Cognitive processing deficits, such as hypoactivation of the left dorsolateral prefrontal cortex (DLPFC) during a working memory updating task, may be a characteristic of the familial risk profile for major depressive disorder (MDD), according to a recent article published in the Journal of Affective Disorders.

Using 72 unaffected first-degree relatives of parent probands with MDD (relatives) and 66 case-wise matched nonrelative control participants, study researchers sought to determine whether deficits in cognitive processing, specifically in the domain of working memory, may be part of the familial risk for MDD. The researchers assessed the cognitive processing abilities of these groups through functional magnetic resonance imaging (fMRI) of specific brain regions (DLPFC, anterior cingulate cortex, and insula regions) while participants performed cognitive processing tasks. Tasks focused on testing the working memory using the n-back test; the cognitive control/response inhibition test, Go/No-go task; and the selective attention, auditory Oddball test, for the relatives and control participants. Additionally, each participant completed the 42 item Depression Anxiety Stress Scales (DASS-42) survey to assess depressive and anxiety symptoms.

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In the researchers’ fMRI analysis, relatives showed significant hypoactivation of the DLPFC (P =.026), during the cognitive processing test (n-back, working memory updating). This coincided with relatives having more omission errors on the n-back task (P =.023). No significant differences in prefrontal activation or test performance were reported for the Go/No-go task or the Oddball test among the relatives. In the behavioral analysis of the DASS-42, both groups of relatives and control participants were within the healthy range. However, the relatives reported a significantly higher amount of subclinical symptoms of depression (P =.028). When comparing the results of the behavioral analysis with the fMRI analysis, the researchers confirmed the difference in DLPFC hypoactivation in relatives was not due to depression or stress symptoms listed in DASS-42 (P =.003) even with more severe symptoms reported. This suggests “that differences in symptoms levels were not driving the effects in the DLPFC and n-back working memory performance.” For both relatives and control participants combined, DLFPC hypoactivation had a significant negative correlation with severity of depressive symptoms on the DASS-42 (r[134]=−19, P =.03), but not for the groups separately.

Limitations of this study fall within the methodology of collection of familial history and family study design. The researchers mention that design has the potential to be open to some bias of unidentified high-risk participants in the control group. Additionally, they make the mention of not being able to compare the neural activation with that of a family member experiencing depression and the potential improvement a large sample size could make on the applicability of their results.

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The researchers interpret their results “as evidence that reduced DLPFC-mediated control of working memory may be a specific neurocognitive marker associated with familial vulnerability to MDD” and call for future research to “identify how the DLPFC is implicated in abnormal working memory updating in familial risk at a level, in which multiple nodes within a circuit, and their functional connectivity, are studied.”

Multiple authors declare affiliations with the pharmaceutical industry. Please see original reference for a full list of authors’ disclosures.

Watters AJ, Carpenter JS, Harris AWF, Korgaonkar MS, Williams LM. Characterizing neurocognitive markers of familial risk for depression using multi-modal imaging, behavioral and self-report measures [published online April 17, 2019]. J Affect Disord. doi: 10.1016/j.jad.2019.04.078