Browsing by Author "Kilgard, Michael P."
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Item A Suite of Automated Tools to Quantify Hand and Wrist Motor Function after Cervical Spinal Cord Injury(BioMed Central Ltd.) Grasse, Katelyn M.; Hays, Seth A.; Rahebi, Kimiya C.; Warren, Victoria S.; Garcia, Elizabeth A.; Wigginton, Jane G.; Kilgardi Mchael P.; Rennaker, Robert L.; 0000-0003-4225-241X (Hays, SA); 13146094343400332984 (Hays, SA); Grasse, Katelyn M.; Hays, Seth A.; Rahebi, Kimiya C.; Warren, Victoria S.; Garcia, Elizabeth A.; Wigginton, Jane G.; Kilgard, Michael P.; Rennaker, Robert L.Background: Cervical spinal cord injury (cSCI) often causes chronic upper extremity disability. Reliable measurement of arm function is critical for development of therapies to improve recovery after cSCI. In this study, we report a suite of automated rehabilitative tools to allow simple, quantitative assessment of hand and wrist motor function. Methods: We measured range of motion and force production using these devices in cSCI participants with a range of upper limb disability and in neurologically intact participants at two time points separated by approximately 4 months. Additionally, we determined whether measures collected with the rehabilitative tools correlated with standard upper limb assessments, including the Graded Redefined Assessment of Strength, Sensibility, and Prehension (GRASSP) and the Jebsen Hand Function Test (JHFT). Results: We find that the rehabilitative devices are useful to provide assessment of upper limb function in physical units over time in SCI participants and are well-correlated with standard assessments. Conclusions: These results indicate that these tools represent a reliable system for longitudinal evaluation of upper extremity function after cSCI and may provide a framework to assess the efficacy of strategies aimed at improving recovery of upper limb function. ©2019 The Author(s).Item Abnormal Emotional Learning in a Rat Model of Autism Exposed to Valproic Acid in Utero(Frontiers Research Foundation) Banerjee, Anwesha; Engineer, Crystal T.; Sauls, Bethany L.; Morales, Anna A.; Ploski, Jonathan E.\\Kilgard, Michael P.; Kilgard, Michael P.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. We therefore sought to further examine anxiety and emotional learning in an environmentally induced animal model of ASD that utilizes the administration of the known teratogen, valproic acid (VPA) during gestation. Specifically we exposed dams to one of two different doses of VPA (500 and 600 mg/kg) or vehicle on day 12.5 of gestation and examined the resultant progeny. Our data indicate that animals exposed to VPA in utero exhibit enhanced anxiety in the open field test and normal object recognition memory compared to control animals. Animals exposed to 500 mg/kg of VPA displayed normal acquisition of auditory fear conditioning, and exhibited reduced extinction of fear memory and normal litter survival rates as compared to control animals. We observed that animals exposed to 600 mg/kg of VPA exhibited a significant reduction in the acquisition of fear conditioning, a significant reduction in social interaction and a significant reduction in litter survival rates as compared to control animals. VPA (600 mg/kg) exposed animals exhibited similar shock sensitivity and hearing as compared to control animals indicating the fear conditioning deficit observed in these animals was not likely due to sensory deficits, but rather due to deficits in learning or memory retrieval. In conclusion, considering that progeny from dams exposed to rather similar doses of VPA exhibit striking differences in emotional learning, the VPA model may serve as a useful tool to explore the molecular and cellular mechanisms that contribute to not only ASD, but also emotional learning.Item Closed-Loop Neuromodulation Restores Network Connectivity and Motor Control After Spinal Cord Injury(eLife Sciences Publications Ltd) Ganzer, Patrick D.; Darrow, Michael J.; Meyers, Eric C.; Solorzano, Bleyda R.; Ruiz, Andrea D.; Robertson, Nicole M.; Adcock, Katherine S.; James, Justin T.; Jeong, Han S.; Becker, April M.; Goldberg, Mark P.; Pruitt, David T.; Hays, Seth A.; Kilgard, Michael P.; Rennaker, Robert L. II; Ganzer, Patrick D.; Darrow, Michael J.; Meyers, Eric C.; Solorzano, Bleyda R.; Ruiz, Andrea D.; Robertson, Nicole M.; Adcock, Katherine S.; James, Justin T.; Jeong, Han S.; Pruitt, David T.; Hays, Seth A.; Kilgard, Michael P.; Rennaker, Robert L. IIRecovery from serious neurological injury requires substantial rewiring of neural circuits. Precisely-timed electrical stimulation could be used to restore corrective feedback mechanisms and promote adaptive plasticity after neurological insult, such as spinal cord injury (SCI) or stroke. This study provides the first evidence that closed-loop vagus nerve stimulation (CLV) based on the synaptic eligibility trace leads to dramatic recovery from the most common forms of SCI. The addition of CLV to rehabilitation promoted substantially more recovery of forelimb function compared to rehabilitation alone following chronic unilateral or bilateral cervical SCI in a rat model. Triggering stimulation on the most successful movements is critical to maximize recovery. CLV enhances recovery by strengthening synaptic connectivity from remaining motor networks to the grasping muscles in the forelimb. The benefits of CLV persist long after the end of stimulation because connectivity in critical neural circuits has been restored.Item Cortical Map Plasticity as a Function of Vagus Nerve Stimulation Rate(Elsevier Inc.) Buell, Elizabeth P.; Loerwald, Kristofer W.; Engineer, Crystal T.; Borland, Michael S .; Buell, John M.; Kelly, C. A.; Khan, I. I.; Hays, Seth A.; Kilgard, Michael P.; Buell, Elizabeth P.; Loerwald, Kristofer W.; Engineer, Crystal T.; Borland, Michael S .; Buell, John M.; Kelly, C. A.; Khan, I. I.; Hays, Seth A.; Kilgard, Michael P.Background: Repeatedly pairing a brief train of vagus nerve stimulation (VNS) with an external event can reorganize the sensory or motor cortex. A 30 Hz train of sixteen VNS pulses paired with a tone significantly increases the number of neurons in primary auditory cortex (A1) that respond to tones near the paired tone frequency. The effective range of VNS pulse rates for driving cortical map plasticity has not been defined. Objective/Hypothesis: This project investigated the effects of VNS rate on cortical plasticity. We expected that VNS pulse rate would affect the degree of plasticity caused by VNS-tone pairing. Methods: Rats received sixteen pulses of VNS delivered at a low (7.5 Hz), moderate (30 Hz), or high (120 Hz) rate paired with 9 kHz tones 300 times per day over a 20 day period. Results: More A1 neurons responded to the paired tone frequency in rats from the moderate rate VNS group compared to naïve controls. The response strength was also increased in these rats. In contrast, rats that received high or low rate VNS failed to exhibit a significant increase in the number of neurons tuned to sounds near 9 kHz. Conclusion: Our results demonstrate that the degree of cortical plasticity caused by VNS-tone pairing is an inverted-U function of VNS pulse rate. The apparent high temporal precision of VNS-tone pairing helps identify optimal VNS parameters to achieve the beneficial effects from restoration of sensory or motor function.Item Effects of Vagus Nerve Stimulation on Caloric Intake, Dopamine Signaling, and Self-administration(2022-05-01T05:00:00.000Z) Brougher, Jackson John; Thorn, Catherine; Stillman, Robert; Kroener, Sven; Price, Theodore; Kilgard, Michael P.Vagus nerve stimulation (VNS) offers an effective, minimally evasive means for eliciting changes within the central nervous system. Preclinically, VNS has been utilized for its ability to drive plasticity within the motor and auditory cortices which have further been developed as therapeutic approaches to improve recovery after neural injury. However, precise mechanisms and off target effects of VNS are not fully characterized. Here, we try to develop the understanding of VNS in three different, but linked, experiments. In the first, we sought to measure the effects of VNS on caloric intake. The vagus nerve is a key mediator of gut-brain signaling, and we found that VNS would indeed decrease caloric intake. Next, we examined the necessity of dopamine, a key neuromodulator in motor skill learning, in VNS driven motor cortical reorganization. Here, VNS is either not reliant on, or is able to overcome the absence of dopamine. Last, we examined lateralization of the vagus nerve and found that the right cervical branch, but not the left, is capable of activating mesolimbic dopaminergic nuclei and promoting self-stimulation like behaviors. Together these findings both help to inform future VNS-related studies and opens new avenues of research into the mechanisms and applications of VNS.Item Effects of Vagus Nerve Stimulation on Extinction of Conditioned Fear and Post-Traumatic Stress Disorder Symptoms in RatsNoble, Lindsey J.; Gonzalez, I. J.; Meruva, V. B.; Callahan, Kathleen A.; Belfort, Benjamin D.; Ramanathan, K. R.; Meyers, Eric; Kilgard, Michael P.; Rennaker, Robert L.; McIntyre, Christa K.; Noble, Lindsey J.; Gonzalez, I. J.; Meruva, V. B.; Callahan, Kathleen A.; Belfort, Benjamin D.; Ramanathan, K. R.; Meyers, Eric; Kilgard, Michael P.; Rennaker, Robert L.; McIntyre, Christa K.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. The present study examined whether vagus nerve stimulation (VNS) augments extinction of conditioned fear and attenuates PTSD-like symptoms in an animal model of PTSD. To model PTSD, rats were subjected to a single prolonged stress (SPS) protocol, which consisted of restraint, forced swim, loss of consciousness, and 1 week of social isolation. Like PTSD patients, rats subjected to SPS show impaired extinction of conditioned fear. The SPS procedure was followed, 1 week later, by auditory fear conditioning (AFC) and extinction. VNS or sham stimulation was administered during half of the extinction days, and was paired with presentations of the conditioned stimulus. One week after completion of extinction training, rats were given a battery of behavioral tests to assess anxiety, arousal and avoidance. Results indicated that rats given SPS 1 week prior to AFC (PTSD model) failed to extinguish the freezing response after eleven consecutive days of extinction. Administration of VNS reversed the extinction impairment and attenuated reinstatement of the conditioned fear response. Delivery of VNS during extinction also eliminated the PTSD-like symptoms, such as anxiety, hyperarousal and social avoidance for more than 1 week after VNS treatment. These results provide evidence that extinction paired with VNS treatment can lead to remission of fear and improvements in PTSD-like symptoms. Taken together, these findings suggest that VNS may be an effective adjunct to exposure therapy for the treatment of PTSD.Item Enhancing Plasticity in Central Networks Improves Motor and Sensory Recovery after Nerve Damage(Springer Nature, 2019-12-19) Meyers, Eric C.; Kasliwal, Nimit; Solorzano, Bleyda R.; Lai, Elaine; Bendale, Geetanjali; Berry, Abigail; Ganzer, Patrick D.; Romero-Ortega, Mario; Rennaker, Robert L.; Kilgard, Michael P.; Hays, Seth A.; 0000-0002-2013-5450 (Meyers, EC); 0000-0001-6314-9062 (Kasliwal, N); 0000-0003-2576-2629 (Romero-Ortega, M); 0000-0003-4225-241X (Hays, SA); Meyers, Eric C.; Kasliwal, Nimit; Solorzano, Bleyda R.; Lai, Elaine; Bendale, Geetanjali; Berry, Abigail; Ganzer, Patrick D.; Romero-Ortega, Mario; Rennaker, Robert L.; Kilgard, Michael P.; Hays, Seth A.Nerve damage can cause chronic, debilitating problems including loss of motor control and paresthesia, and generates maladaptive neuroplasticity as central networks attempt to compensate for the loss of peripheral connectivity. However, it remains unclear if this is a critical feature responsible for the expression of symptoms. Here, we use brief bursts of closed-loop vagus nerve stimulation (CL-VNS) delivered during rehabilitation to reverse the aberrant central plasticity resulting from forelimb nerve transection. CL-VNS therapy drives extensive synaptic reorganization in central networks paralleled by improved sensorimotor recovery without any observable changes in the nerve or muscle. Depleting cortical acetylcholine blocks the plasticity-enhancing effects of CL-VNS and consequently eliminates recovery, indicating a critical role for brain circuits in recovery. These findings demonstrate that manipulations to enhance central plasticity can improve sensorimotor recovery and define CL-VNS as a readily translatable therapy to restore function after nerve damage.Item Evaluating targeted plasticity therapy for new indications(2021-04-21) Adcock, Katherine Shea; Kilgard, Michael P.; Hays, SethTargeted plasticity therapy has recently emerged as a potential intervention to reverse maladaptive plasticity. Vagus nerve stimulation (VNS) triggers release of plasticity enhancing neuromodulators, and promotes event-specific plasticity when coupled with an event. Through event specific plasticity, VNS therapy can improve recovery after neurological injury. Studies have consistently shown that VNS paired with various rehabilitative therapies improves recovery in a range of injury models. We sought to extend these findings to two additional, fundamentally distinct models. Here, we first characterize sensory and motor function in a new peripheral nerve injury model that captures aspects of pain. Meyers and colleagues demonstrated that injury to the median and ulnar nerve cause motor dysfunction and sensory loss. While injury to the median and ulnar nerve is one example of peripheral nerve injury, there are several different types of nerve injury that result in different outcomes. The phenotype of nerve injury is largely dependent on what nerve is injured, and the extent of injury. While both the median ulnar nerve injury and radial nerve injury result in motor dysfunction, the different variations of nerve injury produce opposite effects on somatosensory function. Instead of sensory loss, radial nerve injury causes mechanical hypersensitivity, and can serve as a model of pain. We then investigate the effects of VNS after radial nerve injury. VNS did not improve motor or sensory function after radial nerve injury, suggesting that some aspects of nerve injury may not benefit from VNS. In another study, we characterize auditory and motor function in a genetically induced neurodevelopmental disorder. The neurodevelopmental disorder, Rett Syndrome, is caused by a genetic mutation to the gene Mecp2, and results in a regression of already acquired skills. Our results demonstrate that Mecp2 rats display deficits in skilled motor learning and auditory discrimination, which is consistent with the clinical manifestation in individuals with Rett Syndrome. Impaired performance corresponds to dysregulation neural function in auditory and motor networks in Mecp2 models. We next investigated whether VNS tone pairing could improve neural processing of sounds in the auditory cortex. Our findings provide initial evidence that VNS sound pairing can restore auditory processing, and lay the groundwork for future studies examining the functional consequences of VNS tone pairing. Overall, these studies identify conditions that may limit the effects of VNS, and establishes a framework for future clinical applications.Item Improving Auditory Responses After Hearing Loss(2022-05-01T05:00:00.000Z) Riley, Jonathan; Warner-Czyz, Andrea; Kilgard, Michael P.; Rennaker II, Robert L.; Hays, Seth; Engineer, CrystalNoise-induced hearing loss is a common and debilitating neurological injury. Exposure to loud sounds can result in damage to cochlear structures and subsequently to losses in the transduction of acoustic signals into neural activity. The loss of neural activity leads to auditory pathways having less information available to them to process and evaluate any given acoustic scene. For patients with noise-induced hearing loss, the degradation of acoustic processing leads to difficulties in communication. Challenges in communication for patients with noise-induced hearing loss arise from trouble understanding speech—especially in noisy environments. Ineffective communication can lead to lost productivity and social withdrawal, which profoundly degrade the quality of life for people with noise-induced hearing loss. In addition to the loss of acoustic input, noise-induced hearing loss also results in adaptive changes throughout the auditory pathway. The nature and impact of these adaptations remains unclear and techniques which can probe these adaptations by precisely modulating neural activity are needed. Vagus nerve stimulation (VNS) paired with sound presentation has been shown to induce stimulus-specific plasticity in the auditory cortex. To explore the possibility that VNS paired with sounds might enhance neural responses to auditory cues following noise-induced hearing loss, a rodent model of noise-induced hearing loss was established. The model covered a wide range of behavioral impairments and demonstrated behavioral deficits in speech sound detection and discrimination. Importantly, rats with severe hearing loss demonstrated behavioral deficits most akin to clinical complaints—difficulty discriminating speech in the presence of noise. The present rodent model was then used to evaluate the ability of VNS paired with speech sound presentation to alter neural responses to speech sounds following noise-induced hearing loss. For rats with moderate hearing loss and which had intact neural responses to speech sounds, VNS-speech pairing did not significantly alter the neural responses to speech sounds. However, for rats with severe noiseinduced hearing loss, VNS-speech pairing doubled the response strength to the consonant portion of the speech sound, significantly improved neural discriminability, and did not alter the response to the vowel. For rats with profound hearing loss, the response strength to the vowel portion of the speech sounds was doubled and neural detection improved. Taken together, these findings suggest that when neural responses are present but weakened, such as with the consonant portion in the severe group or the vowel in profound group, VNS-speech pairing can strengthen those responses. However, when responses are absent, such as with the lack of any evoked response to the consonant in the profound group, VNS-speech pairing does not strengthen a response which is not present. Where responses were robust, such as with the moderate group and the vowel response in severe rats, VNS-speech paring does not interfere with those responses. This proof-of-concept work demonstrates that the auditory pathways remain plastic following noise-induced hearing loss and that they are manipulable using VNS-speech pairing. Future work is needed to establish if the plastic changes induced by VNS-speech pairing result in improved behavioral outcomes.Item Neuromodulatory Pathways Required for Targeted Plasticity Therapy(2018-05) Hulsey, Daniel Robertson; 0000-0003-3243-6282 (Hulsey, DR); Kilgard, Michael P.Targeted plasticity therapy (TPT) utilizes vagus nerve stimulation (VNS) paired with physical rehabilitation to direct plasticity and promote recovery. Pre-clinical trials in stroke, spinal cord injury, traumatic brain injury, and peripheral nerve injury models show improved functional recovery after VNS-pairing when compared to physical rehabilitation alone. Pairing VNS with motor movements in neurologically intact animals leads to expansion of task-specific cortical representations. Precise timing of VNS is required to drive plasticity and functional recovery. VNS engages pro-plasticity neuromodulators, but there is no direct evidence that they mediate VNS effects. Acute responses to VNS in key neuromodulatory centers are also unknown. This dissertation work aims to elucidate the neuromodulatory pathways required for VNS directed plasticity underlying TPT. A reliable preparation driving expansion of proximal forelimb representation in rats after one week of VNS pairing on a lever-press task is used in two experiments. Targeted neurotoxins selectively deplete cholinergic, noradrenergic, and serotonergic innervation of the cortex in experimental animals, testing the necessity of each key neuromodulatory pathway to VNS effects. Intracortical microstimulation reveal cortical representations to compare across groups. The third experiment characterizes locus coeruleus (LC) responses to parametric variation of VNS. It uses acute VNS cuff implants and standard LC recording techniques to elucidate phasic response characteristics to a wide range of VNS intensity, pulse width, and frequency. The results of this dissertation replicate previous findings that VNS drives robust plasticity in the motor cortex following VNS-movement pairings. Cholinergic, noradrenergic, and serotonergic depletion each block the effects of VNS. The cortical depletion of acetylcholine was complete, while noradrenergic and serotonergic lesions were confined to the experimental hemisphere. This result suggests that each neuromodulator system uniquely contributes to VNS-directed plasticity and TPT. Recordings from the LC reveal rapid phasic activity in response to VNS. Increases in intensity and pulse width monotonically increase LC activation. Alterations in stimulation frequency do not influence total driven activity, but allow for temporal shaping of the response. These results make substantial contributions to elucidating the mechanisms, resoundingly confirming the neuromodulatory basis for TPT and VNS-directed plasticity. They can help guide clinical considerations in terms of patient selection based on pharmacological profiles. Additionally, they contribute to efforts to optimize stimulation parameters by elucidating responses characteristics in a key neuromodulatory center.Item Norepinephrine and Serotonin are Required for Vagus Nerve Stimulation Directed Cortical Plasticity(Academic Press Inc., 2019-06-07) Hulsey, Daniel R.; Shedd, Cristine M.; Sarker, Sadmaan F.; Kilgard, Michael P.; Hays, Seth A.; 0000-0003-4225-241X (Hays, SA); 13146094343400332984 (Hays, SA); Hulsey, Daniel R.; Shedd, Cristine M.; Sarker, Sadmaan F.; Kilgard, Michael P.; Hays, Seth A.Vagus nerve stimulation (VNS) paired with forelimb training drives robust, specific reorganization of movement representations in the motor cortex. This effect is hypothesized to be mediated by VNS-dependent engagement of neuromodulatory networks. VNS influences activity in the locus coeruleus (LC) and dorsal raphe nucleus (DRN), but the involvement of these neuromodulatory networks in VNS-directed plasticity is unknown. We tested the hypothesis that cortical norepinephrine and serotonin are required for VNS-dependent enhancement of motor cortex plasticity. Rats were trained on a lever pressing task emphasizing proximal forelimb use. Once proficient, all rats received a surgically implanted vagus nerve cuff and cortical injections of either immunotoxins to deplete serotonin or norepinephrine, or vehicle control. Following surgical recovery, rats received half second bursts of 0.8 mA or sham VNS after successful trials. After five days of pairing intracortical microstimulation (ICMS) was performed in the motor cortex contralateral to the trained limb. VNS paired with training more than doubled cortical representations of proximal forelimb movements. Depletion of either cortical norepinephrine or serotonin prevented this effect. The requirement of multiple neuromodulators is consistent with earlier studies showing that these neuromodulators regulate synaptic plasticity in a complimentary fashion. ©2019 Elsevier Inc.Item Pairing Sound with Vagus Nerve Stimulation Modulates Cortical Synchrony and Phase Coherence in Tinnitus: An Exploratory Retrospective Study(Nature Publishing Group) Vanneste, Sven; Martin, Jeffrey S.; Rennaker, Robert L.; Kilgard, Michael P.; 0000 0001 2879 2132 (Rennaker, RL); 0000 0001 3852 473X (Kilgard, MP); 0000-0002-9906-1836 (Vanneste, S); Vanneste, Sven; Martin, Jeffrey S.; Rennaker, Robert L.; Kilgard, Michael P.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. Since previous studies observed that gamma activity in the auditory cortex is correlated with tinnitus loudness, we assessed resting-state source-localized EEG before and after one to three months of VNS-tone pairing in chronic tinnitus patients. VNS-tone pairing reduced gamma band activity in left auditory cortex. VNStone pairing also reduced the phase coherence between the auditory cortex and areas associated with tinnitus distress, including the cingulate cortex. These results support the hypothesis that VNS-tone pairing can direct therapeutic neural plasticity. Targeted plasticity therapy might also be adapted to treat other conditions characterized by hypersynchronous neural activity.Item Similarity of Cortical Activity Patterns Predicts Generalization Behavior(Public Library of Science) Engineer, Crystal T.; Perez, Claudia A.; Carraway, Ryan S.; Chang, Kevin Q.; Roland, Jarod L.; Sloan, Andrew M.; Kilgard, Michael P.; 0000 0001 3852 473X (Kilgard, MP)Humans and animals readily generalize previously learned knowledge to new situations. Determining similarity is critical for assigning category membership to a novel stimulus. We tested the hypothesis that category membership is initially encoded by the similarity of the activity pattern evoked by a novel stimulus to the patterns from known categories. We provide behavioral and neurophysiological evidence that activity patterns in primary auditory cortex contain sufficient information to explain behavioral categorization of novel speech sounds by rats. Our results suggest that category membership might be encoded by the similarity of the activity pattern evoked by a novel speech sound to the patterns evoked by known sounds. Categorization based on featureless pattern matching may represent a general neural mechanism for ensuring accurate generalization across sensory and cognitive systems.;Item Speech Sound Processing Deficits and Training-Induced Neural Plasticity in Rats with Dyslexia Gene Knockdown(Public Library of Science) Centanni, Tracy M.; Chen, Fuyi; Booker, Anne M.; Engineer, Crystal T.; Sloan, Andrew M.; Rennaker, Robert L.; LoTurco, Joseph J.; Kilgard, Michael P.; 0000 0001 3852 473X (Kilgard, MP); 0000 0001 2879 2132 (Rennaker, RL)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. We tested the hypothesis that KIA- rats would be impaired at speech sound discrimination. KIA- rats needed twice as much training in quiet conditions to perform at control levels and remained impaired at several speech tasks. Focused training using truncated speech sounds was able to normalize speech discrimination in quiet and background noise conditions. Training also normalized trial-by-trial neural variability and temporal phase locking. Cortical activity from speech trained KIA- rats was sufficient to accurately discriminate between similar consonant sounds. These results provide the first direct evidence that assumed reduced expression of the dyslexia-associated gene KIAA0319 can cause phoneme processing impairments similar to those seen in dyslexia and that intensive behavioral therapy can eliminate these impairments. ;Item Targeting Auditory Cortex Plasticity Using Vagus Nerve Stimulation(2019-05) Buell, Elizabeth Paige; Kilgard, Michael P.Neuroplasticity refers to the ability of the nervous system to change in response to experience or injury. These changes can be positive (i.e., language acquisition) or negative (i.e., tinnitus). The release of neuromodulators like norepinephrine are critical for neuroplasticity, and regions responsible for their release are modulated by vagus nerve stimulation (VNS). When VNS is paired with a sensory stimulus, specific and lasting changes are observed in the nervous system. In addition, VNS is FDA-approved in the treatment of drug resistant epilepsy and depression, and has been proven to be safe and effective for thousands of patients. Several patients benefited from VNS tone-pairing therapy as a treatment for tinnitus in recent clinical trials. However, no patient was completely cured of his/her tinnitus. A potential reason for these results is that more plasticity must be driven in VNS tone-paired treatment for patients to have maximal benefit. Therefore, VNS parameters must be evaluated to ensure the best settings for driving plasticity are being used clinically. To accomplish this goal, the rate, train duration, and number of VNS pulses were evaluated. Results suggest that 30 Hz is better at driving plasticity than rates a much higher (120 Hz) or lower (7.5 Hz) levels. Longer (2000 ms) VNS pulse trains are not capable of driving plasticity. However, it is possible to drive plasticity using one-fourth of the stimulation used in previous experiments. These results suggest that the magnitude of plasticity driven by VNS is sensitive to changes in multiple stimulation parameters. The high temporal precision of VNS-tone pairing protocols may help to explain the cellular mechanisms responsible for the beneficial effects of precisely timed VNS during restoration of sensory or motor functionItem Task Learning as a Mechanism of Transfer in Cognitive Intervention: Neuro-cognitive Predictors and Outcomes of Early, Middle and Late Stages of Task Learning(2021-12-01T06:00:00.000Z) Smith, Evan Taylor; Kilgard, Michael P.; Basak, Chandramallika; Park, Denise C.; Fishwick, Paul; Evans, JuliaInvestigation into methods of addressing cognitive loss exhibited later in life is of paramount importance to the field of cognitive aging. The passive protective factors of cognitive reserve and continued education, as well as the active factor of cognitive intervention, have all been found to ameliorate expected declines in cognition in adults aged sixty-five and up, and all three of these factors heavily involve the learning process. This dissertation presents three studies derived from a longitudinal cognitive intervention, each designed to illuminate factors which influence the learning process and in turn how that process bolsters cognition. The cognitive intervention in question was a working-memory-based video-game-like training task, designed to be both engaging and adaptive to the abilities of individual participants. The first study identified a measure of verbal episodic memory as well as the volume of a brain region involved in language, verbal memory and cognitive control (the left inferior frontal gyrus) as predictors of individual learning rates on the training task. These two neuro-cognitive measures were more predictive of task learning when considered in conjunction than when considered separately, indicating a complimentary effect. The second study compared daily performance on the training task with several daily factors known to influence cognition, including perceived wellbeing, stress, business, and sleep. Auto-regressive analyses conducted in Study 2 were able to identify meaningful predictors of performance-over-time on the training task in fifty percent of cases. This pattern of influences varied greatly between participants, indicating a highly individualized influence of these variables. The third study observed that individual differences in learning of the training task were related to training-related gains in a measure of nonverbal reasoning, with participants who learned the training task faster showing relatively greater transfer (i.e. gains) to that measure of reasoning. Collectively, the three studies presented in this dissertation offer a novel insight into training-related cognitive benefits via the identification of a discreet “path of transfer” resultant from this training. Specifically, these studies identify a pattern of influence by which verbal episodic memory (and its related brain region) is determinant of learning of a working-memory task (the training task), and learning of that task itself is determinant of training-related gains to nonverbal reasoning. This pattern of findings serves as a testable hypothesis for future studies of working-memory based cognitive training in older adults, and this “path of transfer” approach may serve as a useful tool in examining the concept of transfer more generally.Item The Role of Noradrenergic Signaling in Vagus Nerve Stimulation Dependent Motor Cortical Plasticity(August 2023) Tseng, Ching-Tzu 1992-; Thorn, Catherine; Rennaker II, Robert L.; Kilgard, Michael P.; Rincón-Cortés, Millie; McIntyre Rodriguez, ChristaThe combination of vagus nerve stimulation (VNS) and motor rehabilitation is being reported as a promising therapy for enhancing motor function recovery after neural injuries. Recent preclinical studies in rats have shown that VNS in conjunction with skilled forelimb training leads to substantial reorganization of the somatotopic cortical motor map, which has been shown to be important for VNS efficacy. However, most of the preclinical research have been conducted in female rats, even though the risk of neural injuries of all kinds is considerably greater in males than in females. Furthermore, the neural mechanisms underlying VNS-induced neuroplasticity remain unclear. Here, we aim to deepen our understanding of VNS through three different, but linked, projects. First, we test whether VNS generates plasticity differently between male and females. Results from our experiments indicate that VNS is equally effective in inducing plasticity in both sexes. Second, we assess the necessity of activation of alpha2-adrenergic receptors (alpha2-ARs), the key regulator in governance of noradrenaline (NA) release and synaptic plasticity in the central nervous system (CNS), in VNS effect. Our results show that infusion of alpha2-ARs antagonist blocks VNS-driven neuroplasticity. Finally, we examine the effect of phasic activation of the locus coeruleus (LC), the noradrenergic center in the CNS, on motor cortical plasticity. We found that 10 Hz, but not 3 or 30 Hz, LC stimulation paired with learned motor task promote motor cortical map reorganization. Taken together, these findings inform the generalization of VNS therapy to the general population and broaden the understanding of LC-NA mechanisms underlying VNS-driven plasticity.Item Understanding and Optimizing Vagus Nerve Stimulation Directed Cortical Plasticity(2018-05) Borland, Michael; Kilgard, Michael P.Vagus nerve stimulation (VNS) is a tool that has been used to treat epilepsy, depression and enhance memory. In the last few years VNS has been observed to direct cortical plasticity when paired with a sensory or motor event. Now VNS is being examined as a new tool to treat tinnitus and stroke by reversing pathological brain plasticity. The VNS pairing therapy has improved several patient’s conditions who are suffering from tinnitus or paralysis from stroke. Even though several patients benefited from the VNS pairing therapy none were completely cured, and some patients had little to no benefit. One reason for this could be that the VNS parameters have not been optimized. When VNS is used to treat epilepsy, depression or to enhance memory, a certain VNS current intensity range has been beneficial to people. My study revealed that VNS-tone pairing enhances cortical plasticity over a twofold range of VNS intensity at 0.4 mA and 0.8 mA. Another VNS parameter my study looked at was the interval between nerve stimulations for the VNS-tone pairing therapy. VNS-tone pairing therapy with a longer interstimulus interval significantly increased the degree of map plasticity compared to the same stimulation with a shorter interval. These observations confirm that the interval between VNStone pairing events and intensity current influences the degree of cortical plasticity. The final parameter my experiments observed was the number of stimulations VNS-tone pairing achieved in a session. Decreasing the number of stimulation in the VNS-tone pairing did not enhance cortical plasticity.Item Vagus Nerve Stimulation and Rehabilitation Improves Recovery of a Motor Task after Neurological Injury(2015-06-25) Choi, Rachel; Meyers, Eric; Ganzer, Patrick; Hays, Seth; Kilgard, Michael P.; Rennaker, Robert L.; 0000 0001 3852 473X (Kilgard, MP); 0000 0001 2879 2132 (Rennaker, RL)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. Sprague-Dawley rats affected by a spinal cord contusion at C5 and administered VNS paired with rehabilitation exhibited significant recovery of forelimb strength on an isometric pull task. We also propose similar recovery of supination function in Sprague-Dawley rats affected by endothelin-1‐induced focal motor cortex ischemic stroke. Thus, VNS paired with rehabilitation may be an effective therapeutic tool in the event of neurological injury such as ischemic stroke or spinal cord injury.Item Vagus Nerve Stimulation Intensity Regulates Targeted Plasticity(2021-03-26) Morrison, Robert Andrew; Kilgard, Michael P.Vagus nerve stimulation (VNS) paired with motor rehabilitation enhances recovery of function after neurological injury in rats and humans. This effect is ascribed to VNS-dependent facilitation of synaptic plasticity in motor networks triggered by increases in neuromodulatory activity. Based on plasticity’s role in VNS-enhancement of rehabilitation, it is possible that greater levels of synaptic reorganization lead to greater recovery. Thus, defining stimulation strategies that maximize plasticity may provide a means to optimize the efficacy of VNS therapy, improving subsequent recovery for patients. The stimulation parameters of VNS, including intensity, frequency, and duration, can influence the level of activity in relevant neuromodulatory nuclei. However, levels of neuromodulatory activity alone are not an accurate predictor of degree of plasticity. Previous studies in auditory cortex report an inverted-U relationship between VNS intensity and plasticity, such that moderate intensity VNS yields greater cortical plasticity than low or high intensity VNS. Here, we first investigate the effects of increasing VNS intensity on motor cortex plasticity when paired with forelimb training. We demonstrate that there is an inverted-U relationship between VNS intensity and subsequent plasticity, as VNS at moderate intensities paired with forelimb training drives expansion of associated forelimb representations in motor cortex, while low and high intensities do not. We then go on to investigate VNS-mediated plasticity in jaw motor cortex using a new behavioral paradigm emphasizing the jaw musculature, demonstrating that VNS can enhance synaptic reorganization in orofacial circuits. We validate this new behavioral paradigm by re-examining the inverted-U relationship between VNS intensity and degree of plasticity, replicating our previous findings with a higher resolution and demonstrating that there is a narrower range of effective VNS intensities than previously thought. Although high intensity VNS fails to enhance plasticity when delivered alone, it is unclear whether the mechanisms engaged by high intensity VNS interact with and disrupt subsequent moderate intensity VNS. We tested the interaction of moderate and high intensity VNS trains to probe the mechanisms that may underlie VNS-dependent plasticity, showing that high intensity VNS engages mechanisms that disrupt VNS-dependent synaptic plasticity. Lastly, based on our findings that VNS can enhance synaptic plasticity in orofacial circuits, we discuss the possibility of using VNS as an adjuvant to rehabilitation for post-stroke motor speech disorders. VNS paired with upper limb rehabilitation enhances upper limb function after stroke, and our findings suggests that VNS may enhance synaptic plasticity in networks related to poststroke motor speech disorders in a similar manner. We outline the rationale for pairing VNS with rehabilitation for dyspraxia and dysphagia to enhance plasticity in orofacial circuits mediating orofacial function, which could lead to greater recovery than with just rehabilitation alone.