Characterizing neurocognitive markers of familial risk for depression using multi-modal imaging, behavioral and self-report measures

Background: Major depressive disorder (MDD) is associated with poorer behavioral performance in domains of working memory and associated cognitive systems for cognitive control and attention. Functional neuroimaging studies show altered functioning in MDD in frontal executive control circuits implicated in these cognitive processes. It is not yet known whether poor cognitive performance involving these circuits is part of the familial risk for MDD, and we addressed this issue using a mull-modal imaging, behavioral and self-report approach in unaffected first-degree relatives of parent probands with MDD. Methods: 72 unaffected adult first-degree relatives of probands with MDD (mean age 30.5 +/- 13.4 years) with and 66 case-wise matched non-relative controls underwent functional magnetic resonance imaging during performance of 'n-back' working memory task, a Go/No-go task assessing cognitive control and an Auditory Oddball test of selective attention. Groups were compared on imaging data analyzed voxel wise with a focus on dorsolateral prefrontal cortex, anterior cingulate cortex and insula regions of interest, and on corresponding behavioral accuracy and reaction time data. Symptoms were assessed using self-report scales. Results: Relatives were distinguished by comparatively decreased activation in the left dorsolateral prefrontal cortex (DLPFC) during updating of working memory. Behaviorally, relatives also showed more errors of omission during working memory updating. DLPFC hypo-activation was associated with greater depressive symptom severity. Conclusions: Deficits in cognitive processing may be part of the profile of familial risk for depression, preceding illness onset, specifically in the domain of working memory.