Mapping a Causal Prefrontal Pathway for Amygdala Modulation Utilizing Invasive and Noninvasive Brain Stimulation and Recording Methods in Humans

PROJECT SUMMARY While the amygdala is a key focus in psychiatric treatments and invasive modulation of amygdala activity has shown promise in treating certain refractory cases, its widespread use among millions of treatment-resistant patients is impractical and entails inherent neurosurgery-related risks. The development of transcranial magnetic stimulation (TMS) provides a potential noninvasive alternative. However, the effective modulation of the amygdala with TMS is hindered by the lack of knowledge in pinpointing a TMS-accessible cortical site that can reliably target and modulate the amygdala. The dorsolateral prefrontal cortex (DLPFC) emerges as a promising candidate for stimulation based on findings from extensive preliminary data, published work, and large human connectome datasets. The overall objective in this proposal to determine whether and how DLPFC repetitive stimulation modulates the amygdala activity with an unparalleled combination of invasive and noninvasive stimulation and recording methods in humans. The central hypothesis is that both invasive and noninvasive stimulation of DLPFC modulate the amygdala activity through their functional connectivity mechanism. This central hypothesis will be tested by pursuing three specific aims: determine invasive modulatory effects of intracranial stimulation of DLPFC on the amygdala recorded with intracranial EEG (iEEG) in epilepsy patients (Aim 1), translate stimulation with noninvasive TMS of DLPFC while tracking modulatory effects on the amygdala with iEEG in epilepsy patients (Aim 2a) and with functional MRI in healthy individuals (Aim 2b), and evaluate the role of DLPFC-amygdala functional connectivity in predicting modulatory effects of DLPFC stimulation on the amygdala (Aim 3). The proposed research is innovative, because it can determine a unique causal prefrontal pathway for noninvasive amygdala modulation in humans. It also represents the first attempt of any group worldwide to creatively combine multimodal cutting- edge brain stimulation and recordings to comprehensively evaluate modulatory effects of DLPFC stimulation on the human amygdala. The proposed research is significant because it is expected to provide compelling and conclusive causal evidence of amygdala modulation by DLPFC stimulation and inform a novel circuit- based strategy that can efficiently pinpoint a stimulation site within the DLPFC for noninvasive amygdala modulation. Ultimately, such knowledge will facilitate the rational design of personalized, circuit-guided noninvasive neuromodulatory therapies aimed at modulating the amygdala for psychiatric disorders.