Brain Aging in Specific Phobia: An ENIGMA-Anxiety Mega-Analysis

medRxiv [Preprint]. 2025 Mar 20:2025.03.19.25323474. doi: 10.1101/2025.03.19.25323474.

ABSTRACT

INTRODUCTION: Specific phobia (SPH) is a prevalent anxiety disorder and may involve advanced biological aging. However, brain age research in psychiatry has primarily examined mood and psychotic disorders. This mega-analysis investigated brain aging in SPH participants within the ENIGMA-Anxiety Working Group.

METHODS: 3D brain s tructural MRI scans from 17 international samples (600 SPH individuals, of whom 504 formally diagnosed and 96 questionnaire-based cases; 1,134 controls; age range: 22-75 years) were processed with FreeSurfer. Brain age was estimated from 77 subcortical and cortical regions with a publicly available ENIGMA brain age model. The brain-predicted age difference (brain-PAD) was calculated as brain age minus chronological age. Linear mixed-effect models examined group differences in brain-PAD and moderation by age.

RESULTS: No significant group difference in brain-PAD manifested ( β _diagnosis (SE)=0.37 years (0.43), p =0.39). A negative diagnosis-by-age interaction was identified, which was most pronounced in formally diagnosed SPH ( β _{diagnosis-by-age} =-0.08 (0.03), pFDR =0.02). This interaction remained significant when excluding participants with anxiety comorbidities, depressive comorbidities, and medication use. Post-hoc analyses revealed a group difference for formal SPH diagnosis in younger participants (22-35 years; β _diagnosis =1.20 (0.60), p <0.05, mixed-effects d (95% confidence interval)=0.14 (0.00-0.28)), but not older participants (36-75 years; β _diagnosis =0.07 (0.65), p =0.91).

CONCLUSIONS: Brain aging did not relate to SPH in the full sample. However, a diagnosis-by-age interaction was observed across analyses, and was strongest in formally diagnosed SPH. Post-hoc analyses showed a subtle advanced brain aging in young adults with formally diagnosed SPH. Taken together, these findings indicate the importance of clinical severity, impairment and persistence, and may suggest a slightly earlier end to maturational processes or subtle decline of brain structure in SPH.

PMID:40166564 | PMC:PMC11957081 | DOI:10.1101/2025.03.19.25323474