The neuro-anatomical substrates of major depressive disorder (MDD) are still not well understood, despite many neuroimaging studies over the past few decades. Here we present the largest ever worldwide study by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Major Depressive Disorder Working Group on cortical structural alterations in MDD. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2148 MDD patients and 7957 healthy controls were analysed with harmonized protocols at 20 sites around the world. To detect consistent effects of MDD and its modulators on cortical thickness and surface area estimates derived from MRI, statistical effects from sites were meta-analysed separately for adults and adolescents. Adults with MDD had thinner cortical gray matter than controls in the orbitofrontal cortex (OFC), anterior and posterior cingulate, insula and temporal lobes (Cohen's d effect sizes: −0.10 to −0.14). These effects were most pronounced in first episode and adult-onset patients (>21 years). Compared to matched controls, adolescents with MDD had lower total surface area (but no differences in cortical thickness) and regional reductions in frontal regions (medial OFC and superior frontal gyrus) and primary and higher-order visual, somatosensory and motor areas (d: −0.26 to −0.57). The strongest effects were found in recurrent adolescent patients. This highly powered global effort to identify consistent brain abnormalities showed widespread cortical alterations in MDD patients as compared to controls and suggests that MDD may impact brain structure in a highly dynamic way, with different patterns of alterations at different stages of life.

Classical Pavlovian fear conditioning remains the most widely employed experimental model of fear and anxiety, and continues to inform contemporary pathophysiological accounts of clinical anxiety disorders. Despite its widespread application in human and animal studies, the neurobiological basis of fear conditioning remains only partially understood. Here we provide a comprehensive meta-analysis of human fear-conditioning studies carried out with functional magnetic resonance imaging (fMRI), yielding a pooled sample of 677 participants from 27 independent studies. As a distinguishing feature of this meta-analysis, original statistical brain maps were obtained from the authors of 13 of these studies. Our primary analyses demonstrate that human fear conditioning is associated with a consistent and robust pattern of neural activation across a hypothesized genuine network of brain regions resembling existing anatomical descriptions of the 'central autonomic-interoceptive network'. This finding is discussed with a particular emphasis on the neural substrates of conscious fear processing. Our associated meta-analysis of functional deactivations-a scarcely addressed dynamic in fMRI fear-conditioning studies-also suggests the existence of a coordinated brain response potentially underlying the 'safety signal' (that is, non-threat) processing. We attempt to provide an integrated summary on these findings with the view that they may inform ongoing studies of fear-conditioning processes both in healthy and clinical populations, as investigated with neuroimaging and other experimental approaches.

This study directly supports the hypothesis that OCD is associated with functional alterations of brain corticostriatal networks. Specifically, our findings emphasize abnormal and heightened functional connectivity of ventrolimbic corticostriatal regions in patients with OCD.

Analyses of functional interactions between large-scale brain networks have identified two broad systems that operate in apparent competition or antagonism with each other. One system, termed the default mode network (DMN), is thought to support internally oriented processing. The other system acts as a generic external attention system (EAS) and mediates attention to exogenous stimuli. Reports that the DMN and EAS show anticorrelated activity across a range of experimental paradigms suggest that competition between these systems supports adaptive behavior. Here, we used functional MRI to characterize functional interactions between the DMN and different EAS components during performance of a recollection task known to coactivate regions of both networks. Using methods to isolate task-related, context-dependent changes in functional connectivity between these systems, we show that increased cooperation between the DMN and a specific right-lateralized frontoparietal component of the EAS is associated with more rapid memory recollection. We also show that these cooperative dynamics are facilitated by a dynamic reconfiguration of the functional architecture of the DMN into core and transitional modules, with the latter serving to enhance integration with frontoparietal regions. In particular, the right posterior cingulate cortex may act as a critical information-processing hub that provokes these context-dependent reconfigurations from an intrinsic or default state of antagonism. Our findings highlight the dynamic, contextdependent nature of large-scale brain dynamics and shed light on their contribution to individual differences in behavior.complex | graph | modularity | rest | connectome I ncreasing evidence points to a fundamental distinction between two large-scale functional systems in the brain (1-4). One system, comprising regions of lateral prefrontal and parietal cortex, dorsal anterior cingulate, and anterior insula/frontoopercular regions, typically shows increased activation during performance of challenging cognitive tasks and has been implicated in attentional and cognitive control functions (5, 6). It may thus be generally referred to as an external attention system (EAS), but it has also been labeled the task-positive and extrinsic network (3, 4). The other system, often called the default mode network (DMN), is localized primarily to midline posterior and anterior cortical regions, the angular gyri, and medial and lateral temporal cortices (7,8). It often shows decreased activity during tasks requiring attention to external stimuli (9, 10) and increased activity during unconstrained thought, introspection, and self-related processing (7, 11). The apparent antagonism between these two systems is mirrored in their spontaneous dynamics, which are often strongly anticorrelated (2). These competitive interactions are thought to promote adaptive and efficient alternation between DMN-dominated introspective thought and EAS-mediated processing of external stimuli (1-4).Several lines of evidence support thi...

Cognitive deficits, especially poor response inhibition, are likely to be persistent features, at least of some forms, of adult-onset MDD. More studies are necessary to examine cognitive dysfunction in remitted psychotic, melancholic and bipolar spectrum MDD. Cognitive deficits overall appear to be more common among patients with late-onset depression, supporting the theories suggesting that possible vascular and neurodegenerative factors play a role in a substantial number of these patients.

The brain's default mode network (DMN) has become closely associated with self-referential mental activity, particularly in the resting-state. While the DMN is important for such processes, it has functions other than self-reference, and self-referential processes are supported by regions outside of the DMN. In our study of 88 participants, we examined self-referential and resting-state processes to clarify the extent to which DMN activity was common and distinct between the conditions. Within areas commonly activated by self-reference and rest we sought to identify those that showed additional functional specialization for self-referential processes: these being not only activated by self-reference and rest but also showing increased activity in self-reference versus rest. We examined the neural network properties of the identified 'core-self' DMN regions-in medial prefrontal cortex (MPFC), posterior cingulate cortex (PCC), and inferior parietal lobule-using dynamic causal modeling. The optimal model identified was one in which self-related processes were driven via PCC activity and moderated by the regulatory influences of MPFC. We thus confirm the significance of these regions for self-related processes and extend our understanding of their functionally specialized roles.

IMPORTANCE Dysregulation of corticostriatal circuitry has long been thought to be critical in the etiology of psychotic disorders, although the differential roles played by dorsal and ventral systems in mediating risk for psychosis have been contentious.OBJECTIVE To use resting-state functional magnetic resonance imaging to characterize disease-related, risk-related, and symptom-related changes of corticostriatal functional circuitry in patients with first-episode psychosis and their unaffected first-degree relatives. DESIGN, SETTING, AND PARTICIPANTSThis case-control cross-sectional study was conducted at a specialist early psychosis clinic, GlaxoSmithKline Clinical Unit, and magnetic resonance imaging facility. Nineteen patients with first-episode psychosis, 25 of their unaffected first-degree relatives, and 26 healthy control subjects were included in this study. MAIN OUTCOMES AND MEASURESVoxelwise statistical parametric maps testing differences in the strength of functional connectivity between 6 striatal seed regions of interest (3 caudate and 3 putamen) per hemisphere and all other brain regions.RESULTS Disease-related changes, reflecting differences between patients and control subjects, involved widespread dysregulation of corticostriatal systems characterized most prominently by a dorsal-to-ventral gradient of hypoconnectivity to hyperconnectivity between striatal and prefrontal regions. A similar gradient was evident in comparisons between relatives and control subjects, identifying it as a genetically inherited risk phenotype. In patients, functional connectivity in risk-affected and disease-affected dorsal frontostriatal circuitry correlated with the severity of both positive and negative symptoms.CONCLUSIONS AND RELEVANCE First-episode psychosis is associated with pronounced dysregulation of corticostriatal systems, characterized most prominently by hypoconnectivity of dorsal and hyperconnectivity of ventral frontostriatal circuits. These changes correlate with symptom severity and are also apparent in unaffected first-degree relatives, suggesting that they represent a putative risk phenotype for psychotic illness.

The notion of a ''default mode of brain function'' has taken on certain relevance in human neuroimaging studies and in relation to a network of lateral parietal and midline cortical regions that show prominent activity fluctuations during passive imaging states, such as rest. In this study, we perform three fMRI experiments that demonstrate consistency and specialization in the default mode network. Correlated activity fluctuations of default mode network regions are identified during (i) eyes-closed spontaneous rest, (ii) activation by moral dilemma, and (iii) deactivation by Stroop task performance. Across these imaging states, striking uniformity is shown in the basic anatomy of the default mode network, but with both tasks clearly and differentially modulating this activity compared with spontaneous fluctuations of the network at rest. Against rest, moral dilemma is further shown to evoke regionally specific activity increases of hypothesized functional relevance. Mapping spontaneous and task-related brain activity will help to constrain the meaning of the default mode network. These findings are discussed in relation to recent debate on the topic of default modes of brain function.activation ͉ deactivation ͉ default mode ͉ functional MRI ͉ spontaneous activity