Robert L. Rennaker - US grants

DESCRIPTION (provided by applicant): ABSTRACT Cortical processing of sensory information plays a critical role in sensory discrimination, object recognition and memory. Cortical sensory processing has been shown to be highly dynamic, with past experience, current context and expectations shaping how the world is perceived on a moment by moment basis. Disorders of sensory processing constitute a major component of impairments induced by CNS disease and aging, as well as congenital disorders such as schizophrenia and autism. In the olfactory sensory (piriform) cortex diverse stimulus features are synthesized into perceptual wholes through afferent and intrinsic fiber convergence and plasticity, allowing familiar odor objects to be remembered. The intrinsic, association fiber system in priform cortex is extensive, and based on anatomical data and new physiological data supported by an R21 to the co-PI's, plays a role in shaping cortical ensemble activity in response to odorant stimuli. Thus, our data demonstrate that odorants evoke distributed unit ensemble activity throughout anterior piriform cortex (aPCX), with individual components of the ensemble contributing to multiple odorant representations. In the present proposal, which extends the R21-supported research, we propose to address three previously untested hypotheses regarding cortical ensemble function in olfaction using multi-electrode array and paired single-unit recording in anesthetized and awake rats. Aim 1 will test the hypothesis that cell ensemble membership size and the probability of correlated activity in paired single-units will be greater in the posterior PCX (pPCX) than in aPCX due to the more extensive intrinsic excitatory association fiber system in pPCX. Aim 2 will test the hypothesis that manipulations of the neuromodulators ACh and NE to PCX, which selectively affect intrinsic fiber synaptic efficacy, will modulate ensemble membership size, odorant specificity and probability of correlated activity in paired single-units. Finally, Aim 3 will test the hypothesis that behavioral state will modulate ensemble size, odorant specificity and probability of correlated activity in cell pairs, potentially via a cholinergic or noradrenergic mechanism. Together, these aims will begin to explore how cortical ensembles merge the myriad odorant features encoded by peripheral circuits into odorant objects, and how attention and arousal may modulate odor discrimination. PUBLIC HEALTH RELEVANCE Cortical processing of information plays a critical role in sensory perception, memory, movement and cognition. Thus, understanding how circuits within the cortex process information is important for understanding and treating disorders of information processing. This proposal takes advantage of a relatively simple cortical circuit (the piriform cortex) performing relatively complex information processing tasks (odor object discrimination) to explore how groups of neurons work together as an ensemble to interpret sensory input.

DESCRIPTION (provided by applicant): This grant proposes the development and testing of a highly advanced neural interface system that incorporates the best features of modern neural interfaces into a single system. The Micro Neural Interface (MNI) system is comprised of up to 100 independent, wireless, biological sensors with on-board signal conditioning and spike detection. Each probe communicates with and is powered via a 2.4 GHz wireless RF transceiver. Individual probes can be implanted within cortical and subcortical structures. The MNI system has two operating modes: time stamp and streaming. In time stamp mode, each MNI probe is queried sequentially such that data from all probes is collected every 1000 5s. Each probe is independently programmed with two threshold settings to provide basic spike discrimination. In the streaming mode, a single probe transmits neural data that is digitized with 8 bits of resolution at 10 KHz to a basestation. This mode allows the user to examine the spike waveforms and perform manual spike sorting on an external PC, but it can address only a single probe at a time. Threshold crossings are also transmitted during the streaming mode to allow functional verification. Two specific aims are proposed for this research SA1) Development of wireless Micro-Neural Interface (MNI) probes and basestation. SA2) In-vivo testing of the MNI system in rodents. PUBLIC HEALTH RELEVANCE: Narrative The significance of this work to human health is that it will result in a highly novel neural interface design. First, the MNI system will provide researchers and potentially clinicians with unparalleled access to neural activity across cortical and subcortical structures. This access will allow scientist to understand distributed neural processing and provide a tool for more in-depth understanding of neurological disorders. Second, the MNI system may be used as a Brain Machine Interface.

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.

ABSTRACT Stroke is highly prevalent, debilitating, and lacks consistently effective post-injury interventions. We have developed an innovative technique using vagus nerve stimulation (VNS) delivered during rehabilitation to engage plasticity-enhancing neuromodulatory circuits and improve recovery of motor and sensory function after stroke. Our preclinical findings demonstrate that VNS paired with rehabilitative training enhances recovery in multiple models of neurological injury, including ischemic stroke, intracerebral hemorrhage, traumatic brain injury, and spinal cord injury. Moreover, our two recent clinical studies in chronic stroke patients indicate that VNS is safe and yields a significant three-fold increase in recovery of upper limb function compared to rehabilitation without VNS. While the scientific and clinical evidence is encouraging, the VNS device used to perform these studies is substantially limited by an inflexible stimulation paradigm, lead fragility, limited battery life, large size, and high cost. These technical limitations preclude effective translation of this potentially transformative therapy. We have developed a novel low-cost, clinical-grade VNS system that obviates these deficiencies. The system consists of a miniature wireless, lead-less, passive implantable stimulator that is placed on the vagus nerve and an external power and communications module that controls the implantable stimulator. The implantable device is manufactured at the wafer level using an automated process with materials that are FDA-approved for human use and MRI-compatible, thus providing reliability and lowering cost 25-fold compared to commercially-available devices. The implantable stimulator is hermetically encapsulated in biocompatible glass and is 50 times smaller than existing VNS devices, reducing the invasiveness of the implant surgery. Moreover, the implanted device is passive and harvests power from the external module, eliminating the need for a bulky implanted battery and surgical revision for battery replacement. Much of the required testing is complete, but final verification and validation is necessary to allow IDE submission and clinical evaluation. In this proposal, we outline a series of critical steps to translate this robust, cost-effective device to provide tangible improvements in the lives of stroke patients. In the UG3 phase, we will finalize verification and validation of the embedded software and create a design history file. Additionally, we will confirm biocompatibility in a chronic large animal study and finalize package sterility testing. Once complete, we will gain approval for an IDE. In the UH3 phase, we will perform a double-blind, randomized, placebo-controlled crossover study to evaluate the VNS therapy system in chronic stroke patients. Successful completion of this project will move this device from the verge of translation into human trials with a direct focus on a subsequent pivotal trial.