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
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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 contrast to the hyperactivity observed in posterior sgACC, MDD has also been associated with decreased activity in the pgACC and anterior sgACC (Drevets et al., 1997, 1992). Additionally, ruminative thought and depression severity in MDD are positively correlated with elevated resting-state functional connectivity between anterior sgACC and posterior cingulate as well as between posterior sgACC and other regions within the DMN (Berman et al., 2011; Greicius et al., 2007). "
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    ABSTRACT: Depression is a prevalent psychiatric condition characterized by sad mood and anhedonia. Neuroscientific research has consistently identified abnormalities in a network of brain regions in major depression, including subregions of the anterior cingulate cortex (ACC). However, few studies have investigated whether the same neural correlates of depression symptom severity are apparent in subclinical or healthy subjects. In the current study, we used resting-state fMRI to examine functional connectivity for subregions of the ACC in N = 28 participants with subclinical levels of depression. In regression analyses, we examined relationships between depression severity and functional connectivity for pregenual ACC (pgACC), anterior subgenual ACC (sgACC), and posterior sgACC seed regions. Additionally, we examined relationships between ACC subregion connectivity and trait levels of positive and negative affect. We found distinct associations between depression severity and functional connectivity of ACC subregions. Higher depression severity was associated with reduced pgACC-striatum connectivity and reduced anterior sgACC-anterior insula connectivity. Consistent with resting-state findings in major depression, higher depression severity was also related to greater anterior sgACC-posterior cingulate connectivity and greater posterior sgACC-dorsolateral prefrontal connectivity. Lastly, there were distinct correlations between connectivity for anterior versus posterior ACC subregions and positive and negative affective traits. These findings provide novel support linking subclinical depression to the same neural substrates associated with major depression. More broadly, these results contribute to an emerging literature on dimensional approaches to psychiatric illness.
    Journal of Psychiatric Research 10/2015; 71:103-111. DOI:10.1016/j.jpsychires.2015.10.005 · 3.96 Impact Factor
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    • "thy controls , depressed patients showed increased resting state functional connectivity of the DMN areas , such as the subgenual cingulate cortex and thalamus , especially increased medial PFC ( mPFC ) functional connectivity with other resting - state brain networks , including the cognitive control network , affective network , and DMN itself ( Greicius et al . , 2007 ; Sheline et al . , 2010 ) . Other researchers found that part of the DMN areas showed decreased resting state functional connectivity , such as the PCC / PCu and caudate , cerebellar regions and other DMN areas ( e . g . , mPFC and PCC / PCu ; Bluhm et al . , 2009 ; Liu et al . , 2012 ) . Zhu et al . ( 2012 ) observed increased anterio"
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    ABSTRACT: Previous studies have focused on resting-state default mode network (DMN) alterations in the development and maintenance of depression; however, only a few studies have addressed DMN changes during task-related processing and their results are inconsistent. Therefore, we explored DMN patterns in young adult patients with first-episode, treatment-naïve major depressive disorder (MDD) performing an implicit emotional processing task. Patients with MDD (N = 29) and healthy controls (N = 33) were subjected to functional magnetic resonance imaging (fMRI) at rest and while performing a gender judgment task. Group independent component analysis (ICA) was used to identify DMN component under task state for both groups. The DMN of participants with MDD had decreased functional connectivity in bilateral prefrontal areas compared to controls. Right prefrontal gyrus connectivity for MDD patients correlated negatively with scores on maladaptive scales of the Cognitive Emotion Regulation Questionnaire (CERQ). Our findings suggest that depressed people have altered DMN patterns during implicit emotional processing, which might be related to impaired internal monitoring and emotional regulation ability.
    Frontiers in Psychology 08/2015; 6:1198. DOI:10.3389/fpsyg.2015.01198 · 2.80 Impact Factor
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    • "The effects that we observed include the sub-and perigenual ACC which are particularly associated with rumination (Zhu et al., 2012). The posterior parts of the DMN have been proposed as specific regions where normalization of abnormal activity and functional connectivity takes place after SSRI treatment (Greicius et al., 2007; Kraus et al., 2014; Li et al., 2013). "
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    ABSTRACT: The serotonergic system is widely distributed throughout the central nervous system. It is well known as a mood regulating system, although it also contributes to many other functions. With resting state functional magnetic resonance imaging (RS-fMRI) it is possible to investigate whole brain functional connectivity. We used this non-invasive neuroimaging technique to measure acute pharmacological effects of the selective serotonin reuptake inhibitor sertraline (75mg) in 12 healthy volunteers. In this randomized, double blind, placebo-controlled, crossover study, RS-fMRI scans were repeatedly acquired during both visits (at baseline and 3, 5, 7 and 9h after administering sertraline or placebo). Within-group comparisons of voxelwise functional connectivity with ten functional networks were examined (p<0.005, corrected) using a mixed effects model with cerebrospinal fluid, white matter, motion parameters, heart rate and respiration as covariates. Sertraline induced widespread effects on functional connectivity with multiple networks; the default mode network, the executive control network, visual networks, the sensorimotor network and the auditory network. A common factor among these networks was the involvement of the precuneus and posterior cingulate cortex. Cognitive and subjective measures were taken as well, but yielded no significant treatment effects, emphasizing the sensitivity of RS-fMRI to pharmacological challenges. The results are consistent with the existence of an extensive serotonergic system relating to multiple brain functions with a possible key role for the precuneus and cingulate. Copyright © 2015. Published by Elsevier Inc.
    NeuroImage 08/2015; 122. DOI:10.1016/j.neuroimage.2015.08.012 · 6.36 Impact Factor
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