Jon T. Willie - US grants

Abstract The purpose of the current proposal is to examine the real-time function of the emotional (affective) system in neurosurgery patients who undergo the placement of depth electrodes for clinical purposes. Specifically, we plan to study patients with electrodes in the amygdala and the anterior cingulate for routine seizure focus monitoring in medically refractory epilepsy. These structures have critical roles in emotional function, and the presence of depth electrodes allows us to record local neuronal activity as well as apply small electrical currents to stimulate for research purposes. The proposed research examines the hypothesis that behavioral correlates of emotional processing may predict adverse neuropsychiatric outcomes to epilepsy surgery. This predictive ability would be potentially transformative, given that as many as 37% of patients receiving surgical treatment for severe epilepsy experience a worsening of existing depressive symptoms or the development of de novo major depressive disorder following surgery. Similarly negative outcomes for language were commonplace before the development of stimulation-based language mapping protocols, which have used brain stimulation outside the operating room to identify language-critical structures in individual epilepsy patients, prompting the development of individualized surgical plans to avoid these important regions. The current proposal seeks to take the first step toward the development of a potential companion protocol to map the emotional circuitry in individual surgical patients, in an attempt to similarly reduce rates of postoperative depression. The Specific Aims of this proposal include: 1) To test the hypothesis that amygdala and cingulate stimulation induce transient affective bias by comparing bias induced by amygdala, cingulate, sham, and extra-limbic stimulation on a within-subjects basis. 2) To test the hypothesis that stimulation-induced affective bias is able to predict neuropsychiatric outcomes of medial temporal lobe resection surgery, by relating the findings of Aims 1 with changes in depression scale scores at the 6-month postoperative visit.

PROJECT SUMMARY/ABSTRACT Direct electrical stimulation (DES) of the basolateral complex of the amygdala (BLA) can improve declarative memory, reflecting the role of the BLA in modulating memory processes in medial temporal lobe (MTL) regions as a function of emotional arousal. Thus, DES can reveal mechanisms of BLA-mediated memory enhancement relevant to human mental health and disease. DES of the BLA can be used to interrogate the function of memory circuits, especially how neuronal oscillations in the MTL support declarative memory. First, BLA is hypothesized to wield the capacity to prioritize long-term retention of information initially encountered adjacent in time. Second, the BLA preferentially projects to anterior MTL regions and thus is hypothesized to preferentially modulate memory processes in those anatomic regions, processes thought to support memory for non-spatial items more so than memory for spatial locations. Third, although emotional arousal, amygdala activity, MTL activity, and memory performance are typically correlated, we hypothesize that DES will reveal that BLA outputs to other MTL regions cause improved memory performance by directly eliciting pro-memory oscillatory states in those networks. The expected outcomes represent a significant advancement for the basic science of normal memory function and significant movement towards novel therapeutics designed to emulate endogenous mechanisms of memory enhancement.