Individuals with high anxiety show heightened neural activation in affective processing regions, including the amygdala and insula. Activations have been shown to be correlated with anxiety severity, but although anxiety is a heterogeneous state, prior studies have not systematically disentangled whether neural activity in affective processing circuitry is uniquely related to specific domains of anxiety. Forty-five young adults were tested on an emotional face processing task during functional magnetic resonance imaging. Participants completed the Social Interactional Anxiety Scale, Anxiety Sensitivity Index, and Spielberger Trait Anxiety Inventory. Using a robust multiple regression approach, we examined the effects of social anxiety, anxiety sensitivity, and trait anxiety (which overlapped with depressive symptoms, and can therefore be considered a measure of negative affectivity) on activation in insula, amygdala, and medial prefrontal cortex, in response to emotional faces. Adjusting for negative affectivity and anxiety sensitivity, social anxiety was associated with activity in left amygdala, right insula, and subgenual anterior cingulate across all emotional faces. When comparing negative and positive faces directly, greater negative affectivity was uniquely associated with less activity to positive faces in left amygdala, left anterior insula, and dorsal anterior cingulate. The current findings support the hypothesis that hyperactivity in brain areas during general emotional face processing is predominantly a function of social anxiety. In comparison, hypoactivity to positively valenced faces was predominantly associated with negative affectivity. Implications for the understanding of emotion processing in anxiety are discussed.

The goal of this study was to compare brain structure between individuals with generalized anxiety disorder (GAD) and healthy controls. Previous studies have generated inconsistent findings, possibly due to small sample sizes, or clinical/analytic heterogeneity. To address these concerns, we combined data from 28 research sites worldwide through the ENIGMA-Anxiety Working Group, using a single, pre-registered mega-analysis. Structural magnetic resonance imaging data from children and adults (5-90 years) were processed using FreeSurfer. The main analysis included the regional and vertex-wise cortical thickness, cortical surface area, and subcortical volume as dependent variables, and GAD, age, age-squared, sex, and their interactions as independent variables. Nuisance variables included IQ, years of education, medication use, comorbidities, and global brain measures. The main analysis (1020 individuals with GAD and 2999 healthy controls) included random slopes per site and random intercepts per scanner. A secondary analysis (1112 individuals with GAD and 3282 healthy controls) included fixed slopes and random intercepts per scanner with the same variables. The main analysis showed no effect of GAD on brain structure, nor interactions involving GAD, age, or sex. The secondary analysis showed increased volume in the right ventral diencephalon in male individuals with GAD compared to male healthy controls, whereas female individuals with GAD did not differ from female healthy controls. This mega-analysis combining worldwide data showed that differences in brain structure related to GAD are small, possibly reflecting heterogeneity or those structural alterations are not a major component of its pathophysiology.

Differentiating whether an action leads to an outcome by chance or by an underlying statistical regularity that signals environmental change profoundly affects adaptive behavior. Previous studies have shown that anxious individuals may not appropriately differentiate between these situations. This investigation aims to precisely quantify the process deficit in anxious individuals and determine the degree to which these process dysfunctions are specific to anxiety.

Hyperarousal symptoms in generalized anxiety disorder (GAD) are often incongruent with the observed physiological state, suggesting that abnormal processing of interoceptive signals is a characteristic feature of the disorder. To examine the neural mechanisms underlying interoceptive dysfunction in GAD, we evaluated whether adrenergic modulation of cardiovascular signaling differentially affects the heartbeat evoked potential (HEP), an electrophysiological marker of cardiac interoception, during concurrent electroencephalogram and functional magnetic resonance imaging (EEG-fMRI) scanning. Intravenous infusions of the peripheral adrenergic agonist isoproterenol (0.5 and 2.0 micrograms, μg) were administered in a randomized, double-blinded and placebo-controlled fashion to dynamically perturb the cardiovascular system while recording the associated EEG-fMRI responses. During the 0.5 μg isoproterenol infusion, the GAD group (n=24) exhibited significantly larger changes in HEP amplitude in an opposite direction than the HC group (n=24). In addition, the GAD group showed significantly larger absolute HEP amplitudes than HC during saline infusions, when cardiovascular tone did not increase. No significant group differences in HEP amplitude were identified during the 2.0 μg isoproterenol infusion. Using analyzable blood oxygenation level dependent fMRI data from participants with concurrent EEG-fMRI data (21 GAD and 21 HC), we found that the aforementioned HEP effects were uncorrelated with fMRI signals in the insula, ventromedial prefrontal cortex, dorsal anterior cingulate cortex, amygdala, and somatosensory cortex, brain regions implicated in cardiac signal processing according to prior fMRI studies. These findings provide additional evidence of dysfunctional cardiac interoception in GAD and identify neural processes at the electrophysiological level that may be independent from blood oxygen level-dependent responses during peripheral adrenergic stimulation.

The ENIGMA group on Generalized Anxiety Disorder (ENIGMA-Anxiety/GAD) is part of a broader effort to investigate anxiety disorders using imaging and genetic data across multiple sites worldwide. The group is actively conducting a mega-analysis of a large number of brain structural scans. In this process, the group was confronted with many methodological challenges related to study planning and implementation, between-country transfer of subject-level data, quality control of a considerable amount of imaging data, and choices related to statistical methods and efficient use of resources. This report summarizes the background information and rationale for the various methodological decisions, as well as the approach taken to implement them. The goal is to document the approach and help guide other research groups working with large brain imaging data sets as they develop their own analytic pipelines for mega-analyses.

Depressive pathology, which includes both heightened negative affect (e.g., anxiety) and reduced positive affect (e.g., anhedonia), is known to be associated with sub-optimal decision-making, particularly in uncertain environments. Here, we use a computational approach to quantify and disambiguate how individual differences in these affective measures specifically relate to different aspects of learning and decision-making in reward-based choice behavior. Fifty-three individuals with a range of depressed mood completed a two-armed bandit task, in which they choose between two arms with fixed but unknown reward rates. The decision-making component, which chooses among options based on current expectations about reward rates, is modeled by two different decision policies: a learning-independent Win-stay/Lose-shift (WSLS) policy that ignores all previous experiences except the last trial, and Softmax, which prefers the arm with the higher expected reward. To model the learning component for the Softmax choice policy, we use a Bayesian inference model, which updates estimated reward rates based on the observed history of trial outcomes. Softmax with Bayesian learning better fits the behavior of 55% of the participants, while the others are better fit by a learning-independent WSLS strategy. Among Softmax "users", those with higher anhedonia are less likely to choose the option estimated to be most rewarding. Moreover, the Softmax parameter mediates the inverse relationship between anhedonia and overall monetary gains. On the other hand, among WSLS "users", higher state anxiety correlates with increasingly better ability of WSLS, relative to Softmax, to explain subjects' trial-by-trial choices. In summary, there is significant variability among individuals in their reward-based, exploratory decision-making, and this variability is at least partly mediated in a very specific manner by affective attributes, such as hedonic tone and state anxiety.

Prior neuroimaging studies support the hypothesis that anticipation, an important component of anxiety, may be mediated by activation within the insular and medial prefrontal cortices including the anterior cingulate cortex. However, there is an insufficient understanding of how affective anticipation differs across anxiety groups in emotional brain loci and networks. We examined 14 anxiety positive (AP) and 14 anxiety normative (AN) individuals completing an affective picture anticipation task during functional magnetic resonance imaging (fMRI). Brain activation was examined across groups for cued anticipation (to aversive or pleasant stimuli). Both groups showed greater activation in the bilateral anterior insula during cued differential anticipation (i.e., aversive vs. pleasant), and activation on the right was significantly higher in AP compared to AN subjects. Functional connectivity showed that the left anterior insula was involved in a similar network during pleasant anticipation in both groups. The left anterior insula during aversive and the right anterior insula during all anticipation conditions coactivated with a cortical network consisting of frontal and parietal lobes in the AP group to a greater degree. These results are consistent with the hypothesis that anxiety is related to greater anticipatory reactivity in the brain and that there may be functional asymmetries in the brain that interact with psychiatric traits.

This study employed a series of heartbeat perception tasks to assess the hypothesis that cardiac interoceptive processing in individuals with depression/anxiety (N = 221), and substance use disorders (N = 136) is less flexible than that of healthy individuals (N = 53) in the context of physiological perturbation. Cardiac interoception was assessed via heartbeat tapping when: (1) guessing was allowed; (2) guessing was not allowed; and (3) experiencing an interoceptive perturbation (inspiratory breath hold) expected to amplify cardiac sensation. Healthy participants showed performance improvements across the three conditions, whereas those with depression/anxiety and/or substance use disorder showed minimal improvement. Machine learning analyses suggested that individual differences in these improvements were negatively related to anxiety sensitivity, but explained relatively little variance in performance. These results reveal a perceptual insensitivity to the modulation of interoceptive signals that was evident across several common psychiatric disorders, suggesting that interoceptive deficits in the realm of psychopathology manifest most prominently during states of homeostatic perturbation.

Floatation-REST (Reduced Environmental Stimulation Therapy), an intervention that attenuates exteroceptive sensory input to the nervous system, has recently been found to reduce state anxiety across a diverse clinical sample with high levels of anxiety sensitivity (AS). To further examine this anxiolytic effect, the present study investigated the affective and physiological changes induced by Floatation-REST and assessed whether individuals with high AS experienced any alterations in their awareness for interoceptive sensation while immersed in an environment lacking exteroceptive sensation.

Exposure-based therapy (EXP) and behavioral activation (BA) are empirically-supported behavioral intervention techniques that target avoidance and approach behavior to alleviate symptoms. Although EXP is an established treatment for generalized anxiety disorder (GAD), the effectiveness of BA for GAD has not been directly tested or compared with that of EXP. This study examined the efficacy of EXP and BA for adults with GAD.

Several studies have recently suggested that an abnormal processing of respiratory interoceptive and nociceptive (painful) stimuli may contribute to eating disorder (ED) pathophysiology. Mood and anxiety disorders (MA) are also characterized by abnormal respiratory symptoms, and show substantial comorbidity with ED. However, no studies have examined both respiratory and pain processing simultaneously within ED and MA. The present study systematically evaluated responses to perturbations of respiratory and nociceptive signals across the levels of physiology, behavior, and symptom report in a transdiagnostic ED sample (n = 51) that was individually matched to MA individuals (n = 51) and healthy comparisons (HC; n = 51). Participants underwent an inspiratory breath-holding challenge as a probe of respiratory interoception and a cold pressor challenge as a probe of pain processing. We expected both clinical groups to report greater stress and fear in response to respiratory and nociceptive perturbation than HCs, in the absence of differential physiological and behavioral responses. During breath-holding, both the ED and MA groups reported significantly more stress, feelings of suffocation, and suffocation fear than HC, with the ED group reporting the most severe symptoms. Moreover, anxiety sensitivity was related to suffocation fear only in the ED group. The heightened affective responses in the current study occurred in the absence of group differences in behavioral (breath hold duration, cold pressor duration) and physiological (end-tidal carbon dioxide, end-tidal oxygen, heart rate, skin conductance) responses. Against our expectations, there were no group differences in the response to cold pain stimulation. A matched-subgroup analysis focusing on individuals with anorexia nervosa (n = 30) produced similar results. These findings underscore the presence of abnormal respiratory interoception in MA and suggest that hyperreactivity to respiratory signals may be a potentially overlooked clinical feature of ED.

Recent neurocomputational theories have hypothesized that abnormalities in prior beliefs and/or the precision-weighting of afferent interoceptive signals may facilitate the transdiagnostic emergence of psychopathology. Specifically, it has been suggested that, in certain psychiatric disorders, interoceptive processing mechanisms either over-weight prior beliefs or under-weight signals from the viscera (or both), leading to a failure to accurately update beliefs about the body. However, this has not been directly tested empirically. To evaluate the potential roles of prior beliefs and interoceptive precision in this context, we fit a Bayesian computational model to behavior in a transdiagnostic patient sample during an interoceptive awareness (heartbeat tapping) task. Modelling revealed that, during an interoceptive perturbation condition (inspiratory breath-holding during heartbeat tapping), healthy individuals (N = 52) assigned greater precision to ascending cardiac signals than individuals with symptoms of anxiety (N = 15), depression (N = 69), co-morbid depression/anxiety (N = 153), substance use disorders (N = 131), and eating disorders (N = 14)-who failed to increase their precision estimates from resting levels. In contrast, we did not find strong evidence for differences in prior beliefs. These results provide the first empirical computational modeling evidence of a selective dysfunction in adaptive interoceptive processing in psychiatric conditions, and lay the groundwork for future studies examining how reduced interoceptive precision influences visceral regulation and interoceptively-guided decision-making.

Survey-based studies show that neighborhood disadvantage is associated with community reported mental health problems. However, fewer studies have examined whether neighborhood characteristics have measurable impact on mental health status of individuals in general and whether neighborhood characteristics impact positive/negative valence processing at both behavioral and brain levels. This study addressed these questions by investigating effects of census-based neighborhood affluence on self-reported symptoms, brain functions, and structures associated with positive/negative valence processing in a sample of individuals with mood and anxiety disorders (n = 262). Employing a Bayesian inference approach, our investigation demonstrates that neighborhood affluence fails to be associated with positive/negative valence processing measured across multiple modalities, with the only effects of neighborhood affluence identified in trait anxiety scores. These findings highlight that while community-based relationships between neighborhood characteristics and mental health problems are strong, it is much less clear that these characteristics have a measurable impact on the individual.

Although patient history is essential for informing mental health assessment, diagnosis, and prognosis, there is a dearth of standardized instruments measuring time-dependent factors relevant to psychiatric disorders. Previous research has demonstrated the potential utility of graphical representations, termed life charts, for depicting the complexity of the course of mental illness. However, the implementation of these assessments is limited by the exclusive focus on specific mental illnesses (ie, bipolar disorder) and the lack of intuitive graphical interfaces for data collection and visualization.

Individuals with mood/anxiety disorders may use cannabis for "self-medication," i.e., to induce positive mood or attenuate aversive mood states. However, little neurobiological evidence supports such use. The goal of this investigation was to test the hypothesis that cannabis use attenuates striatal response to reward in those with mood/anxiety disorders. Reward-related processing was measured using a monetary incentive delay task under functional MRI. Individuals with any lifetime mood/anxiety disorder diagnoses and problematic cannabis use ("Mood/Anxiety+CB"; n = 41) were compared with a propensity score-matched group of similar subjects without cannabis use ("Mood/Anxiety-CB"; n = 41), and a cannabis-naïve healthy control group (n = 35). Activations during win- and loss-anticipations were extracted from bilateral nucleus accumbens, dorsal caudate, and dorsolateral putamen. Mixed models were estimated for each region separately for win- and loss-anticipations, with a test for the main effect of group, condition (e.g., high-win, low-win, neutral), and their interaction. A significant main effect of group for win- and loss-anticipation was observed for each striatal region. Specifically, the Mood/Anxiety+CB group exhibited the lowest striatal activations across condition levels relative to both the Mood/Anxiety-CB and healthy group. A significant group-by-condition interaction was only observed for the dorsolateral putamen and indicated divergent activation modulation as a function of win and loss-magnitude for Mood/Anxiety+CB subjects. Finally, individuals with heavier recent cannabis use showed greater attenuation of gain-related activation in all three striatal regions. There was no such relationship for other illicit drugs. These data support the hypothesis that cannabis use in individuals with mood/anxiety disorders is associated with attenuated brain processing of reward magnitude, which may contribute to persistent affective symptoms.

Relapse rates are consistently high for stimulant user disorders. In order to obtain prognostic information about individuals in treatment, machine learning models have been applied to neuroimaging and clinical data. Yet few efforts have been made to test these models in independent samples or show that they can outperform linear models. In this exploratory study, we examine whether machine learning models relative to linear models provide greater predictive accuracy and less overfitting.

Human cytomegalovirus (HCMV) infection is associated with neuropathology in patients with impaired immunity and/or inflammatory diseases. However, the association between gray matter volume (GMV) and HCMV has never been examined in major depressive disorder (MDD) despite the presence of inflammation and impaired viral immunity in a subset of patients. We tested this relationship in two independent samples consisting of 179 individuals with MDD and 41 healthy controls (HC) (sample 1) and 124 MDD participants and 148 HCs (sample 2). HCMV positive (HCMV+) and HCMV negative (HCMV-) groups within each sample were balanced on up to 11 different clinical/demographic variables using inverse probability of treatment weighting. GMV of 87 regions was measured with FreeSurfer. There was a main effect of HCMV serostatus but not diagnosis that replicated across samples. Relative to HCMV- subjects, HCMV+ subjects in sample 1 showed a significant reduction of volume in six regions (puncorrected < 0.05). The reductions in GMV of the right supramarginal gyrus (standardized beta coefficient (SBC) = -0.26) and left fusiform gyrus (SBC = -0.25) in sample 1 were replicated in sample 2: right supramarginal gyrus (puncorrected < 0.05, SBC = -0.32), left fusiform gyrus (PFDR < 0.01, SBC = -0.51). Posthoc tests revealed that the effect of HCMV was driven by differences between the HCMV+ and HCMV- MDD subgroups. HCMV IgG level, a surrogate marker of viral activity, was correlated with GMV in the left fusiform gyrus (r = -0.19, Puncorrected = 0.049) and right supramarginal gyrus (r = -0.19, puncorrected = 0.043) in the HCMV+ group of sample 1. Conceivably, HCMV infection may be a treatable source of neuropathology in vulnerable MDD patients.

Floatation-REST (Reduced Environmental Stimulation Therapy) reduces sensory input to the nervous system through the act of floating supine in a pool of water saturated with Epsom salt. The float experience is calibrated so that sensory signals from visual, auditory, olfactory, gustatory, thermal, tactile, vestibular, gravitational and proprioceptive channels are minimized, as is most movement and speech. This open-label study aimed to examine whether Floatation-REST would attenuate symptoms of anxiety, stress, and depression in a clinical sample. Fifty participants were recruited across a spectrum of anxiety and stress-related disorders (posttraumatic stress, generalized anxiety, panic, agoraphobia, and social anxiety), most (n = 46) with comorbid unipolar depression. Measures of self-reported affect were collected immediately before and after a 1-hour float session, with the primary outcome measure being the pre- to post-float change score on the Spielberger State Anxiety Inventory. Irrespective of diagnosis, Floatation-REST substantially reduced state anxiety (estimated Cohen's d > 2). Moreover, participants reported significant reductions in stress, muscle tension, pain, depression and negative affect, accompanied by a significant improvement in mood characterized by increases in serenity, relaxation, happiness and overall well-being (p < .0001 for all variables). In reference to a group of 30 non-anxious participants, the effects were found to be more robust in the anxious sample and approaching non-anxious levels during the post-float period. Further analysis revealed that the most severely anxious participants reported the largest effects. Overall, the procedure was well-tolerated, with no major safety concerns stemming from this single session. The findings from this initial study need to be replicated in larger controlled trials, but suggest that Floatation-REST may be a promising technique for transiently reducing the suffering in those with anxiety and depression.

Background: The COVID-19 pandemic has brought on far-reaching consequences for adolescents. Adolescents with early life stress (ELS) may be at particular risk. We sought to examine how COVID-19 impacted psychological functioning in a sample of healthy and ELS-exposed adolescents during the pandemic. Methods: A total of 24 adolescents (15 healthy, nine ELS) completed self-report measures prior to and during the COVID-19 pandemic. The effect of COVID-19 on symptoms of depression and anxiety were explored using linear mixed-effect analyses. Results: With the onset of the pandemic, healthy but not ELS-exposed adolescents evidenced increased symptoms of depression and anxiety (ps < 0.05). Coping by talking with friends and prioritizing sleep had a protective effect against anxiety for healthy adolescents (t = -3.76, p = 0.002). Conclusions: On average, this study demonstrated large increases in depression and anxiety in adolescents who were healthy prior to the COVID-19 pandemic, while ELS-exposed adolescents evidenced high but stable symptoms over time.

Major depressive disorder (MDD) is associated with reductions in white matter microstructural integrity as measured by fractional anisotropy (FA), an index derived from diffusion tensor imaging (DTI). The neurotropic herpesvirus, human cytomegalovirus (HCMV), is a major cause of white matter pathology in immunosuppressed populations but its relationship with FA has never been tested in MDD despite the presence of inflammation and weakened antiviral immunity in a subset of depressed patients. We tested the relationship between FA and HCMV infection in two independent samples consisting of 176 individuals with MDD and 44 healthy controls (HC) (Discovery sample) and 88 participants with MDD and 48 HCs (Replication sample). Equal numbers of HCMV positive (HCMV+) and HCMV negative (HCMV-) groups within each sample were balanced on ten different clinical/demographic variables using propensity score matching. Anti-HCMV IgG antibodies were measured using a solid-phase ELISA. In the Discovery sample, significantly lower FA was observed in the right inferior fronto-occipital fasciculus (IFOF) in HCMV+ participants with MDD compared to HCMV- participants with MDD (cluster size 1316 mm3; pFWE < 0.05, d = -0.58). This association was confirmed in the replication sample by extracting the mean FA from this exact cluster and applying the identical statistical model (p < 0.05, d = -0.45). There was no significant effect of diagnosis or interaction between diagnosis and HCMV in either sample. The effect of chronic HCMV infection on white matter integrity may-in at-risk individuals-contribute to the psychopathology of depression. These findings may provide a novel target of intervention for a subgroup of patients with MDD.