This hyperconnectivity pattern in DMN is to be expected given that—as discussed in the introduction—it is a common finding in most studies and was confirmed in a recent meta-analysis (Kaiser et al., 2015).

The other papers found no correlations between clinical symptom improvement and changes in connectivity (Abbott et al., 2013; Li et al., 2013; Posner et al., 201

Andreescu et al. (2013), where—somewhat paradoxically—it was associated to an increased connectivity in the anterior, frontal nodes of the DMN, in which such “frontalization” is interpreted as a possible normalizing effect of antidepressant treatment

Four studies (Andreescu et al., 2013; Li et al., 2013; Posner et al., 2013; Liston et al., 2014) found DMN hyperconnectivity in depressed patients with respect to the control subjects. In all of them, connectivity reductions were observed in DMN after the treatment (Li et al., 2013; Posner et al., 2013; Liston et al., 2014)

Moreover, a recent meta-analysis by Ma (2014) studied the effects of antidepressants on brain activity underlying emotional processing. Their results showed that antidepressant treatments had effects on the activation of limbic core structures such as the amygdala, the thalamus, and ACC, and in other emotional processing structures like MPFC, the insula, and the putamen. Antidepressant medication increased the activity of these structures when the subjects processed positive emotions, whereas the same medication decreased the activity of the same structures while processing negative emotions. For these reasons, it is perfectly plausible to expect that, after the same treatments, the depressed patients will present changes in connectivity related to illness improvement.

In addition, a recent meta-analysis by Kaiser et al. (2015) included 27 seed-based voxel-wise connectivity studies in MDD. That study confirmed the alterations in the connectivity of both rest networks and in network coupling. More specifically, it concluded that this illness is characterized by several connectivity alterations in both networks and in network coupling. More specifically, patients with MDD presented hypoconnectivity within the frontoparietal network, hypoconnectivity between frontoparietal systems and parietal areas of the dorsal attention network, hyperconnectivity within the DMN, and hyperconnectivity between frontoparietal control areas and regions of the default network (Kaiser et al., 2015). The authors also provided a model in which the widespread network dysfunction underlies core affective and cognitive alterations in MDD (Kaiser et

hyperconnectivity of DMN and the SN with CCN is related to rumination in depression (Jacobs et al., 2014).

For example, the alteration of connectivity between cortical-limbic structures such as the connection between the amygdala and ACC, and the amygdala and DLPFC, among others, has been related to the cognitive biases and neuropsychological alterations of depression (Thomas and Elliott, 2009).

some studies report hyperactivation and hypoactivation patterns at the same time between different structures within DMN (Wu et al., 2011).

It has been linked to self-reference processes and their alteration; while the pathological interactions of DMN with other networks such as the SN and the CCN would be linked to the states of pathological rumination frequently presented by depressed patients (Broyd et al., 2009; Belleau et al., 2014; Jacobs et al., 2014).

DMN includes frontal areas such as the ventromedial prefrontal cortex (vmPFC) and portions of the anterior cingulate cortex (ACC), and from the orbitofrontal cortex (OFC) and parietal areas like the posterior cingulate cortex (PCC) and the medial, lateral, and inferior parietal cortex (Raichle et al., 2001; Greicius et al., 2003)

most of the evidence in the literature suggests that, in MDD, connectivity networks at rest and the connectivity networks activated during specific tasks are all altered (Wang et al., 2012). Accordingly, affective disorders have been linked to alterations of the Default Mode Network (DMN), the Affective Network (AN), the Salience Network (SN), and the Cognitive Control Network (CCN), among others (Dutta et al., 2014).

an increase in the activation of the mPFC, the amygdala, and the hippocampus in depressed subjects with respect to the control subjects (Rose et al., 2006; Siegle et al., 2007; Wise et al., 2014)

Depressive Rumination, the Default-Mode Network, and the Dark Matter of Clinical Neuroscience J Paul Hamilton  1 , Madison Farmer  2 , Phoebe Fogelman  3 , Ian H Gotlib  4 Affiliations Expand Affiliations 1 Laureate Institute for Brain Research and College of Health Sciences, University of Tulsa, Tulsa, Oklahoma. Electronic address: paul.hamilton@laureateinstitute.org. 2 Laureate Institute for Brain Research and College of Health Sciences, University of Tulsa, Tulsa, Oklahoma. 3 University of Tennessee, Stanford University, Stanford, California. 4 Department of Psychology, Stanford University, Stanford, California. PMID: 25861700 PMCID: PMC4524294 DOI: 10.1016/j.biopsych.2015.02.020 Free PMC article Item in Clipboard Review Depressive Rumination, the Default-Mode Network, and the Dark Matter of Clinical Neuroscience J Paul Hamilton et al. Biol Psychiatry. 2015. Free PMC article Show details Display options Display options Format Abstract PubMed PMID Biol Psychiatry Actions Search in PubMed Search in NLM Catalog Add to Search . 2015 Aug 15;78(4):224-30. doi: 10.1016/j.biopsych.2015.02.020. Epub 2015 Feb 24. Authors J Paul Hamilton  1 , Madison Farmer  2 , Phoebe Fogelman  3 , Ian H Gotlib  4 Affiliations 1 Laureate Institute for Brain Research and College of Health Sciences, University of Tulsa, Tulsa, Oklahoma. Electronic address: paul.hamilton@laureateinstitute.org. 2 Laureate Institute for Brain Research and College of Health Sciences, University of Tulsa, Tulsa, Oklahoma. 3 University of Tennessee, Stanford University, Stanford, California. 4 Department of Psychology, Stanford University, Stanford, California. PMID: 25861700 PMCID: PMC4524294 DOI: 10.1016/j.biopsych.2015.02.020 Item in Clipboard Full text links CiteDisplay options Display options Format AbstractPubMedPMID Abstract The intuitive association between self-focused rumination in major depressive disorder (MDD) and the self-referential operations performed by the brain's default-mode network (DMN) has prompted interest in examining the role of the DMN in MDD. In this article, we present meta-analytic findings showing reliably increased functional connectivity between the DMN and subgenual prefrontal cortex (sgPFC)-connectivity that often predicts levels of depressive rumination. We also present meta-analytic findings that, while there is reliably increased regional cerebral blood flow in sgPFC in MDD, no such abnormality has been reliably observed in nodes of the DMN. We then detail a model that integrates the body of research presented. In this model, we propose that increased functional connectivity between sgPFC and the DMN in MDD represents an integration of the self-referential processes supported by the DMN with the affectively laden, behavioral withdrawal processes associated with sgPFC-an integration that produces a functional neural ensemble well suited for depressive rumination and that, in MDD, abnormally taxes only sgPFC and not the DMN. This synthesis explains a broad array of existing data concerning the neural substrates of depressive rumination and provides an explicit account of functional abnormalities in sgPFC in MDD. Keywords: Default-mode network; Intrinsic functional connectivity; Major depressive disorder; Medial-dorsal thalamus; Rumination; Subgenual prefrontal cortex. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved. Conflict of interest statement Financial Disclosure Dr. Hamilton, Ms. Farmer, Ms. Fogelman, and Dr. Gotlib have no biomedical financial interests or potential conflicts of interest to report.

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