CBT May Normalize Fronto-Parietal Activation in Unmedicated Pediatric Anxiety

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After undergoing cognitive behavioral therapy, unmedicated pediatric patients with anxiety disorder experienced changes in activation in the fronto-parietal network regions including left and right supplementary motor area, middle frontal gyrus, and superior parietal lobule.

Cognitive-behavioral therapy (CBT) may normalize fronto-parietal activations in unmedicated pediatric anxiety patients, according to a new study.1

The new study found unmedicated youth with anxiety had overactivation in certain brain regions including the frontal and parietal lobes and the amygdala. Yet, CBT normalized the overactivation, improving clinical symptoms and brain functioning in 66% of the participants.

“Understanding the brain circuitry underpinning feelings of severe anxiety and determining which circuits normalize and which do not as anxiety symptoms improve with CBT is critical for advancing treatment and making it more effective for all children,” said lead investigator Simone P. Haller, PhD, from the Emotion and Development Branch of the National Institute of Mental Health, in a press release.

The investigators aimed to investigate how CBT affects brain mechanisms and changes in symptoms in pediatric patients.2 In their study, investigators leveraged data from 69 unmedicated pediatric patients with anxiety disorder who underwent 12 weeks of CBT from 2 randomized clinical trials. Investigators defined being diagnosed with an anxiety disorder as having a diagnosis of generalized anxiety, social anxiety, or separation anxiety disorder. Data was collected for 2 randomized clinical trials evaluating the efficacy of adjunctive computerized cognitive training.

The team age-matched anxiety participants with non-anxiety (control) participants. Both groups completed a threat-processing task during functional MRI before and after treatment: a dot-probe task where participants were told to press a button to indicate the direction of an arrow probe that pointed to either angry-neutral or neutral-neutral face pairs of the same actor. Additionally, to examine whole-brain regional activation changes (threshold: P < .0001), the investigators examined the task-based blood-oxygen-level-dependent response.

Participants had a mean age of 13.20 years with 41% male (anxiety group, n = 69; control group, n = 62). Moreover, the study included an additional sample with separate participants at a temperamental risk for anxiety to evaluate anxiety-related neural differences without treatment (n = 87; mean age, 10.51 years; 41% male).

The team evaluated symptom severity, frequency, distress, avoidance, and interference with the Pediatric Anxiety Rating Scale (PARS). They also used the Clinical Global Impressions Scale improvement scale (CGI-I) weekly; “treatment responders” had CGI-I scores of ≤ 3 and “nonresponders” had scores of >4. The investigators used pre- and post-CBT ratings to assess clinical improvement.

Before CBT, patients with anxiety had overactivation in fronto-parietal attention networks and limbic regions (the amygdala). After CBT, the fronto-parietal normalized, but the limbic responses stayed raised. Patients at risk of anxiety had overlapping clusters form between regions, demonstrating how some regions were associated with anxiety but other regions showed treatment-related changes.

In the anxiety group, PARS and CGI-I scores were significantly improved after treatment (change in PARS score: mean = -4.15; P <0.001). More than half (66%) had a clinically significant reduction in symptoms and were therefore “responders.”

Although a time-point-by-group interaction was observed for mean task response time (P <.001), the interaction was insignificant for any regions. The pretreatment scan showed participants with anxiety was significantly slower to respond among conditions compared to the control group (∼69 ms; P <0.001) and had a larger difference than observed in the posttreatment scan ∼42 ms; P =0.03; estimated difference, ∼27 ms; P <.001).

“Previous work in youths with anxiety disorders has shown that greater activation in prefrontal regions to angry faces predicts better treatment response across CBT and pharmacological treatment,” investigators wrote. “Given the mixed findings, further work is needed.”

After treatment, 13 regions showed activity normalization, particularly the fronto-parietal network regions including left and right supplementary motor area, middle frontal gyrus, and superior parietal lobule.

In contrast, the regions of the temporal gyri (superior and inferior), the left and right inferior, the parietal lobule, and the middle occipital gyrus had no pretreatment differences between the anxiety and control groups. A posttreatment scan showed the anxiety group had significantly less activation compared to the controls.

Regions that had hyperactivation before treatment but did not normalize after the treatment in the anxiety group were the left and right motor cortex, the right amygdala/parahippocampal gyrus, and lateral anterior frontal areas.

Limitations the investigators highlighted included not being able to use a control arm of unmedicated youths with anxiety due to restrictions made by their institution’s review board, the possibility of heterogeneity since they used 2 different randomized trials for data, not using newer network-based analytical techniques instead of established whole-brain procedures to examine task activation patterns, and lastly few of the participants in the high-risk sample met the criteria for anxiety disorder at the time of the scan.

“The data from this study reveal neural mechanisms that change following the acute effects of CBT for pediatric anxiety, as well as potential subcortical and cortical targets that remain dysfunctional after 12 weeks of CBT,” investigators wrote. “Future work may benefit from directly targeting subcortical, automatic, and biased processing to enhance CBT treatment response.”


  1. Cognitive Behavioral Therapy Alters Brain Activity in Children with Anxiety. EurekAlert! January 22, 2024. Accessed January 29, 2023.
  2. Haller SP, Linke JO, Grassie HL, et al. Normalization of Fronto-Parietal Activation by Cognitive-Behavioral Therapy in Unmedicated Pediatric Patients With Anxiety Disorders. Am J Psychiatry. Published online January 24, 2024. doi:10.1176/appi.ajp.20220449