Driving Functional Behavioral Recovery Using Activity-Dependent Stimulation

Abstract

The purpose of this project was to determine if artificially linking spared motor and sensory areas following a cortical lesion would lead to increased behavioral recovery on a skilled reaching task. Sensory-motor integration is critical for skilled movements; disruption of the sensory motor loop due often occurs following primary motor cortical injury and can have a profound negative impact on these skilled behaviors. By reconnecting spared sensory and motor areas after an injury, we hoped to enhance functional recovery. In order to realize this purpose, a novel microdevice had to be developed that would act as bridge to allow the spared pre-motor cortex to communicate with primary somatosensory cortex. Thus this dissertation project had two main goals. 1) Design, build and test an implantable microdevice for activity-dependent stimulation. 2) Test the ability of the device to promote recovery after motor cortical injury. During the course of development, we performed optimization studies of different stimulating electrodes for motor cortical mapping areal measurements, threshold response, and response consistency. The results of this study allowed us to use a single shank multichannel electrode for interfacing with the microdevice. The device development occurred in several discrete steps. The first involved testing functionality of the microchip circuitry for spike detection and stimulation in acute preparations. From these successful trials, we tested, designed, and optimized a substrate for device implantation. The final stage in the device development was to merge the microchip with the device substrate to form an implantable microdevice for the future studies. The resulting testing in ambulatory animals further refined the experimental design. At this stage we had a working, novel device that could deliver activity-dependent stimulation between discrete cortical areas. With device in hand, we were able to test how rodents responded to reconnecting the spared pre-motor and sensory cortices following a traumatic brain injury to primary motor cortex. We found that by delivering activity-dependent stimulation, it was possible to drive significant recovery on a skilled reaching task eight days following the injury, and that continuing the stimulation allowed the animals to fully recover to their baseline skill level. Without this treatment, lesion-control animals had profound deficits that persisted throughout the testing period. We also observed qualitatively different types of reaches between the animals receiving stimulation and those without. A kinematic analysis of the reaching behavior indicated that with activity dependent stimulation, the animals had a slower, more directed approach to the skilled reaching task. This change in reaching behavior represented a successful compensatory mechanism for performing the task that the control animals lacked. The results from this study indicate that activity-dependent stimulation is an effective treatment for behavioral recovery following an M1 lesion in the rodent. The implications of these results have the potential to lead to a novel treatment for a variety of neurological disease and disorders.