Resting-State Functional Connectivity in Major Depression: Abnormally Increased Contributions from Subgenual Cingulate Cortex and Thalamus

Department of Neurology and Neurological Sciences, Stanford University Medical Center, Stanford, California 94305-5235, USA.
Biological Psychiatry (Impact Factor: 10.26). 10/2007; 62(5):429-37. DOI: 10.1016/j.biopsych.2006.09.020
Source: PubMed


Positron emission tomography (PET) studies of major depression have revealed resting-state abnormalities in the prefrontal and cingulate cortices. Recently, fMRI has been adapted to examine connectivity within a specific resting-state neural network--the default-mode network--that includes medial prefrontal and anterior cingulate cortices. The goal of this study was to examine resting-state, default-mode network functional connectivity in subjects with major depression and in healthy controls.
Twenty-eight subjects with major depression and 20 healthy controls underwent 5-min fMRI scans while resting quietly. Independent component analysis was used to isolate the default-mode network in each subject. Group maps of the default-mode network were compared. A within-group analysis was performed in the depressed group to explore effects of depression refractoriness on functional connectivity.
Resting-state subgenual cingulate and thalamic functional connectivity with the default-mode network were significantly greater in the depressed subjects. Within the depressed group, the length of the current depressive episode correlated positively with functional connectivity in the subgenual cingulate.
This is the first study to explore default-mode functional connectivity in major depression. The findings provide cross-modality confirmation of PET studies demonstrating increased thalamic and subgenual cingulate activity in major depression. Further, the within-subject connectivity analysis employed here brings these previously isolated regions of hypermetabolism into the context of a disordered neural network. The correlation between refractoriness and subgenual cingulate functional connectivity within the network suggests that a quantitative, resting-state fMRI measure could be used to guide therapy in individual subjects.

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    • "In accord with these views, our findings suggest that higher cognitive flexibility when responding to external tasks demands may require more efficient disengagement of current self-referential processing, and that such ability might be reduced in mood disorder patients. Depression is indeed known to be characterized by a failure to deactivate regions of the DMN, including ventromedial PFC, ACC, lateral parietal cortex, and lateral temporal cortex[Sheline et al., 2009], together with extra functional connectivity of sgACC and thalamus with the DMN[Greicius et al., 2007]. A study in MDD patients reported that during a self-judgment task, ventro-medial prefrontal regions were less deactivated for patients than healthy subjects, suggesting that MDD patients might fail to downregulate their high resting state activity in sgACC because they remain " stuck in their own self "[Grimm et al., 2009;Yoshimura et al., 2010]. "
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    ABSTRACT: Impairment in mental flexibility may be a key component contributing to cardinal cognitive symptoms among mood disorders patients, particularly thought control disorders. Impaired ability to switch from one thought to another might reflect difficulties in either generating new mental states, inhibiting previous states, or both. However, the neural underpinnings of impaired cognitive flexibility in mood disorders remain largely unresolved. We compared a group of mood disorders patients (n = 29) and a group of matched healthy subjects (n = 32) on a novel task-switching paradigm involving happy and sad faces, that allowed us to separate generation of a new mental set (Switch Cost) and inhibition of the previous set during switching (Inhibition Cost), using fMRI. Behavioral data showed a larger Switch Cost in patients relative to controls, but the average Inhibition Cost did not differ between groups. At the neural level, a main effect of group was found with stronger activation of the subgenual cingulate cortex in patients. The larger Switch Cost in patients was reflected by a stronger recruitment of brain regions involved in attention and executive control, including the left intraparietal sulcus, precuneus, left inferior fontal gyrus, and right anterior cingulate. Critically, activity in the subgenual cingulate cortex was not downregulated by inhibition in patients relative to controls. In conclusion, mood disorder patients have exaggerated Switch Cost relative to controls, and this deficit in cognitive flexibility is associated with increased activation of the fronto-parietal attention networks, combined with impaired modulation of the subgenual cingulate cortex when inhibition of previous mental states is needed. Hum Brain Mapp, 2016. © 2016 Wiley Periodicals, Inc.
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    • "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. "
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    • "Spontaneous thought, DMN, and depression are documented to be associated in case reports (Beck, 1970; 1971/2004), correlational (Deng, Li, & Tang, 2012; Epel et al., 2013; Farrin, Hull, Unwin, Wykes, & David, 2003; Golding & Singer, 1983; Giambra & Traynor, 1978; Greicius et al,, 2007; Johannessen & Berntsen, 2010; Meyer, Finucane, & Jordan, 2011; Stawarczyk et al., 2012), "
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