reflexive forelimb movements before and after unilateral cervical spinal cord injury (cSCI) in rats.
Ganzer PD, Meyers EC, Sloan AM, Maliakkal R, Ruiz A, Kilgard MP, Robert LR 2nd
Vagus nerve stimulation during rehabilitative training enhances recovery of forelimb function after ischemic stroke in aged rats
Advanced age is associated with a higher incidence of stroke and worse functional outcomes. Vagus nerve stimulation (VNS) paired with rehabilitative training has emerged* as a potential method to improve recovery after brain injury but to date has only been evaluated in young rats.
Hays SA, Ruiz A, Bethea T, Khodaparast N, Carmel JB, Rennaker RL 2nd, Kilgard MP
The supination assessment task: An automated method for quantifying forelimb rotational function in rats
Neurological injuries or disease can impair the function of motor circuitry controlling forearm supination, and recovery is often limited. Preclinical animal models are essential tools for developing therapeutic interventions to improve motor function after neurological damage.
Meyers E, Sindhurakar A, Choi R, Solorzano R, Martinez T, Sloan A, Carmel J, Kilgard MP, Rennaker RL 2nd, Hays S
Patent
Methods and systems for therapy of multiple sclerosis
Vagus Nerve Stimulation Delivered with Motor Training Enhances Recovery of Function after Traumatic Brain Injury
Traumatic Brain Injury (TBI) is one of the largest health problems in the United States, and affects nearly 2 million people every year. The effects of TBI, including weakness and loss of coordination, can be debilitating and last years after the initial injury.
Pruitt DT, Schmid AN, Kim LJ, Abe CM, Trieu JL, Choua C, Hays SA, Kilgard MP, Rennaker RL
Knockdown of Dyslexia-Gene Dcdc2 Interferes with Speech Sound Discrimination in Continuous Streams
Dyslexia is the most common developmental language disorder and is marked by deficits in reading and phonological awareness. One theory of dyslexia suggests that the phonological awareness deficit is due to abnormal auditory processing of speech sounds.
Centanni TM, Booker AB, Chen F, Sloan AM, Carraway RS, Rennaker RL, LoTurco JJ, Kilgard MP
Enhancing Rehabilitative Therapies with Vagus Nerve Stimulation
Pathological neural activity could be treated by directing specific plasticity to renormalize circuits and restore function. Rehabilitative therapies aim to promote adaptive circuit changes after neurological disease or injury, but insufficient or maladaptive plasticity often prevents a full recovery.
Hays SA
Reorganization of Motor Cortex by Vagus Nerve Stimulation Requires Cholinergic Innervation
Vagus nerve stimulation (VNS) paired with forelimb training drives robust, specific reorganization of movement representations in the motor cortex. The mechanisms that underlie VNS-dependent enhancement of map plasticity are largely unknown.
Hulsey DR, Hays SA, Khodaparast N, Ruiz A, Das P, Rennaker RL 2nd, Kilgard MP
Patent
Methods, systems, and devices for treating tinnitus with VNS pairing
Selective Disruption of Metabotropic Glutamate Receptor 5-Homer Interactions Mimics Phenotypes of Fragile X Syndrome in Mice
Altered function of the Gq-coupled, Group 1 metabotropic glutamate receptors, specifically mGlu5, is implicated in multiple mouse models of autism and intellectual disability. mGlu5 dysfunction has been most well characterized in the fragile X syndrome mouse model, the Fmr1 knock-out (KO) mouse, where pharmacological and genetic reduction of mGlu5 reverses many phenotypes. mGlu5 is less associated with its scaffolding protein Homer in Fmr1 KO mice, and restoration of mGlu5-Homer interactions by genetic deletion of a short, dominant negative of Homer, H1a, rescues many phenotypes of Fmr1 KO mice.
Guo W, Molinaro G, Collins KA, Hays SA, Paylor R, Worley PF, Szumlinski KK, Huber KM
An Automated Task for the Training and Assessment of Distal Forelimb Function in a Mouse Model of Ischemic Stroke
Behavioral models relevant to stroke research seek to capture important aspects of motor skills typically impaired in human patients, such as coordination of distal musculature. Such models may focus on mice since many genetic tools are available for use only in that species, and since the training and behavioral demands of mice can differ from rats even for superficially similar behavioral readouts.
April M. Becker, Eric Meyers, Andrew Sloan, Robert Rennaker, Michael Kilgard, Mark P. Goldberg
Cortical Map Plasticity as a Function of Vagus Nerve Stimulation Intensity
The primary goal of this study was to determine the range of VNS intensities that can be used to direct cortical map plasticity.
Borland MS, Vrana WA, Moreno NA, Fogarty EA, Buell EP, Sharma P, Engineer CT, Kilgard MP
Safety, Feasibility, and Efficacy of Vagus Nerve Stimulation Paired With Upper-Limb Rehabilitation After Ischemic Stroke
Recent animal studies demonstrate that vagus nerve stimulation (VNS) paired with movement induces movement-specific plasticity in motor cortex and improves forelimb function after stroke.
Jesse Dawson, David Pierce, Anand Dixit, Teresa J. Kimberley, Michele Robertson, Brent Tarver, Omar Hilmi,, John McLean, Kirsten Forbes, Michael P. Kilgard, Robert L. Rennaker, Steven C. Cramer, Matthew Walters and Navzer Engineer
Integration of High-Charge-Injection-Capacity Electrodes onto Polymer Softening Neural Interfaces
Softening neural interfaces are implanted stiff to enable precise insertion, and they soften in physiological conditions to minimize modulus mismatch with tissue. In this work, a high-charge-injection-capacity iridium electrode fabrication process is detailed.
David E. Arreaga-Salas, Adrian Avendaño-Bolívar, Dustin Simon, Radu Reit, Aldo Garcia-Sandoval, Robert L. Rennaker, and Walter Voit
Vagus Nerve Stimulation During Rehabilitative Training Improves Forelimb Recovery After Chronic Ischemic Stroke in Rats
Stroke is a leading cause of long-term disability. Currently, there are no consistently effective rehabilitative treatments for chronic stroke patients. Our recent studies demonstrate that vagus nerve stimulation (VNS) paired with rehabilitative training improves recovery of function in multiple models of stroke.
Navid Khodaparast, Michael P. Kilgard, Reema Casavant, Andrea Ruiz, Iqra Qureshi, Patrick D. Ganzer, Robert L. Rennaker II, Seth A. Hays
Degraded neural and behavioral processing of speech sounds in a rat model of Rett syndrome
Individuals with Rett syndrome have greatly impaired speech and language abilities. Auditory brainstem responses to sounds are normal, but cortical responses are highly abnormal.
Crystal T. Engineer, Kimiya C. Rahebi, Michael S. Borland, Elizabeth P. Buell, Tracy M. Centanni, Melyssa K. Fink, Kwok W. Im, Linda G. Wilson, Michael P. Kilgard
A Within-Animal Comparison of Skilled Forelimb Assessments in Rats
A variety of skilled reaching tasks have been developed to evaluate forelimb function in rodent models. The single pellet skilled reaching task and pasta matrix task have provided valuable insight into recovery of forelimb function in models of neurological injury and disease. Recently, several automated measures have been developed to reduce the cost and time burden of forelimb assessment in rodents.
Andrew M. Sloan, Melyssa K. Fink, Amber J. Rodriguez, Adam M. Lovitz, Navid Khodaparast, Robert L. Rennaker, Seth A. Hays
An Automated Task for the Training and Assessment of Distal Forelimb Function in a Mouse Model of Ischemic Stroke
Behavioral models relevant to stroke research seek to capture important aspects of motor skill typically impaired in human patients, such as coordination of distal musculature. Such models may focus on mice since many genetic tools are available for use only in that species, and since the training and behavioral demands of mice can differ from rats even for superficially similar behavioral readouts.
Andrew M. Sloan , Melyssa K. Fink, Amber J. Rodriguez, Adam M. Lovitz, Navid Khodaparast, Robert L. Rennaker, Seth A. Hays
Retinal oximetry: a novel visual biomarker of retinal metabolic dysfunction in MS
Optic neuropathy occurs very commonly in multiple sclerosis (MS) patients. Optical coherence tomography (OCT) has been shown to be a sensitive, and precise method of quantifying structural retinal changes that occur in MS. It is very likely, however, that metabolic dysfunction precedes such structural changes in the retina; therefore, a method of detecting and measuring these metabolic changes (for example, retinal oxygen utilization) would result in a more sensitive visual biomarker of MS disease activity.
S.C. Beh , M. Lucero , D. Conger , A. Conger , V. Stokes , T.C. Frohman , P.A. Calabresi , R. Rennaker , L.J. Balcer , E.M. Frohman
Ocular motor signatures of cognitive dysfunction in multiple sclerosis
The anatomical and functional overlap between ocular motor command circuitry and the higher-order networks that form the scaffolding for cognition makes for a compelling hypothesis that measures of ocular motility could provide a means to sensitively interrogate cognitive dysfunction in people with multiple sclerosis (MS).
Joanne Fielding, Meaghan Clough, Shin Beh, Lynette Millist, Derek Sears, Ashley N. Frohman, Nathaniel Lizak, Jayne Lim, Scott Kolbe, Robert L. Rennaker II, Teresa C. Frohman, Owen B. White & Elliot M. Frohman
Patent
Methods for enhancing exposure therapy using vagus nerve stimulation
Patent
Systems, methods and devices for paired plasticity
Speech training alters consonant and vowel responses in multiple auditory cortex fields
Speech sounds evoke unique neural activity patterns in primary auditory cortex (A1). Extensive speech sound discrimination training alters A1 responses. While the neighboring auditory cortical fields each contain information about speech sound identity, each field processes speech sounds differently.
Engineer CT, Rahebi KC, Buell EP, Fink MK, Kilgard MP
Activation of the anti-inflammatory reflex blocks lipopolysaccharide-induced decrease in synaptic inhibition in the temporal cortex of the rat
Stress is a potential trigger for a number of neuropsychiatric conditions, including anxiety syndromes and schizophrenic psychoses. The temporal neocortex is a stress-sensitive area involved in the development of such conditions.
Garcia-Oscos F, Peña D, Housini M, Cheng D, Lopez D, Cuevas-Olguin R, Saderi N, Salgado Delgado R, Galindo Charles L, Salgado Burgos H, Rose-John S, Flores G, Kilgard MP, Atzori M.
Pairing Speech Sounds With Vagus Nerve Stimulation Drives Stimulus-specific Cortical Plasticity
Individuals with communication disorders, such as aphasia, exhibit weak auditory cortex responses to speech sounds and language impairments. Previous studies have demonstrated that pairing vagus nerve stimulation (VNS) with tones or tone trains can enhance both the spectral and temporal processing of sounds in auditory cortex, and can be used to reverse pathological primary auditory cortex (A1) plasticity in a rodent model of chronic tinnitus.
Engineer CT, Engineer ND, Riley JR, Seale JD, Kilgard MP
Placebo-Controlled Vagus Nerve Stimulation Paired With Tones in a Patient With Refractory Tinnitus: A Case Report
Classical neuromodulation consists of applying electrical or magnetic stimuli to the nervous system to modulate ongoing activity and connectivity. However, recently, an exciting novel neuromodulation technique was developed in which stimulation of the vagal nerve was paired with simultaneous presentation of tones, demonstrating that it reverses a tinnitus percept in noise-exposed rats.
De Ridder D, Kilgard M, Engineer N, Vanneste S
Vagus Nerve Stimulation and Rehabilitation Improves Recovery of A
Motor Task after Neurological Injury
Ischemic stroke and spinal cord injury are neurological injuries that produce persisting motor deficits. Additionally,the majority of those suffering from impairments due to ischemic stroke or spinal cord injury rarely fully recover complete function with current treatment options. Here, we
investigate the use of vagus nerve stimulation (VNS), which facilitates specific and long-lasting plasticity after injury.
Rachel Choi, Eric Meyers, Patrick Ganzer, Seth Hays, Michael Kilgard, Robert Rennaker
Vagus Nerve Stimulation Improves Motor Function After Chronic Stroke in Adult Rats
Stroke is the leading cause of serious long-term disability. Currently, there is no effective treatment for chronic stroke patients. Neuroplasticity within motor circuitry is believed to support recovery of function after stroke. We have developed a method using vagus nerve stimulation (VNS) paired with motor training to drive robust, specific plasticity in the motor cortex.
Navid Khodaparast, Reema Casavant, Andrea Ruiz, Robert L Rennaker and Michael P Kilgard
Vagus Nerve Stimulation Enhances Neuroplasticity and Forelimb Recovery after Stroke in Aged Rats
Advanced age is a leading risk factor for stroke and is associated with worse recovery. The goal of post-stroke rehabilitative therapies is to enhance neuroplasticity to support the recovery of motor function. Recent studies indicate that vagus nerve stimulation (VNS) paired with rehabilitative training drives robust plasticity and results in significantly enhanced recovery of forelimb function in multiple models of brain injury in young rats.
Seth A Hays, Andrea Ruiz, Daniel R Hulsey, Navid Khodaparast, Thelma Bethea, Jason B Carmel, Robert L Rennaker and Michael P Kilgard
Patent
Systems, methods and devices for treating tinnitus
Vagal nerve stimulation blocks interleukin 6-dependent synaptic hyperexcitability induced by lipopolysaccharide-induced acute stress in the rodent prefrontal cortex
The ratio between synaptic inhibition and excitation (sI/E) is a critical factor in the pathophysiology of neuropsychiatric disease. We recently described a stress-induced interleukin-6 dependent mechanism leading to a decrease in sI/E in the rodent temporal cortex. The aim of the present study was to determine whether a similar mechanism takes place in the prefrontal cortex, and to elaborate strategies to prevent or attenuate it.
Garcia-Oscos F, Peña D, Housini M, Cheng D, Lopez D, Borland MS, Salgado-Delgado R, Salgado H, D'Mello S, Kilgard MP, Rose-John S, Atzori M
A 700mV low power low noise implantable neural recording system design
A low power, low noise implantable neural recording interface for use in a Radio-Frequency Identification (RFID) is presented in this paper. A two stage neural amplifier and 8 bit Pipelined Analog to Digital Converter (ADC) are integrated in this system.
An G, Hutchens C, Rennaker RL 2nd
Pairing vagus nerve stimulation with rehabilitative training enhances functional recovery after traumatic brain injury
Traumatic Brain Injury (TBI) is one of the largest health problems in the United States, and affects nearly two million people every year. The effects of TBI, including weakness and loss of coordination, can be observed years after the initial injury. We have developed a method by which we drive cortical plasticity through stimulation of the vagus nerve during rehabilitative therapy to enhance recovery from TBI.
D. Pruitt, A. Schmid, C. Choua, L. Kim, J. Trieu, C. Abe, K. Flanagan, M. Kilgard, R. L. Rennaker, II;
Abnormal emotional learning in a rat model of autism exposed to valproic acid in utero
Autism Spectrum Disorders (ASD) are complex neurodevelopmental disorders characterized by repetitive behavior and impaired social communication and interactions. Apart from these core symptoms, a significant number of ASD individuals display higher levels of anxiety and some ASD individuals exhibit impaired emotional learning.
Banerjee A, Engineer CT, Sauls BL, Morales AA, Kilgard MP, Ploski JE
An analog front-end circuit with spike detection for implantable neural recording system design
A low power, low noise implantable neural recording interface for use in a power harvested inductive coupling system is presented in this paper. A two stage neural amplifier, selective reference thresholder and a serial communication interface form the neural data logger.
Guanglei An, De Kanishka, Cheng Hao, Rehan Ahmed, Chriswell Hutchens, Robert L. Rennaker
Vagus nerve stimulation enhances extinction of conditioned fear and modulates plasticity in the pathway from the ventromedial prefrontal cortex to the amygdala
Fearful experiences can produce long-lasting and debilitating memories. Extinction of the fear response requires consolidation of new memories that compete with fearful associations.
Peña DF, Childs JE, Willett S, Vital A, McIntyre CK, Kroener S
Patent
Methods, systems, and devices for pairing vagus nerve stimulation with motor therapy in stroke patients
Vagus Nerve Stimulation During Rehabilitative Training Improves Functional Recovery After Intracerebral Hemorrhage
VNS paired with rehabilitative training significantly improved recovery of forelimb function when compared with rehabilitative training without VNS.
Seth A. Hays, Navid Khodaparast, Daniel R. Hulsey, Andrea Ruiz, Andrew M. Sloan, Robert L. Rennaker and Michael P. Kilgard
Speech sound discrimination training improves auditory cortex responses in a rat model of autism
Children with autism often have language impairments and degraded cortical responses to speech. Extensive behavioral interventions can improve language outcomes and cortical responses.
Engineer CT, Centanni TM, Im KW, Kilgard MP
Controlled-cortical impact reduces volitional forelimb strength in rats
Traumatic brain injury (TBI) is one of the largest health problems in the United States and affects both cognitive and motor function. Although weakness is common in TBI patients, few studies have demonstrated a reduction in strength in models of brain injury.
David Pruitt, Seth Hays, Ariel Schmid, Connie Choua, Lily Kim, Jenny Trieu, Michael P. Kilgard, Robert L. Rennaker II
Implanted Miniaturized Antenna for Brain Computer Interface Applications: Analysis and Design
Implantable Brain Computer Interfaces (BCIs) are designed to provide real-time control signals for prosthetic devices, study brain function, and/or restore sensory information lost as a result of injury or disease.
Yujuan Zhao, Robert L. Rennaker, Chris Hutchens, Tamer S. Ibrahim
Behavioral and Neural Discrimination of Speech Sounds After Moderate or Intense Noise Exposure in Rats
Hearing loss is a commonly experienced disability in a variety of populations including veterans and the elderly and can often cause significant impairment in the ability to understand spoken language. In this study, we tested the hypothesis that neural and behavioral responses to speech will be differentially impaired in an animal model after two forms of hearing loss.
Reed AC, Centanni TM, Borland MS, Matney CJ, Engineer CT, Kilgard MP
The timing and amount of vagus nerve stimulation during rehabilitative training affect post-stroke recovery of forelimb strength
Loss of upper arm strength after stroke is a leading cause of disability. Strategies that can enhance the benefits of rehabilitation training could improve motor function after stroke.
Hays, Seth A.; Khodaparast, Navid; Ruiz, Andrea; Sloan, Andrew M.; Hulsey, Daniel R.; Rennaker, Robert L. II; Kilgard, Michael P.
Controlled-Cortical Impact Reduces Rats Ability to Sustain Application of Submaximal Force
Traumatic brain injury (TBI) is an increasingly large health risk in the United States and often results in a severe lack of motor control and weakness. We have recently reported that experimental TBI in rats induces a chronic impairment in maximal volitional forelimb strength. Many activities of daily living, however, require consistent application of controlled submaximal force rather than maximal force.
C. Choua, A. Schmid, L. Kim, J. Trieu, D. Machuca, S. Sterling, S. Shah, S. Khan, D. Pruitt, R.L. Rennaker II
Vagus Nerve Stimulation and Nonparetic Limb Training Modify Stroke Recovery
Vagus nerve stimulation (VNS) is a safe, tolerable treatment that has been shown to drive powerful, long-lasting plasticity especially when paired with somatosensory inputs. VNS paired with rehabilitative training has been shown to improve functional recovery beyond what can be achieved by rehabilitative training alone in models of stroke.
A. Nguyen, N. Khodaparast, S.A. Hays, M.P. Kilgard, R.L. Rennaker
Speech Sound Processing Deficits and Training-Induced Neural Plasticity in Rats with Dyslexia Gene Knockdown
In utero RNAi of the dyslexia-associated gene Kiaa0319 in rats (KIA-) degrades cortical responses to speech sounds and increases trial-by-trial variability in onset latency.
Tracy M. Centanni , Fuyi Chen, Anne M. Booker, Crystal T. Engineer, Andrew M. Sloan, Robert L. Rennaker, Joseph J. LoTurco, Michael P. Kilgard
Environmental Acoustic Enrichment Promotes Recovery from Developmentally Degraded Auditory Cortical Processing
It has previously been shown that environmental enrichment can enhance structural plasticity in the brain and thereby improve cognitive and behavioral function. In this study, we reared developmentally noise-exposed rats in an acoustic-enriched environment for ∼4 weeks to investigate whether or not enrichment could restore developmentally degraded behavioral and neuronal processing of sound frequency.
Xiaoqing Zhu, Fang Wang, Huifang Hu, Xinde Sun, Michael P. Kilgard, Michael M. Merzenich, and Xiaoming Zhou
Degraded speech sound processing in a rat model of fragile X syndrome
Fragile X syndrome is the most common inherited form of intellectual disability and the leading genetic cause of autism. Impaired phonological processing in fragile X syndrome interferes with the development of language skills.
Crystal T. Engineer, , Tracy M. Centanni, Kwok W. Im, Kimiya C. Rahebi, Elizabeth P. Buell, Michael P. Kilgard
Degraded auditory processing in a rat model of autism limits the speech representation in non-primary auditory cortex
Although individuals with autism are known to have significant communication problems, the cellular mechanisms responsible for impaired communication are poorly understood.
Engineer CT, Centanni TM, Im KW, Borland MS, Moreno NA, Carraway RS, Wilson LG, Kilgard MP
Neural Coding of Speech Sounds
Speech sounds are composed of both rapid spectrotemporal changes and slow steady-state portions. The neural coding of speech sounds involves the representation of precise action potential timing across many cortical areas. Behavioral speech sound discrimination accuracy is well predicted by quantifying the similarity between the spatiotemporal response patterns evoked by two sounds.
Michael Kilgard
Vagus Nerve Stimulation Delivered During Motor Rehabilitation Improves Recovery in a Rat Model of Stroke
Neural plasticity is widely believed to support functional recovery following brain damage.
Navid Khodaparast, PhD, Seth A. Hays, PhD, Andrew M. Sloan, PhD, Tabbassum Fayyaz, Daniel R. Hulsey, Robert L. Rennaker II, PhD, Michael P. Kilgard, PhD
A Novel Means of Augmenting Motor Recovery After Ischemic Stroke; Vagus Nerve Stimulation (VNS) Paired with Intensive Upper Limb Rehabilitation
Chronic upper limb impairment is a major predictor of poor functional outcome after stroke. We have developed a rehabilitation intervention to address this issue. It pairs VNS with intensive upper limb training. Our hypothesis is that short bursts of VNS, specifically timed during therapy, will drive cortical plasticity and improve clinical outcomes via timely release of neuromodulators such as acetylcholine and norepinephrine.
Safety and efficacy of vagus nerve stimulation paired with tones for the treatment of tinnitus: a case series
Classical neuromodulation applies current to the nervous system in an attempt to alter ongoing activity. However, classical neuromodulation interferes with activity but does not drive it in a controlled way. Recently, an animal study demonstrated it is possible to drive plasticity in a controlled way by using stimulation of the vagus nerve paired with tones. This reversed the tinnitus percept and pathological neural plasticity in noise-exposed rats with behavioral characteristics of tinnitus. The aim of the current study was to translate this innovative neuromodulation method to humans suffering from tinnitus.
De Ridder D, Vanneste S, Engineer ND, Kilgard MP
Detection and identification of speech sounds using cortical activity patterns
We have developed a classifier capable of locating and identifying speech sounds using activity from rat auditory cortex with an accuracy equivalent to behavioral performance and without the need to specify the onset time of the speech sounds.
T.M. Centanni, , A.M. Sloan, A.C. Reed, C.T. Engineer, R.L. Rennaker II, M.P. Kilgard
Speech training alters tone frequency tuning in rat primary auditory cortex
Previous studies in both humans and animals have documented improved performance following discrimination training.
Crystal T. Engineer, , Claudia A. Perez, Ryan S. Carraway, Kevin Q. Chang, Jarod L. Roland, Michael P. Kilgard
Targeting Plasticity with Vagus Nerve Stimulation to Treat Neurological Disease
Pathological neural activity in a variety of neurological disorders could be treated by directing plasticity to specifically renormalize aberrant neural circuits, thereby restoring normal function.
Seth A. Hays, Robert L. Rennaker, Michael P. Kilgard
Vagus nerve stimulation during rehabilitative training improves forelimb strength following ischemic stroke
Upper limb impairment is a common debilitating consequence of ischemic stroke. Physical rehabilitation after stroke enhances neuroplasticity and improves limb function, but does not typically restore normal movement.
hodaparast N, Hays SA, Sloan AM, Hulsey DR, Ruiz A, Pantoja M, Rennaker RL 2nd, Kilgard MP
Increasing diversity of neural responses to speech sounds across the central auditory pathway
Neurons at higher stations of each sensory system are responsive to feature combinations not present at lower levels. As a result, the activity of these neurons becomes less redundant than lower levels.
Ranasinghe KG, Vrana WA, Matney CJ, Kilgard MP
Studies in RF Power Communication, SAR, and Temperature Elevation in Wireless Implantable Neural Interfaces
Implantable neural interfaces are designed to provide a high spatial and temporal precision control signal implementing high degree of freedom real-time prosthetic systems.
Yujuan Zhao, Lin Tang, Robert Rennaker, Chris Hutchens, Tamer S. Ibrahim
Similarity of Cortical Activity Patterns Predicts generalization Behavior
Humans and animals readily generalize previously learned knowledge to new situations. Determining similarity is critical for assigning category membership to a novel stimulus.
Crystal T. Engineer , Claudia A. Perez, Ryan S. Carraway, Kevin Q. Chang, Jarod L. Roland, Andrew M. Sloan, Michael P. Kilgard
Enabling energy efficient protocol processing for passive RFID sensors using sub/near-threshold circuit
Recent research trend of passive RFID based sensors has posed stringent low power requirement for energy efficient communication, which can be addressed by sub/near-Vt operation with standard CMOS process. This paper discusses new design challenges under scaled voltages and presents critical building blocks for low power protocol processing.
R. Liao, R. Ahmed, C. G. Hutchens, R. L. Rennaker
Investigating the structure and function of the retinohypothalamic tract in multiple sclerosis by optical coherence tomography (OCT) and pupillometry
Objective: To characterize the retinohypothalamic tract in the setting of multiple sclerosis and a history of optic neuritis by directly interrogating the functional output of the hypothalamus via body temperature, early morning melatonin suppression, and sleep, fatigue, and depression questionnaires.
Fear conditioning alters neuron-specific hippocampal place field stability via the basolateral amygdala
It is well established that physical changes to an environment result in plasticity of hippocampal place cell activity, while in the absence of changes, place fields are remarkably stable.
Donzis EJ, Rennaker RL, Thompson LT
Impairment of cortical GABAergic synaptic transmission in an environmental rat model of autism
The biological mechanisms of autism spectrum disorders (ASDs) are largely unknown in spite of extensive research.
Banerjee A, García-Oscos F, Roychowdhury S, Galindo LC, Hall S, Kilgard MP, Atzori M
Patent
Timing control for paired plasticity
Cortical speech-evoked response patterns in multiple auditory fields are correlated with behavioral discrimination ability
Different speech sounds evoke unique patterns of activity in primary auditory cortex (A1).
Centanni TM, Engineer CT, Kilgard MP
A comparison of polymer substrates for photolithographic processing of flexible bioelectronics
Flexible bioelectronics encompass a new generation of sensing devices, in which controlled interactions with tissue enhance understanding of biological processes in vivo.
Dustin Simon, Taylor Ware, Ryan Marcotte, Benjamin R. Lund, Dennis W. Smith Jr., Matthew Di Prima, Robert L. Rennaker, Walter Voit
Rapid remission of conditioned fear expression with extinction training paired with vagus nerve stimulation
Fearful experiences can produce long-lasting and debilitating memories. Extinction of conditioned fear requires consolidation of new memories that compete with fearful associations.
Peña DF, Engineer ND, McIntyre CK
Mechanical cycling stability of organic thin film transistors on shape memory polymers
Organic thin film transistors on shape memory polymers are fabricated by full photolithography.
Avendano-Bolivar A, Ware T, Arreaga-Salas D, Simon D, Voit W
A Two Stage Power Optimized Implantable Neural Amplifier Based on Cascoded Structures
Hutchens, Chris, Renneker, Robert L, II
A 2μW digital baseband core for wireless Micro-Neural-Interface in 0.18μm CMOS
This paper presents the design of a low power digital baseband core with a custom-tailored protocol for wirelessly powered Micro-Neural-Interface (MNI) system on a chip (SoC) to be implanted within the skull to record cortical neural activities.
Ran Liao, Chriswell Hutchens, Robert. L. Rennaker
Thiol-ene/acrylate substrates for softening intracortical electrodes
Neural interfaces have traditionally been fabricated on rigid and planar substrates, including silicon and engineering thermoplastics.
Taylor Ware, Dustin Simon, Clive Liu, Tabassum Musa, Srikanth Vasudevan, Andrew Sloan, Edward W. Keefer, Robert L. Rennaker II, Walter Voit
The bradykinesia assessment task: An automated method to measure forelimb speed in rodents
Bradykinesia in upper extremities is associated with a wide variety of motor disorders; however, there are few tasks that assay forelimb movement speed in rodent models.
Seth A. Hays, Navid Khodaparast, Andrew M. Sloan, Tabbassum Fayyaz, Daniel R. Hulsey, Andrea D. Ruiz, Maritza Pantoja, Michael P. Kilgard, Robert L. Rennaker II
Different timescales for the neural coding of consonant and vowel sounds
Psychophysical, clinical, and imaging evidence suggests that consonant and vowel sounds have distinct neural representations. This study tests the hypothesis that consonant and vowel sounds are represented on different timescales within the same population of neurons by comparing behavioral discrimination with neural discrimination based on activity recorded in rat inferior colliculus and primary auditory cortex.
Perez CA, Engineer CT, Jakkamsetti V, Carraway RS, Perry MS, Kilgard MP
Knockdown of the Dyslexia-Associated Gene Kiaa0319 Impairs Temporal Responses to Speech Stimuli in Rat Primary Auditory Cortex
One in 15 school age children have dyslexia, which is characterized by phoneme-processing problems and difficulty learning to read. Dyslexia is associated with mutations in the gene KIAA0319.
T. M. Centanni, A. B. Booker, A. M. Sloan, F. Chen, B. J. Maher, R. S. Carraway, N. Khodaparast, R. Rennaker, J. J. LoTurco and M. P. Kilgard
A target cell-specific role for presynaptic Fmr1 in regulating glutamate release onto neocortical fast-spiking inhibitory neurons
n the mouse model of Fragile X syndrome, the Fmr1 knock-out, local excitation of layer 4 fast-spiking (FS) inhibitory neurons is robustly decreased by 50%, but the mechanisms mediating this change are unknown. Here, we performed recordings in acutely prepared slices obtained from Fmr1 "mosaic" mice, where Fmr1 is deleted in about half of all neurons, and we found that loss of presynaptic, but not postsynaptic, Fmr1 fully recapitulates the deficit.
Patel AB, Hays SA, Bureau I, Huber KM, Gibson JR
Smart Polymers for Neural Interfaces
Thermomechanical properties of smart polymers can be specifically tuned to address critical problems in neural interfaces. A compilation of materials and approaches is presented from each of three often overlapping research communities: shape memory polymers, hydrogels, and neural interfaces.
Taylor Ware, Dustin Simon, Robert L. Rennaker II & Walter Voit
The isometric pull task: A novel automated method for quantifying forelimb force generation in rats
Reach-to-grasp tasks are commonly used to assess forelimb function in rodent models. While these tasks have been useful for investigating several facets of forelimb function, they are typically labor-intensive and do not directly quantify physiological parameters.
Seth A. Hays, Navid Khodaparast, Andrew M. Sloan, Daniel R. Hulsey, Maritza Pantoja, Andrea D. Ruiz, Michael P. Kilgard, Robert L. Rennaker II
Sub-meninges implantation reduces immune response to neural implants
One in 15 school age children have dyslexia, which is characterized by phoneme-processing problems and difficulty learning to read. Dyslexia is associated with mutations in the gene KIAA0319.
Neil T. Markwardt, Jodi Stokol, Robert L. Rennaker II
Directing neural plasticity to understand and treat tinnitus
The functional organization of cortical and subcortical networks can be altered by sensory experience. Sensory deprivation destabilizes neural networks resulting in increased excitability, greater neural synchronization and increased spontaneous firing in cortical and subcortical neurons.
Navzer D. Engineer, Aage R. Møller, Michael P. Kilgard
Harnessing plasticity to understand learning and treat disease
A large body of evidence suggests that neural plasticity contributes to learning and disease. Recent studies suggest that cortical map plasticity is typically a transient phase that improves learning by increasing the pool of task-relevant responses.
Three-Dimensional Flexible Electronics Enabled by Shape Memory Polymer Substrates for Responsive Neural Interfaces
Planar electronics processing methods have enabled neural interfaces to become more precise and deliver more information. However, this processing paradigm is inherently 2D and rigid.
Neural mechanisms supporting robust discrimination of spectrally and temporally degraded speech
Cochlear implants provide good speech discrimination ability despite highly limited amount of information they transmit compared with normal cochlea.
Experience-Dependent Plasticity and Auditory Cortex
Throughout their lifetimes, individuals are constantly engaged by acoustic environments that leave lasting impressions, such as the sound of a familiar voice or the rhythm of a catchy tune. A fundamental question in auditory neuroscience concerns how and where such acoustic knowledge is acquired and stored in the brain.
Kathryn N. Shepard, Michael P. Kilgard, Robert C. Liu
Speech discrimination after early exposure to pulsed-noise or speech
Early experience of structured inputs and complex sound features generate lasting changes in tonotopy and receptive field properties of primary auditory cortex (A1).
Fabrication of Responsive, Softening Neural Interfaces
A novel processing method is described using photolithography to pattern thin-film flexible electronics on shape memory polymer substrates with mechanical properties tailored to improve biocompatability and enhance adhesion between the polymer substrate and metal layers.
Complex Mixture Discrimination and the Role of Contaminants
Rats were trained in a 2-alternative odor choice task to discriminate between a 10-component odor mixture and the same mixture with one component removed and replaced with 1 of 3 concentrations of a different monomolecular odor (contaminant).