Resting-state functional MRI in depression unmasks increased connectivity between networks via the dorsal nexus

Abstract

To better understand intrinsic brain connections in major depression, we used a neuroimaging technique that measures resting state functional connectivity using functional MRI (fMRI). Three different brain networks-the cognitive control network, default mode network, and affective network-were investigated. Compared with controls, in depressed subjects each of these three networks had increased connectivity to the same bilateral dorsal medial prefrontal cortex region, an area that we term the dorsal nexus. The dorsal nexus demonstrated dramatically increased depression-associated fMRI connectivity with large portions of each of the three networks. The discovery that these regions are linked together through the dorsal nexus provides a potential mechanism to explain how symptoms of major depression thought to arise in distinct networks-decreased ability to focus on cognitive tasks, rumination, excessive self-focus, increased vigilance, and emotional, visceral, and autonomic dysregulation-could occur concurrently and behave synergistically. It suggests that the newly identified dorsal nexus plays a critical role in depressive symptomatology, in effect "hot wiring" networks together; it further suggests that reducing increased connectivity of the dorsal nexus presents a potential therapeutic target.blood oxygen level-dependent signal | resting state F unctional brain imaging has provided an important window into human brain function by identifying brain systems involved in a variety of tasks and stimulus processing activities. Most depression-related functional neuroimaging differences have been identified in task-related studies. Previous functional imaging studies have tended to focus on particular regions of interest or, more recently, on regions within particular networks. One important system, the cognitive control network (CCN), serves attentiondemanding cognitive tasks and exhibits activity increases in frontal and parietal regions associated with top-down modulation of attention and working memory tasks (1). The CCN is involved in decision making and conflict resolution and is known to be impaired in depression (2). A number of previous studies have found depression-related abnormalities in the CCN, mostly involving decreased task-related activity (3-5). Other studies have identified increased task-related "effective" connectivity of the dorsolateral prefrontal cortex (DLPFC) and dorsal cingulate in depression (6, 7).Regions in a separate system, the default mode network (DMN), are defined functionally by their coordinated behavior and commonly have the greatest activity at rest and decreased activity during the performance of goal-directed tasks (8, 9). The DMN is important in self-referential activities, including evaluating salience of internal and external cues, remembering the past, and planning the future (9-11). We recently identified depressionrelated overactivity in tasks involving explicit emotional regulation in regions that fell within the DMN (12), the second network we examined in the present ...

Dysregulation between emotion and theory of mind networks in borderline personality disorder

“…Correlation maps were produced by extracting the BOLD time course from a seed region (10-mm sphere each), and then computing the correlation coefficient between that time course and the time course from all other brain voxels. Based on data from previous connectivity studies (Fox et al, 2006;Sheline et al, 2010;McCarthy et al, 2013), the left and right subgenual anterior cingulate cortex (ACC; 7x ¼ 10, y¼ 35, z ¼2) was extracted as the seed region of interest from the affective network that was modulated between ToM trials and NULL events; and the left and right precuneus ( 7x ¼7, y¼ À60, z ¼ 21) as the seed region of interest in the DMN during NULL events. Thus, the DMN was modulated during rest (NULL events) and the ToM network was modulated by functional variation in ToM and NULL events.…”

“…As we use the term here, functional connectivity describes the relationship between different brain regions and within particular networks by assessing the correlation of their neuronal activity (Nierhaus et al, 2012). Regions within one particular neural network, the default mode network (DMN), have been found to display their greatest levels of activity when at rest, and decreased activity in some DMN sub-regions during task-based stimulation (Sheline et al, 2010;Zhang and Li, 2012b). During these periods of "active rest", the DMN is thought to be involved in internal processes such as selfreferential processing, inner speech, emotional control, episodic memory, and ToM processes (Spreng et al, 2009;Wolf et al, 2011).…”

“…As a result, it has been identified as an important region in the study of the psychopathology of various disorders typified by emotion dysregulation (Stevens et al, 2011). Furthermore, the ACC is known as a good seed region to investigate the affective network (Sheline et al, 2010;McCarthy et al, 2013). The second part of the study addressed the gap in research on the DMN in BPD patients by mapping the functional connectivity corresponding to the precuneus seed region within the DMN in a sample of BPD patients compared with healthy controls during resting state.…”

Relation between patterns of intrinsic network connectivity, cognitive functioning, and symptom presentation in trauma‐exposed patients with major depressive disorder

“…The vmPFC not only represents a core region of the DMN (Buckner et al., 2008), but it is also a critical region involved in self‐referential processing (Lemogne, Delaveau, Freton, Guionnet, & Fossati, 2012; Northoff et al., 2006). This finding suggests hyperconnectivity within the DMN in patients with MDD, and is consistent with previous studies in patients with depression (Alexopoulos et al., 2012; Kaiser, Andrews‐Hanna, Wager, & Pizzagalli, 2015; Sheline, Price, Yan, & Mintun, 2010) (but see de Kwaasteniet et al. (2015) and Zhu et al.…”

Molecular, Functional, and Structural Imaging of Major Depressive Disorder

“…The DMN, consisting of the posterior cingulate cortex and medial prefrontal cortex (PFC) as its core areas [65,66] and the precuneus and temporo-parietal cortices, underlies the psychological process of introspection-the mind turning internally as it moves away from externally-concentrated thoughts [67][68][69]. A majority of studies have demonstrated that the DMN is hyperactive in MDD [70,71], and this may account for the rumination states in MDD [72]. The CCN, consisting of the dorsolateral PFC and pregenual ACC [73,74], is thought to be involved in the top-down modulation of attention and the regulation of emotional responses [75,76].…”