Increased Default Mode Network Connectivity in Individuals at High Familial Risk for Depression

• (Increased Default Mode Network Connectivity in Individuals at High Familial Risk for Depression)[https://pmc.ncbi.nlm.nih.gov/articles/PMC4869043/]

• Research into the pathophysiology of major depressive disorder (MDD) has focused largely on individuals already affected by MDD. Studies have thus been limited in their ability to disentangle effects that arise as a result of MDD from precursors of the disorder. By studying individuals at high familial risk for MDD, we aimed to identify potential biomarkers indexing risk for developing MDD, a critical step toward advancing prevention and early intervention. Using resting-state functional connectivity MRI (rs-fcMRI) and diffusion MRI (tractography), we examined connectivity within the default mode network (DMN) and between the DMN and the central executive network (CEN) in 111 individuals, aged 11–60 years, at high and low familial risk for depression. Study participants were part of a three-generation longitudinal, cohort study of familial depression. Based on rs-fcMRI, individuals at high vs low familial risk for depression showed increased DMN connectivity, as well as decreased DMN-CEN-negative connectivity. These findings remained significant after excluding individuals with a current or lifetime history of depression. Diffusion MRI measures based on tractography supported the findings of decreased DMN-CEN-negative connectivity. Path analyses indicated that decreased DMN-CEN-negative connectivity mediated a relationship between familial risk and a neuropsychological measure of impulsivity. Our findings suggest that DMN and DMN-CEN connectivity differ in those at high vs low risk for depression and thus suggest potential biomarkers for identifying individuals at risk for developing MDD.

• Current approaches are effective in treating major depressive disorder (MDD), yet more than half of patients either fail to remit or drop out of treatment prematurely (Rush et al, 2006). Even in those who respond, significant impairments including underemployment, disability, and disproportionate levels of medical illness persist (Kessler et al, 1997; Paradiso et al, 1997; Keller, 2003). An alternative strategy is to identify those at high risk for developing MDD with the goal of advancing prevention and early intervention. Critical to advancing this preventive approach, however, is the identification of biomarkers predictive of the development of MDD.

• Research into the pathophysiology of MDD has focused largely on individuals already affected by MDD. Studies have thus been limited in their ability to disentangle effects that arise as a result of the disorder from predictors of the disorder. By focusing our research on individuals at risk for developing MDD, we have tried to circumvent this limitation (Peterson et al, 2009; Dubin et al, 2012). Toward this end, we used resting-state functional connectivity MRI (rs-fcMRI) to examine the connectivity of the brain's default mode network (DMN) in individuals at high and low familial risk for depression. The DMN is a collection of brain regions that reliably deactivate during goal-directed behaviors (Raichle and Snyder, 2007). We focused on DMN connectivity because prior studies suggest increased DMN connectivity is associated with MDD (Greicius et al, 2007; Sheline et al, 2009). Prior studies, however, have seldom examined whether increased DMN connectivity is an antecedent or consequence of MDD, and thus it remains unknown whether increased DMN connectivity represents a potential biomarker predictive of depression.

• We also examined connectivity between the DMN and the central executive network (CEN), encompassing the dorsolateral prefrontal and parietal cortices. The DMN and the CEN habitually work in opposing directions in relation to attentional demands—as attentional demands increase, CEN activation increases while DMN activation decreases; conversely, during periods of rest or internally focused cognitions, CEN activation decreases while DMN activation increases (Raichle et al, 2001; Fox et al, 2005; Grady et al, 2010). This inverse relationship between the DMN and CEN is reflected in negative connectivity (or anticorrelations) between these two networks in healthy individuals (Fox et al, 2005; Biswal et al, 2010; Whitfield-Gabrieli and Ford, 2012). DMN-CEN anticorrelations may be altered in MDD (Sheline et al, 2010; Hamilton et al, 2011) and may reflect impairments in attentional control or impulsivity (Posner et al, 2014); however, similar to DMN connectivity, DMN-CEN anticorrelations have scarcely been examined in individuals at risk for, but not yet affected by, depression.

• We used rs-fcMRI to examine DMN and DMN-CEN functional connectivity in individuals from a longitudinal cohort study of families at high and low risk for depression. Based on prior literature (Sheline et al, 2009; Posner et al, 2013), we hypothesized that compared with individuals at low familial risk, those at high risk for depression would demonstrate increased connectivity within the DMN, as well as decreased negative connectivity (ie, reduced anticorrelations) between the DMN and CEN. Using diffusion MRI, we then explored whether measures of DMN and DMN-CEN functional connectivity could be corroborated with diffusion tractography. Last, we used path analyses to explore associations between familiar risk for depression, connectivity measures, and affective symptoms and impulsivity.

• Posner, J., Cha, J., Wang, Z., Talati, A., Warner, V., Gerber, A., Peterson, B. S., & Weissman, M. (2016). Increased Default Mode Network Connectivity in Individuals at High Familial Risk for Depression. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 41(7), 1759–1767. [https://doi.org/10.1038/npp.2015.342]