Michael P. Kilgard - US grants

The insights derived from neuroscience studies of cortical plasticity have been indispensable in the development of treatment strategies for a number of neurological disorders, including dyslexia, tinnitus, and stroke. However, because most of these studies were focused on relatively simple sensory stimuli, our understanding of the plasticity principles that shape the cortical representation of more complex stimuli, such as speech, remains rudimentary. The proposed experiments document how experience-dependent plasticity improves the auditory cortex representation of spectro temporally complex stimuli and, by advancing our understanding of brain mechanisms involved in the learning of language, will aid in the treatment of communicative disorders. Using simple stimuli, we have demonstrated that electrical stimulation of the cholinergic nucleus basalis (NB) generates robust cortical plasticity that parallels natural learning. The proposed experiments will extend this series by pairing NB stimulation with complex spectrotemporal stimuli. Two different coding strategies, which have demonstrated stimulation of the cholinergic nucleus basis (NB) generates robust cortical plasticity that parallels natural learning. The proposed experiments will extend this series by pairing NB stimulation with complex spectrotemporal stimuli. Two different strategies, which have been proposed to represent the neural basis of memory, emerge with natural learning of behaviorally important complexes stimuli. In the first, complex features are represented by the distributed activity of neurons (coarse coding); while in the second, complex stimuli are represented with specialized filters tuned to specific spectrotemporal transitions (sparse coding). Our preliminary evidences indicates that NB-stimulation leads to representational plasticity that combines both coding strategies. In addition to sharpening spectral and temporal responses generally, NB activation paired with a spectrotemporal sequence created combination selective neural responses that do not exist in naive cortex. These results demonstrate that combination selectivity is not limited to species/specific vocalizations, and representations of the acoustic environment. Our continuing studies will examine several other acoustic stimuli to determine precisely what stimulus features are required to generate each element of representational plasticity observed in our preliminary results.

DESCRIPTION (provided by applicant): Approximately one out of every fifteen children entering elementary school in the U.S. has a significant developmental language impairment of unknown origin. Detailed studies of speech acoustics have significantly improved understanding and treatment of language impairments. These studies also provide the foundation needed to investigate the neural representation of speech. While peripheral representations have been extensively studied, relatively little is known about the cortical mechanisms that contribute to speech processing. The objective of this proposal is to define the distributed response of mammalian auditory cortex neurons to human speech sounds and to determine what experience-dependent changes in the neural representation of speech are possible. The first aim of the project will be to precisely document the distributed response of auditory cortex neurons to speech sounds. Our preliminary results (from awake and anesthetized recordings in two distinct auditory fields) indicate that frequency bandwidth and forward masking time course appear to account for speech responses of most auditory cortex neurons. The second aim will be to document the distributed cortical response to exaggerated speech sounds that have been used to treat language-learning impairments in thousands of children. Our initial findings indicate that the cortical activity patterns generated by modified speech are more distinct than the patterns generated by natural speech sounds. The third aim will be to establish how cortical neurons are modified by exposure to natural and modified speech sounds. The results of the proposed studies will add to our understanding of neural mechanisms that could contribute to speech processing and learning in human auditory cortex. Insights derived from these studies will influence the use and development of behavioral and sensory rehabilitation of language impairments.

DESCRIPTION (provided by applicant): One out of every 150 people in the United States is affected by autism. Autistic individuals are severely impaired in their ability to process the subtle cues used in everyday communication and social interactions. Recent functional imaging studies have revealed serious deficits in speech sound discrimination in both children and adults with autism. The latency increase of speech evoked neural responses is well correlated with the degree of cognitive and language impairments. Unfortunately, the poor resolution of human imaging techniques obscures the neural basis of the impairment. We propose to evaluate speech sound coding in the valproic acid (VPA) animal model of autism, and quantify the beneficial effects of two common autism therapies: auditory training and environmental enrichment. Speech sounds evoke specific spatiotemporal patterns of cell firing in the central auditory system of normal rats. The first aim of the project is to determine the consequence of VPA exposure on the collicular and cortical representations of speech sounds. Our preliminary results indicate that in utero VPA exposure severely degrades the precise spatiotemporal patterns evoked by speech sounds in auditory cortex. As in autism, the longer latency in our animal model is significantly greater for speech sounds compared to tones. The second aim of the project is to determine the behavioral consequences of VPA exposure on speech sound discrimination. If the neural spatiotemporal representations of speech sounds are degraded, then it is possible that certain speech sounds may not be distinguishable in VPA treated rats. We therefore predict that speech sound discrimination will be impaired in VPA exposed rats. The third aim is to determine the effects of speech training and environmental enrichment on speech evoked activity in VPA exposed rats. Based on previous studies, we predict that both speech training and environmental enrichment will relieve the degradation of the cortical responses to speech sounds and restore speech sound discrimination to control levels in VPA treated rats. The results of the proposed studies will add to our understanding of the neural mechanisms that are associated with speech sound coding. Insights derived from these studies may influence the development of new behavioral and sensory techniques to treat the communication impairments in autism that result in part from degraded speech sound discrimination.

DESCRIPTION (provided by applicant): Stroke is a leading cause of disability, with an estimated 795,000 cases reported in the US each year. As many as 70% of patients who suffer a stroke display a long-term impairment in upper extremity motor function. Many stroke patients exhibit associated risk factors which can impair recovery of function, such as advanced age. The development of rehabilitative strategies to improve the recovery of motor function in the context of advanced age is of key importance. We propose to evaluate a novel early stage therapy to improve stroke recovery which utilizes stimulation of the vagus nerve paired with rehabilitative training. Pairing vagus nerve stimulation (VNS) with movement results in highly specific, long-lasting neuroplasticity in rat primary motor cortex. Furthermore, VNS delivered during rehabilitation improves recovery of forelimb speed and strength after an ischemic lesion of the motor cortex in young adult rats. To evaluate if VNS paired with physical rehabilitation may be useful in stroke patients, we propose to test the therapy in a model that more accurately represents the clinical population. Because advanced age is a leading risk factor for stroke and may limit plasticity, the experiments described in this proposal will evaluate VNS in a model of stroke at an advanced age. The first aim of the study will assess the ability of VNS paired with rehabilitative training to improve recovery of motor function after ischemic stroke in aged rats. The second aim of this proposal will examine structural plasticity mechanisms that underlie recovery after stroke. The third aim of the study will assess the ability of VNS paired with physical training to enhance map plasticity in motor cortex of aged rats. We hypothesize that in aged rats, VNS paired with physical training will result in improved recovery of function, increased structural plasticity, and enhanced map plasticity beyond physical training alone. The results of the proposed experiments will clarify the relationship between advanced age and recovery of motor function are stroke. Insights from these studies will help to delineate the clinical population for which VNS paired with physical rehabilitation is likely to confer therapeutc benefits and improve the likelihood of successful translation of the therapy.

PROJECT ABSTRACT Spinal cord injury (SCI) is a major cause of disability, currently affecting 276,000 individuals in the U.S. alone and millions more worldwide. Cervical SCI (cSCI) accounts for 55% of all SCIs and typically results in impaired upper extremity motor function. The majority of cSCI patients have bilateral damage to the spinal cord. Identifying and developing rehabilitative therapies that promote recovery of upper extremity function after bilateral cSCI is of great clinical importance. We propose to evaluate a novel therapeutic intervention which uses precisely timed stimulation of the vagus nerve paired with rehabilitative training. Pairing vagus nerve stimulation (VNS) with movement engages pro- plasticity neuromodulatory systems and results in highly specific, long-lasting neuroplasticity in rat motor cortex. Based on this enhancement of plasticity, our recent results demonstrate that VNS paired with rehabilitation significantly enhances recovery of forelimb motor function in rat models of ischemic stroke, hemorrhagic stroke, and traumatic brain injury. Moreover, our preliminary results suggest that VNS therapy is effective in a unilateral model of SCI. To test this in a model that more accurately represents the clinical SCI population, we propose to evaluate VNS paired with rehabilitative training in a model of chronic, bilateral cSCI and examine the neuroplasticity in cortical and spinal motor networks that may underlie recovery. In addition, we will define the role of two key neuromodulatory systems, the cholinergic and noradrenergic systems, in recovery after SCI. We hypothesize the VNS paired with rehabilitative training will support functional and anatomical plasticity in descending motor networks to enhance recovery of function after bilateral cSCI. The results of the proposed experiments will clarify the relationship between bilateral cervical spinal damage, neuroplasticity, neuromodulatory function, and upper limb motor recovery. Moreover, this proposal will provide a proof-of-concept evaluation of VNS paired with rehabilitative training to improve recovery of forelimb function after a severe bilateral SCI and elucidate the mechanisms that support recovery.