TY - JOUR
T1 - Structural Brain Correlates of Childhood Inhibited Temperament
T2 - An ENIGMA-Anxiety Mega-Analysis
AU - Bas-Hoogendam, Janna Marie
AU - Bernstein, Rachel A.
AU - Benson, Brenda E.
AU - Frank, Samuel E.C.
AU - Buss, Kristin A.
AU - Gunther, Kelley E.
AU - Pérez-Edgar, Koraly
AU - Salum, Giovanni A.
AU - Jackowski, Andrea
AU - Bressan, Rodrigo A.
AU - Zugman, André
AU - Degnan, Kathryn A.
AU - Filippi, Courtney A.
AU - Fox, Nathan A.
AU - Henderson, Heather A.
AU - Tang, Alva
AU - Zeytinoglu, Selin
AU - Harrewijn, Anita
AU - Hillegers, Manon H.J.
AU - Muetzel, Ryan L.
AU - White, Tonya
AU - van IJzendoorn, Marinus H.
AU - Schwartz, Carl E.
AU - Felicione, Julia M.
AU - DeYoung, Kathryn A.
AU - Shackman, Alexander J.
AU - Smith, Jason F.
AU - Tillman, Rachael M.
AU - van den Berg, Yvonne H.M.
AU - Cillessen, Antonius H.N.
AU - Roelofs, Karin
AU - Tyborowska, Anna
AU - Hill, Shirley Y.
AU - Battaglia, Marco
AU - Tettamanti, Marco
AU - Dougherty, Lea R.
AU - Jin, Jingwen
AU - Klein, Daniel N.
AU - Leung, Hoi Chung
AU - Avery, Suzanne N.
AU - Blackford, Jennifer Urbano
AU - Clauss, Jacqueline A.
AU - Bjork, James M.
AU - Hettema, John M.
AU - Moore, Ashlee A.
AU - Roberson-Nay, Roxann
AU - Sawyers, Chelsea
AU - Hayden, Elizabeth P.
AU - Liu, Pan
AU - Vandermeer, Matthew R.J.
AU - Goldsmith, H. Hill
AU - Planalp, Elizabeth M.
AU - Nichols, Thomas E.
AU - Thompson, Paul M.
AU - Westenberg, P. Michiel
AU - van der Wee, Nic J.A.
AU - Groenewold, Nynke A.
AU - Stein, Dan J.
AU - Winkler, Anderson M.
AU - Pine, Daniel S.
N1 - Publisher Copyright:
©2025 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. This is an open access article under the CC BY license. http://creativecommons.org/licenses/by/4.0/
PY - 2026/4
Y1 - 2026/4
N2 - Objective: Childhood inhibited temperament (cIT) is associated with an increased risk for developing internalizing psychopathology. Neurobiological characteristics identified by structural magnetic resonance imaging (MRI) may elucidate the neural substrates for cIT, but studies are scarce and often focus on particular regions of interest. Moreover, current findings lack replication. This preregistered analysis from the ENIGMA-Anxiety Working Group examined structural brain characteristics associated with cIT using a comprehensive whole-brain approach. Method: Temperament assessments (behavioral observations, parent/teacher reports or self-reports on cIT before age 13 years) and MRI data (age at scan, 6-25 years) from international research sites (Europe, North America, South America) were pooled for mega-analysis. Following image processing and quality control, associations between cIT and brain structure were examined in 3,803 participants. Subcortical volumes, cortical thickness, and surface area (main analyses) and detailed subcortical characteristics (eg, subnuclei, subfields, partial volume effects; exploratory analyses) were considered. Results: In the full sample, cIT showed no relation with brain structure, either as a main effect or in interactions with sex or age. Subgroup analyses (based on cIT assessment type) revealed cIT by sex interactions on mean cortical thickness (pMC-FWER = .037) and thickness of the right superior parietal region (pMC-FWER = .029) in youth with parent/teacher reports on cIT levels. Exploratory analyses revealed findings in the hippocampus, putamen, and caudate, but most did not survive statistical correction for multiple testing. Conclusion: This mega-analysis found no consistent associations between cIT and regional brain structure, although the role of parietal regions warrants further investigation. Future studies should consider brain function in cIT, preferably using longitudinal designs. Plain language summary: Inhibited temperament during childhood is a risk factor for the development of anxiety and depression later in life. A preregistered study from the international ENIGMA-Anxiety Working Group investigated whether characteristics of brain structure are associated with the level of childhood inhibited temperament, using brain scans and data on temperamental traits from participants aged 6 to 25 years, which have been previously acquired at research sites worldwide (total sample > 3,800 subjects). Analyses revealed no consistent correlations between brain structure and inhibited temperament. Study Registration Information: Structural Brain Correlates of Childhood Inhibited Temperament: An ENIGMA-Anxiety Mega-analysis.https://www.jaacap.org/article/S0890-8567(22)00299-4/fulltext
AB - Objective: Childhood inhibited temperament (cIT) is associated with an increased risk for developing internalizing psychopathology. Neurobiological characteristics identified by structural magnetic resonance imaging (MRI) may elucidate the neural substrates for cIT, but studies are scarce and often focus on particular regions of interest. Moreover, current findings lack replication. This preregistered analysis from the ENIGMA-Anxiety Working Group examined structural brain characteristics associated with cIT using a comprehensive whole-brain approach. Method: Temperament assessments (behavioral observations, parent/teacher reports or self-reports on cIT before age 13 years) and MRI data (age at scan, 6-25 years) from international research sites (Europe, North America, South America) were pooled for mega-analysis. Following image processing and quality control, associations between cIT and brain structure were examined in 3,803 participants. Subcortical volumes, cortical thickness, and surface area (main analyses) and detailed subcortical characteristics (eg, subnuclei, subfields, partial volume effects; exploratory analyses) were considered. Results: In the full sample, cIT showed no relation with brain structure, either as a main effect or in interactions with sex or age. Subgroup analyses (based on cIT assessment type) revealed cIT by sex interactions on mean cortical thickness (pMC-FWER = .037) and thickness of the right superior parietal region (pMC-FWER = .029) in youth with parent/teacher reports on cIT levels. Exploratory analyses revealed findings in the hippocampus, putamen, and caudate, but most did not survive statistical correction for multiple testing. Conclusion: This mega-analysis found no consistent associations between cIT and regional brain structure, although the role of parietal regions warrants further investigation. Future studies should consider brain function in cIT, preferably using longitudinal designs. Plain language summary: Inhibited temperament during childhood is a risk factor for the development of anxiety and depression later in life. A preregistered study from the international ENIGMA-Anxiety Working Group investigated whether characteristics of brain structure are associated with the level of childhood inhibited temperament, using brain scans and data on temperamental traits from participants aged 6 to 25 years, which have been previously acquired at research sites worldwide (total sample > 3,800 subjects). Analyses revealed no consistent correlations between brain structure and inhibited temperament. Study Registration Information: Structural Brain Correlates of Childhood Inhibited Temperament: An ENIGMA-Anxiety Mega-analysis.https://www.jaacap.org/article/S0890-8567(22)00299-4/fulltext
KW - adolescence
KW - anxiety disorders
KW - childhood
KW - magnetic resonance imaging (MRI)
KW - temperament
UR - https://www.scopus.com/pages/publications/105014950984
U2 - 10.1016/j.jaac.2025.06.026
DO - 10.1016/j.jaac.2025.06.026
M3 - Article
C2 - 40619094
AN - SCOPUS:105014950984
SN - 0890-8567
VL - 65
SP - 577
EP - 604
JO - Journal of the American Academy of Child and Adolescent Psychiatry
JF - Journal of the American Academy of Child and Adolescent Psychiatry
IS - 4
ER -