Twenty million Americans suffer from peripheral nerve injury that leads to significant changes in cortical and subcortical neuronal activity. Evidence from human imaging studies suggests that the degree of post- injury plasticity and cortical remapping may be maladaptive and positively correlated to the levels of sensory dysfunctions and phantom limb pain. In an animal model of peripheral nerve injury we demonstrated that post-injury increases in functional magnetic resonance imaging (fMRI) responses reflect in fact, increases in inhibitory interneurons activity. Thus, we hypothesize that post-injury increase in inhibitory interneurons activity delays neurorehabilitation. However, the majority of current neurorehabilitation strategies focus on surgical nerve repair which neglect to address the dramatic changes occurring in the brain level. Indeed, studies show that patients continue to suffer from sensory dysfunctions despite nerve repair surgeries. We have recently demonstrated that limb injury in adult rats induces short- and long-term plasticity changes that affect S1 activity; an effect that can be readily mapped with non-invasive, ultra-high field, and high-resolution fMRI. The plasticity was manifested in changes in the excitability of cortical laye 5 inhibitory interneurons in the affected primary somatosensory cortex (S1), and was mediated via the transcallosal projections. We used optogenetics methods to modulate cortical activity in the injured rats and successfully restored the balance between excitation and inhibition. Therefore, post-injury neuronal changes leading to a shift in the excitation-inhibition balance have the potential to be reshaped with neuromodulation strategies. The goal of this proposal is to develop state-of-the-art neuromodulation strategies to augment recovery including transcranial magnetic stimulation (TMS) and a novel, minimally-invasive, neuronal-specific technology. Utilizing multimodal technical approaches we will determine how injury affects plasticity mechanisms in the molecular, cellular, network and behavioral levels, and whether the neuromodulation strategies employed here can minimize sensory dysfunctions associated with injury and facilitate rehabilitation. We anticipate that these strategies could be translated into he clinical setting as alternatives or adjuvants to traditional surgical nerve repairs, and also be usd to modulate neuronal function in other neurological disorders.

Public Health Relevance

Twenty million Americans suffer from peripheral nerve injury due to war, car accidents, and autoimmune and metabolic disorders, such as diabetes. Despite advances in surgical nerve repair methods, patients often suffer from sensory dysfunction and chronic pain. Evidence from human and animals studies suggests that injury induces changes occurring not only in the peripheral nerves but also in the brain, and that the latter may influenc recovery and neurorehabilitation. The goal of this proposal is to determine how injury affects molecular, cellular and network activity in the rodent brain. We also aim to develop state-of-the-art neuromodulation strategies to augment recovery based on transcranial magnetic stimulation and a novel, minimally- invasive, neuronal-specific technology.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Acute Neural Injury and Epilepsy Study Section (ANIE)
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Jakeman, Lyn B
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Hugo W. Moser Research Institute Kennedy Krieger
United States
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