Luke A. Johnson - US grants

The long-term goal of this project is to understand the neural mechanisms underlying restored hearing by cochlear implants (CI). We propose a new non-human primate model for CI research, the common marmoset (Callithrix jacchus). Marmosets have a rich vocal repertoire, are highly communicative, and can potentially be used to study vocal production and auditory feedback mechanisms related to speech processing in CI subjects. Its hearing range is similar to that of humans and its auditory cortex shares similar organizations as humans, making it a valuable model to address issues in CI research pertaining to human users. As a first step towards our long term goal, we will examine the basic response properties of neurons in marmoset AC to electrical stimulation of the cochlea using both acute and chronic recording techniques. Aim 1 is to map activation areas in AC elicited by acoustic tone and electric current pulse stimuli. First, neural activity will be recorded from many sites across the tonotopic axis of primary AC in response to acoustic stimuli. The animal will then be deafened and implanted with a multi-channel CI electrode, and similar mapping will be conducted in response to electric stimulation. Activity patterns across AC in response to acoustic and electric stimuli will be compared, and the specificity and cochlear frequency-place areas of stimulation will be assessed. To allow for complete mapping in a short amount of time, this study will be done acutely in anesthetized marmosets. Because no one has ever attempted CI in marmosets, the experiments proposed in Aim 1 are necessary for us to establish this new CI model. Clinical CI processors use modulated pulse trains to transmit temporal features important in speech, so it is of great interest how such signals are represented in the brain. Since anesthesia influences temporal processing of cortical neurons, Aim 2 is to study the neural representation of temporally modulated electric pulse trains in awake, chronically implanted marmosets. The results of these aims will help elucidate brain processes involved in electric hearing, and establish the marmoset as a viable model for future CI research. The research and training goals in this grant define a year-by-year plan for the applicant that help prepare him to become an independent and successful academic researcher. The methods and procedures he will learn will allow him to (a) perform and critically analyze auditory research, (b) disseminate knowledge through written publications, (c) orally communicate research findings, (d) organize research goals through grant writing, and (e) conduct proper research practices through continued ethics training. To complete these objectives, the pre-doctoral student will be closely mentored by two sponsors in the Dept of Biomedical Engineering and Otolaryngology - Head & Neck Surgery. A detailed plan for training and mentorship is presented.

? DESCRIPTION (provided by applicant): The goal of this study is to identify the specific neurophysiological changes that occur within and across key nodal points of the pallidothalamocortical motor circuit with the onset of Parkinson's disease and how these evolve as motor signs become increasingly more severe. This will be done by simultaneously recording and comparing the activity from populations of neurons across multiple nodal points in the basal ganglia thalamo-cortical motor circuit at rest and during movement during normal, mild, moderate and severe stages of parkinsonism in the same monkeys using sequential, low dose administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP). Structures that will be examined include the primary and supplementary motor cortices, the premotor cortex, the internal and external segments of the globus pallidus (GPi and GPe, respectively), the subthalamic nucleus (STN), and the motor thalamus including ventralis anterior, ventralis lateralis pars oralis, and ventralis posterior lateralis pars oralis. Specific ims 1 and 2 will characterize changes in synchronized oscillations, bursting patterns, receptive field properties and phase amplitude coupling across basal ganglia- cortical and thalamo-cortical regions, respectively, with the animal at rest and during both passive movement and the performance of a trained motor task. Specific aim 2 will further examine the differential role of subnuclei of the motor thalamus in the development of bradykinesia/akinesia, rigidity and tremor through the application of discrete, fiber-sparing lesions. Specific aim 3 will use LFP recordings across the pallidothalamocortical circuit to characterize changes in effective connectivity between the pallidum, STN, motor thalamus and PMC, SMA and MC as a function of parkinsonian state. By examining the direction and strength of changes in effective connectivity at rest and during movement at different stages of PD we will be able to clarify the type, location and evolution of changes in effective connectivity as parkinsonian motor signs develop and progress in severity. A better understanding of the role of individual motor circuits and the types of physiological changes that occur within these circuits and how they relate to the development of individual motor signs will provide the rationale for the development of new targets, and technology therapies such as deep brain stimulation, transcranial electrical stimulation and gene therapy that are directed at restoring a more normal pattern of activity in the basal ganglia thalamic circuit.

PROJECT SUMMARY/ABSTRACT Over 75% of people with Parkinson's disease (PD) have significant sleep-wake disturbances that are major contributors to decreased quality of life that can be more disabling and resistant to treatment than the motor symptoms of PD. Currently, the mechanisms contributing to disordered sleep in people with PD are poorly understood and there is a critical need for therapeutic inventions to improve sleep quality. Studies suggest that the basal ganglia thalamo-cortical (BGTC) circuit plays an important role in maintaining normal sleep-wake behavior, and the observation that MPTP non-human primate models of PD with selective basal ganglia dopaminergic lesions have extensive sleep alterations further implicates the BGTC circuitry in playing an important mechanistic role in sleep physiology. This project will provide new insight into the pathophysiology of sleep-wake disturbances in PD by characterizing the changes in sleep-related neuronal activity and physiological interactions that occur between subcortical and cortical structures in the BGTC circuit during progressively more severe parkinsonian states. It will compare how deep brain stimulation (DBS) in the subthalamic nucleus and pallidum modifies these interactions to influence sleep-wake behavior, providing data with immediate translational value by identifying whether DBS in one target is more effective than another in normalizing sleep- related neuronal activity and improving sleep-wake behavior. Furthermore, knowledge about how changes in neuronal activity across the BGTC correlates with altered sleep from normal, parkinsonian, and parkinsonian+DBS conditions will provide the basis to develop more effective stimulation strategies that utilize target-specific physiological biomarkers and closed-loop control paradigms tailored to individual patient's sleep disturbances.