Desynchronization and Plasticity of Striato-frontal Connectivity in Major Depressive Disorder

Abstract

Major depressive disorder (MDD) is associated with dysfunctional corticolimbic networks, making functional connectivity studies integral for understanding the mechanisms underlying MDD pathophysiology and treatment. Resting-state functional connectivity (RSFC) studies analyze patterns of temporally coherent intrinsic brain activity in "resting-state networks" (RSNs). The default-mode network (DMN) has been of particular interest to depression research; however, a single RSN is unlikely to capture MDD pathophysiology in its entirety, and the DMN itself can be characterized by multiple RSNs. This, coupled with conflicting previous results, underscores the need for further research. Here, we measured RSFC in MDD by targeting RSNs overlapping with corticolimbic regions and further determined whether altered patterns of RSFC were restored with electroconvulsive therapy (ECT). MDD patients exhibited hyperconnectivity between ventral striatum (VS) and the ventral default-mode network (vDMN), while simultaneously demonstrating hypoconnectivity with the anterior DMN (aDMN). ECT influenced this pattern: VS-vDMN hyperconnectivity was significantly reduced while VS-aDMN hypoconnectivity only modestly improved. RSFC between the salience RSN and dorsomedial prefrontal cortex was also reduced in MDD, but was not affected by ECT. Taken together, our results support a model of ventral/dorsal imbalance in MDD and further suggest that the VS is a key structure contributing to this desynchronization.

Effect of Electroconvulsive Therapy on Striatal Morphometry in Major Depressive Disorder

“…On the basis of our a priori hypotheses derived from prior findings showing ECT-related changes of functional connectivity in the striatum/pallidum with ECT (Leaver et al, 2015), a two-tailed alpha level of 0.05 was the threshold for significance for volumetric analyses. Surface-based analyses controlled for false positives using false discovery rate (Benjamini and Hochberg, 1995) using a 5% false positive rate, surface-wise.…”

“…Deficits in brain activation and functional connectivity in basal ganglia substructures are suggested to normalize with different antidepressant treatments (Stoy et al, 2012;Admon et al, 2015). In ECT-treated patients, we recently showed a hyperconnectivity between the ventral striatum and ventral default-mode network, while simultaneously demonstrating hypoconnectivity with the anterior default-mode network, patterns that were modulated by ECT (Leaver et al, 2015). These results suggest that the striatum is involved in functional desynchronization between dorsal and ventral cortico-limbic neural circuits in major depression and that normalization of these functional disturbances can occur with ECT.…”

“…Table 1 summarizes the demographic and clinical characteristics of our cohort. Subjects in this study overlap with those in two recent investigations of hippocampal and amygdala morphometry and functional connectivity (Leaver et al, 2015). All participants provided written informed consent as approved by the UCLA Institutional Review Board.…”

“…We thus developed a machine-learning framework to determine whether morphometric differences, prior to treatment, might predict patients' responsiveness to ECT. On the basis of our observations of restoration of functional connectivity (Leaver et al, 2015), we predicted that ECT-related structural plasticity would also occur in ventral striatal and connected basal ganglia regions.…”

Modulation of Intrinsic Brain Activity by Electroconvulsive Therapy in Major Depression

“…The mPFC may play a particular role in depression and treatment response (3); the sgACC exhibits volume loss and hyperconnectivity in MD (36; 58; 59), and BA 25 is a current target of deep brain stimulation (DBS) in clinical trials (60). The vmPFC is also modulated by pharmacological treatment of MDD (60; 61), and the ventral striatal loop and mesolimbic reward pathway are implicated in depression (37; 49; 50; 62), including ECT response (42; 62). …”