شبکه های اتصال عملکردی در مقیاس بزرگ گسسته شکل از پیشگوه در داروی ساده افسردگی اول قسمت

Research suggests an imbalance in neural activity within large-scale networks as an important pathophysiological aspect of depression. Yet, there is little consensus about to the abnormality within the default mode network (DMN) in major depressive disorder (MDD). In the present study, 16 first-episode, medication-naïve patients with MDD and 16 matched healthy controls underwent functional magnetic resonance imaging (fMRI) at rest. With the precuneus (a central node of the DMN) as a seed region, functional connectivity (FC) was measured across the entire brain. The association between the FC of the precuneus with overall symptom severity was assessed using the Hamilton Depression Rating Scale. Patients with MDD exhibited a more negative relationship between the precuneus and the non-DMN regions, including the sensory processing regions (fusiform gyrus, postcentral gyrus) and the secondary motor cortex (supplementary motor area and precentral gyrus). Moreover, greater severity of depression was associated with greater anti-correlation between the precuneus and the temporo-parietal junction as well as stronger positive connectivity between the precuneus and the dorsomedial prefrontal cortex. These results indicate that dissociated large-scale networks of the precuneus may contribute to the clinical expression of depression in MDD.

Major depressive disorder (MDD) is characterized by sad feelings, inability to experience pleasure from normally rewarding experiences (anhedonia), negative rumination, and cognitive deficits such as dysfunctional attention and memory (Li et al., 2010). A prevailing concept in the pathophysiology of depression posits impairment in communication between distributed brain regions such as the cortico-limbic network (Wang et al., 2012 and American Psychiatric Association, 2013), sensory processing (Fu et al., 2007), attentional and emotion processing systems (Carballedo et al., 2011 and Hamilton et al., 2012). In particular, functional dependencies (or functional connectivity, FC) have been reported between brain regions in a task-free, resting state where the subject is not engaged in any goa- directed behavior (Wang et al., 2012). This approach allows the study of a large-scale networks of regions that show correlated brain activity, including the default mode network (DMN), which is associated with unrestricted and often self-directed mental processes that are of particular importance in depression (Sheline et al., 2009 and Nejad et al., 2013). The DMN encompasses a set of brain regions including the medial prefrontal cortex (MPFC) and the anterior cingulate cortex (ACC), lateral parietal regions including the angular gyrus, and the posterior cingulate cortex (PCC)/precuneus (Laird et al., 2009). Of the several regions that constitute the DMN, the precuneus forms a central node. Many FC studies have reliably reproduced the DMN by investigating the correlations in functional magnetic resonance imaging (fMRI) signals recorded from the precuneus (Bluhm et al., 2009, Sheline et al., 2010, Zhou et al., 2010 and Scheidegger et al., 2012). Converging evidence suggests a crucial role for the precuneus in the integration of mental processing through its role in cognitive control processes such as visual imagery, episodic memory and self-directed operations (Cavanna and Trimble, 2006). Zhu et al. (2012) found that the reduced FC within the DMN between the precuneus/PCC and the bilateral angular gyrus was associated with abnormal over-general autobiographical memory in drug-naïve first-episode MDD, highlighting the importance of this region in the pathophysiology of depression. A pattern of anti-correlated connectivity between the DMN and other regions is often observed in fMRI studies, whereby greater activity in the DMN is associated with reduced activity in other networks. Evidence that these negative partial correlations are meaningful is provided by the observation that during tasks that entail attention to external stimuli, the DMN shows reduced activation relative to baseline, while those regions with which it is anti-correlated at rest (after controlling for global signal) show increased activation (Fox et al., 2005). Previous reports (Chang and Glover, 2009, Fox et al., 2009, Carbonell et al., 2011 and Chai et al., 2012) suggested that the anti-correlations between task-positive and the DM networks might be an intrinsic property of the brain rather than an artifact induced by the regression of the global average signal, while some other studies (Chang and Glover, 2009, Murphy et al., 2009, Weissenbacher et al., 2009, Jo et al., 2010 and Anderson et al., 2011) found that regression of the global average signal influenced the consequence of anti-correlations. The anti-correlation might be reliably obtained after controlling for the mean blood oxygen level dependent (BOLD) signal derived from fMRI (global average signal). Several studies have focused on abnormal connectivity within the DMN in patients with MDD, although the findings were not entirely consistent and were poorly related to the clinical severity of depression (Wang et al., 2012). Greicius et al. (2007) used an independent component approach (ICA) that selected a set of regions with shared fMRI signal fluctuations and a high degree of spatial similarity to the DMN, and reported increased connectivity with the thalamus and the subgenual ACC in depression. Bluhm et al. (2009), who used a seed-based approach and constrained search limited to regions hypothesized to be important in depression, could not replicate this observation. However, Schilbach et al. (2014), in a meta-analytic approach to identify an introspective socio-affective (ISA) network, reported the connection between the ACC and the precuneus was significantly increased. In addition, another study (Belleau et al., 2014) found a greater subgenual ACC connectivity with the left medial temporal gyrus, the left cingulate gyrus, and the right posterior cingulate/retrosplenial cortex during externally focused thought induction in individuals with MDD. To date, most of the previous reports supported the “hyperconnectivity hypothesis” of depression (see also Perrin et al., 2012). Considering two competing large scale systems – the DMN and a task-positive network (TPN) that is normally activated in response to task stimuli – Zhou et al. (2010) demonstrated an abnormally pronounced anti-correlation between core regions of these two networks. An anti-correlation found between the TPN and a task-negative network (TNN) during the resting state, which may contribute to the function of the DMN (Pizzagalli, 2010 and Marchetti et al., 2012). In the resting state, one DMN component can temporally dominate over the other, explaining how functional connectivity influences psychopathological features of MDD such as rumination and dysfunctional attention (Pizzagalli, 2010 and Marchetti et al., 2012). Other authors noted an abnormal dominance of the DMN over the TPN (Hamilton et al., 2011) and a persistence of DMN activity during task processing (Grimm et al., 2009). This ‘interference’ of the DMN is associated with maladaptive ruminations (Hamilton et al., 2011) and increased clinical severity (Grimm et al., 2009) of depression. Interestingly, Sheline et al. (2010) demonstrated increased connectivity between the precuneus and a region of the dorsomedial prefrontal cortex (dMPFC). In fact, this dMPFC region (termed the dorsal nexus) showed hyperconnectivity not only with the DMN, but also with a cognitive control network and an affective network, suggesting that traditional boundaries defining large-scale systems may be altered in depression (Marchetti et al., 2012). Reorganised functional boundaries – especially among the two competing large-scale brain networks, the DMN and the TPN – have been directly demonstrated in depression (Zhou et al., 2010). These studies highlight the importance of studying connectivity in an unconstrained, whole-brain fashion. Hyperconnectivity between the DMN and the dorsal nexus has been demonstrated in previously treated individuals with recurrent depression; this hyperconnectivity was related to overall clinical severity measured using Hamilton Depression Rating Scale (HAMD) (Sheline et al., 2010). DMN hyperconnectivity with the dorsal nexus has also been demonstrated in previously depressed but recovered subjects (Nixon et al., 2014) and first degree relatives of depressed subjects (Norbury et al., 2011), but so far not reported in medication-naïve, first-episode depression. To our knowledge, only two previous studies have examined DMN connectivity in medication-naïve first-episode subjects. Zhou et al. (2010) studied the spatial consistency of the DMN and the TPN in MDD in 18 subjects with a low level of clinical severity (17-item HAMD mean score=16.7). They constrained the connectivity analysis within spatial masks that defined the DMN and the TPN. Zhu et al. (2012) studied a larger sample of 35 patients, and constrained their FC analysis to the spatial component defining the DMN; abnormal DMN connectivity was related to rumination and over-general autobiographical memory. These studies have highlighted the crucial importance of the DMN and its interaction with the TPN in individuals with depression who have not been exposed to antidepressants. Nevertheless, due to the constrained nature of the analyses, it is unclear how the interaction of the DMN with the rest of the brain – for example, regions such as the dorsal nexus, and sensory and limbic regions implicated in depression – are affected in first-episode, antidepressant-naïve patients. Further it is unclear if the aberrations in DMN connectivity are related to the clinical severity of depression in an untreated, first-episode sample. The present study is primarily focused on studying the connectivity of the precuneus, a central DMN node, with the rest of the brain in currently depressed, but never-medicated, first-episode subjects in a task-free resting state. We also studied the relationship between the FC of the precuneus and the overall clinical severity in these subjects. We hypothesized that depressed subjects would show an aberrant increase in positive connectivity between the precuneus and other regions in the DMN, those especially affecting the dorsomedial prefrontal cortex, but greater anti-correlation with brain regions outside of the DMN system. Given the observations suggesting DMN dominance in depression (Grimm et al., 2009 and Hamilton et al., 2011), we also expected that more severe depression would be seen in patients with more pronounced dissociation networks of the precuneus in the DMN and non-DMN regions, though we did not have an a priori hypothesis on the specific brain regions in relation to clinical severity.

Across both groups, the precuneus seed exhibited strong positive connections bilaterally with the other recognized sites of the DMN. Specifically, the precuneus seed showed significant positive connectivity to the bilateral angular gyrus, bilateral superior frontal gyrus, and right anterior cingulate gyrus, extending to the left middle frontal gyrus, bilateral middle temporal gyrus, left hippocampus and parahippocampal gyrus. Significant negative regression coefficients were observed in large bilateral clusters encompassing the superior, middle, and inferior frontal gyrus, inferior parietal gyrus, supplementary motor area/sensorimotor regions (precentral and postcentral gyrus), supramarginal gyrus, inferior and superior temporal gyrus, and insula, which include regions of the TPN (Fig. 1, Details of FC in the entire sample are provided in Table S1 in the Supplementary Material).