Structural Brain Correlates of Childhood Inhibited Temperament: An ENIGMA-Anxiety Mega-Analysis

Janna Marie Bas-Hoogendam; Rachel A Bernstein; Brenda E Benson; Samuel E C Frank; Kristin A Buss; Kelley E Gunther; Koraly Pérez-Edgar; Giovanni A Salum; Andrea Jackowski; Rodrigo A Bressan; André Zugman; Kathryn A Degnan; Courtney A Filippi; Nathan Fox; Heather A Henderson; Alva Tang; Selin Zeytinoglu; Anita Harrewijn; Manon H J Hillegers; Ryan L Muetzel; Tonya White; Marinus H van IJzendoorn; Carl Robert Emden Schwartz; Julia Felicione; Kathryn A DeYoung; Alexander J Shackman; Jason F Smith; Rachael Tillman; Yvonne H M van den Berg; Antonius H N Cillessen; Karin Roelofs; Anna Tyborowska; Shirley Y Hill; Marco Battaglia; Marco Tettamanti; Lea R Dougherty; Jingwen Jin; Daniel N Klein; Hoi-Chung Leung; Suzanne N Avery; Jennifer Urbano Blackford; Jacqueline A Clauss; James M Bjork; John M Hettema; Ashlee A Moore; Roxann Roberson-Nay; Chelsea Sawyers; Elizabeth P Hayden; Pan Liu; Matthew R J Vandermeer; H Hill Goldsmith; Elizabeth M Planalp; Thomas E Nichols; Paul M Thompson; P Michiel Westenberg; Nic J A van der Wee; Nynke A Groenewold; Dan J Stein; Anderson M Winkler; Daniel S Pine

doi:10.1016/j.jaac.2025.06.026

Structural Brain Correlates of Childhood Inhibited Temperament: An ENIGMA-Anxiety Mega-Analysis

J Am Acad Child Adolesc Psychiatry. 2025 Jul 4:S0890-8567(25)00330-2. doi: 10.1016/j.jaac.2025.06.026. Online ahead of print.

Authors

Janna Marie Bas-Hoogendam¹, Rachel A Bernstein², Brenda E Benson², Samuel E C Frank², Kristin A Buss³, Kelley E Gunther⁴, Koraly Pérez-Edgar³, Giovanni A Salum⁵, Andrea Jackowski⁶, Rodrigo A Bressan⁶, André Zugman², Kathryn A Degnan⁷, Courtney A Filippi⁸, Nathan Fox⁹, Heather A Henderson¹⁰, Alva Tang¹¹, Selin Zeytinoglu¹², Anita Harrewijn¹³, Manon H J Hillegers¹⁴, Ryan L Muetzel¹⁴, Tonya White¹⁵, Marinus H van IJzendoorn¹⁶, Carl Robert Emden Schwartz¹⁷, Julia Felicione¹⁸, Kathryn A DeYoung⁹, Alexander J Shackman⁹, Jason F Smith⁹, Rachael Tillman⁹, Yvonne H M van den Berg¹⁹, Antonius H N Cillessen¹⁹, Karin Roelofs¹⁹, Anna Tyborowska¹⁹, Shirley Y Hill²⁰, Marco Battaglia²¹, Marco Tettamanti²², Lea R Dougherty⁹, Jingwen Jin²³, Daniel N Klein²⁴, Hoi-Chung Leung²⁴, Suzanne N Avery²⁵, Jennifer Urbano Blackford²⁶, Jacqueline A Clauss²⁷, James M Bjork²⁸, John M Hettema²⁹, Ashlee A Moore³⁰, Roxann Roberson-Nay³¹, Chelsea Sawyers²⁸, Elizabeth P Hayden³², Pan Liu³³, Matthew R J Vandermeer³², H Hill Goldsmith³⁴, Elizabeth M Planalp³⁴, Thomas E Nichols³⁵, Paul M Thompson³⁶, P Michiel Westenberg³⁷, Nic J A van der Wee³⁸, Nynke A Groenewold³⁹, Dan J Stein³⁹, Anderson M Winkler⁴⁰, Daniel S Pine²

Affiliations

¹ Leiden University, Leiden, the Netherlands; Leiden University Medical Center, Leiden, the Netherlands; Leiden Institute for Brain and Cognition, Leiden, the Netherlands; National Institute of Mental Health, Bethesda, Maryland. Electronic address: j.m.hoogendam@fsw.leidenuniv.nl.
² National Institute of Mental Health, Bethesda, Maryland.
³ The Pennsylvania State University, University Park, Pennsylvania.
⁴ The Pennsylvania State University, University Park, Pennsylvania; University of Maryland, College Park, Maryland.
⁵ Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; National Institute of Developmental Psychiatry, São Paulo, Brazil; Child Mind Institute, New York, New York.
⁶ Federal University of São Paulo, São Paulo, Brazil.
⁷ The Catholic University of America, Washington, DC.
⁸ New York University Grossman School of Medicine, New York, New York.
⁹ University of Maryland, College Park, Maryland.
¹⁰ University of Waterloo, Waterloo, Ontario, Canada.
¹¹ University of Texas at Dellas, Richardson, Texas.
¹² University of Maryland, College Park, Maryland; Tulane University, New Orleans, Louisiana.
¹³ Erasmus University Rotterdam, Rotterdam, the Netherlands.
¹⁴ Erasmus University Medical Center, Rotterdam, the Netherlands.
¹⁵ National Institute of Mental Health, Bethesda, Maryland; Erasmus University Medical Center, Rotterdam, the Netherlands.
¹⁶ UCL, London, United Kingdom; Universidad San Sebastián, Chile.
¹⁷ Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
¹⁸ Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Tufts University, Medford, Massachusetts.
¹⁹ Radboud University, Behavioural Science Institute, Nijmegen, the Netherlands.
²⁰ University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
²¹ University of Toronto, Toronto, Ontario, Canada; Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
²² University of Milan-Bicocca, Milan, Italy.
²³ The University of Hong Kong, Hong Kong.
²⁴ Stony Brook University, Stony Brook, New York.
²⁵ Vanderbilt University Medical Center, Nashville, Tennessee.
²⁶ Vanderbilt University Medical Center, Nashville, Tennessee; Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, Nebraska.
²⁷ Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; University of Maryland Medical School, Baltimore, Maryland.
²⁸ Virginia Commonwealth University, Richmond, Virginia.
²⁹ Texas A&M University, Bryan, Texas.
³⁰ State University of New York, Oswego, New York.
³¹ University of Virginia, Charlottesville, Virginia.
³² Western University, London, ON, Canada.
³³ Western University, London, ON, Canada; University of Alberta, Edmonton, AB, Canada.
³⁴ University of Wisconsin-Madison, Madison, Wisconsin.
³⁵ University of Oxford, Oxford, United Kingdom.
³⁶ University of Southern California, Marina del Rey, California.
³⁷ Leiden University, Leiden, the Netherlands; Leiden Institute for Brain and Cognition, Leiden, the Netherlands.
³⁸ Leiden University Medical Center, Leiden, the Netherlands; Leiden Institute for Brain and Cognition, Leiden, the Netherlands.
³⁹ University of Cape Town, Cape Town, South Africa.
⁴⁰ National Institute of Mental Health, Bethesda, Maryland; The University of Texas Rio Grande Valley, Brownsville, Texas.

PMID: 40619094
DOI: 10.1016/j.jaac.2025.06.026

Abstract

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 pre-registered 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, parental/teacher reports or self-reports on cIT before age 13) 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 (e.g. subnuclei, subfields, partial volume effects; exploratory analyses) were considered.

Results: In the full sample, cIT showed no relation with brain structure, neither as a main effect nor in interactions with sex or age. Subgroup analyses (based on cIT-assessment type) revealed cIT by sex interactions on mean cortical thickness (p_MC-FWER = 0.037) and thickness of the right superior parietal region (p_MC-FWER = 0.029) in youth with parental/teacher reports on cIT-levels. Exploratory analyses revealed findings in 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.

Keywords: Magnetic Resonance Imaging (MRI); adolescence; anxiety disorders; childhood; temperament.