Neurophysiological mechanisms underlying rTMS treatment of addiction

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Neuromodulatory treatments, such as repetitive transcranial magnetic stimulation (rTMS) applied to dorsolateral prefrontal cortex (DLPFC), have shown efficacy in reducing cocaine craving. This grant seeks to understand the neurophysiological mechanisms underlying rTMS efficacy in reducing cocaine induced behaviors at a circuit level, and, more broadly, the effects of rTMS on single cell physiology. Two rhesus monkeys will perform a decision-making task in which they choose between iv cocaine and a natural reward. Parametric manipulations of reward amounts or probability will enable quantification of how monkeys value cocaine in relation to natural rewards. As the monkey develops a preference for cocaine, we will record simultaneously in DLPFC and two brain areas known to represent the values of rewards during economic decision-making, the orbitofrontal cortex (OFC) and amygdala. We will test the hypothesis that neuronal activity recorded in DLPFC, OFC and amygdala is correlated with how monkeys value cocaine. As monkeys escalate cocaine self-administration, reflecting an increase in how cocaine is valued, we hypothesize that OFC and amygdala will update neural representations of the value of cocaine (Aim 1). Monkeys will then enter a cross-over rTMS vs. sham trial design. They will receive either rTMS at 15Hz, 100% RMT (resting motor threshold) or sham, every other day for 20 sessions in left DLPFC (area 9/46d). The days without rTMS, monkeys will undergo a recording session with the same choice paradigm. We hypothesize that rTMS will cause a decline in preference for cocaine, a parallel shift in the encoding of relative value in OFC and amygdala, and restoration of baseline activity in DLPFC for monkeys undergoing rTMS vs. sham monkeys (Aim 2). Recordings will continue for 3 months after the last treatment to assess the duration of rTMS induced electrophysiological changes. Different frequencies and different networks will be tested if needed. This grant will be the first to characterize directly neuronal responses in relation to rTMS hours and days after applications. This will advance rTMS treatment of substance abuse by elucidating the circuits and mechanisms responsible for conferring clinical benefits, which in turn may provide key insights for developing and targeting improved therapeutics in the future.