Volume of subcortical brain regions in social anxiety disorder: mega-analytic results from 37 samples in the ENIGMA-Anxiety Working Group.

There is limited convergence in neuroimaging investigations into volumes of subcortical brain regions in social anxiety disorder (SAD). The inconsistent findings may arise from variations in methodological approaches across studies, including sample selection based on age and clinical characteristics. The ENIGMA-Anxiety Working Group initiated a global mega-analysis to determine whether differences in subcortical volumes can be detected in adults and adolescents with SAD relative to healthy controls. Volumetric data from 37 international samples with 1115 SAD patients and 2775 controls were obtained from ENIGMA-standardized protocols for image segmentation and quality assurance. Linear mixed-effects analyses were adjusted for comparisons across seven subcortical regions in each hemisphere using family-wise error (FWE)-correction. Mixed-effects d effect sizes were calculated. In the full sample, SAD patients showed smaller bilateral putamen volume than controls (left: d = -0.077, pFWE = 0.037; right: d = -0.104, pFWE = 0.001), and a significant interaction between SAD and age was found for the left putamen (r = -0.034, pFWE = 0.045). Smaller bilateral putamen volumes (left: d = -0.141, pFWE < 0.001; right: d = -0.158, pFWE < 0.001) and larger bilateral pallidum volumes (left: d = 0.129, pFWE = 0.006; right: d = 0.099, pFWE = 0.046) were detected in adult SAD patients relative to controls, but no volumetric differences were apparent in adolescent SAD patients relative to controls. Comorbid anxiety disorders and age of SAD onset were additional determinants of SAD-related volumetric differences in subcortical regions. To conclude, subtle volumetric alterations in subcortical regions in SAD were detected. Heterogeneity in age and clinical characteristics may partly explain inconsistencies in previous findings. The association between alterations in subcortical volumes and SAD illness progression deserves further investigation, especially from adolescence into adulthood.

The generalization of behavioral control over physical threats to social stressors in humans: A pilot fMRI study.

Behavioral control, the ability to manage one's exposure to a given stressor, influences the impacts of both the present and future stressors. Behavioral control over a stressor may decrease stress caused by the stressor, and promote resilience towards future stressors. A lack of behavioral control may exacerbate the stress response and lead to learned helplessness, a generalized view that one cannot control other, unrelated stressors in their environment. The ventromedial prefrontal cortex (vmPFC) may detect the presence of behavioral control over a stressor and communicate this to subcortical regions involved in stress responses, such as the nucleus accumbens (NAc). Building on previous research in animals and humans, we piloted a paradigm to investigate how behavioral control over a physical threat (electric shocks), generalized to responses for a subsequent social stressor (anticipation of public speaking). Our manipulation of behavioral control effected perceived control between groups, increased stress across but not between groups, and no effects generalized to the subsequent social stressor in behavioral, physiological, or neural responses. We discuss refinements to the paradigm to strengthen the manipulation, the potential impacts of statistical power on the present results, and metrics to measure the generalization of behavioral control in addition to vmPFC-subcortical connectivity.

A randomized pharmacological fMRI trial investigating D-cycloserine and brain plasticity mechanisms in learned pain responses.

Learning and negative outcome expectations can increase pain sensitivity, a phenomenon known as nocebo hyperalgesia. Here, we examined how a targeted pharmacological manipulation of learning would impact nocebo responses and their brain correlates. Participants received either a placebo (n = 27) or a single 80 mg dose of D-cycloserine (a partial NMDA receptor agonist; n = 23) and underwent fMRI. Behavioral conditioning and negative suggestions were used to induce nocebo responses. Participants underwent pre-conditioning outside the scanner. During scanning, we first delivered baseline pain stimulations, followed by nocebo acquisition and extinction phases. During acquisition, high intensity thermal pain was paired with supposed activation of sham electrical stimuli (nocebo trials), whereas moderate pain was administered with inactive electrical stimulation (control trials). Nocebo hyperalgesia was induced in both groups (p < 0.001). Nocebo magnitudes and brain activations did not show significant differences between D-cycloserine and placebo. In acquisition and extinction, there were significantly increased activations bilaterally in the amygdala, ACC, and insula, during nocebo compared to control trials. Nocebo acquisition trials also showed increased vlPFC activation. Increased opercular activation differentiated nocebo-augmented pain aggravation from baseline pain. These results support the involvement of integrative cognitive-emotional processes in nocebo hyperalgesia.

Functional Connectivity Between Extrastriate Body Area and Default Mode Network Predicts Depersonalization Symptoms in Major Depression: Findings From an A Priori Specified Multinetwork Comparison.

BACKGROUND: Depersonalization/derealization disorder is a dissociative disorder characterized by feelings of unreality and detachment from the self and surroundings. Depersonalization/derealization disorder is classified as a primary disorder, but depersonalization symptoms are frequently observed in mood and anxiety disorders. In the context of major depressive disorder (MDD), depersonalization symptoms are associated with greater depressive severity as indexed by treatment resistance, inpatient visits, and duration of depressive episodes. In the current investigation, we tested four network-based, neural-functional hypotheses of depersonalization in MDD. These hypotheses were framed in terms of functional relationships between 1) extrastriate body area and default mode network (DMN); 2) hippocampus and DMN; 3) medial prefrontal cortex and ventral striatum; and 4) posterior and anterior insular cortex. METHODS: We conducted functional magnetic resonance imaging during resting state on 28 female patients with MDD and 27 control subjects with no history of a psychiatric disorder. Functional connectivity between seed and target regions as specified by our network-level hypotheses was computed and correlated with scores on the Cambridge Depersonalization Scale. We used a conservative, unbiased bootstrapping procedure to test the significance of neural-behavioral correlations observed under each of the four models tested. RESULTS: Of the four neural-functional models of depersonalization symptoms tested, only the model proposing that reduced connectivity between the extrastriate body area and DMN predicts higher levels of depersonalization symptoms in MDD was confirmed. CONCLUSIONS: Our results indicate that depersonalization/derealization disorder symptoms in patients with depression are related to reduced functional connectivity between brain regions that are proposed to support processing of body-related (extrastriate body area) and autobiographical (DMN) information.

The relation between statistical power and inference in fMRI.

Statistically underpowered studies can result in experimental failure even when all other experimental considerations have been addressed impeccably. In fMRI the combination of a large number of dependent variables, a relatively small number of observations (subjects), and a need to correct for multiple comparisons can decrease statistical power dramatically. This problem has been clearly addressed yet remains controversial-especially in regards to the expected effect sizes in fMRI, and especially for between-subjects effects such as group comparisons and brain-behavior correlations. We aimed to clarify the power problem by considering and contrasting two simulated scenarios of such possible brain-behavior correlations: weak diffuse effects and strong localized effects. Sampling from these scenarios shows that, particularly in the weak diffuse scenario, common sample sizes (n = 20-30) display extremely low statistical power, poorly represent the actual effects in the full sample, and show large variation on subsequent replications. Empirical data from the Human Connectome Project resembles the weak diffuse scenario much more than the localized strong scenario, which underscores the extent of the power problem for many studies. Possible solutions to the power problem include increasing the sample size, using less stringent thresholds, or focusing on a region-of-interest. However, these approaches are not always feasible and some have major drawbacks. The most prominent solutions that may help address the power problem include model-based (multivariate) prediction methods and meta-analyses with related synthesis-oriented approaches.

Voxel-based morphometry multi-center mega-analysis of brain structure in social anxiety disorder.

Social anxiety disorder (SAD) is a prevalent and disabling mental disorder, associated with significant psychiatric co-morbidity. Previous research on structural brain alterations associated with SAD has yielded inconsistent results concerning the direction of the changes in gray matter (GM) in various brain regions, as well as on the relationship between brain structure and SAD-symptomatology. These heterogeneous findings are possibly due to limited sample sizes. Multi-site imaging offers new opportunities to investigate SAD-related alterations in brain structure in larger samples. An international multi-center mega-analysis on the largest database of SAD structural T1-weighted 3T MRI scans to date was performed to compare GM volume of SAD-patients (n = 174) and healthy control (HC)-participants (n = 213) using voxel-based morphometry. A hypothesis-driven region of interest (ROI) approach was used, focusing on the basal ganglia, the amygdala-hippocampal complex, the prefrontal cortex, and the parietal cortex. SAD-patients had larger GM volume in the dorsal striatum when compared to HC-participants. This increase correlated positively with the severity of self-reported social anxiety symptoms. No SAD-related differences in GM volume were present in the other ROIs. Thereby, the results of this mega-analysis suggest a role for the dorsal striatum in SAD, but previously reported SAD-related changes in GM in the amygdala, hippocampus, precuneus, prefrontal cortex and parietal regions were not replicated. Our findings emphasize the importance of large sample imaging studies and the need for meta-analyses like those performed by the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium.

Social anxiety disorder: a critical overview of neurocognitive research.

Social anxiety is a common disorder characterized by a persistent and excessive fear of one or more social or performance situations. Behavioral inhibition is one of the early indicators of social anxiety, which later in life may advance into a certain personality structure (low extraversion and high neuroticism) and the development of maladaptive cognitive biases. While there are several effective psycho- and pharmacotherapy options, a large number of patients benefit insufficiently from these therapies. Brain and neuroendocrine research can help uncover both the biological basis of social anxiety and potentially provide indicators, 'biomarkers,' that may be informative for early disease detection or treatment response, above and beyond self-report data. Several large-scale brain networks related to emotion, motivation, cognitive control, and self-referential processing have been identified, and are affected in social anxiety. Social anxiety is further characterized by increased cortisol response and lower testosterone levels. These neuroendocrine systems are also related to altered connectivity patterns, such as reduced amygdala-prefrontal coupling. Much work is needed however to further elucidate such interactions between neuroendocrine functioning and large-scale brain networks. Despite the great promise of brain research in uncovering the neurobiological basis of social anxiety, several methodological and conceptual issues also need to be considered. WIREs Cogn Sci 2016, 7:218-232. doi: 10.1002/wcs.1390 For further resources related to this article, please visit the WIREs website.

Neural sensitivity to social reward and punishment anticipation in social anxiety disorder.

An imbalance in the neural motivational system may underlie Social Anxiety Disorder (SAD). This study examines social reward and punishment anticipation in SAD, predicting a valence-specific effect: increased striatal activity for punishment avoidance compared to obtaining a reward. Individuals with SAD (n = 20) and age, gender, and education case-matched controls (n = 20) participated in a functional magnetic resonance imaging (fMRI) study. During fMRI scanning, participants performed a Social Incentive Delay (SID) task to measure the anticipation of social reward and punishment. The left putamen (part of the striatum) showed a valence-specific interaction with group after correcting for medication use and comorbidity. The control group showed a relatively stronger activation for reward vs. punishment trials, compared to the social anxiety group. However, post-hoc pairwise comparisons were not significant, indicating that the effect is driven by a relative difference. A connectivity analysis (Psychophysiological interaction) further revealed a general salience effect: SAD patients showed decreased putamen-ACC connectivity compared to controls for both reward and punishment trials. Together these results suggest that the usual motivational preference for social reward is absent in SAD. In addition, cortical control processes during social incentive anticipation may be disrupted in SAD. These results provide initial evidence for altered striatal involvement in both valence-specific and valence-nonspecific processing of social incentives, and stress the relevance of taking motivational processes into account when studying social anxiety.

Neuroticism modulates amygdala-prefrontal connectivity in response to negative emotional facial expressions.

Neuroticism is associated with the experience of negative affect and the development of affective disorders. While evidence exists for a modulatory role of neuroticism on task induced brain activity, it is unknown how neuroticism affects brain connectivity, especially the crucial coupling between the amygdala and the prefrontal cortex. Here we investigate this relation between functional connectivity and personality in response to negative facial expressions. Sixty healthy control participants, from the Netherlands Study on Depression and Anxiety (NESDA), were scanned during an emotional faces gender decision task. Activity and functional amygdala connectivity (psycho-physiological interaction [PPI]) related to faces of negative emotional valence (angry, fearful and sad) was compared to neutral facial expressions, while neuroticism scores were entered as a regressor. Activity for fearful compared to neutral faces in the dorsomedial prefrontal (dmPFC) cortex was positively correlated with neuroticism scores. PPI analyses revealed that right amygdala-dmPFC connectivity for angry and fearful compared to neutral faces was positively correlated with neuroticism scores. In contrast, left amygdala-anterior cingulate cortex (ACC) connectivity for angry, fearful and sad compared to neutral faces was negatively related to neuroticism levels. DmPFC activity has frequently been associated with self-referential processing in social cognitive tasks. Our results therefore suggest that high neurotic participants display stronger self-referential processing in response to negative emotional faces. Second, in line with previous reports on ACC function, the negative correlation between amygdala-ACC connectivity and neuroticism scores might indicate that those high in neuroticism display diminished control function of the ACC over the amygdala. These connectivity patterns might be associated with vulnerability to developing affective disorders such as depression and anxiety.

Neural state and trait bases of mood-incongruent memory formation and retrieval in first-episode major depression.

Mood-congruent cognitive biases constitute critical factors for the vulnerability to depression and its maintenance. One important aspect is impaired memory for positive information during depression and after recovery. To elucidate its state (during depression only) and trait (during depression and recovery) related neural bases, we investigated medication free depressed, recovered, and healthy individuals with functional MRI while they memorized and recognized happy and neutral face stimuli. The imaging results revealed group differences in mood-incongruent successful memory encoding and retrieval activity already in the absence of significant memory performance differences. State effects were observed in the amygdala and posterior cingulate cortex. Whereas the amygdala was generally involved in memory formation, its activity predicted subsequent forgetting of neutral faces in depressed patients. Furthermore, the amygdala and posterior cingulate cortex were involved in memory retrieval of happy faces in depressed patients only. Trait effects were observed in the fusiform gyrus and prefrontal cortex. The fusiform gyrus was involved in memory formation and retrieval of happy faces in both patient groups, whereas it was involved in memory formation and retrieval of neutral faces in healthy individuals. Similar trait effects were observed during memory retrieval in the orbitofrontal cortex and left inferior frontal gyrus. Thus, while memory processing of positive information in the amygdala and posterior cingulate cortex is biased during depression only, memory processing in the fusiform gyrus and prefrontal cortex is biased also after recovery. These distinct neural mechanisms may respectively constitute symptom maintenance and cognitive vulnerability factors for depression.