Cortical and Subcortical Brain Alterations in Specific Phobia and Its Animal and Blood-Injection-Injury Subtypes: A Mega-Analysis From the ENIGMA Anxiety Working Group

Kevin Hilbert*, Ole Jonas Boeken, Till Langhammer, Nynke A Groenewold, Janna Marie Bas-Hoogendam, Moji Aghajani, André Zugman, Fredrik Åhs, Volker Arolt, Katja Beesdo-Baum, Johannes Björkstrand, Jennifer U Blackford, Laura Blanco-Hinojo, Joscha Böhnlein, Robin Bülow, Marta Cano, Narcis Cardoner, Xavier Caseras, Udo Dannlowski, Katharina DomschkeLydia Fehm, Brandee Feola, Mats Fredrikson, Liesbet Goossens, Hans J Grabe, Dominik Grotegerd, Raquel E Gur, Alfons O Hamm, Anita Harrewijn, Ingmar Heinig, Martin J Herrmann, David Hofmann, Andrea P Jackowski, Andreas Jansen, Antonia N Kaczkurkin, Merel Kindt, Ellen N Kingsley, Tilo Kircher, Anna L Klahn, Katja Koelkebeck, Axel Krug, Harald Kugel, Bart Larsen, Elisabeth J Leehr, Lieselotte Leonhardt, Martin Lotze, Jürgen Margraf, Jarosław Michałowski, Markus Muehlhan, Igor Nenadić, Pedro M Pan, Paul Pauli, Wenceslao Peñate, Andre Pittig, Jens Plag, Jesus Pujol, Jan Richter, Francisco L Rivero, Giovanni A Salum, Theodore D Satterthwaite, Axel Schäfer, Judith Schäfer, Anne Schienle, Silvia Schneider, Elisabeth Schrammen, Koen Schruers, Stefan M Schulz, Esther Seidl, Rudolf M Stark, Frederike Stein, Benjamin Straube, Thomas Straube, Andreas Ströhle, Boris Suchan, Sophia I Thomopoulos, Carlos Ventura-Bort, Renee Visser, Henry Völzke, Albert Wabnegger, André Wannemüller, Julia Wendt, Julian Wiemer, Hans-Ulrich Wittchen, Katharina Wittfeld, Barry Wright, Yunbo Yang, Anna Zilverstand, Peter Zwanzger, Dick J Veltman, Anderson M Winkler, Daniel S Pine, Neda Jahanshad, Paul M Thompson, Dan J Stein, Nic J A Van der Wee, Ulrike Lueken

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

OBJECTIVE: 

Specific phobia is a common anxiety disorder, but the literature on associated brain structure alterations exhibits substantial gaps. The ENIGMA Anxiety Working Group examined brain structure differences between individuals with specific phobias and healthy control subjects as well as between the animal and blood-injection-injury (BII) subtypes of specific phobia. Additionally, the authors investigated associations of brain structure with symptom severity and age (youths vs. adults).

METHODS: 

Data sets from 31 original studies were combined to create a final sample with 1,452 participants with phobia and 2,991 healthy participants (62.7% female; ages 5-90). Imaging processing and quality control were performed using established ENIGMA protocols. Subcortical volumes as well as cortical surface area and thickness were examined in a preregistered analysis.

RESULTS: 

Compared with the healthy control group, the phobia group showed mostly smaller subcortical volumes, mixed surface differences, and larger cortical thickness across a substantial number of regions. The phobia subgroups also showed differences, including, as hypothesized, larger medial orbitofrontal cortex thickness in BII phobia (N=182) compared with animal phobia (N=739). All findings were driven by adult participants; no significant results were observed in children and adolescents.

CONCLUSIONS: 

Brain alterations associated with specific phobia exceeded those of other anxiety disorders in comparable analyses in extent and effect size and were not limited to reductions in brain structure. Moreover, phenomenological differences between phobia subgroups were reflected in diverging neural underpinnings, including brain areas related to fear processing and higher cognitive processes. The findings implicate brain structure alterations in specific phobia, although subcortical alterations in particular may also relate to broader internalizing psychopathology.

Original languageEnglish
Article numberappiajp20230032
JournalAmerican Journal of Psychiatry
DOIs
Publication statusE-pub ahead of print - 11 Jun 2024

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