In addition to the well-known cognitive deficits that result from traumatic brain injury (TBI) motor weakness is also a significant, yet understudied problem that occurs in over half of injured individuals. Beyond acute interventions, there are currently no generally accepted medical treatments for promoting functional recovery after TBI. Although brain regions may spontaneously reorganize to restore some lost function after injury, it is not clear which components of this plasticity may serve as a prognostic biomarker of good recovery, and which result from behavioral compensatory mechanisms that are not beneficial to outcome. Motor cortex excitability is impaired after concussion in athletes and can persist to nearly 30 years since the last concussion. This dysfunction is associated with compromised synaptic plasticity and reductions in motor learning skills, as well as reduced inhibition from the opposite cortex. In fact, neuroimaging studies after TBI have documented post-injury somatosensory cortical map changes where stimulation of the affected limb leads to activation within the intact, contra- lesional hemisphere, rather than the normal activation of cortex opposite to the limb. It is still unknown however, whether contra-lesional activation is performing a temporary, beneficial role, or whether it is interfering with recovery of ipsi-lesional plasticit. We show preliminary data using a unilateral concussive rat model of TBI that indicates an ipsi- to-contra-lesional shift of the affected forelimb cortical map occurs during alterations in trans- hemispheric excitability. We also show that early, but not delayed, temporary silencing of the contra-lesional cortex promotes recovery of affected forelimb function and recovery of the ipsi-lesional cortical map, suggesting that contra-lesional cortex prevents map reorganization and recovery of limb function. Based upon these data, the central hypothesis of the proposed research is that: unilateral TBI induces hyper-excitability in the contra-lesional cortex and alter the hemispheric balance of excitation-inhibition, such that the intact cortex remotely confers an increased inhibitory drive upon the injured cortex, preventing ipsi-lesional cortical map reorganization and the recovery of forelimb function. We propose proof-of-concept experiments to test this hypothesis using pharmacologic and rehabilitative interventions, as well as a clinically-relevant aim designed to test whether the combination of a properly timed, pharmacological intervention to promote a period of greater cortical map plasticity together with rehabilitation, will result in a persistent recovery of the affected forelimb deficits. We will use quantitative evoked and resting state functional magnetic resonance imaging and forelimb reaching tasks, together with paired-pulse sensory-evoked potential electrophysiology as readouts to determine the effect of intervention. Alterations in the excitatory-inhibitory balance have also previously been shown in the hippocampal-prelimbic circuit so that the proof-of-concept approaches that we take in this proposal to learn how to reestablish a more normal excitatory-inhibitory balance are likely to be generalizable to cognitive circuit dysfunction that are also a major hall mark of TBI.
Beyond acute interventions, there are currently no generally accepted medical treatments for promoting functional recovery after traumatic brain injury (TBI). Symptoms that persist after TBI are largely a result of lost connections within the brain. These results in an imbalance of neuronal function across the brain and this can impede the reorganization of neuronal networks to new brain regions, preventing further functional recovery. We believe that pharmacologically readjusting the balance of excitation and inhibition within the brain will result in enhancements in brain function, so that when combined with existing rehabilitative paradigms, improved behavioral outcome will occur.
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