Multi-site DBS with precise timing control focusing on synaptic plasticity

PROJECT SUMMARY Deep Brain Stimulation (DBS) is a prevalent therapy approved by the U.S. Food and Drug Administration that uses electrical stimulation of brain nuclei to treat the symptoms associated with movement disorders. However, a lack of immediate feedback to determine its efficacy for treating other disorders has led to suboptimal therapeutic effects. Thus, re-imagining DBS may lead to more effective therapies that treat the root cause of the disorder, and not just address its symptoms. These therapies may require exploring innovative approaches that leverage our understanding of neural plasticity mechanisms. Spike-timing dependent plasticity (STDP) is a well characterized phenomenon that can induce neuroplasticity via phase-locked activation of pre- and post-synaptic neural elements. Here, we propose a novel approach that combines STDP and DBS (STDP-DBS) and is capable of selectively changing maladaptive plasticity associated with pathologic neural activity and behavior observed across multiple neurologic and psychiatric disorders, including alcohol addiction. In this proposal, STDP-DBS applied with precise timing at two regions of the brain such as the Globus Pallidus internus (GPi) and the Anterior Cingulate Cortex (ACC) will enable selective bidirectional gain control of cortico- striato-pallidal signaling. In turn, this will allow control of maladaptive neural signaling that contributes to the pathology of neurologic disease while avoiding off-target disruption of non-pathological brain activity, in turn minimizing potential side effects of conventional DBS. The work proposed here represents the first steps toward correcting maladaptive plasticity associated with neurologic and psychiatric disorders. In turn, this may enable a new avenue for treatment of a wide range of disorders such as addiction, Tourette’s syndrome, obsessive compulsive disorder, schizophrenia, Parkinson’s disease, major depressive disorder, and many others.