Using fMRI of Autobiographical Memory Recall to Determine Risk and Resilience Endophenotypes in Familial Major Depressive Disorder

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Abstract Major depressive disorder (MDD) is a highly disabling condition affecting 60 million Americans. Patients with MDD experience difficulty recalling autobiographical memories (AMs), and this cognitive deficit is related to poor psychosocial functioning. Patients with MDD exhibit blunted amygdala hemodynamic activity during positive AM recall and enhanced activity during negative AM recall relative to healthy individuals, and training to directly increase the amygdala response during positive AM recall improves depressive symptoms, implicating the amygdala hemodynamic response during positive AM recall as a causal mechanism underlying recovery from MDD. Furthermore, in cross-sectional studies looking at individuals at high-risk for developing MDD based on personal or family history, amygdala activity during positive AM recall is significantly associated with the presence of depressive symptoms. We aim to examine whether this correctable mechanism also convers vulnerability or resilience to developing MDD in a longitudinal design following young adults at high- risk for developing MDD. Healthy individuals with a first-degree family relative diagnosed with MDD (n=150) and healthy controls (n=50) will perform an autobiographical memory task while undergoing functional magnetic resonance imaging (fMRI). Participants will then be followed for two years to determine whether criteria for MDD are met. Our goal is to determine whether amygdala activity (Aim 1) and its interaction with activity in other regions implicated in self-referential processing (including the precuneus Aim 2) during positive AM recall is associated with risk or resilience in a sample of participants at high-risk for receiving an MDD diagnosis. Furthermore, as MDD is more prevalent in females than males, and as the relationship between AM recall deficits and depressive symptoms is only evident in females, we expect sex to moderate the relationship between overgeneral AM, regional hemodynamic activity, and depressive symptoms (Aim 3). The long term goal of this research is to identify neuroscience-based interventions that can prevent the onset of depression and thus prevent a lifetime of illness, as well as to better identify individuals in need of preventative interventions. As fMRI is expensive and not widely available for clinical use, we will also collect concurrent EEG data during fMRI in order to determine if reliable signatures of amygdala activity can be identified (Exploratory Aim) so that more widely available and affordable technology can be used in the future.