Anxiety is related to indices of cortical maturation in typically developing children and adolescents

Erik Newman^{1

2}, Wesley K Thompson^{3

4}, Hauke Bartsch⁵, Donald J Hagler Jr^{5

6}, Chi-Hua Chen^{3

5}, Timothy T Brown^{5

7}, Joshua M Kuperman^{5

6}, Connor McCabe^{8

9}, Yoonho Chung^{8

5

10}, Ondrej Libiger¹¹, Natacha Akshoomoff^{8

3}, Cinnamon S Bloss¹¹, B J Casey¹², Linda Chang¹³, Thomas M Ernst¹³, Jean A Frazier¹⁴, Jeffrey R Gruen^{15

16}, David N Kennedy¹⁴, Sarah S Murray¹⁷, Elizabeth R Sowell^{18

19}, Nicholas Schork¹¹, Tal Kenet²⁰, Walter E Kaufmann²¹, Stewart Mostofsky²², David G Amaral²³, Anders M Dale^{5

6

7

24}, Terry L Jernigan^{8

3

6

24}

Affiliations

¹ Center for Human Development, University of California, San Diego, 9500 Gilman Drive, MC 0115, La Jolla, CA, 92093, USA. enewman@ucsd.edu.
² Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA. enewman@ucsd.edu.
³ Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.
⁴ Stein Institute for Research on Aging, University of California, San Diego, La Jolla, CA, USA.
⁵ Multimodal Imaging Laboratory, University of California, San Diego, La Jolla, CA, USA.
⁶ Department of Radiology, University of California, San Diego, La Jolla, CA, USA.
⁷ Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.
⁸ Center for Human Development, University of California, San Diego, 9500 Gilman Drive, MC 0115, La Jolla, CA, 92093, USA.
⁹ Department of Psychology, University of Washington, Seattle, WA, USA.
¹⁰ Department of Psychology, Yale University, New Haven, CT, USA.
¹¹ Scripps Genomic Medicine, Scripps Translational Science Institute and Scripps Health, La Jolla, CA, USA.
¹² Sackler Institute for Developmental Psychobiology, Weil Cornell Medical College, New York, NY, USA.
¹³ Department of Medicine, University of Hawaii and Queen's Medical Center, Honolulu, HI, USA.
¹⁴ Department of Psychiatry, University of Massachusetts Medical School, Boston, MA, USA.
¹⁵ Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA.
¹⁶ Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
¹⁷ Department of Pathology, University of California, San Diego, La Jolla, CA, USA.
¹⁸ Department of Pediatrics, University of Southern California, Los Angeles, CA, USA.
¹⁹ Children's Hospital, Los Angeles, CA, USA.
²⁰ Department of Neurology and Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, USA.
²¹ Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
²² Kennedy Krieger Institute and Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²³ Department of Psychiatry and Behavioral Sciences, University of California, Davis, Davis, CA, USA.
²⁴ Department of Cognitive Science, University of California, San Diego, La Jolla, CA, USA.

PMID: 26183468
PMCID: PMC5064818
DOI: 10.1007/s00429-015-1085-9

Anxiety is related to indices of cortical maturation in typically developing children and adolescents

Erik Newman et al. Brain Struct Funct. 2016 Jul.

. 2016 Jul;221(6):3013-25.

doi: 10.1007/s00429-015-1085-9. Epub 2015 Jul 17.

Authors

Affiliations

¹ Center for Human Development, University of California, San Diego, 9500 Gilman Drive, MC 0115, La Jolla, CA, 92093, USA. enewman@ucsd.edu.
² Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA. enewman@ucsd.edu.
³ Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.
⁴ Stein Institute for Research on Aging, University of California, San Diego, La Jolla, CA, USA.
⁵ Multimodal Imaging Laboratory, University of California, San Diego, La Jolla, CA, USA.
⁶ Department of Radiology, University of California, San Diego, La Jolla, CA, USA.
⁷ Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.
⁸ Center for Human Development, University of California, San Diego, 9500 Gilman Drive, MC 0115, La Jolla, CA, 92093, USA.
⁹ Department of Psychology, University of Washington, Seattle, WA, USA.
¹⁰ Department of Psychology, Yale University, New Haven, CT, USA.
¹¹ Scripps Genomic Medicine, Scripps Translational Science Institute and Scripps Health, La Jolla, CA, USA.
¹² Sackler Institute for Developmental Psychobiology, Weil Cornell Medical College, New York, NY, USA.
¹³ Department of Medicine, University of Hawaii and Queen's Medical Center, Honolulu, HI, USA.
¹⁴ Department of Psychiatry, University of Massachusetts Medical School, Boston, MA, USA.
¹⁵ Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA.
¹⁶ Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
¹⁷ Department of Pathology, University of California, San Diego, La Jolla, CA, USA.
¹⁸ Department of Pediatrics, University of Southern California, Los Angeles, CA, USA.
¹⁹ Children's Hospital, Los Angeles, CA, USA.
²⁰ Department of Neurology and Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, USA.
²¹ Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
²² Kennedy Krieger Institute and Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²³ Department of Psychiatry and Behavioral Sciences, University of California, Davis, Davis, CA, USA.
²⁴ Department of Cognitive Science, University of California, San Diego, La Jolla, CA, USA.

PMID: 26183468
PMCID: PMC5064818
DOI: 10.1007/s00429-015-1085-9

Abstract

Anxiety is a risk factor for many adverse neuropsychiatric and socioeconomic outcomes, and has been linked to functional and structural changes in the ventromedial prefrontal cortex (VMPFC). However, the nature of these differences, as well as how they develop in children and adolescents, remains poorly understood. More effective interventions to minimize the negative consequences of anxiety require better understanding of its neurobiology in children. Recent research suggests that structural imaging studies may benefit from clearly delineating between cortical surface area and thickness when examining these associations, as these distinct cortical phenotypes are influenced by different cellular mechanisms and genetic factors. The present study examined relationships between cortical surface area and thickness of the VMPFC and a self-report measure of anxiety (SCARED-R) in 287 youths aged 7-20 years from the Pediatric Imaging, Neurocognition, and Genetics (PING) study. Age and gender interactions were examined for significant associations in order to test for developmental differences. Cortical surface area and thickness were also examined simultaneously to determine whether they contribute independently to the prediction of anxiety. Anxiety was negatively associated with relative cortical surface area of the VMPFC as well as with global cortical thickness, but these associations diminished with age. The two cortical phenotypes contributed additively to the prediction of anxiety. These findings suggest that higher anxiety in children may be characterized by both delayed expansion of the VMPFC and an altered trajectory of global cortical thinning. Further longitudinal studies will be needed to confirm these findings.

Keywords: Anxiety; Brain development; Cortical surface area; Cortical thickness; Magnetic resonance imaging; Ventromedial prefrontal cortex.

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Conflict of interest statement

Jean A. Frazier has received research support from GlaxoSmithKline, Pfizer, Inc., Neuren, Roche, and Seaside Therapeutics, NICHD, NIMH, NINDS and has served on a Data Safety Monitoring Board for Forest Pharmaceuticals. Anders M. Dale is a founder of and holds equity interest in CorTechs Labs, La Jolla, CA and serves on its scientific advisory board. The terms of this arrangement have been reviewed and approved by UC San Diego, in accordance with its conflict of interest policies. All other authors reported no biomedical financial interests or potential conflicts of interest.

Figures

**Fig. 1**
Effects of ROI measures on anxiety as a function of age. Anxiety scores are adjusted for scanner, GAFs, gender, and all interactions between ROI measures, age, and gender. It is also adjusted for total cortical area in the VMPFC surface area model. Slopes for younger and older participants were computed at the first and third quantile for age, respectively. VMPFC surface area units are expressed in terms of mean partial membership-weighted voxel expansion factors. Mean cortical thickness units are in mm. a The relationship between VMPFC surface area and anxiety scores in younger vs. older participants. b The relationship between mean cortical thickness and anxiety scores in younger vs. older participants

**Fig. 2**
Apparent age trajectories of cortical development by anxiety level. ROI measures are adjusted for scanner, GAFs, gender, and all interactions between anxiety, age and gender. VMPFC surface area is also adjusted for total cortical area. Slopes for low and high anxiety were computed at the first and third quantile for anxiety, respectively. a VMPFC surface area changes with age in low vs. high anxiety children. b Mean thickness changes with age in low vs. high anxiety children

**Fig. 3**
Anxiety scores mapped onto cortical surface expansion and thickness. Maps show the vertex-wise variability of effects on surface area and thickness at ages 7, 14, and 21 in order to visualize the moderating effect of age on the relationship between these structural phenotypes and anxiety. The models used to compute these maps controlled for scanner, GAFs, and gender. Surface expansion maps also controlled for total surface area. Vertex maps labeled “Age 14” were actually computed at the mean age for the sample (13.84) in order to be able to visualize the main effect for anxiety with age held constant

See this image and copyright information in PMC

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Anxiety is related to indices of cortical maturation in typically developing children and adolescents

Affiliations

Anxiety is related to indices of cortical maturation in typically developing children and adolescents

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

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Medical