Importance Major depressive disorder (MDD) has been linked to imbalanced communication among large-scale brain networks, as reflected by abnormal resting-state functional connectivity (rsFC). However, given variable methods and results across studies, identifying consistent patterns of network dysfunction in MDD has been elusive. Objective To investigate network dysfunction in MDD through a meta-analysis of rsFC studies. Data Sources Seed-based voxelwise rsFC studies comparing individuals with MDD with healthy controls (published before June 30, 2014) were retrieved from electronic databases (PubMed, Web of Science, and EMBASE) and authors contacted for additional data. Study Selection Twenty-seven seed-based voxel-wise rsFC data sets from 25 publications (556 individuals with MDD and 518 healthy controls) were included in the meta-analysis. Data Extraction and Synthesis Coordinates of seed regions of interest and between-group effects were extracted. Seeds were categorized into seed-networks by their location within a priori functional networks. Multilevel kernel density analysis of between-group effects identified brain systems in which MDD was associated with hyperconnectivity (increased positive or reduced negative connectivity) or hypoconnectivity (increased negative or reduced positive connectivity) with each seed-network. Results Major depressive disorder was characterized by hypoconnectivity within the frontoparietal network, a set of regions involved in cognitive control of attention and emotion regulation, and hypoconnectivity between frontoparietal systems and parietal regions of the dorsal attention network involved in attending to the external environment. Major depressive disorder was also associated with hyperconnectivity within the default network, a network believed to support internally oriented and self-referential thought, and hyperconnectivity between frontoparietal control systems and regions of the default network. Finally, the MDD groups exhibited hypoconnectivity between neural systems involved in processing emotion or salience and midline cortical regions that may mediate top-down regulation of such functions. Conclusions and Relevance Reduced connectivity within frontoparietal control systems and imbalanced connectivity between control systems and networks involved in internal or external attention may reflect depressive biases toward internal thoughts at the cost of engaging with the external world. Meanwhile, altered connectivity between neural systems involved in cognitive control and those that support salience or emotion processing may relate to deficits regulating mood. These findings provide an empirical foundation for a neurocognitive model in which network dysfunction underlies core cognitive and affective abnormalities in depression.

https://jamanetwork.com/journals/jamapsychiatry/articlepdf/2203837/yoi150007.pdf

Large-Scale Network Dysfunction in Major Depressive Disorder: A Meta-analysis of Resting-State Functional Connectivity.

Resting-state functional connectivity in major depressive disorder: A review

Major depressive disorder (MDD) is common and disabling, but its neuropathophysiology remains unclear. Most studies of functional brain networks in MDD have had limited statistical power and data analysis approaches have varied widely. The REST-meta-MDD Project of resting-state fMRI (R-fMRI) addresses these issues. Twenty-five research groups in China established the REST-meta-MDD Consortium by contributing R-fMRI data from 1,300 patients with MDD and 1,128 normal controls (NCs). Data were preprocessed locally with a standardized protocol before aggregated group analyses. We focused on functional connectivity (FC) within the default mode network (DMN), frequently reported to be increased in MDD. Instead, we found decreased DMN FC when we compared 848 patients with MDD to 794 NCs from 17 sites after data exclusion. We found FC reduction only in recurrent MDD, not in first-episode drug-naive MDD. Decreased DMN FC was associated with medication usage but not with MDD duration. DMN FC was also positively related to symptom severity but only in recurrent MDD. Exploratory analyses also revealed alterations in FC of visual, sensory-motor, and dorsal attention networks in MDD. We confirmed the key role of DMN in MDD but found reduced rather than increased FC within the DMN. Future studies should test whether decreased DMN FC mediates response to treatment. All R-fMRI indices of data contributed by the REST-meta-MDD consortium are being shared publicly via the R-fMRI Maps Project.

https://www.pnas.org/content/pnas/116/18/9078.full.pdf

Reduced default mode network functional connectivity in patients with recurrent major depressive disorder.

The array of end organ innervations of the vagus nerve, coupled with increased basic science evidence, has led to vagus nerve stimulation (VNS) being explored as a management option in a number of clinical disorders, such as heart failure, migraine and inflammatory bowel disease. Both invasive (surgically implanted) and non-invasive (transcutaneous) techniques of VNS exist. Transcutaneous VNS (tVNS) delivery systems rely on the cutaneous distribution of vagal afferents, either at the external ear (auricular branch of the vagus nerve) or at the neck (cervical branch of the vagus nerve), thus obviating the need for surgical implantation of a VNS delivery device and facilitating further investigations across a wide range of uses. The concept of electrically stimulating the auricular branch of the vagus nerve (ABVN), which provides somatosensory innervation to several aspects of the external ear, is relatively more recent compared with cervical VNS; thus, there is a relative paucity of literature surrounding its operation and functionality. Despite the increasing body of research exploring the therapeutic uses of auricular transcutaneous VNS (tVNS), a comprehensive review of the cutaneous, intracranial and central distribution of ABVN fibres has not been conducted to date. A review of the literature exploring the neuroanatomical basis of this neuromodulatory therapy is therefore timely. Our review article explores the neuroanatomy of the ABVN with reference to (1) clinical surveys examining Arnold's reflex, (2) cadaveric studies, (3) fMRI studies, (4) electrophysiological studies, (5) acupuncture studies, (6) retrograde tracing studies and (7) studies measuring changes in autonomic (cardiovascular) parameters in response to auricular tVNS. We also provide an overview of the fibre composition of the ABVN and the effects of auricular tVNS on the central nervous system. Cadaveric studies, of which a limited number exist in the literature, would be the 'gold-standard' approach to studying the cutaneous map of the ABVN; thus, there is a need for more such studies to be conducted. Functional magnetic resonance imaging (fMRI) represents a useful surrogate modality for discerning the auricular sites most likely innervated by the ABVN and the most promising locations for auricular tVNS. However, given the heterogeneity in the results of such investigations and the various limitations of using fMRI, the current literature lacks a clear consensus on the auricular sites that are most densely innervated by the ABVN and whether the brain regions secondarily activated by electrical auricular tVNS depend on specific parameters. At present, it is reasonable to surmise that the concha and inner tragus are suitable locations for vagal modulation. Given the therapeutic potential of auricular tVNS, there remains a need for the cutaneous map of the ABVN to be further refined and the effects of various stimulation parameters and stimulation sites to be determined.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/joa.13122

The anatomical basis for transcutaneous auricular vagus nerve stimulation.

Importance Major depressive disorder (MDD) frequently emerges during adolescence and can lead to persistent illness, disability, and suicide. The maturational changes that take place in the brain during adolescence underscore the importance of examining neurobiological mechanisms during this time of early illness. However, neural mechanisms of depression in adolescents have been understudied. Research has implicated the amygdala in emotion processing in mood disorders, and adult depression studies have suggested amygdala-frontal connectivity deficits. Resting-state functional magnetic resonance imaging is an advanced tool that can be used to probe neural networks and identify brain-behavior relationships. Objective To examine amygdala resting-state functional connectivity (RSFC) in adolescents with and without MDD using resting-state functional magnetic resonance imaging as well as how amygdala RSFC relates to a broad range of symptom dimensions. Design, Setting, and Participants A cross-sectional resting-state functional magnetic resonance imaging study was conducted within a depression research program at an academic medical center. Participants included 41 adolescents and young adults aged 12 to 19 years with MDD and 29 healthy adolescents (frequency matched on age and sex) with no psychiatric diagnoses. Main Outcomes and Measures Using a whole-brain functional connectivity approach, we examined the correlation of spontaneous fluctuation of the blood oxygen level–dependent signal of each voxel in the whole brain with that of the amygdala. Results Adolescents with MDD showed lower positive RSFC between the amygdala and hippocampus, parahippocampus, and brainstem ( z >2.3, corrected P R  = −.523, P  = .01), dysphoria ( R  = −.455, P  = .05), and lassitude ( R  = −.449, P  = .05) and was positively correlated with well-being ( R  = .470, P  = .03). Patients also demonstrated greater (positive) amygdala-precuneus RSFC ( z >2.3, corrected P Conclusions and Relevance Impaired amygdala-hippocampal/brainstem and amygdala-precuneus RSFC have not previously been highlighted in depression and may be unique to adolescent MDD. These circuits are important for different aspects of memory and self-processing and for modulation of physiologic responses to emotion. The findings suggest potential mechanisms underlying both mood and vegetative symptoms, potentially via impaired processing of memories and visceral signals that spontaneously arise during rest, contributing to the persistent symptoms experienced by adolescents with depression.

https://jamanetwork.com/journals/jamapsychiatry/articlepdf/1895669/jamapsychiatry_Cullen_2014_oi_140052.pdf

Abnormal Amygdala Resting-State Functional Connectivity in Adolescent Depression

BackgroundConvergent studies provide support for abnormalities in the structure and functioning of the prefrontal cortex (PFC) and the amygdala, the key components of the neural system that subserves emotional processing in major depressive disorder (MDD). We used resting-state functional magnetic resonance imaging (fMRI) to examine potential amygdala–PFC functional connectivity abnormalities in treatment-naive subjects with MDD.MethodsResting-state fMRI data were acquired from 28 individuals with MDD and 30 healthy control (HC) subjects. Amygdala–PFC functional connectivity was compared between the MDD and HC groups.ResultsDecreased functional connectivity to the left ventral PFC (VPFC) from the left and right amygdala was observed in the MDD group, compared with the HC group (p < 0.05, corrected).ConclusionsThe treatment-naive subjects with MDD showed decreased functional connectivity from the amygdala to the VPFC, especially to the left VPFC. This suggests that these connections may play an important role in the neuropathophysiology of MDD at its onset.

/pdf/decreased-functional-connectivity-between-the-amygdala-and-saqmyyhaxf.pdf

Decreased functional connectivity between the amygdala and the left ventral prefrontal cortex in treatment-naive patients with major depressive disorder: a resting-state functional magnetic resonance imaging study.

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Decreased functional connectivity between the amygdala and the left ventral prefrontal cortex in treatment-naive patients with major depressive disorder: a resting-state functional magnetic resonance imaging study.