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 Analysis of Behavioral Activation/Inhibition Systems and Brain Volume in Individuals With and Without Major Depressive Disorder or Social Anxiety Disorder.

BACKGROUND: Social anxiety disorder (SAD) and major depressive disorder (MDD) are characterized by behavioral abnormalities in motivational systems, namely the behavioral inhibition system (BIS) and behavioral activation system (BAS). Limited studies indicate brain volume in regions that support emotion, learning/memory, reward, and cognitive functions relate to BIS/BAS. To increase understanding of BIS/BAS, the current study used a network approach. METHODS: Patients with SAD (n = 59), patients with MDD (n = 64), and healthy control participants (n = 36) completed a BIS/BAS questionnaire and structural magnetic resonance imaging scans; volumetric regions of interest comprised cortical and limbic structures based on previous BIS/BAS studies. A Bayesian Gaussian graphical model was used for each diagnostic group, and groups were compared. Among network metrics, bridge centrality was of primary interest. Analysis of variance evaluated BIS/BAS behaviors between groups. RESULTS: Bridge centrality showed hippocampus positively related to BAS, but not to BIS, in the MDD group; no findings were observed in the SAD or control groups. Yet, network density (i.e., overall strength of relationships between variables) and degree centrality (i.e., overall relationship between one variable to all other variables) showed that cortical (e.g., precuneus, medial orbitofrontal) and subcortical (e.g., amygdala, hippocampus) regions differed between diagnostic groups. Analysis of variance results showed BAS was lower in the MDD/SAD groups compared with the control group, while BIS was higher in the SAD group relative to the MDD group, which in turn was higher than the control group. CONCLUSIONS: Preliminary findings indicate that network-level aberrations may underlie motivational abnormalities in MDD and SAD. Evidence of BIS/BAS differences builds on previous work that points to shared and distinct motivational differences in internalizing psychopathologies.

Neural reactivity to threat impacts the association between bullying victimization and suicide risk in youth.

Bullying victimization is a risk factor for suicidal ideation, suicide behaviors, and death by suicide in youth. However, not all victims of bullying report suicidal thoughts and behaviors, suggesting that there may be certain subgroups who are at high risk for suicide. Neuroimaging studies suggest that individual differences in neurobiological threat reactivity may contribute to increased vulnerability to suicide, particularly in the context of repeated exposure to bullying. The purpose of the present study was to examine the unique and interactive effects of past-year bullying victimization and neural reactivity to threat on suicide risk in youth. Ninety-one youth (ages 16-19) completed self-report measures of past-year bullying victimization and current suicide risk. Participants also completed a task designed to probe neural reactivity to threat. Specifically, participants passively viewed negative or neutral images during functional magnetic resonance imaging. Bilateral anterior insula (AIC) and amygdala (AMYG) reactivity to threat/negative images (>neutral images) was used to capture threat sensitivity. Greater bullying victimization was associated with increased suicide risk. There was also a bullying by AIC reactivity interaction such that among individuals with high AIC reactivity, greater bullying was associated with increased suicide risk. Among individuals with low AIC reactivity, there was no association between bullying and suicide risk. Results suggest that youth with increased AIC reactivity to threat may be particularly vulnerable to suicide in the context of bullying. These individuals may represent a high-risk group for subsequent suicide behavior and AIC function may be a promising objective prevention target.

Behavioral and brain reactivity to uncertain stress prospectively predicts binge drinking in youth.

Prior studies show that individuals with alcohol use disorder exhibit exaggerated behavioral and brain reactivity to uncertain threats (U-threat). It is posited this brain-based factor emerges early in life and contributes to the onset and escalation of alcohol problems. However, no study to date has tested this theory using a longitudinal within-subjects design. Ninety-five young adults, ages 17-19, with minimal alcohol exposure and established risk factors for alcohol use disorder participated in this multi-session study with a 1-year tracking period. Startle eyeblink potentiation and brain activation were collected at separate baseline sessions during the well-validated No-Predictable-Unpredictable (NPU) threat-of-shock task designed to probe reactivity to U-threat and predictable threat (P-threat). Participants self-reported their drinking behavior over the past 90 days at baseline and one-year later. We fit a series of multilevel hurdle models to model the binary outcome of whether binge drinking occurred and the continuous outcome of number of binge drinking episodes. Zero-inflated binary submodels revealed that greater baseline startle reactivity, bilateral anterior insula (AIC) reactivity, and dorsal anterior cingulate cortex (dACC) reactivity to U-threat were associated with increased probability of binge drinking. There were no other associations between reactivity to U- and P-threat and probability of binge drinking and number of binging episodes. These results demonstrate that exaggerated reactivity to U-threat is a brain-based individual difference factor that connotes risk for problem drinking. These findings also add to a growing literature implicating AIC and dACC dysfunction in the pathophysiology of alcohol use disorder.

Neural reactivity to neutral and aversive stimuli: Evidence for altered precuneus function in internalizing psychopathologies.

Individuals with internalizing psychopathologies (IPs) demonstrate a negativity bias in emotion and self-related processing that contributes to negative interpretation of neutral information. However, most neuroimaging studies of emotional experience in IPs do not specifically investigate reactivity to neutral stimuli. Thus, little is known about the neural processes underlying emotional experience for neutral stimuli and how those processes may differ between groups and during neutral versus negative stimuli. To address this gap, we asked: (1) does neural reactivity to neutral and negative stimuli differ between IPs and control groups in brain regions associated with emotional and self-referential processing, and (2) does neural activity during neutral condition relate to clinical symptoms? Adults with IPs (n = 103) and healthy volunteers (HVs; n = 40) completed a well-validated fMRI task probing neural responses to neutral and negative images. A flexible factorial model revealed a significant group-by-condition interaction, such that individuals with IPs had less precuneus activation during the neutral condition relative to HVs. In IPs, precuneus activation during the neutral condition was negatively correlated with depression symptom severity. Individuals with IPs demonstrate abnormal precuneus reactivity to neutral stimuli that is associated with depression symptoms. This may reflect altered default mode network activity and/or self-referential processing in IPs.

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.

Anterior cingulate cortex activation during attentional control as a transdiagnostic marker of psychotherapy response: a randomized clinical trial.

Anterior cingulate cortex (ACC) response during attentional control in the context of task-irrelevant emotional faces is a promising biomarker of cognitive behavioral therapy (CBT) outcome in patients with social anxiety disorder (SAD). However, it is unclear whether this biomarker extends to major depressive disorder (MDD) and is specific to CBT outcome. In the current study, 72 unmedicated patients with SAD (n = 39) or MDD (n = 33) completed a validated emotional interference paradigm during functional magnetic resonance imaging before treatment. Participants viewed letter strings superimposed on task-irrelevant threat and neutral faces under low perceptual load (high interference) and high perceptual load (low interference). Biomarkers comprised anatomy-based rostral ACC (rACC) and dorsal ACC (dACC) response to task-irrelevant threat (>neutral) faces under low and high perceptual load. Patients were randomly assigned to 12 weeks of CBT or supportive therapy (ST) (ClinicalTrials.gov identifier: NCT03175068). Clinician-administered measures of social anxiety and depression severity were obtained at baseline and every 2 weeks throughout treatment (7 assessments total) by an assessor blinded to the treatment arm. A composite symptom severity score was submitted to latent growth curve models. Results showed more baseline rACC activity to task-irrelevant threat>neutral faces under low, but not high, perceptual load predicted steeper trajectories of symptom improvement throughout CBT or ST. Post-hoc analyses indicated this effect was driven by subgenual ACC (sgACC) activation. Findings indicate ACC activity during attentional control may be a transdiagnostic neural predictor of general psychotherapy outcome.

Anterior cingulate cortex activity during attentional control corresponds with rumination in depression and social anxiety.

Rumination and worry are transdiagnostic perseverative cognitions that have overlapping and distinct characteristics. While the mechanisms of perseverative cognitions remain incomplete, limited data indicate anterior cingulate cortex (ACC) as it relates to top-down functions contributes to perseverative cognitions in internalizing conditions. The current study extends this work in patients with major depression (n = 39) or social anxiety (n = 42). During fMRI, participants viewed images comprising letter strings superimposed on task-irrelevant threatening or neutral faces. To moderate task difficulty, there was a low perceptual load condition where the target letter was in a string of identical letters and high load condition with the target letter in a mixed letter string increasing task difficulty. Regions of interest (ROI) comprised dorsal ACC and rostral ACC. Bilateral amygdala was also examined. Results showed diagnostic groups had similar levels of rumination and worry. Exploratory hierarchical regression analysis comprising clinical measures, task performance, and the 4 ROIs revealed significantly less dorsal ACC engagement during low (vs. high) load to task-irrelevant faces corresponded with more rumination, but not worry, regardless of diagnostic status. However, the ACC finding did not survive Bonferroni correction. Preliminary results suggest dorsal ACC response during attentional control may serve as a transdiagnostic mechanism of rumination.

Impact of exogenous estradiol on task-based and resting-state neural signature during and after fear extinction in healthy women.

Fluctuations of endogenous estrogen modulates fear extinction, but the influence of exogenous estradiol is less studied. Moreover, little focus has been placed on the impact of estradiol on broad network connectivity beyond the fear extinction circuit. Here, we examined the effect of acute exogenous estradiol administration on fear extinction-induced brain activation, whole-brain functional connectivity (FC) during the fear extinction task and post-extinction resting-state. Ninety healthy women (57 using oral contraceptives [OC], 33 naturally cycling [NC]) were fear conditioned on day 1. They ingested an estradiol or placebo pill prior to extinction learning on day 2 (double-blind design). Extinction memory was assessed on day 3. Task-based functional MRI data were ascertained on days 2 and 3 and resting-state data were collected post-extinction on day 2 and pre-recall on day 3. Estradiol administration significantly modulated the neural signature associated with fear extinction learning and memory, consistent with prior studies. Importantly, estradiol administration induced significant changes in FC within multiple networks, including the default mode and somatomotor networks during extinction learning, post-extinction, and during extinction memory recall. Exploratory analyses revealed that estradiol impacted ventromedial prefrontal cortex (vmPFC) activation and FC differently in the NC and OC women. The data implicate a more diffused and significant effect of acute estradiol administration on multiple networks. Such an effect might be beneficial to modulating attention and conscious processes in addition to engaging neural processes associated with emotional learning and memory consolidation.

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.

Shared and unique neural circuitry underlying temporally unpredictable threat and reward processing.

Temporally unpredictable stimuli influence behavior across species, as previously demonstrated for sequences of simple threats and rewards with fixed or variable onset. Neuroimaging studies have identified a specific frontolimbic circuit that may become engaged during the anticipation of temporally unpredictable threat (U-threat). However, the neural mechanisms underlying processing of temporally unpredictable reward (U-reward) are incompletely understood. It is also unclear whether these processes are mediated by overlapping or distinct neural systems. These knowledge gaps are noteworthy given that disruptions within these neural systems may lead to maladaptive response to uncertainty. Here, using functional magnetic resonance imaging data from a sample of 159 young adults, we showed that anticipation of both U-threat and U-reward elicited activation in the right anterior insula, right ventral anterior nucleus of the thalamus and right inferior frontal gyrus. U-threat also activated the right posterior insula and dorsal anterior cingulate cortex, relative to U-reward. In contrast, U-reward elicited activation in the right fusiform and left middle occipital gyrus, relative to U-threat. Although there is some overlap in the neural circuitry underlying anticipation of U-threat and U-reward, these processes appear to be largely mediated by distinct circuits. Future studies are needed to corroborate and extend these preliminary findings.

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.

Parsing differences in amygdala volume among individuals with and without social and generalized anxiety disorders across the lifespan.

Structural differences in the amygdala (AMG) are implicated in anxiety and observed among individuals with generalized (GAD) and social anxiety (SAD) disorders. Findings have been mixed, perhaps because studies rarely examine differences between GAD and SAD, test comorbidity, or examine age-related differences. We tested AMG volume differences among a sample of adults and youth with/without SAD and GAD. Participants (N = 242; ages 7-60 years) completed an MRI scan, diagnostic interviews, and anxiety symptom measures. Groups were formed from diagnostic interviews: 1) Typically developing (TD; n = 91); 2) GAD (n = 53); 3) SAD (n = 35); and 4) comorbid SAD/GAD (n = 63). We used analysis of covariance with a bonferroni correction to examine group differences in AMG volume. The SAD and comorbid SAD/GAD groups exhibited increased bilateral AMG volume compared to the TD group. GAD and TD groups did not differ from each other in AMG size. The SAD, but not the comorbid SAD/GAD group, displayed greater right AMG size relative to the GAD group. SAD and comorbid SAD/GAD groups did not differ from the GAD group in left AMG volume. SAD and SAD/GAD groups did not exhibit different bilateral AMG size. Linear regression analyses demonstrated that greater social anxiety but not generalized anxiety symptom severity was associated with enlarged AMG volume. Age was not associated with AMG volume and nor did age moderate any group or symptom effects. Future longitudinal studies should examine whether larger AMG volume is a unique biomarker for SAD across the lifespan.