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 A. Fox; Heather A. Henderson; Alva Tang; Selin Zeytinoglu; Anita Harrewijn; Manon H.J. Hillegers; Ryan L. Muetzel; Tonya White; Marinus H. van IJzendoorn; Carl E. Schwartz; Julia M. Felicione; Kathryn A. DeYoung; Alexander J. Shackman; Jason F. Smith; Rachael M. 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

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 A. Fox
, Heather A. Henderson
, Alva Tang
, Selin Zeytinoglu
, Anita Harrewijn
, Manon H.J. Hillegers
, Ryan L. Muetzel

Tonya White, Marinus H. van IJzendoorn, Carl E. Schwartz, Julia M. Felicione, Kathryn A. DeYoung, Alexander J. Shackman, Jason F. Smith, Rachael M. 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

Research output: Contribution to journal › Article › peer-review

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 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 (p_MC-FWER = .037) and thickness of the right superior parietal region (p_MC-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. 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

Original language	English
Journal	Journal of the American Academy of Child and Adolescent Psychiatry
DOIs	https://doi.org/10.1016/j.jaac.2025.06.026
State	Accepted/In press - 2025
Externally published	Yes

Keywords

adolescence
anxiety disorders
childhood
magnetic resonance imaging (MRI)
temperament

Access to Document

10.1016/j.jaac.2025.06.026

Cite this

Bas-Hoogendam, J. M., Bernstein, R. A., Benson, B. E., Frank, S. E. C., Buss, K. A., Gunther, K. E., Pérez-Edgar, K., Salum, G. A., Jackowski, A., Bressan, R. A., Zugman, A., Degnan, K. A., Filippi, C. A., Fox, N. A., Henderson, H. A., Tang, A., Zeytinoglu, S., Harrewijn, A., Hillegers, M. H. J., ... Pine, D. S. (Accepted/In press). Structural Brain Correlates of Childhood Inhibited Temperament: An ENIGMA-Anxiety Mega-Analysis. Journal of the American Academy of Child and Adolescent Psychiatry. https://doi.org/10.1016/j.jaac.2025.06.026

@article{e4434e91f37b4f59a08be356b59b1fd1,

title = "Structural Brain Correlates of Childhood Inhibited Temperament: An ENIGMA-Anxiety Mega-Analysis",

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 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. 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",

keywords = "adolescence, anxiety disorders, childhood, magnetic resonance imaging (MRI), temperament",

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

note = "Publisher Copyright: {\textcopyright} 2025 American Academy of Child and Adolescent Psychiatry",

year = "2025",

doi = "10.1016/j.jaac.2025.06.026",

language = "English",

journal = "Journal of the American Academy of Child and Adolescent Psychiatry",

issn = "0890-8567",

publisher = "Elsevier Inc.",

}

Bas-Hoogendam, JM, Bernstein, RA, Benson, BE, Frank, SEC, Buss, KA, Gunther, KE, Pérez-Edgar, K, Salum, GA, Jackowski, A, Bressan, RA, Zugman, A, Degnan, KA, Filippi, CA, Fox, NA, Henderson, HA, Tang, A, Zeytinoglu, S, Harrewijn, A, Hillegers, MHJ, Muetzel, RL, White, T, van IJzendoorn, MH, Schwartz, CE, Felicione, JM, DeYoung, KA, Shackman, AJ, Smith, JF, Tillman, RM, van den Berg, YHM, Cillessen, AHN, Roelofs, K, Tyborowska, A, Hill, SY, Battaglia, M, Tettamanti, M, Dougherty, LR, Jin, J, Klein, DN, Leung, HC, Avery, SN, Blackford, JU, Clauss, JA, Bjork, JM, Hettema, JM, Moore, AA, Roberson-Nay, R, Sawyers, C, Hayden, EP, Liu, P, Vandermeer, MRJ, Goldsmith, HH, Planalp, EM, Nichols, TE, Thompson, PM, Westenberg, PM, van der Wee, NJA, Groenewold, NA, Stein, DJ, Winkler, AM & Pine, DS 2025, 'Structural Brain Correlates of Childhood Inhibited Temperament: An ENIGMA-Anxiety Mega-Analysis', Journal of the American Academy of Child and Adolescent Psychiatry. https://doi.org/10.1016/j.jaac.2025.06.026

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.

PY - 2025

Y1 - 2025

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. 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. 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

JO - Journal of the American Academy of Child and Adolescent Psychiatry

JF - Journal of the American Academy of Child and Adolescent Psychiatry

ER -

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

Abstract

Keywords

Access to Document

Fingerprint

Cite this