Peripheral nerve injury is a frequent source of disability and a particular challenge for rehabilitation in the Veteran population. Although techniques for surgical repair have progressed, outcomes remain unpredictable. In the past, connections of the periphery to the brain had been thought to be fixed in adults, but there is a growing recognition of plasticity in brain function associated with removal of peripheral sensory input. For instance, it is known that sensory cortex associated with denervated body regions become reassigned, and disordered cortical function persists after repair of a surgical lesion. However, successful use of the limbs requires not just brain connections to peripheral targets, but also the coordinated participation o numerous activities within the brain, including interaction with other sensory sites as well as motor, visual, and cognitive areas. We therefore hypothesize that disruption of interactive brain activity underlies rehabilitation challenges after nerve injury repair. New noninvasive technology now exists to assess the integrated performance of the brain. Specifically, functional magnetic resonance imaging (fMRI) can indicate coordinated activation of various brain loci, while resting state functional connectivity MRI (rs-fMRI) reveals patterns of communication between brain sites in the absence of stimuli. Our preliminary data show substantial disruption of coordinated brain function following experimental nerve injury and repair. We have the long-term goals of defining this phenomenon in temporal and anatomic detail, which would lay the groundwork for developing an imaging biomarker that could guide personalized rehabilitation that targets appropriate specific functions. We have the additional goal of testing whether artificially maintaining afferent sensory neuron activity to the brain during the healing phase after repair may lessen or prevent brain disorganization. In the work proposed in this SPiRE application, we will obtain initial observations to substantiate our hypotheses by defining brain responses to nerve injury/repair with and without supplying replacement afferent activity, in a limited number of animals in a longitudinal fashion, using our novel techniques. Further, we will develop the means to achieve neuronal stimulation for treatment of untethered animals using implantable optogenetic light sources that activate photosensitive channels expressed in sensory neurons after viral gene delivery. We believe that extending the rehabilitation perspective beyond the nerve repair to include brain function may open the door to a new level of refined rehabilitation assessment, planning, and success.
Recovering from nerve injury is a critical rehabilitation challenge that many Veterans face. Although skillful nerve repair surgery is an important first step, there continue to be bad outcomes with incomplete recovery of use of the limb. When nerve input to the brain is lost, there are fundamental changes in how the brain works, including disordered communication between different parts of the brain. We believe that these changes persist after nerve injury even when the nerve repair is successful. We will examine brain function using advanced imaging techniques (functional magnetic resonance imaging - fMRI) in rats after experimental nerve injury, to learn about loss of brain activity coordination. In the clinical setting, this coud provide a marker that, by looking at the whole brain and its integrated operation, could guide personalized rehabilitation planning and possibly improve recovery. We will additionally test whether substituting artificial nerve activity during the healing phase maintains coordinated brain activity, which could also be adapted for treating patients.
