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Anxiety disorders are the most common mental disorders in adolescents. However, only 50% of pediatric patients with anxiety disorders respond to the first-line pharmacologic treatments—selective serotonin reuptake inhibitors (SSRIs). Thus, identifying the neurofunctional targets of SSRIs and finding pretreatment or early-treatment neurofunctional markers of SSRI treatment response in this population is clinically important. We acquired pretreatment and early-treatment (2 weeks into treatment) functional magnetic resonance imaging during a continuous processing task with emotional and neutral distractors in adolescents with generalized anxiety disorder (GAD, N = 36) randomized to 8 weeks of double-blind escitalopram or placebo. Generalized psychophysiological interaction analysis was conducted to examine the functional connectivity of the amygdala while patients viewed emotional pictures. Full-factorial analysis was used to investigate the treatment effect of escitalopram on amygdala connectivity. Correlation analyses were performed to explore whether pretreatment and early (week 2) treatment-related connectivity were associated with treatment response (improvement in anxiety) at week 8. Compared to placebo, escitalopram enhanced emotional processing speed and enhanced negative right amygdala-bilateral ventromedial prefrontal cortex (vmPFC) and positive left amygdala-right angular gyrus connectivity during emotion processing. Baseline amygdala-vmPFC connectivity and escitalopram-induced increased amygdala-angular gyrus connectivity at week 2 predicted the magnitude of subsequent improvement in anxiety symptoms. These findings suggest that amygdala connectivity to hubs of the default mode network represents a target of acute SSRI treatment. Furthermore, pretreatment and early-treatment amygdala connectivity could serve as biomarkers of SSRI treatment response in adolescents with GAD. The trial registration for the study is ClinicalTrials.gov Identifier: NCT02818751.

Blockade of corticotropin-releasing factor receptor 1 (CRF1) suppresses stress-induced alcohol seeking in rodents, but clinical translation remains. Here, we first showed that the CRF1 antagonist verucerfont potently blocks hypothalamic-pituitary adrenal (HPA) axis activation in adrenalectomized rats. We then evaluated verucerfont for its ability to block HPA axis activation and reduce stress-induced alcohol craving in alcohol-dependent patients. Anxious, alcohol-dependent women (age 21-65 years, n=39) were admitted to the NIH Clinical Center and completed withdrawal treatment before enrollment if needed. One-week single-blind placebo was followed by randomized double-blind verucerfont (350 mg per day) or placebo for 3 weeks. Verucerfont effects on the HPA axis were evaluated using the dexamethasone-CRF test. Craving was evaluated using two established protocols, one that combines a social stressor with physical alcohol cue exposure, and one that uses guided imagery to present personalized stress, alcohol, or neutral stimuli. An fMRI session examined brain responses to negative affective stimuli and alcohol cues. In contrast to our recent observations with another CRF1 antagonist, pexacerfont, verucerfont potently blocked the HPA axis response to the dexamethasone-CRF test, but left alcohol craving unaffected. Right amygdala responses to negative affective stimuli were significantly attenuated by verucerfont, but responses to alcohol-associated stimuli were increased in some brain regions, including left insula. Discontinuation rates were significantly higher in the verucerfont group. Our findings provide the first translational evidence that CRF1 antagonists with slow receptor dissociation kinetics may have increased efficacy to dampen HPA axis responses. The findings do not support a clinical efficacy of CRF1 blockade in stress-induced alcohol craving and relapse.

Anxiety is an adaptive response that promotes harm avoidance, but at the same time excessive anxiety constitutes the most common psychiatric complaint. Moreover, current treatments for anxiety—both psychological and pharmacological—hover at around 50% recovery rates. Improving treatment outcomes is nevertheless difficult, in part because contemporary interventions were developed without an understanding of the underlying neurobiological mechanisms that they modulate. Recent advances in experimental models of anxiety in humans, such as threat of unpredictable shock, have, however, enabled us to start translating the wealth of mechanistic animal work on defensive behaviour into humans. In this article, we discuss the distinction between fear and anxiety, before reviewing translational research on the neural circuitry of anxiety in animal models and how it relates to human neuroimaging studies across both healthy and clinical populations. We highlight the roles of subcortical regions (and their subunits) such as the bed nucleus of the stria terminalis, the amgydala, and the hippocampus, as well as their connectivity to cortical regions such as dorsal medial and lateral prefrontal/cingulate cortex and insula in maintaining anxiety responding. We discuss how this circuitry might be modulated by current treatments before finally highlighting areas for future research that might ultimately improve treatment outcomes for this common and debilitating transdiagnostic symptom.

Use of Cannabis, the most widely used illicit drug worldwide, is associated with acute anxiety, and anxiety disorders following regular use. The precise neural and receptor basis of these effects have not been tested in man. Employing a combination of functional MRI (fMRI) and positron emission tomography (PET), we investigated whether the effects of delta-9-tetrahydrocannabinol (delta-9-THC), the main psychoactive ingredient of cannabis, on anxiety and on amygdala response while processing fearful stimuli were related to local availability of its main central molecular target, cannabinoid-1 (CB1) receptors in man. Fourteen healthy males were studied with fMRI twice, one month apart, following an oral dose of either delta-9-THC (10 mg) or placebo, while they performed a fear-processing task. Baseline availability of the CB1 receptor was studied using PET with [ 11 C]MePPEP, a CB1 inverse agonist radioligand. Relative to the placebo condition, delta-9-THC induced anxiety and modulated right amygdala activation while processing fear. Both these effects were positively correlated with CB1 receptor availability in the right amygdala. These results suggest that the acute effects of cannabis on anxiety in males are mediated by the modulation of amygdalar function by delta-9-THC and the extent of these effects are related to local availability of CB1 receptors.

Premature-born infants have impaired amygdala structure, presumably due to increased stress levels of premature birth mediated by the amygdala. However, accounting for lifelong plasticity of amygdala, it is unclear whether such structural changes persist into adulthood. To address this problem, we stated the following questions: first, are whole amygdala volumes reduced in premature-born adults? And second, as adult anxiety traits are often increased after prematurity and linked with amygdala structure, are alterations in amygdala associated with adults’ anxiety traits after premature birth? We addressed these questions by automated amygdala segmentation of MRI volumes in 101 very premature-born adults (< 32 weeks of gestation and/or birth weight below 1500 g) and 108 full-term controls at 26 years of age of a prospectively and longitudinally collected cohort. We found significantly lower whole amygdala volumes in premature-born adults. While premature-born adults had significantly higher T score for avoidant personality reflecting increased social anxiety trait, this trait was not correlated with amygdala volume alterations. Results demonstrate reduced amygdala volumes in premature born adults. Data suggest lasting effects of prematurity on amygdala structure.

Anxiety’s prevalence is increasing, making it a widespread mental health concern. However, scale‐based diagnostic methods have limitations. Music therapy helps regulate emotions and alleviate anxiety symptoms. Functional near‐infrared spectroscopy (fNIRS) offers a novel approach to diagnosing mental disorders by measuring changes in the concentrations of oxygenated hemoglobin (HbO) and deoxygenated hemoglobin (HbR) in the superficial layers of the brain, thereby reflecting brain activation. This is the first study to use fNIRS to examine the impact of music therapy on anxiety. fNIRS was used to measure changes in HbO and HbR in the superficial brain regions of individuals with anxiety symptoms to evaluate music therapy effectiveness and identify brain regions associated with anxiety. This study recruited 83 participants: 17 comprised the healthy control group, and 66 comprised the anxiety group. The anxiety group was divided into an intervention group (34 participants) and a waiting‐list group (32 participants). The intervention group underwent 12 music therapy sessions and exhibited significant changes compared with the waiting group. These changes included connectivity between Wernicke’s area and the dorsolateral prefrontal cortex (DLPFC) as well as the visual association cortex and Broca’s triangular area. These results suggested that the connectivity characteristics of these brain regions were associated with anxiety. Music therapy significantly improved brain network connectivity characteristics in individuals with anxiety symptoms. Furthermore, fNIRS indicators could serve as biomarkers for the auxiliary identification of anxiety symptoms, aiding early identification and intervention. Trial Registration: ClinicalTrials.gov identifier: NCT05648539

Mechanisms and predictors for the successful treatment of anxiety and depression have been elusive, limiting the effectiveness of existing treatments and curtailing the development of new interventions. In this study, we evaluated the utility of three widely used neural probes of emotion (experience, regulation, and perception) in their ability to predict symptom improvement and correlate with symptom change following two first-line treatments—selective serotonin reuptake inhibitors (SSRIs) and cognitive-behavioral therapy (CBT). Fifty-five treatment-seeking adults with anxiety and/or depression were randomized to 12 weeks of SSRI or CBT treatment (ClinicalTrials.gov identifier: NCT01903447). Functional magnetic resonance imaging (fMRI) was used to examine frontolimbic brain function during emotion experience, regulation, and perception, as probed by the Emotion Regulation Task (ERT; emotion experience and regulation) and emotional face assessment task (EFAT; emotion perception). Brain function was then related to anxiety and depression symptom change. Results showed that both SSRI and CBT treatments similarly attenuated insula and amygdala activity during emotion perception, and greater treatment-related decrease in insula and amygdala activity was correlated with greater reduction in anxiety symptoms. Both treatments also reduced amygdala activity during emotion experience but brain change did not correlate with symptom change. Lastly, greater pre-treatment insula and amygdala activity during emotion perception predicted greater anxiety and depression symptom improvement. Thus, limbic activity during emotion perception is reduced by both SSRI and CBT treatments, and predicts anxiety and depression symptom improvement. Critically, neural reactivity during emotion perception may be a non-treatment-specific mechanism for symptom improvement.

Movie‐watching fMRI has emerged as a theoretically viable platform for studying neurobiological substrates of affective states and emotional disorders such as pathological anxiety. However, using anxiety‐inducing movie clips to probe relevant states impacted by psychopathology could risk exacerbating in‐scanner movement, decreasing signal quality/quantity and thus statistical power. This could be especially problematic in target populations such as children who typically move more in the scanner. Consequently, we assessed: (1) the extent to which an anxiety‐inducing movie clip altered in‐scanner data quality (movement, censoring, and DVARS) in a pediatric sample with and without anxiety disorders (n = 78); and (2) investigated interactions between anxiety symptoms and movie‐attenuated motion in a highly powered, transdiagnostic pediatric sample (n = 2058). Our results suggest anxiogenic movie‐watching in fact reduces in‐scanner movement compared to resting‐state, increasing the quantity/quality of data. In one measure, pathological anxiety appeared to impact movie‐attenuated motion, but the effect was small. Given potential boosts to data quality, future developmental neuroimaging studies of anxiety may benefit from the use of movie paradigms. Children and adolescents are a difficult‐to‐image population due their tendency to move during scanning sessions. Our results suggest youth show lower in‐scanner movement when viewing anxiogenic and non‐anxiogenic movie clips compared to rest.

Background: Major depressive disorder (MDD) is a psychiatric disorder characterized by alterations in global signal (GS) topography across various neural networks and brain regions, including the default mode network and sensorimotor‐related areas. While previous research has demonstrated the potential of global brain activity measures to differentiate MDD from healthy controls (HCs), specific changes in GS distribution among MDD patients with and without anxiety remain poorly understood. This study aims to investigate anxiety‐related alterations in GS topography in MDD and their associations with clinical symptoms. Methods: Resting‐state functional magnetic resonance imaging (fMRI) and T1‐weighted imaging data were collected from 334 MDD patients with anxiety, 145 MDD patients without anxiety, and 307 HCs as part of the REST‐meta‐MDD consortium. We computed GS topography using GS correlation (GSCORR) and assessed structural–functional interaction (SFI) by examining the relationship between gray matter volume and GS for each subject. Results: Our analysis revealed no significant differences in GS topography among the three groups at either the whole‐brain or network levels. However, decreased GSCORR was observed in the right precentral gyrus, insula, and posterior parieto‐occipital cortex in anxious MDD patients compared to HC. SFI analyses indicated anxiety‐related alterations in the sensorimotor network, precuneus, putamen, and middle temporal gyrus. Moreover, GSCORR in the inferior parietal lobe and cerebellum exhibited specific correlation trends with anxiety and depression symptoms, respectively. Conclusions: These findings underscore an abnormal topographic shift in global brain activity in MDD patients with anxiety, offering a new insight into understanding brain dysfunction associated with this disorder.

Anxiety disorders are common in autism spectrum disorder (ASD) and associated with social–communication impairment and repetitive behavior symptoms. The neurobiology of anxiety in ASD is unknown, but amygdala dysfunction has been implicated in both ASD and anxiety disorders. Using resting-state functional magnetic resonance imaging, we compared amygdala–prefrontal and amygdala–striatal connections across three demographically matched groups studied in the Autism Brain Imaging Data Exchange (ABIDE): ASD with a comorbid anxiety disorder (N = 25; ASD + Anxiety), ASD without a comorbid disorder (N = 68; ASD-NoAnx), and typically developing controls (N = 139; TD). Relative to ASD-NoAnx and TD controls, ASD + Anxiety individuals had decreased connectivity between the amygdala and dorsal/rostral anterior cingulate cortex (dACC/rACC). The functional connectivity of these connections was not affected in ASD-NoAnx, and amygdala connectivity with ventral ACC/medial prefrontal cortex (mPFC) circuits was not different in ASD + Anxiety or ASD-NoAnx relative to TD. Decreased amygdala–dorsomedial prefrontal cortex (dmPFC)/rACC connectivity was associated with more severe social impairment in ASD + Anxiety; amygdala–striatal connectivity was associated with restricted, repetitive behavior (RRB) symptom severity in ASD-NoAnx individuals. These findings suggest comorbid anxiety in ASD is associated with disrupted emotion-monitoring processes supported by amygdala–dACC/mPFC pathways, whereas emotion regulation systems involving amygdala–ventromedial prefrontal cortex (vmPFC) are relatively spared. Our results highlight the importance of accounting for comorbid anxiety for parsing ASD neurobiological heterogeneity.