Brain activity during reappraisal and associations with psychotherapy response in social anxiety and major depression: a randomized trial.

BACKGROUND: Cognitive behavioral therapy (CBT) is an effective treatment for patients with social anxiety disorder (SAD) or major depressive disorder (MDD), yet there is variability in clinical improvement. Though prior research suggests pre-treatment engagement of brain regions supporting cognitive reappraisal (e.g. dorsolateral prefrontal cortex [dlPFC]) foretells CBT response in SAD, it remains unknown if this extends to MDD or is specific to CBT. The current study examined associations between pre-treatment neural activity during reappraisal and clinical improvement in patients with SAD or MDD following a trial of CBT or supportive therapy (ST), a common-factors comparator arm. METHODS: Participants were 75 treatment-seeking patients with SAD (n = 34) or MDD (n = 41) randomized to CBT (n = 40) or ST (n = 35). Before randomization, patients completed a cognitive reappraisal task during functional magnetic resonance imaging. Additionally, patients completed clinician-administered symptom measures and a self-report cognitive reappraisal measure before treatment and every 2 weeks throughout treatment. RESULTS: Results indicated that pre-treatment neural activity during reappraisal differentially predicted CBT and ST response. Specifically, greater trajectories of symptom improvement throughout treatment were associated with less ventrolateral prefrontal cortex (vlPFC) activity for CBT patients, but more vlPFC activity for ST patients. Also, less baseline dlPFC activity corresponded with greater trajectories of self-reported reappraisal improvement, regardless of treatment arm. CONCLUSIONS: If replicated, findings suggest individual differences in brain response during reappraisal may be transdiagnostically associated with treatment-dependent improvement in symptom severity, but improvement in subjective reappraisal following psychotherapy, more broadly.

Network Diffusion Embedding Reveals Transdiagnostic Subnetwork Disruption and Potential Treatment Targets in Internalizing Psychopathologies.

Network diffusion models are a common and powerful way to study the propagation of information through a complex system and they offer straightforward approaches for studying multimodal brain network data. We developed an analytic framework to identify brain subnetworks with perturbed information diffusion capacity using the structural basis that best maps to resting state functional connectivity and applied it towards a heterogeneous dataset of internalizing psychopathologies (IPs), a set of psychiatric conditions in which similar brain network deficits are found across the swath of the disorders, but a unifying neuropathological substrate for transdiagnostic symptom expression is currently unknown. This research provides preliminary evidence of a transdiagnostic brain subnetwork deficit characterized by information diffusion impairment of the right area 8BM, a key brain region involved in organizing a broad spectrum of cognitive tasks, which may underlie previously reported dysfunction of multiple brain circuits in the IPs. We also demonstrate that models of neuromodulation involving targeting this brain region normalize IP diffusion dynamics towards those of healthy controls. These analyses provide a framework for multimodal methods that identify both brain subnetworks with disrupted information diffusion and potential targets of these subnetworks for therapeutic neuromodulatory intervention based on previously well-characterized methodology.

Brain response to emotional faces in anxiety and depression: neural predictors of cognitive behavioral therapy outcome and predictor-based subgroups following therapy.

BACKGROUND: Neuroimaging studies have shown variance in brain response to emotional faces predicts cognitive behavioral therapy (CBT) outcome. An important next step is to determine if individual differences in neural predictors of CBT response represent distinct patient groups. METHODS: In total, 90 patients with internalizing disorders completed a face-matching task during functional magnetic resonance imaging before and after 12 weeks of CBT and 45 healthy controls completed the task before and after 12 weeks. Patients exhibiting a pre-to-post CBT >50% reduction in symptom severity on two measures were considered treatment responders. Regions of interest (ROIs) for angry, fearful, and happy faces were submitted to receiver operating characteristic (ROC) curve analysis. Significant ROIs were then submitted to decision tree analysis to classify responder/non-responder subgroups. Psychophysiological interactions (PPI) were used to explore functional connectivity in the region(s) that delineated subgroups. RESULTS: A total of 51 patients were treatment responders and ROC curve results were significant for all face types though specific regions varied. Decision tree results revealed superior occipital response to angry faces identified patient subgroups such that the subgroup with 'high' occipital activity had more responders than the 'low' occipital subgroup. Following CBT, the high, relative to low, occipital subgroup was less symptomatic. Controls exhibited stable superior occipital activation over time. Whole-brain PPI showed reduced baseline superior occipital-postcentral gyrus functional connectivity in responders compared to non-responders. CONCLUSIONS: Preliminary findings indicate patients characterized by relatively more pre-treatment superior occipital gyrus engagement to angry faces and reduced superior occipital-postcentral gyrus connectivity, relative to non-responders, may represent a phenotype likely to benefit from CBT.

Neural reactivity to affective stimuli and internalizing symptom dimensions in a transdiagnostic patient sample.

BACKGROUND: Internalizing psychopathologies (IPs) are highly comorbid and exhibit substantial overlap, such as aberrant affective reactivity. Neural reactivity to emotional images, measured via the late positive potential (LPP) event-related potential (ERP) component, has been utilized to index affective reactivity in IPs. The LPP is often examined in isolation with a specific disorder, ignoring overlap between IPs. The current study examined how transdiagnostic IP symptom dimensions relate to neural affective reactivity in a highly comorbid patient sample. METHODS: Participants (N = 99) completed a battery of IP symptom assessments as well as a target categorization task while viewing pleasant, unpleasant, and neutral images during electroencephalography recording. ERPs to each image valence were averaged from 400 to 1000 ms following picture onset at pooled centroparietal and occipital electrodes to calculate the LPP. A principal components analysis performed on the IP symptom measures resulted in two factors: affective distress/misery and fear-based anxiety. RESULTS: Fear-based anxiety was associated with enhanced LPP reactivity to unpleasant, but not pleasant, images. Distress/misery was related to attenuated average LPP reactivity across images. CONCLUSIONS: Results revealed a dissociable effect of IP symptom factors in a transdiagnostic sample such that enhanced reactivity to negative images was specific to enhanced fear-based anxiety symptoms while distress/misery symptoms predicted blunted affective reactivity. Neural affective reactivity may serve as an objective biological marker to elucidate the nature of psychological concerns in individuals with comorbid IPs.

Resting state functional connectivity correlates of rumination and worry in internalizing psychopathologies.

BACKGROUND: Rumination and worry are repetitive negative thinking (RNT) tendencies that contribute to the development and maintenance of internalizing psychopathologies. Accruing data suggest rumination and worry represent overlapping and unique transdiagnostic cognitive processes. Yet, prior neuroimaging research has mostly focused on rumination in depression, which points to involvement of resting-state brain activity in default mode, executive, salience, and/or affective networks. METHODS: The current study examined relations between brain activity during rest and RNT in a transdiagnostic sample. Resting-state fMRI data was analyzed in 80 unmedicated patients with internalizing conditions. Regression analysis, controlling for anxiety and depression symptoms, was performed with seed regions implicated in default mode, executive, salience, and affective networks. Rumination and worry were assessed with standard self-report measures. RESULTS: Whole-brain regression results showed more rumination and worry jointly corresponded with greater positive resting-state functional connectivity (rsFC) between the amygdala and prefrontal regions (i.e., middle frontal gyrus, inferior frontal gyrus). Conversely, more worry (controlling for rumination) corresponded with greater negative rsFC between amygdala and precuneus. No significant results were observed for rumination alone (controlling for worry). CONCLUSIONS: Findings indicate the affective network plays a role in RNT, and distinct patterns of connectivity between amygdala and regions implicated in the executive and default mode networks were observed across patients with internalizing conditions. Results suggest different mechanisms contribute to RNT as a unitary construct and worry as a unique construct.

Differences in cortical thinning across development among individuals with and without anxiety disorders.

BACKGROUND: Anxiety is associated with aberrant patterns of cortical thickness in regions implicated in emotion regulation. However, few studies have examined cortical thickness differences between individuals with anxiety and healthy controls (HCs) across development, particularly during childhood when cortical thinning begins and anxiety risk increases. A better understanding of age-related changes in cortical thickness patterns among anxious individuals is essential to develop plausible targets for early identification. METHODS: The current study examined how age impacted differences in cortical thickness patterns between HCs and anxious individuals. Participants included 233 individuals (ages 7-35) with a current anxiety disorder (n = 149) or no lifetime history of psychopathology (n = 84). Cortical thickness of regions that are implicated in emotion regulation (ventromedial prefrontal cortex [vmPFC], rostral anterior cingulate [rACC], and insula) were assessed. RESULTS: All regions showed significant thinning with age, except left rACC and right insula. However, rates of thinning differed among anxious and HC participants, with anxious participants demonstrating slower rates of right vmPFC thinning. Regions of significance analyses indicated that anxious, relative to HC, participants exhibited thinner right vmPFC before age 11, but thicker right vmPFC after age 24. CONCLUSIONS: Current findings suggest that anxious individuals do not demonstrate normative right vmPFC cortical thinning, which may lead them to exhibit both thinner vmPFC in middle childhood and thicker vmPFC in adulthood compared with HCs. These findings may provide plausible targets for identification of anxiety risk that differ based on developmental stage.

Altered dynamic electroencephalography connectome phase-space features of emotion regulation in social anxiety.

Emotion regulation deficits are commonly observed in social anxiety disorder (SAD). We used manifold-learning to learn the phase-space connectome manifold of EEG brain dynamics in twenty SAD participants and twenty healthy controls. The purpose of the present study was to utilize manifold-learning to understand EEG brain dynamics associated with emotion regulation processes. Our emotion regulation task (ERT) contains three conditions: Neutral, Maintain and Reappraise. For all conditions and subjects, EEG connectivity data was converted into series of temporally-consecutive connectomes and aggregated to yield this phase-space manifold. As manifold geodesic distances encode intrinsic geometry, we visualized this space using its geodesic-informed minimum spanning tree and compared neurophysiological dynamics across conditions and groups using the corresponding trajectory length. Results showed that SAD participants had significantly longer trajectory lengths during Neutral and Maintain. Further, trajectory lengths during Reappraise were significantly associated with the habitual use of reappraisal strategies, while Maintain trajectory lengths were significantly associated with the negative affective state during Maintain. In sum, an unsupervised connectome manifold-learning approach can reveal emotion regulation associated phase-space features of brain dynamics.

Principal component analysis and brain-based predictors of emotion regulation in anxiety and depression.

BACKGROUND: Reappraisal, an adaptive emotion regulation strategy, is associated with frontal engagement. In internalizing psychopathologies (IPs) such as anxiety and depression frontal activity is atypically reduced suggesting impaired regulation capacity. Yet, successful reappraisal is often demonstrated at the behavioral level. A data-driven approach was used to clarify brain and behavioral relationships in IPs. METHODS: During functional magnetic resonance imaging, anxious [general anxiety disorder (n = 43), social anxiety disorder (n = 72)] and depressed (n = 47) patients reappraised negative images to reduce negative affect ('ReappNeg') and viewed negative images ('LookNeg'). After each trial, the affective state was reported. A cut-point (i.e. values <0 based on ΔReappNeg-LookNeg) demarcated successful reappraisers. Neural activity for ReappNeg-LookNeg, derived from 37 regions of interest, was submitted to Principal Component Analysis (PCA) to identify unique components of reappraisal-related brain response. PCA factors, symptom severity, and self-reported habitual reappraisal were submitted to discriminant function analysis and linear regression to examine whether these data predicted successful reappraisal (yes/no) and variance in reappraisal ability. RESULTS: Most patients (63%) were successful reappraisers according to the behavioral criterion (values<0; ΔReappNeg-LookNeg). Discriminant function analysis was not significant for PCA factors, symptoms, or habitual reappraisal. For regression, more activation in a factor with high loadings for frontal regions predicted better reappraisal facility. Results were not significant for other variables. CONCLUSIONS: At the individual level, more activation in a 'frontal' factor corresponded with better reappraisal facility. However, neither brain nor behavioral variables classified successful reappraisal (yes/no). Findings suggest individual differences in regions strongly implicated in reappraisal play a role in on-line reappraisal capability.

Transdiagnostic neural correlates of volitional emotion regulation in anxiety and depression.

BACKGROUND: Individuals who suffer from anxiety and/or depression face difficulty in adaptively managing emotional responses, while accumulating evidence suggests impaired emotion regulation is a transdiagnostic feature of psychopathology. Effectual regulation in the context of negative stimuli is characterized by engagement of the prefrontal cortex (PFC) coupled with reduced amygdala reactivity. In anxiety disorders and major depression, PFC underengagement and atypical PFC-amygdala connectivity has been observed, although patient findings based on case-control studies have been mixed with regard to magnitude, locality, and extent of dysfunction. As anxiety disorders and major depression are heterogeneous disorders and frequently comorbid with one another, delineating relationships between reappraise-related substrates and symptoms may advance our understanding of emotion dysregulation in these populations. METHODS: We examined PFC activation and its functional connectivity (FC) to the amygdala using functional magnetic resonance imaging in a large sample of patients (N = 174) with primary generalized anxiety disorder (n = 47), social anxiety disorder (n = 78), or major depressive disorder (n = 49) during a reappraisal-based emotion regulation task. Comorbidity was permitted and the majority of participants had a concurrent psychiatric illnesses. RESULTS: Across participants, whole-brain results showed that (1) greater anxiety and depression symptom severity was related to less engagement of the dorsal anterior cingulate cortex (ACC) and (2) less FC between the amygdala and ventrolateral PFC. Results were driven by anxiety, while depression symptoms were not significant. CONCLUSION: These findings demonstrate that individual differences in anxiety and depression may help explain ACC and PFC dysfunction during emotion regulation observed across anxiety and depressive disorders.

Neuroimaging Predictors and Mechanisms of Treatment Response in Social Anxiety Disorder: an Overview of the Amygdala.

PURPOSE OF REVIEW: Aberrant amygdala activity is implicated in the neurobiology of social anxiety disorder (SAD) and is, therefore, a treatment target. However, the extent to which amygdala predicts clinical improvement or is impacted by treatment has not been critically examined. This review highlights recent neuroimaging findings from clinical trials and research that test links between amygdala and mechanisms of action. RECENT FINDINGS: Neuropredictor studies largely comprised psychotherapy where improvement was foretold by amygdala activity and regions beyond amygdala such as frontal structures (e.g., anterior cingulate cortex, medial prefrontal cortex) and areas involved in visual processes (e.g., occipital regions, superior temporal gyrus). Pre-treatment functional connectivity between amygdala and frontal areas was also shown to predict improvement signifying circuits that support emotion processing and regulation interact with treatment. Pre-to-post studies revealed decreases in amygdala response and altered functional connectivity in amygdala pathways regardless of treatment modality. In analogue studies of fear exposure, greater reduction in anxiety was predicted by less amygdala response to a speech challenge and amygdala activity decreased following exposures. Yet, studies have also failed to detect amygdala effects reporting instead treatment-related changes in regions and functional systems that support sensory, emotion, and regulation processes. An array of regions in the corticolimbic subcircuits and extrastriate cortex appear to be viable sites of action. The amygdala and amygdala pathways predict treatment outcome and are altered following treatment. However, further study is needed to establish the role of the amygdala and other candidate regions and brain circuits as sites of action.

Neural correlates of explicit and implicit emotion processing in relation to treatment response in pediatric anxiety.

BACKGROUND: Approximately 40%-45% of youth with anxiety disorders do not achieve remission (or a substantial reduction in symptoms) following treatment, highlighting the need to identify predictors of treatment response. Given the well-established link between attentional biases and anxiety disorders in youth and adults, this study examined the neural correlates of directing attention toward and away from emotional faces in relation to pediatric anxiety treatment response. METHOD: Prior to beginning treatment with the selective serotonin reuptake inhibitor (SSRI) sertraline or cognitive behavior therapy (CBT), 37 youth (age 7-19 years) with generalized and/or social anxiety disorder completed a task with conditions that manipulated whether participants were instructed to match emotional faces (explicit emotion processing) or match shapes in the context of emotional face distractors (implicit emotion processing) during functional magnetic resonance imaging. RESULTS: Results revealed that reduced activation in superior frontal gyrus (SFG), encompassing the dorsal anterior cingulate cortex (ACC) and dorsomedial prefrontal cortex (PFC), during implicit processing of emotional faces predicted a greater reduction in anxiety severity pre-to-post treatment. Post hoc analyses indicated that effects were not significantly moderated by the type of treatment or anxiety type. CONCLUSIONS: Findings suggest that less recruitment of SFG, including the dorsal ACC and dorsomedial PFC, during implicit emotion processing predicts a greater reduction in youth anxiety symptoms pre-to-post treatment. Youth who exhibit reduced activation in these areas while matching shapes in the context of emotional face distractors may have more to gain from CBT and SSRI treatment due to preexisting deficits in attentional control. These findings suggest that neuroimaging may be a useful tool for predicting which youth are most likely to benefit from anxiety treatment.

Transdiagnostic neural correlates of affective face processing in anxiety and depression.

BACKGROUND: It is unknown whether there are neurobiologic differences between various anxiety and depressive disorders, or whether they are characterized by shared neurobiologic variation that cuts across diagnostic boundaries. For instance, multiple anxiety disorders and depression may be characterized by abnormalities in blood oxygen-level dependent (BOLD) response during the processing of affective scenes and faces. To interrogate the shared or unique nature of these aberrations, research that examines the influence of transdiagnostic, dimensional predictors across multiple diagnoses is needed. METHODS: One hundred ninety-nine individuals, 142 with primary diagnoses of social anxiety disorder (SAD), generalized anxiety disorder (GAD), or major depressive disorder (MDD) and 57 free from psychiatric diagnoses (healthy controls, HCs), performed a face-matching task involving fearful, angry, and happy faces (and geometric shapes) while undergoing functional magnetic resonance imaging. RESULTS: Across the three primary diagnoses, anxiety symptom scores were associated with increased Angry > Shapes activation in the bilateral insula, anterior/midcingulate, and dorsolateral prefrontal cortex (dlPFC), while depressive symptoms were associated with reduced dlPFC activation for Angry > Shapes. Patient > HC differences were limited to non a priori regions, and no differences in BOLD activation were observed between diagnostic groups. CONCLUSIONS: (1) Activation in paralimbic, cingulate, and lateral prefrontal regions in response to angry faces is associated with transdiagnostic anxiety and depressive symptomatology. (2) Anxiety and depressive symptoms may exert opposing influences on lateral prefrontal activation. (3) Abnormal threat processing in GAD, SAD, and MDD may reflect shared neural dysfunction that varies with symptom load.

Subjective and objective sleep quality modulate emotion regulatory brain function in anxiety and depression.

BACKGROUND: Disturbances in emotion regulation and sleep are shared across anxiety and mood disorders. Poor sleep has been shown to impair cognitive processes which may undermine cognitive regulatory function. However, it remains unknown if sleep quality impacts regulatory mechanisms in clinical anxiety and depression. METHODS: During fMRI, 78 patients with social anxiety disorder, generalized anxiety disorder, and/or major depressive disorder completed a validated emotion regulation task, which involved reappraisal (i.e., decrease negative affect) as compared to viewing aversive images. Sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI) and actigraphy, representing subjective and objective measures of sleep, respectively. Regression analysis was conducted with the PSQI and actigraphy sleep efficiency, duration, and wake-after sleep onset variables. RESULTS: PSQI and actigraphy measures indicated that the majority of patients experienced problematic sleep, however, subjective and objective sleep measures were uncorrelated. Whole-brain voxel-wise regression analysis, controlling for diagnosis, revealed worse self-reported sleep corresponded with less reappraise-related activation in the dorsal anterior cingulate cortex (DACC). The same analysis performed with actigraphy data showed less sleep efficiency positively corresponded with DACC activation. Post-hoc stepwise regression analysis showed these sleep measures predicted DACC activity whereas anxiety and depression symptoms did not. CONCLUSIONS: Individual differences in self-perceived and objective sleep quality differentially modulated the DACC, which is implicated in cognitive reappraisal. Findings suggest neural correlates of emotion regulation tracks different aspects of the sleep experience. Results also indicate sleep disturbance may play a role in the emotion dysregulation observed in anxiety and depressive disorders.

Age-related changes in amygdala-frontal connectivity during emotional face processing from childhood into young adulthood.

The ability to process and respond to emotional facial expressions is a critical skill for healthy social and emotional development. There has been growing interest in understanding the neural circuitry underlying development of emotional processing, with previous research implicating functional connectivity between amygdala and frontal regions. However, existing work has focused on threatening emotional faces, raising questions regarding the extent to which these developmental patterns are specific to threat or to emotional face processing more broadly. In the current study, we examined age-related changes in brain activity and amygdala functional connectivity during an fMRI emotional face matching task (including angry, fearful, and happy faces) in 61 healthy subjects aged 7-25 years. We found age-related decreases in ventral medial prefrontal cortex activity in response to happy faces but not to angry or fearful faces, and an age-related change (shifting from positive to negative correlation) in amygdala-anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC) functional connectivity to all emotional faces. Specifically, positive correlations between amygdala and ACC/mPFC in children changed to negative correlations in adults, which may suggest early emergence of bottom-up amygdala excitatory signaling to ACC/mPFC in children and later development of top-down inhibitory control of ACC/mPFC over amygdala in adults. Age-related changes in amygdala-ACC/mPFC connectivity did not vary for processing of different facial emotions, suggesting changes in amygdala-ACC/mPFC connectivity may underlie development of broad emotional processing, rather than threat-specific processing. Hum Brain Mapp 37:1684-1695, 2016. © 2016 Wiley Periodicals, Inc.

NEURAL REACTIVITY TO REWARD AS A PREDICTOR OF COGNITIVE BEHAVIORAL THERAPY RESPONSE IN ANXIETY AND DEPRESSION.

BACKGROUND: Cognitive behavioral therapy (CBT) is a well-established treatment for anxiety and depression; however, response to CBT is heterogeneous across patients and many remain symptomatic after therapy, raising the need to identify prospective predictors for treatment planning. Altered neural processing of reward has been implicated in both depression and anxiety, and improving hedonic capacity is a goal of CBT. However, little is known about how neural response to reward relates to CBT outcomes in depression and anxiety. The current study used the reward positivity (RewP) event-related potential (ERP) component to examine whether neural reactivity to reward would predict CBT response in a sample of patients with anxiety without depression (n = 30) and comorbid anxiety and depression (CAD, n = 22). METHODS: Participants completed a guessing reward ERP paradigm before completing 12 weeks of standard CBT. RESULTS: The majority of the sample (68%; 35 out of 52 patients) responded to treatment, and those with a reduced RewP at baseline were more likely to respond to treatment. A reduced RewP was also associated with a greater pre-to-post CBT reduction in depressive symptoms among individuals with CAD, but not among individuals with pure anxiety. CONCLUSIONS: CBT may be most beneficial in reducing depressive symptoms for individuals who demonstrate decreased reward reactivity prior to treatment. CBT may target reward brain function, leading to greater improvement in symptoms. These effects may be strongest, and therefore most meaningful, for individuals with reward-processing deficits prior to treatment.

Comorbid anxiety increases cognitive control activation in Major Depressive Disorder.

BACKGROUND: Major Depressive Disorder (MDD) and anxiety disorders often co-occur, with poorer treatment response and long-term outcomes. However, little is known about the shared and distinct neural mechanisms of comorbid MDD and anxiety (MDD+Anx). This study examined how MDD and MDD+Anx differentially impact cognitive control. METHODS: Eighteen MDD, 29 MDD+Anx, and 54 healthy controls (HC) completed the Parametric Go/No-Go (PGNG) during fMRI, including Target, Commission, and Rejection trials. RESULTS: MDD+Anx had more activation in the anterior dorsolateral prefrontal cortex, hippocampus, and caudate during Rejections, and inferior parietal lobule during correct Targets than MDD and HC. During Rejections HC had greater activation in a number of cognitive control regions compared to MDD; in the posterior cingulate compared to MDD+Anx; and in the fusiform gyrus compared to all MDD. During Commissions HC had greater activation in the right inferior frontal gyrus than all MDD. MDD had more activation in the mid-cingulate, inferior parietal lobule, and superior temporal gyrus than MDD+Anx during Commissions. CONCLUSIONS: Despite similar performance, MDD and MDD+Anx showed distinct differences in neural mechanisms of cognitive control in relation to each other, as well as some shared differences in relation to HC. The results were consistent with our hypothesis of hypervigilance in MDD+Anx within the cognitive control network, but inconsistent with our hypothesis that there would be greater engagement of salience and emotion network regions. Comorbidity of depression and anxiety may cause increased heterogeneity in study samples, requiring further specificity in detection and measurement of intermediate phenotypes and treatment Targets.

Altered activation of the rostral anterior cingulate cortex in the context of emotional face distractors in children and adolescents with anxiety disorders.

BACKGROUND: Pediatric and adult anxiety disorder patients exhibit attention bias to threat and difficulty disengaging attention away from threat. Cognitive frameworks suggest that these patterns are associated with hyperactivation of regions associated with detecting threat, such as the amygdala, and hypoactivation of regions associated with regulating attention, including the lateral prefrontal cortex and rostral anterior cingulate cortex (rACC). The aim of the present study was to examine the neural correlates of these processes in children and adolescents with anxiety disorders. METHODS: Participants with an anxiety disorder 7 to 19 years old (n = 34) and typically developing controls (n = 35) underwent fMRI scanning. During scanning, they completed a task with conditions that manipulated whether participants were instructed to match emotional faces (direct emotion processing) or match shapes in the context of emotional face distractors (attentional control). RESULTS: Results revealed a significant difference in rACC activation during shape versus face matching, with controls evidencing greater rACC activation relative to patients. CONCLUSIONS: This study identifies abnormalities in rACC activation as a potential neural mediator associated with pediatric anxiety disorders, which can inform frameworks for understanding their development and treatment.

Crime Risk and Depression Differentially Relate to Aspects of Sleep in Patients with Major Depression or Social Anxiety.

Individuals with internalizing conditions such as depression or anxiety are at risk of sleep difficulties. Social-ecological models of sleep health propose factors at the individual (e.g., mental health) and neighborhood (e.g., crime risk) levels that contribute to sleep difficulties. However, these relationships have been under-researched in terms of internalizing conditions. Therefore, the current study comprised participants diagnosed with major depression (n = 24) or social anxiety (n = 35). Sleep measures included actigraphic variables (i.e., total sleep time, waking after sleep onset, sleep onset latency) and subjective sleep quality. Geocoding was used to assess nationally-normed crime risk exposure at the person level (e.g., murder, assault) and property level (e.g., robbery, burglary). Analyses consisted of independent t-tests to evaluate potential differences between diagnostic groups. To examine relationships, multiple regressions were used with internalizing symptoms, crime risk, and age as independent variables and sleep measures as the dependent variable. The t-test results revealed that groups differed in symptoms and age but not sleep or neighborhood crime. Regression results revealed crime risk positively corresponded with sleep onset latency but no other sleep measures. Also, only depression positively corresponded with total sleep time. Preliminary findings suggest exposure to crime and depression relate differentially to facets of sleep in individuals with internalizing conditions.

Default Mode Network Hypoalignment of Function to Structure Correlates With Depression and Rumination.

BACKGROUND: Recent studies have begun to examine how signals in the brain correspond to the underlying white matter structure using tools from the field of graph signal processing to quantify brain function alignment to brain network topology. Here, we applied this framework for the first time toward a transdiagnostic cohort of individuals with internalizing psychopathologies, including mood and anxiety disorders, to uncover how such alignment within the default mode network (DMN) is related to depression and rumination symptoms. METHODS: Both diffusion-weighted and resting-state functional magnetic resonance imaging were obtained from participants at baseline (n = 60 patients, n = 19 healthy control participants). Patients were randomized to 12 weeks of treatment with either a selective serotonin reuptake inhibitor or cognitive behavioral therapy, and symptom scales were readministered posttreatment (n = 46 patients at follow-up). Using graph signal processing methodology, we quantified the alignment of functional signals to their underlying white matter structural networks. RESULTS: We found that signal alignment within the posterior DMN was decreased in patients with internalizing psychopathologies compared with healthy control participants and was inversely (negatively) correlated with baseline depression and rumination scales. Signal alignment within the posterior DMN was also correlated with the ratio of total within-DMN to extra-DMN functional connectivity for these regions. CONCLUSIONS: These findings are consistent with previous literature regarding pathological promiscuity of posterior DMN connectivity and provide the first graph signal processing-based analyses in a transdiagnostic cohort of patients with internalizing psychopathologies.

Aberrant amygdala-frontal cortex connectivity during perception of fearful faces and at rest in generalized social anxiety disorder.

BACKGROUND: Generalized social anxiety disorder (gSAD) is characterized by exaggerated amygdala reactivity to social signals of threat, but if and how the amygdala interacts with functionally and anatomically connected prefrontal cortex (PFC) remains largely unknown. Recent evidence points to aberrant amygdala connectivity to medial PFC in gSAD at rest, but it is difficult to attribute functional relevance without the context of threat processing. Here, we address this by studying amygdala-frontal cortex connectivity during viewing of fearful faces and at rest in gSAD patients. METHODS: Twenty patients with gSAD and 17 matched healthy controls (HCs) participated in functional magnetic resonance imaging of an emotional face matching task and a resting state task. Functional connectivity and psychophysiological interaction analysis were used to assess amygdala connectivity. RESULTS: Compared to HCs, gSAD patients exhibited less connectivity between amygdala and the rostral anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC) while viewing fearful faces. gSAD patients also showed less connectivity between amygdala and rostral ACC at rest in the absence of fearful faces. DLPFC connectivity was negatively correlated with LSASFear (where LSAS is Liebowitz Social Anxiety Scale). CONCLUSIONS: Task and rest paradigms provide unique and important information about discrete and overlapping functional networks. In particular, amygdala coupling to DLPFC may be a phasic abnormality, emerging only in the presence of a social predictor of threat, whereas amygdala coupling to the rostral ACC may reflect both phasic and tonic abnormalities. These findings prompt further studies to better delineate intrinsic and externally evoked brain connectivity in anxiety and depression in relation to amygdala dysfunction.