<b>Candidate pathophysiological mechanisms contributing to elevated risk of major depressive disorder among carriers of the </b><b><i>FMR</i></b><b>1 premutation</b>

<p dir="ltr">For decades researchers have attempted to uncover the etiology of depression with the hope that this will inform new prevention and treatment efforts in order to reduce the global public health burden of this common disease. Ultimately this research has yielded few results with large enough effect sizes to yield wide explanatory value. Thus, the field is increasingly recognizing the necessity of identifying and phenotyping sub-groups of individuals at high risk for depression, with the hope that mapping etiological pathways to disease onset will be somewhat more possible within these homogeneous groups. Women who carry the <i>FMR</i>1 premutation (PMC), a single-gene premutation that affects approximately 1:200 women, represent one such group, with 54% developing depression by age 50. The current study aimed to better understand why PMC have such high incidence of depression by examining candidate physiological pathways which may help to explain how a genetic premutation present from birth results in high rates of psychiatric illness decades later. To this end, 40 female PMC and 21 matched controls completed an EEG and MRI session, neuropsychological testing, clinical interviews, and self-report surveys. We found that PMC exhibited a distinct spatial pattern of brain activity relative to controls in general feedback processing, and that PMC exhibited a distinct topographic distribution of error-related processing relative to controls, such that PMC exhibited a relatively less frontal distribution than is typical. We also found that among PMC cerebellar glutathione concentration was positively correlated with self-reported internalizing symptoms. Finally, we found that reproductive status moderated the relationship between symptoms of depression and neural sensitivity to rewards. We discuss these findings in terms of parallels with psychophysiological findings from phenotypically similar groups, person characteristics within subgroups of PMC that might represent even more homogenous groups with regard to depression risk, and risk factors that may be shared with the general population.</p>