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

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.

Keywords: Animal Phobia; Blood Injection Injury Phobia; ENIGMA; Mega-Analysis; Neuroimaging; Specific Phobia.

FIGURE 1.. Significant differences between specific phobia subjects and healthy controls^a

^aThe bar chart (left) provides effect sizes between groups of individuals with specific phobia and healthy controls, error bars are standard errors. Positive effect sizes signify larger volume, surface area and thickness in specific phobia compared to healthy controls. The graphical depiction (right) shows the significant differences in the brain. Panel (A) shows subcortical volumes, panel (B) cortical thickness and panel (C) cortical surface area.

FIGURE 2.. Significant differences between animal phobia subjects and BII phobia subjects^a

^aThe bar chart (above) provides effect sizes between groups of individuals with animal phobia and BII phobia, error bars are standard errors. Positive effect sizes signify larger volume, surface area and thickness in animal phobia subjects compared to BII phobia subjects. The graphical depiction (below) shows the significant differences in cortical thickness between animal phobia and BII phobia subjects.

FIGURE 3.. Significant differences between animal phobia subjects and healthy controls and BII phobia subjects and healthy controls^a

^aThe bar chart (left) provides effect sizes between groups of individuals with animal phobia subjects and healthy controls in green and between BII phobia subjects and healthy controls in orange. Error bars are standard errors. Positive effect sizes signify larger volume, surface area and thickness in the respective phobia subgroup compared to healthy controls. The graphical depiction (right) shows the significant differences between animal phobia subjects and HC (upper right) and BII phobia subjects and HC (lower right) in the brain. Panel (A) shows subcortical volumes, panel (B) cortical thickness and panel (C) cortical surface area.