Optical voltage imaging analysis of the cellular and network mechanisms of deep brain stimulation Deep brain stimulation (DBS) directly stimulates brain tissue via implanted electrodes. DBS has emerged as a well-established therapy, FDA approved for several neurological and psychiatric disorders, and is increasingly explored for a variety of brain diseases. However, the neurophysiological mechanisms of DBS remain largely unknown. DBS therapeutic outcomes and time courses are diverse and depend on the specific disease conditions targeted. Since DBS effect for movement disorders is consistent with pharmacological lesion or surgical removal of the target brain tissue, DBS was first thought to inhibit local neural activity, likely via membrane depolarization induced action potential blockade or glia mediated adenosine release. However, electrode recordings and biophysical modeling studies suggest that electrical pulses can directly excite axons leading to antidromic activation of neurons projecting to the stimulated area or orthodromic activation of downstream postsynaptic neurons. An alternative theory is that DBS entrains or paces neural activity which interferes with individual neuron’s responding to synaptic inputs and thereby creates information lesion that disrupts pathological network patterns. While these theories are attractive, direct experimental testing of the neurophysiological effects of DBS in the brain has been challenging due to electrical interference on electrode-based recordings. Recently, we pioneered the development of a high-performance genetically encoded voltage indicator SomArchon, which allows optical fluorescence imaging of membrane voltage from individual neurons in awake mammals during behavior. In this study, we will measure the real-time neuronal effect of DBS by performing optical membrane voltage imaging using SomArchon, free of electrical stimulation artifact. We will systematically probe the cellular and network mechanisms of DBS in STN, GPi and VIM, the three FDA approved targets for Parkinson’s disease. Our central hypothesis is that DBS creates information lesion both at the stimulation sites and in the connected circuits, leading to potent disruption of pathological network activities, which underlies the therapeutic mechanisms of DBS.

Deep brain stimulation (DBS) has been FDA approved for managing several brain disorders, including Parkinson’s disease (PD), and has been increasingly explored for many other neurological and psychiatric diseases. However, the therapeutic mechanisms of DBS remain largely unknown. This study aims to examine the cellular and network mechanisms of DBS using simultaneous single cell voltage imaging and optogenetics techniques.