Brain Functional Connectivity and Anatomical Features as Predictors of Cognitive Behavioral Therapy Outcome for Anxiety in Youths.

Background: Because pediatric anxiety disorders precede the onset of many other problems, successful prediction of response to the first-line treatment, cognitive-behavioral therapy (CBT), could have major impact. However, existing clinical models are weakly predictive. The current study evaluates whether structural and resting-state functional magnetic resonance imaging can predict post-CBT anxiety symptoms. Methods: Two datasets were studied: (A) one consisted of n=54 subjects with an anxiety diagnosis, who received 12 weeks of CBT, and (B) one consisted of n=15 subjects treated for 8 weeks. Connectome Predictive Modeling (CPM) was used to predict treatment response, as assessed with the PARS; additionally we investigated models using anatomical features, instead of functional connectivity. The main analysis included network edges positively correlated with treatment outcome, and age, sex, and baseline anxiety severity as predictors. Results from alternative models and analyses also are presented. Model assessments utilized 1000 bootstraps, resulting in a 95% CI for R2, r and mean absolute error (MAE). Outcomes: The main model showed a mean absolute error of approximately 3.5 (95%CI: [3.1-3.8]) points a R2 of 0.08 [-0.14 - 0.26] and r of 0.38 [0.24 - 0.511]. When testing this model in the left-out sample (B) the results were similar, with a MAE of 3.4 [2.8 - 4.7], R2-0.65 [-2.29 - 0.16] and r of 0.4 [0.24 - 0.54]. The anatomical metrics showed a similar pattern, where models rendered overall low R2. Interpretation: The analysis showed that models based on earlier promising results failed to predict clinical outcomes. Despite the small sample size, the current study does not support extensive use of CPM to predict outcome in pediatric anxiety.

Evaluating the development and well-being assessment (DAWBA) in pediatric anxiety and depression.

Enhancing screening practices and developing scalable diagnostic tools are imperative in response to the increasing prevalence of youth mental health challenges. Structured lay psychiatric interviews have emerged as one such promising tool. However, there remains limited research evaluating structured psychiatric interviews, specifically their characterization of internalizing disorders in treatment-seeking youth. This study evaluates the relationship between the Development and Well-Being Assessment (DAWBA), a structured psychiatric interview, and established measures of pediatric anxiety and depression, including the Screen for Child Anxiety Related Disorders (SCARED), the Pediatric Anxiety Rating Scale (PARS), and the Mood and Feelings Questionnaire (MFQ). The study comprised two independent clinical samples of treatment-seeking youth: sample one included 55 youth with anxiety and 29 healthy volunteers (HV), while sample two included 127 youth with Major Depressive Disorder and 73 HVs. We examined the association between the DAWBA band scores, indicating predicted risk for diagnosis, the SCARED and PARS (sample one), and the MFQ (sample two). An exploratory analysis was conducted in a subset of participants to test whether DAWBA band scores predicted the change in anxiety symptoms (SCARED, PARS) across a 12-week course of cognitive behavioral therapy. The results revealed that the DAWBA significantly predicted the SCARED, PARS and MFQ measures at baseline; however, it did not predict changes in anxiety symptoms across treatment. These findings suggest that the DAWBA may be a helpful screening tool for indexing anxiety and depression in treatment-seeking youth but is not especially predictive of longitudinal trajectories in symptomatology across psychotherapy.

Normalization of Fronto-Parietal Activation by Cognitive-Behavioral Therapy in Unmedicated Pediatric Patients With Anxiety Disorders.

OBJECTIVE: Anxiety disorders are prevalent among youths and are often highly impairing. Cognitive-behavioral therapy (CBT) is an effective first-line treatment. The authors investigated the brain mechanisms associated with symptom change following CBT. METHODS: Unmedicated youths diagnosed with an anxiety disorder underwent 12 weeks of CBT as part of two randomized clinical trials testing the efficacy of adjunctive computerized cognitive training. Across both trials, participants completed a threat-processing task during functional MRI before and after treatment. Age-matched healthy comparison youths completed two scans over the same time span. The mean age of the samples was 13.20 years (SD=2.68); 41% were male (youths with anxiety disorders, N=69; healthy comparison youths, N=62). An additional sample including youths at temperamental risk for anxiety (N=87; mean age, 10.51 years [SD=0.43]; 41% male) was utilized to test the stability of anxiety-related neural differences in the absence of treatment. Whole-brain regional activation changes (thresholded at p<0.001) were examined using task-based blood-oxygen-level-dependent response. RESULTS: Before treatment, patients with an anxiety disorder exhibited altered activation in fronto-parietal attention networks and limbic regions relative to healthy comparison children across all task conditions. Fronto-parietal hyperactivation normalized over the course of treatment, whereas limbic responses remained elevated after treatment. In the at-risk sample, overlapping clusters emerged between regions showing stable associations with anxiety over time and regions showing treatment-related changes. CONCLUSIONS: Activation in fronto-parietal networks may normalize after CBT in unmedicated pediatric anxiety patients. Limbic regions may be less amenable to acute CBT effects. Findings from the at-risk sample suggest that treatment-related changes may not be attributed solely to the passage of time.

Cortical Thickness and Subcortical Gray Matter Volume in Pediatric Anxiety Disorders.

Perturbations in the prefrontal cortex (PFC), hippocampus, and amygdala are implicated in the development of anxiety disorders. However, most structural neuroimaging studies of patients with anxiety disorders utilize adult samples, and the few studies in youths examine small samples, primarily with volume-based measures. This study tested the hypothesis that cortical thickness of PFC regions and gray matter volume of the hippocampus and amygdala differ between pediatric anxiety disorder patients and healthy volunteers (HVs). High-resolution 3-Tesla T1-weighted MRI scans were acquired in 151 youths (75 anxious, 76 HV; ages 8-18). Analyses tested associations of brain structure with anxiety diagnosis and severity across both groups, as well as response to cognitive-behavioral therapy in a subset of 53 patients. Cortical thickness was evaluated both within an a priori PFC mask (small-volume corrected) and using an exploratory whole-brain-corrected (p<0.05) approach. Anxious relative to healthy youths exhibited thicker cortex in the left ventromedial PFC (vmPFC) and left precentral gyrus. Both anxiety diagnosis and symptom severity were associated with smaller right hippocampal volume. In patients, thinner cortex in parietal and occipital cortical regions was associated with worse treatment response. Pediatric anxiety was associated with structural differences in vmPFC and hippocampus, regions implicated in emotional processing and in developmental models of anxiety pathophysiology. Parietal and occipital cortical thickness were related to anxiety treatment response but not baseline anxiety.

Complementary Features of Attention Bias Modification Therapy and Cognitive-Behavioral Therapy in Pediatric Anxiety Disorders.

OBJECTIVE: In the treatment of anxiety disorders, attention bias modification therapy (ABMT) and cognitive-behavioral therapy (CBT) may have complementary effects by targeting different aspects of perturbed threat responses and behaviors. ABMT may target rapid, implicit threat reactions, whereas CBT may target slowly deployed threat responses. The authors used amygdala-based connectivity during a threat-attention task and a randomized controlled trial design to evaluate potential complementary features of these treatments in pediatric anxiety disorders. METHOD: Prior to treatment, youths (8-17 years old) with anxiety disorders (N=54), as well as healthy comparison youths (N=51), performed a threat-attention task during functional MRI acquisition. Task-related amygdala-based functional connectivity was assessed. Patients with and without imaging data (N=85) were then randomly assigned to receive CBT paired with either active or placebo ABMT. Clinical response was evaluated, and pretreatment amygdala-based connectivity profiles were compared among patients with varying levels of clinical response. RESULTS: Compared with the CBT plus placebo ABMT group, the CBT plus active ABMT group exhibited less severe anxiety after treatment. The patient and healthy comparison groups differed in amygdala-insula connectivity during the threat-attention task. Patients whose connectivity profiles were most different from those of the healthy comparison group exhibited the poorest response to treatment, particularly those who received CBT plus placebo ABMT. CONCLUSIONS: The study provides evidence of enhanced clinical effects for patients receiving active ABMT. Moreover, ABMT appears to be most effective for patients with abnormal amygdala-insula connectivity. ABMT may target specific threat processes associated with dysfunctional amygdala-insula connectivity that are not targeted by CBT alone. This may explain the observation of enhanced clinical response to CBT plus active ABMT.