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Examining Associations Between Amygdala Volumes and Anxiety Symptoms in Autism Spectrum Disorder

Published:October 21, 2021DOI:https://doi.org/10.1016/j.bpsc.2021.10.010

      Abstract

      Background

      Anxiety is one of the most common co-occurring conditions in people with autism spectrum disorder. The amygdala has been identified as being associated with anxiety in populations with and without autism, yet associations in autism were based on relatively small or developmentally constrained samples, leaving questions as to whether these results hold at different developmental ages and in a larger, more robust sample.

      Methods

      Structural neuroimaging and parent report of anxiety symptoms of children ages 5–13 years with (n = 123) and without (n = 171) a diagnosis of autism were collected from the University of Maryland and three sites from the Autism Brain Imaging Data Exchange. Standardized residuals for bilateral amygdala volumes were computed adjusting for site, hemispheric volumes, and covariates (age, sex, Full Scale IQ).

      Results

      Clinically significant anxiety symptoms did not differentiate amygdala volumes between groups (i.e., autism and anxiety, autism without anxiety, without autism or anxiety). No significant association between left or right amygdala volumes and anxiety scores was observed among the sample of individuals with autism. Meta-analytic and Bayes factor estimations provided additional support for the null hypothesis. Age, sex, and autism severity did not moderate associations between anxiety and amygdala volumes.

      Conclusions

      No relation between amygdala volumes and anxiety symptoms in children with autism was observed in the largest sample to investigate this question. We discuss directions for future research to determine whether additional factors including age or method of assessment may contribute to this lack of association.

      Keywords

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      References

        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders: DSM-5.
        5th ed. American Psychiatric Association, Arlington, VA, Washington, DC2013
        • Rosen T.E.
        • Mazefsky C.A.
        • Vasa R.A.
        • Lerner M.D.
        Co-occurring psychiatric conditions in autism spectrum disorder.
        Int Rev Psychiatry. 2018; 30: 40-61
      1. Kent R, Chapter SE: Prevalence of anxiety in autism spectrum disorders. In: Kerns CM, Renno P, Storch EA, Kendall PC, Wood JJ, editors. Anxiety in Children and Adolescents With Autism Spectrum Disorder, vol. 2. Cambridge: Academic Press, 5–32.

        • Yarger H.A.
        • Redcay E.
        A conceptual model of risk and protective factors associated with internalizing symptoms in autism spectrum disorder: A scoping review, synthesis, and call for more research.
        Dev Psychopathol. 2020; 32: 1254-1272
        • Cody H.
        • Pelphrey K.
        • Piven J.
        Structural and functional magnetic resonance imaging of autism.
        Int J Dev Neurosci. 2002; 20: 421-438
        • Nordahl C.W.
        • Scholz R.
        • Yang X.
        • Buonocore M.H.
        • Simon T.
        • Rogers S.
        • Amaral D.G.
        Increased rate of amygdala growth in children aged 2 to 4 years with autism spectrum disorders: A longitudinal study.
        Arch Gen Psychiatry. 2012; 69: 53-61
        • Morgan J.T.
        • Nordahl C.W.
        • Schumann C.M.
        Chapter 3.5: The amygdala in autism spectrum disorders.
        in: Buxbaum J.D. Hof P.R. The Neuroscience of Autism Spectrum Disorders. Academic Press, San Diego2013: 297-312
        • Mosconi M.W.
        • Cody-Hazlett H.
        • Poe M.D.
        • Gerig G.
        • Gimpel-Smith R.
        • Piven J.
        Longitudinal study of amygdala volume and joint attention in 2- to 4-year-old children with autism.
        Arch Gen Psychiatry. 2009; 66: 509-516
        • Schumann C.M.
        • Barnes C.C.
        • Lord C.
        • Courchesne E.
        Amygdala enlargement in toddlers with autism related to severity of social and communication impairments.
        Biol Psychiatry. 2009; 66: 942-949
        • Gilpin N.W.
        • Herman M.A.
        • Roberto M.
        The central amygdala as an integrative hub for anxiety and alcohol use disorders.
        Biol Psychiatry. 2015; 77: 859-869
        • LeDoux J.E.
        • Pine D.S.
        Using neuroscience to help understand fear and anxiety: A two-system framework.
        Am J Psychiatry. 2016; 173: 1083-1093
        • Juranek J.
        • Filipek P.A.
        • Berenji G.R.
        • Modahl C.
        • Osann K.
        • Spence M.A.
        Association between amygdala volume and anxiety level: Magnetic resonance imaging (MRI) study in autistic children.
        J Child Neurol. 2006; 21: 1051-1058
        • Nordahl C.W.
        • Iosif A.M.
        • Young G.S.
        • Hechtman A.
        • Heath B.
        • Lee J.K.
        • et al.
        High psychopathology subgroup in young children with autism: Associations with biological sex and amygdala volume.
        J Am Acad Child Adolesc Psychiatry. 2020; 59: 1353-1363.e2
        • Herrington J.D.
        • Maddox B.B.
        • Kerns C.M.
        • Rump K.
        • Worley J.A.
        • Bush J.C.
        • et al.
        Amygdala volume differences in autism spectrum disorder are related to anxiety.
        J Autism Dev Disord. 2017; 47: 3682-3691
        • Birmaher B.
        • Khetarpal S.
        • Brent D.
        • Cully M.
        • Balach L.
        • Kaufman J.
        • Neer S.M.
        The Screen for Child Anxiety Related Emotional Disorders (SCARED): Scale construction and psychometric characteristics.
        J Am Acad Child Adolesc Psychiatry. 1997; 36: 545-553
        • Achenbach T.M.
        Manual for the Child Behavior Checklist/4–18 and 1991 Profile.
        11th print ed. University of Vermont Department of Psychiatry, Burlington, Vermont1997
        • Schumann C.M.
        • Hamstra J.
        • Goodlin-Jones B.L.
        • Lotspeich L.J.
        • Kwon H.
        • Buonocore M.H.
        • et al.
        The amygdala is enlarged in children but not adolescents with autism; the hippocampus is enlarged at all ages.
        J Neurosci. 2004; 24: 6392-6401
        • Courchesne E.
        • Campbell K.
        • Solso S.
        Brain growth across the life span in autism: Age-specific changes in anatomical pathology.
        Brain Res. 2011; 1380: 138-145
        • Courchesne E.
        • Pierce K.
        • Schumann C.M.
        • Redcay E.
        • Buckwalter J.A.
        • Kennedy D.P.
        • Morgan J.
        Mapping early brain development in autism.
        Neuron. 2007; 56: 399-413
        • Zuo C.
        • Wang D.
        • Tao F.
        • Wang Y.
        Changes in the development of subcortical structures in autism spectrum disorder.
        NeuroReport. 2019; 30: 1062-1067
        • Merikangas K.R.
        • He J.P.
        • Burstein M.
        • Swanson S.A.
        • Avenevoli S.
        • Cui L.
        • et al.
        Lifetime prevalence of mental disorders in U.S. Adolescents: Results from the National Comorbidity Survey Replication–Adolescent Supplement (NCS-A).
        J Am Acad Child Adolesc Psychiatry. 2010; 49: 980-989
        • Uljarević M.
        • Hedley D.
        • Rose-Foley K.
        • Magiati I.
        • Cai R.Y.
        • Dissanayake C.
        • et al.
        Anxiety and depression from adolescence to old age in autism spectrum disorder.
        J Autism Dev Disord. 2020; 50: 3155-3165
        • Warnell K.R.
        • Pecukonis M.
        • Redcay E.
        Developmental relations between amygdala volume and anxiety traits: Effects of informant, sex, and age.
        Dev Psychopathol. 2018; 30: 1503-1515
        • Albaugh M.D.
        • Nguyen T.V.
        • Ducharme S.
        • Collins D.L.
        • Botteron K.N.
        • D’Alberto N.
        • et al.
        Age-related volumetric change of limbic structures and subclinical anxious/depressed symptomatology in typically developing children and adolescents.
        Biol Psychol. 2017; 124: 133-140
        • Maenner M.J.
        • Shaw K.A.
        • Baio J.
        • EdS1
        • Washington A.
        • Patrick M.
        • et al.
        Prevalence of autism spectrum disorder among children aged 8 years — Autism and Developmental Disabilities Monitoring Network, 11 sites, United States, 2016. 2020; 69: 1-12
        • Brierley B.
        • Shaw P.
        • David A.S.
        The human amygdala: A systematic review and meta-analysis of volumetric magnetic resonance imaging.
        Brain Res Brain Res Rev. 2002; 39: 84-105
        • Ruigrok A.N.V.
        • Salimi-Khorshidi G.
        • Lai M.C.
        • Baron-Cohen S.
        • Lombardo M.V.
        • Tait R.J.
        • Suckling J.
        A meta-analysis of sex differences in human brain structure.
        Neurosci Biobehav Rev. 2014; 39: 34-50
        • Liao M.
        • Yang F.
        • Zhang Y.
        • He Z.
        • Su L.
        • Li L.
        Lack of gender effects on gray matter volumes in adolescent generalized anxiety disorder.
        J Affect Disord. 2014; 155: 278-282
        • Li G.
        • Chen M.-H.
        • Li G.
        • Wu D.
        • Lian C.
        • Sun Q.
        • et al.
        A longitudinal MRI study of amygdala and hippocampal subfields for infants with risk of autism.
        Graph Learn Med Imaging. 2019; 11849: 164-171
        • Zhang W.
        • Groen W.
        • Mennes M.
        • Greven C.
        • Buitelaar J.
        • Rommelse N.
        Revisiting subcortical brain volume correlates of autism in the ABIDE dataset: Effects of age and sex.
        Psychol Med. 2018; 48: 654-668
        • Radeloff D.
        • Ciaramidaro A.
        • Siniatchkin M.
        • Hainz D.
        • Schlitt S.
        • Weber B.
        • et al.
        Structural alterations of the social brain: A comparison between schizophrenia and autism.
        PLoS One. 2014; 9e106539
        • Dziobek I.
        • Fleck S.
        • Rogers K.
        • Wolf O.T.
        • Convit A.
        The ‘amygdala theory of autism’ revisited: Linking structure to behavior.
        Neuropsychologia. 2006; 44: 1891-1899
        • Baribeau D.A.
        • Vigod S.
        • Pullenayegum E.
        • Kerns C.M.
        • Mirenda P.
        • Smith I.M.
        • et al.
        Repetitive behavior severity as an early indicator of risk for elevated anxiety symptoms in autism spectrum disorder.
        J Am Acad Child Adolesc Psychiatry. 2020; 59: 890-899.e3
        • Nacewicz B.M.
        • Dalton K.M.
        • Johnstone T.
        • Long M.T.
        • McAuliff E.M.
        • Oakes T.R.
        • et al.
        Amygdala volume and nonverbal social impairment in adolescent and adult males with autism.
        Arch Gen Psychiatry. 2006; 63: 1417-1428
        • Di Martino A.
        • O’Connor D.
        • Chen B.
        • Alaerts K.
        • Anderson J.S.
        • Assaf M.
        • et al.
        Enhancing studies of the connectome in autism using the autism brain imaging data exchange II.
        Sci Data. 2017; 4: 170010
        • Achenbach T.M.
        Rescorla L: Manual for the ASEBA School-Age Forms & Profiles: An Integrated System of Multi-Informant Assessment.
        ASEBA, Burlington, Vermont2001
        • Lord C.
        • Rutter M.
        • DiLavore P.C.
        • Risi S.
        Autism Diagnostic Observation Schedule.
        2nd ed. CA: WPS(ADOS-2), Los Angeles2012
        • Lord C.
        • Rutter M.
        • Le Couteur A.
        Autism Diagnostic Interview-Revised: A revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders.
        J Autism Dev Disord. 1994; 24: 659-685
        • Achenbach T.M.
        • Rescorla L.A.
        Achenbach system of empirically based A: ASEBA Preschool Forms & Profiles: An Integrated System of Multi-Informant Assessment.
        ASEBA, Burlington, VT2000
        • Jiang H.
        • van Zijl P.C.M.
        • Kim J.
        • Pearlson G.D.
        • Mori S.
        DtiStudio: Resource program for diffusion tensor computation and fiber bundle tracking.
        Comput Methods Programs Biomed. 2006; 81: 106-116
        • Mori S.
        • Wu D.
        • Ceritoglu C.
        • Li Y.
        • Kolasny A.
        • Vaillant M.A.
        • et al.
        MRICloud: Delivering high-throughput MRI neuroinformatics as cloud-based software as a service.
        Comput Sci Eng. 2016; 18: 21-35
        • Hayes A.F.
        • Little T.D.
        Introduction to Mediation, Moderation, and Conditional Process Analysis: A Regression-Based Approach.
        2nd ed. The Guilford Press, New York2018
        • Johnson W.E.
        • Li C.
        • Rabinovic A.
        Adjusting batch effects in microarray expression data using empirical Bayes methods.
        Biostatistics. 2007; 8: 118-127
        • Fortin J.P.
        • Cullen N.
        • Sheline Y.I.
        • Taylor W.D.
        • Aselcioglu I.
        • Cook P.A.
        • et al.
        Harmonization of cortical thickness measurements across scanners and sites.
        NeuroImage. 2018; 167: 104-120
        • Jarosz A.F.
        • Wiley J.
        What are the odds? A practical guide to computing and reporting Bayes factors.
        J Problem Solving. 2014; 7
        • Kerns C.M.
        • Winder-Patel B.
        • Iosif A.M.
        • Nordahl C.W.
        • Heath B.
        • Solomon M.
        • Amaral D.G.
        Clinically significant anxiety in children with autism spectrum disorder and varied intellectual functioning.
        J Clin Child Adolesc Psychol. 2020; : 1-16
      2. Andrews D, Aksman L, Kerns C, Lee JK, Harvey D, Waizbard-Bartov E, et al. (2021): Association of amygdala development with anxiety in autism spectrum disorder. Presented at International Society for Autism Research Conference, December 8, 2021, Austin, Texas.

        • Nordahl C.W.
        • Mello M.
        • Shen A.M.
        • Shen M.D.
        • Vismara L.A.
        • Li D.
        • et al.
        Methods for acquiring MRI data in children with autism spectrum disorder and intellectual impairment without the use of sedation.
        J Neurodev Disord. 2016; 8: 20
        • Constantino J.N.
        • Abbacchi A.M.
        • Saulnier C.
        • Klaiman C.
        • Mandell D.S.
        • Zhang Y.
        • et al.
        Timing of the diagnosis of autism in African American children.
        Pediatrics. 2020; 146e20193629
        • Seguin D.
        • Pac S.
        • Wang J.
        • Nicolson R.
        • Martinez-Trujillo J.
        • Duerden E.G.
        Amygdala subnuclei development in adolescents with autism spectrum disorder: Association with social communication and repetitive behaviors.
        Brain Behav. 2021; 11: e2299
        • Wechsler D.
        Wechsler Intelligence Scale for Children.
        Pearson, Austin, Texas2003
        • Wechsler D.
        Wechsler Intelligence Scale for Children.
        Pearson, Austin, Texas2014
        • Wechsler D.
        Wechsler Abbreviated Scale of Intelligence.
        Pearson, Austin, Texas2011
        • Elliott C.D.
        Differential Ability Scales-II.
        Pearson, Austin, Texas2007
        • Kaufman A.S.
        • Kaufman N.L.
        Kaufman Brief Intelligence Test.
        2nd ed. Pearson, Bloomington, Minnesota2004

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        Biological Psychiatry: Cognitive Neuroscience and NeuroimagingVol. 7Issue 9
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          Erratum to: “Examining Associations Between Amygdala Volumes and Anxiety Symptoms in Autism Spectrum Disorder,” by Yarger et al. (Biol Psychiatry Cogn Neurosci Neuroimaging 2021); https://doi.org/10.1016/j.bpsc.2021.10.010 .
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