Brain aging in specific phobia: An ENIGMA-anxiety mega-analysis

Blake, Kimberly, Hilbert, Kevin, Ipser, Jonathan, Han, Laura, Bas-Hoogendam, Janna Marie, Ahs, Fredrik, Bauer, Jochen, Beesdo-Baum, Katja, Bjorkstrand, Johannes, Blanco-Hinojo, Laura, Bohnleim, Joscha, Bulow, Robin, Cano, Marta, Cardoner, Narcis, Caseras, Xavier ORCID: https://orcid.org/0000-0002-8490-6891, Dannlowski, Udo, Fredrikson, Mats, Goossens, Liesbet, Grade, Hans, Grotegerd, Dominik, Hahn, Tim, Hamm, Alfons, Heinig, Ingmar, Kindt, Martin, Kircher, Tilo, Klahn, Anna, Koelkebeck, Katja, Krug, Axel, Leechr, Elisabeth, Lotze, Martin, Margraf, Juergen, Muehlhan, Markus, Nenadic, Igor, Penate, Wenceslao, Pittig, Andre, Plag, Jens, Pujol, Jesus, Richter, Jan, Ribberbusch, Isabelle, Rivero, Francisco, Schafer, Axel, Schafer, Judith, Schiencle, Anne, Schrammen, Elisabeth, Schruers, Koen, Seidl, Esther, Stark, Rudolf, Straube, Benjamin, Straube, Thomas, Strohle, Andreas, Teutenberg, Lea, Thomopoulos, Sophia, Ventura-Bort, Carlos, Visser, Renee, Volzke, Henry, Wabnegger, Albert, Wendt, Julia, Wittchen, Hans-Ulrich, Wittfeld, Katharina, Yang, Yunbo, Zilverstand, Anna, Zwanzger, Peter, Schmaal, Lianne, Aghajani, Moji, Pine, Daniel, Thompson, Paul, Vander Wee, Nic, Stein, Dan, Lueken, Ulrike and Groenewold, Nynke 2025. Brain aging in specific phobia: An ENIGMA-anxiety mega-analysis. [Online]. medRxiv: OpenRxiv. Available at: https://doi.org/10.1101/2025.03.19.25323474

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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 structural 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 (βdiagnosis (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 (βdiagnosis-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; βdiagnosis=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; βdiagnosis=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.

Item Type:	Website Content
Date Type:	Published Online
Status:	Submitted
Schools:	Schools > Medicine Research Institutes & Centres > MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher:	OpenRxiv
Date of Acceptance:	20 March 2025
Last Modified:	09 Jun 2025 11:01
URI:	https://orca.cardiff.ac.uk/id/eprint/178224

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