Deep Brain Stimulation of the Cerebellar Dentate Nucleus to Enhance Chronic, Post-Traumatic Brain Injury Rehabilitation

ABSTRACT
The overall goal of this research is to develop and translate effective neurostimulation-based therapies to
facilitate neurologic recovery for patients with chronic, persistent deficits secondary to acquired brain injury.
Despite progress in acute intervention strategies, traumatic brain injury (TBI) remains a leading cause of long-
term disability in the United States and there is an on-going need for novel approaches to facilitate recovery and
rehabilitation for survivors. Our group has shown previously that deep brain stimulation (DBS) of the lateral
cerebellar nucleus (LCN), the origin of the ascending dentatothalamocortical (DTC) pathway with widespread
influence (via thalamus) across frontal and parietal cortical regions as well as to the basal ganglia, enhances
motor rehabilitation in a chronic rodent model of middle cerebral artery ischemia. Therapeutic gains were
associated with changes in perilesional cerebral cortical excitability, enhanced cerebral cortical reorganization,
and evidence of increased synaptogenesis in perilesional cortex. Here, we will evaluate whether therapeutic
benefit can be similarly realized for persistent motor and cognitive deficits following TBI, using a controlled
cortical impact (CCI) model in rodents. Moreover, we will further characterize the LCN DBS-induced physiological
and cellular changes that occur across perilesional cortical regions. In addition to the supporting evidence
afforded by our prior work in rodent models of middle cerebral artery ischemia and our early results from human
translation of that work, we provide preliminary evidence of behavioral efficacy and underlying physiological
mechanisms in two treatment models: rats with induced motor deficits following fluid percussion injury (FPI) TBI
over sensorimotor cortex as well as animals that showed cognitive deficits following bi-frontal CCI targeting
medial prefrontal cortical regions. In the current proposal, our specific aims are 1) to confirm and extend our
preliminary findings regarding LCN DBS' effects on post-TBI motor recovery, 2) to evaluate the potential LCN
DBS to improve post-TBI cognitive function, 3) to characterize the nature of LCN DBS-mediated perilesional and
DTC pathway reorganization post-CCI injury; and 4) to examine the cellular and molecular changes in
perilesional cortical regions associated with LCN DBS. This study will provide preclinical evidence and support
for future translational efforts of this novel therapeutic approach to enhancing chronic, post-TBI deficits.

Grant Number: 5R01NS116384-05
NIH Institute/Center: NIH
Principal Investigator: KENNETH BAKER