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Location-dependent threat and associated neural abnormalities in clinical anxiety.

ABSTRACT: Anxiety disorders are characterized by maladaptive defensive responses to distal or uncertain threats. Elucidating neural mechanisms of anxiety is essential to understand the development and maintenance of anxiety disorders. In fMRI, patients with pathological anxiety (ANX, n = 23) and healthy controls (HC, n = 28) completed a contextual threat learning paradigm in which they picked flowers in a virtual environment comprising a danger zone in which flowers were paired with shock and a safe zone (no shock). ANX compared with HC showed 1) decreased ventromedial prefrontal cortex and anterior hippocampus activation during the task, particularly in the safe zone, 2) increased insula and dorsomedial prefrontal cortex activation during the task, particularly in the danger zone, and 3) increased amygdala and midbrain/periaqueductal gray activation in the danger zone prior to potential shock delivery. Findings suggest that ANX engage brain areas differently to modulate context-appropriate emotional responses when learning to discriminate cues within an environment.

SUBMITTER: Suarez-Jimenez B

PROVIDER: S-EPMC8568971 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Location-dependent threat and associated neural abnormalities in clinical anxiety.

Suarez-Jimenez Benjamin B Balderston Nicholas L NL Bisby James A JA Leshin Joseph J Hsiung Abigail A King John A JA Pine Daniel S DS Burgess Neil N Grillon Christian C Ernst Monique M

Communications biology 20211104 1

Anxiety disorders are characterized by maladaptive defensive responses to distal or uncertain threats. Elucidating neural mechanisms of anxiety is essential to understand the development and maintenance of anxiety disorders. In fMRI, patients with pathological anxiety (ANX, n = 23) and healthy controls (HC, n = 28) completed a contextual threat learning paradigm in which they picked flowers in a virtual environment comprising a danger zone in which flowers were paired with shock and a safe zone ...[more]

PMID: 34737386

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Project description:BackgroundAnxiety and irritability frequently co-occur in youth and are mediated by aberrant threat responses. However, empirical evidence on neural mechanisms underlying this co-occurrence is limited. To address this, we apply data-driven latent phenotyping to data from a prior report of a well-validated threat extinction recall fMRI paradigm.MethodsParticipants included 59 youth (28 anxiety disorder, 31 healthy volunteers; Mage=13.15 yrs) drawn from a transdiagnostic sample of 331 youth, in which bifactor analysis was conducted to derive latent factors representing shared vs. unique variance of dimensionally-assessed anxiety and irritability. Participants underwent threat conditioning and extinction. Approximately three weeks later, during extinction recall fMRI, participants made threat-safety discriminations under two task conditions: current threat appraisal and explicit recall of threat contingencies. Linear mixed-effects analyses examined associations of a "negative affectivity" factor reflecting shared anxiety and irritability variance with whole-brain activation and task-dependent amygdala connectivity.ResultsDuring recall of threat-safety contingencies, higher negative affectivity was associated with greater prefrontal (ventrolateral/ventromedial, dorsolateral, orbitofrontal), motor, temporal, parietal, and occipital activation. During threat appraisal, higher negative affectivity was associated with greater amygdala-inferior parietal lobule connectivity to threat/safety ambiguity.LimitationsSample included only healthy youth and youth with anxiety disorders. Results may not generalize to other diagnoses for which anxiety and irritability are also common, and our negative affectivity factor should be interpreted as anxiety disorders with elevated irritability. Reliability of some subfactors was poor.ConclusionsAberrant amygdala-prefrontal-parietal circuitry during extinction recall of threat-safety stimuli may be a mechanism underlying the co-occurrence of pediatric anxiety and irritability.

Project description: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.

Project description:ContextSocial anxiety disorder is thought to involve emotional hyperreactivity, cognitive distortions, and ineffective emotion regulation. While the neural bases of emotional reactivity to social stimuli have been described, the neural bases of emotional reactivity and cognitive regulation during social and physical threat, and their relationship to social anxiety symptom severity, have yet to be investigated.ObjectiveTo investigate behavioral and neural correlates of emotional reactivity and cognitive regulation in patients and controls during processing of social and physical threat stimuli.DesignParticipants were trained to implement cognitive-linguistic regulation of emotional reactivity induced by social (harsh facial expressions) and physical (violent scenes) threat while undergoing functional magnetic resonance imaging and providing behavioral ratings of negative emotion experience.SettingAcademic psychology department.ParticipantsFifteen adults with social anxiety disorder and 17 demographically matched healthy controls.Main outcome measuresBlood oxygen level-dependent signal and negative emotion ratings.ResultsBehaviorally, patients reported greater negative emotion than controls during social and physical threat but showed equivalent reduction in negative emotion following cognitive regulation. Neurally, viewing social threat resulted in greater emotion-related neural responses in patients than controls, with social anxiety symptom severity related to activity in a network of emotion- and attention-processing regions in patients only. Viewing physical threat produced no between-group differences. Regulation during social threat resulted in greater cognitive and attention regulation-related brain activation in controls compared with patients. Regulation during physical threat produced greater cognitive control-related response (ie, right dorsolateral prefrontal cortex) in patients compared with controls.ConclusionsCompared with controls, patients demonstrated exaggerated negative emotion reactivity and reduced cognitive regulation-related neural activation, specifically for social threat stimuli. These findings help to elucidate potential neural mechanisms of emotion regulation that might serve as biomarkers for interventions for social anxiety disorder.

Project description:BackgroundDespite the high prevalence of generalized anxiety disorder (GAD) and its negative impact on society, its neurobiology remains obscure. This study characterizes the neurostructural abnormalities associated with key symptoms of GAD, focusing on indicators of impaired emotion regulation (excessive worry, poor concentration, low mindfulness, and physiological arousal).MethodsThese domains were assessed in 19 (16 women) GAD patients and 19 healthy controls matched for age and gender, using questionnaires and a low demand behavioral task performed before and after an induction of perseverative cognition (i.e. worry and rumination). Continuous pulse oximetry was used to measure autonomic physiology (heart rate variability; HRV). Observed cognitive and physiological changes in response to the induction provided quantifiable data on emotional regulatory capacity. Participants underwent structural magnetic resonance imaging; voxel-based morphometry was used to quantify the relationship between gray matter volume and psychological and physiological measures.ResultsOverall, GAD patients had lower gray matter volume than controls within supramarginal, precentral, and postcentral gyrus bilaterally. Across the GAD group, increased right amygdala volume was associated with prolonged reaction times on the tracking task (indicating increased attentional impairment following the induction) and lower scores on the 'Act with awareness' subscale of the Five Facets Mindfulness Questionnaire. Moreover in GAD, medial frontal cortical gray matter volume correlated positively with the 'Non-react mindfulness' facet. Lastly, smaller volumes of bilateral insula, bilateral opercular cortex, right supramarginal and precentral gyri, anterior cingulate and paracingulate cortex predicted the magnitude of autonomic change following the induction (i.e. a greater decrease in HRV).ConclusionsResults distinguish neural structures associated with impaired capacity for cognitive, attentional and physiological disengagement from worry, suggesting that aberrant competition between these levels of emotional regulation is intrinsic to symptom expression in GAD.

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Location-dependent threat and associated neural abnormalities in clinical anxiety.

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Location-dependent threat and associated neural abnormalities in clinical anxiety.

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