Repairing spinal injuries is an important yet elusive goal of modern medicine. Our group has recently demonstrated that intraspinal stimulation may lead to some level of plasticity and recovery after incomplete spinal cord injury. One challenge in complete regeneration of the brain and spinal cord is that the presence of peri-neuronal nets limits plasticity at synapses in the adult central nervous system. Chondroitinase ABC (ChABC) is an enzyme known to dissolve chondroitin sulphate proteoglycans in these plasticity-inhibiting peri-neuronal nets. When delivered near a spinal cord injury, ChABC can lead to significant levels of recovery. Our goal is to determine whether the combination of intraspinal stimulation and ChABC augments recovery after incomplete spinal cord injury. Our experimental paradigm involves training rats in a forelimb reaching task before performing incomplete contusion injuries at the C4 vertebral level. Spinal stimulating wires are then implanted below the injury, and animals are randomly assigned to one of two groups that receive ChABC or ChABC + spinal stimulation. Animals are then given daily spinal stimulation treatments and are tested at the forelimb reaching task for several months to assess their level of recovery. We expect to see rats that receiving the ChABC treatment succeed at the reaching task with greater frequency than those that only receive spinal stimulation. In addition, these ChABC-treated rats should, over time, regain a greater degree of skilled motor-function than their stimulation-only counterparts. In related experiments, spinal stimulation triggered from brain activity may be an even more powerful and specific cue for plasticity. Additional experiments may test the combined effects of ChABC with brain-triggered stimulation, even in the uninjured adult spinal cord. If this is indeed the case, our work could lead to an effective combination therapy for repairing human spinal injuries.

There are currently very few effective treatments to repair damage resulting from spinal cord injury (SCI). The project I have been working on in the Moritz Lab involves the exploration of Intraspinal Microstimulation (ISMS) and its ability to promote functional recovery after SCI in a rodent animal model. Our group employs a unilateral incomplete spinal cord contusion injury using the Ohio State University contusion device at the level of the fourth lamina in the cervical spine, or C4. We then place stimulating wires in the spinal cord, specifically in the ventral gray matter caudal to the injury at C6-C8, in order to deliver ISMS to the motor pools innervating the triceps and other forelimb muscles. My independent project in the lab is a histological analysis of triceps and forelimb muscles taken from the SCI models to determine whether the use of ISMS preferentially recruits fatigue resistant (FR) muscle fibers in the affected forelimb of these rats. After paresis resulting from SCI, muscles atrophy and undergo a "slow-to-fast" transition in the myosin heavy chain (MHC) isoform content. My goal is to examine whether ISMS can slow or even reverse this slow-to-fast conversion after SCI. I am using immunohistochemistry to differentiate muscle fiber types in the triceps muscle. I stain for the unique MHC isoform that is expressed by the various slow and fast type fibers. My hypothesis is that there will be a higher population of type I and type IIA FR fibers in the stimulated muscles of ISMS group than in the control group, which will mostly consist of fast fatigable types IIB and type IID. The long-term goal of my project is to determine the benefits of using ISMS as a neural prosthesis and regenerative therapy for individuals who have suffered from spinal cord contusion injuries.

In primates, ventral striatum contains many reinforcement sites. These sites, when stimulated with electrical current, mimic behavioral reinforcement. Monkeys trained to perform behavioral tasks will often work solely for stimulation at these sites without food reward. Using these sites, we can further understand the plasticity of the brain by altering neural activity through conditioned changes in connectivity. We implanted moveable stimulating electrodes near the nucleus accumbens. Reinforcement sites are identified by whether stimulation elicits reinforcement behavior. This is done by the use of alternating reinforced and non-reinforced trials (R/NR) while the monkey performs a simple manual force step-tracking program by controlling a cursor’s movement on a computer screen with forces generated with their wrist. Their objective is to move the cursor into different boxes representing different wrist forces. During each R period, the monkey receives electrical stimulation at the potential reinforcement site for every completed trial. During NR periods, however, the monkey has the opportunity to work but no stimulation is given for completed trials. If the number of completed trials is significantly higher during R periods than NR periods, a reinforcement site has been found. We next condition single neuron firing rates using this reinforcing stimulation. Chronically implanted micro-wires record discriminated neuron activity from primary motor cortex. We determine the cell’s baseline firing rate and trigger stimulation of the reinforcement site on action potentials that exceed this rate-threshold. Our objective is to train the monkey to increase the cell’s activity for reinforcing stimulation in set time periods. This experiment enables us to condition volitional control of brain activity to manipulate neural prosthetics and restore motor function in paralyzed patients. Since this conditioning can also be done with an autonomous brain-computer interface, this paradigm can be extended to freely behaving monkeys and has the potential to be applied to humans.

Thanks to advances in safety equipment and emergency care, most spinal cord injuries that occur in people today are incomplete, leaving a portion of the spinal cord neural tissue intact. Further, recent research has shown that there is plasticity and axonal sprouting following injury, expanding the possibilities for rehabilitation from what was once considered a permanent and unrecoverable injury. Our goal is to enhance this process and work towards functional recovery. Dopamine, a powerful neurotransmitter involved in processes such as learning, memory and motivation, plays an integral role in brain plasticity. We are currently testing whether pairing dopamine release with functional movements can increase plasticity of the remaining active pathways and lead to increased functional recovery following an injury in the same way that it can form powerful associations between behaviors and reward sensations. Recently concluded tests followed the recoveries of two rats which received dopamine-releasing electrical brain stimulation paired with functional movements of an impaired limb following identical unilateral cervical spinal cord injuries. These rats activated the stimulation by using their impaired forelimb to push a lever which activated their medial forebrain bundle, a key pathway in the mesocorticolimbic dopamine system. One of these animals showed a significant recovery, nearly to full pre-injury movement capability, and much greater than control animals that received no dopamine stimulation (results in the second animal were inconclusive). Ongoing experiments will compare animals receiving dopamine-releasing stimulation paired with movement of the injured limb to control animals where phasic dopamine release is uncorrelated with movement. These experiments may lead directly to novel methods for promoting nervous system recovery from injury by using dopaminergic pathways to promote and reinforce neural plasticity. This may lead to therapies which allow people with incomplete spinal cord injuries to improve functional motor skills.

Stroke is the leading cause of adult disability in the United States. Motor impairments often remain even after extensive physical therapy. To improve rehabilitation outcomes in severely affected individuals, we hypothesize that electrical stimulation could rewire the brain such that non-lesioned brain areas take over the function of lesioned areas. Mechanisms that modify connections in the brain rely on temporal associations on the order of tens of milliseconds. For targeted rewiring, we propose stimulation of the non-lesioned areas be triggered from activation of muscles weakened by stroke. This will provide a tight temporal association between muscle activity and brain activation and should boost the neural drive to the affected muscles. As an initial test of the proposed stimulation therapy, we trained neurologically-intact pigtailed macaques to make bimanual hand movements in response to visual cues. The macaques were implanted with electrodes at the surface of the brain that stimulated and recorded neural activity. Electrodes were located over left and right motor areas and over areas with less direct involvement in hand movements. Experimental sessions began with baseline neural activity recordings while the animal performed bimanual hand movements in the absence of stimulation. Next, movement-triggered stimulation was applied for 2-6 hours. Across sessions, a number of parameters were explored in this phase including the stimulus timing relative to movement, the stimulus intensity, and whether a motor or non-motor electrode was being stimulated. Each session ended with another recording in the absence of stimulation. The stimulation effect was quantified by changes in neural activity and behavior (i.e. reaction time between visual cue and movement onset) between pre-stimulus and post-stimulus recordings in each session. Significant stimulus-induced changes in reaction time were found to be a function of both stimulus timing and stimulus location. The results indicate that movement-triggered stimulation can powerfully modulate motor output.

The spinal cord represents a key site of convergence for sensory feedback and cortical commands, but determining how each contributes to movement has not been uncovered.  Understanding how spinal circuits are structured and utilized to generate complex movements will be necessary to understand how the nervous system processes multiple inputs.  One approach to understanding motor circuits is to know how the output effects of neurons change between tasks.  Here we investigate the state of the spinal cord by stimulating at specific sites in the cord and recording electromyographic activity (EMG) in the forelimb muscles of a non-human primate.  By comparing the output effects of stimulation between two behaviors, a flexion/extension wrist task and a reaching task, we hope to understand the effects of cortical and sensory interactions in shaping motor output.  In addition, by creating a spinal map of stimulus triggered EMG activity, we hope to reveal the functional organization of spinal outputs during the behaviors.  In this experiment, we compare the effects of stimulus triggered averages of EMG between these two tasks at various sties in the cord.  Our results show a change in the effects on EMG activity dependent on the behavior performed in roughly 2/3 of sites.  Indicating that the configuration of the circuit that our electrode stimulates is dependent on the task performed.  When the non-human primate performs a wrist task, cortical input and sensory feedback recruit specific spinal pathways to activity certain muscles in order to perform the task.  When the task is altered, different cortical inputs and sensory feedback may inhibit or further excite that circuit, changing EMG activity.  Understanding the circuits responsible for the control of arm movements and how these circuits change with varying tasks, may allow us to utilize and exploit these spinal circuits to treat patients with spinal cord injury.