Insistence on sameness relates to increased covariance of gray matter structure in autism spectrum disorder

Ian W Eisenberg, Gregory L Wallace, Lauren Kenworthy, Stephen J Gotts, Alex Martin, Ian W Eisenberg, Gregory L Wallace, Lauren Kenworthy, Stephen J Gotts, Alex Martin

Abstract

Background: Autism spectrum disorder (ASD) is characterized by atypical development of cortical and subcortical gray matter volume. Subcortical structural changes have been associated with restricted and repetitive behavior (RRB), a core component of ASD. Behavioral studies have identified insistence on sameness (IS) as a separable RRB dimension prominent in high-functioning ASD, though no simple brain-behavior relationship has emerged. Structural covariance, a measure of morphological coupling among brain regions using magnetic resonance imaging (MRI), has proven an informative measure of anatomical relationships in typical development and neurodevelopmental disorders. In this study, we use this measure to characterize the relationship between brain structure and IS.

Methods: We quantified the structural covariance of cortical and subcortical gray matter volume in 55 individuals with high-functioning ASD using 3T MRI. We then related these structural metrics to individual IS scores, as assessed by the Repetitive Behavior Scale-Revised (RBS-R).

Results: We found that increased coupling among subcortical regions and between subcortical and cortical regions related to greater IS symptom severity. Most pronounced, the striatum and amygdala participated in a plurality of identified relationships, indicating a central role for these structures in IS symptomatology. These structural associations were specific to IS and did not relate to any of the other RRB subcomponents measured by the RBS-R.

Conclusions: This study indicates that behavioral dimensions in ASD can relate to the coordination of development across multiple brain regions, which might be otherwise obscured using typical brain-behavior correlations. It also expands the structures traditionally related to RRB in ASD and provides neuroanatomical evidence supportive of IS as a separate RRB dimension.

Trial registration: ClinicalTrials.gov NCT01031407.

Keywords: Autism; Insistence on sameness; MRI; Repetitive behavior; Structural covariance; Subcortex.

Figures

Fig. 1
Fig. 1
Intra-subcortical median-split analysis. Intra-subcortical volume Region X Region covariance matrices shown for a the high IS group, b low IS group, and c high-low difference. Color indicates the Pearson r value, or, in c, the r value difference. In c, the three differences surviving correction for multiple comparisons are displayed in the lower triangle. Tha thalamus, Cau caudate, Put putamen, Pal pallidum, Hip hippocampus, Amy amygdala, Acc nucleus accumbens
Fig. 2
Fig. 2
Intra-subcortical correlational analysis. Intra-subcortical correlational analysis showing the relationship between IS severity and Region X Region structural covariance, as measured by a single-subject covariance analog (see “Statistical analysis” section). FDR cutoff indicated by **. Relationships that survive FDR correction are displayed in the lower triangle. See Additional file 6: Table S1 for exact r and p values for significant relationships
Fig. 3
Fig. 3
Cortico-subcortical correlational analysis. Subcortical-cortico correlational analysis showing the relationship between IS severity and Region X Region structural covariance (a), as measured by a single-subject covariance analog (see “Statistical analysis” section). Cortical regions are ordered by hemisphere 1 and FDR cutoff is indicated by **. Relationships that survive FDR correction are highlighted by making non-significant differences partially transparent. See Additional file 8: Table S2 for exact r and p values for significant relationships. b shows a subset of these significant relationships: cortical regions whose relationship with the putamen (red), amygdala (blue), or both (purple) significantly related to IS severity

References

    1. Alexander-Bloch A, Giedd J, Bullmore E. Imaging structural co-variance between human brain regions. Nat Rev Neurosci. 2013;14:322–36. doi: 10.1038/nrn3465.
    1. American Psychiatric Association . The diagnostic and statistical manual of mental disorders, 5th edition (DSM-5) Washington: American Psychiatric Association; 2013.
    1. Anderson JS, Nielsen J, Froehlich AL, DuBray MB, Druzgal TJ, Cariello AN, et al. Functional connectivity magnetic resonance imaging classification of autism. Brain. 2011;134(Pt 12):3742–54. doi: 10.1093/brain/awr263.
    1. Barnea-Goraly N, Frazier TW, Piacenza L, Minshew NJ, Keshavan MS, Reiss AL, et al. A preliminary longitudinal volumetric MRI study of amygdala and hippocampal volumes in autism. Prog Neuropsychopharmacol Biol Psychiatry. 2014;48:124–8. doi: 10.1016/j.pnpbp.2013.09.010.
    1. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B. 1995;57:289–300.
    1. Bernhardt BC, Valk SL, Silani G, Bird G, Frith U, Singer T. Selective disruption of sociocognitive structural brain networks in autism and alexithymia. Cereb Cortex (New York, N.Y. : 1991). 2013;23863687. doi:10.1093/cercor/bht182.
    1. Bishop SL, Richler J, Lord C. Association between restricted and repetitive behaviors and nonverbal IQ in children with autism spectrum disorders. Child Neuropsychol. 2006;12(4–5):247–67. doi: 10.1080/09297040600630288.
    1. Buckner RL, Head D, Parker J, Fotenos AF, Marcus D, Morris JC, et al. A unified approach for morphometric and functional data analysis in young, old, and demented adults using automated atlas-based head size normalization: reliability and validation against manual measurement of total intracranial volume. NeuroImage. 2004;23(2):724–38. doi: 10.1016/j.neuroimage.2004.06.018.
    1. Cuccaro ML, Shao Y, Grubber J, Slifer M, Wolpert CM, Donnelly SL, et al. Factor analysis of restricted and repetitive behaviors in autism using the Autism Diagnostic Interview-R. Child Psychiatry Hum Dev. 2003;34(1):3–17. doi: 10.1023/A:1025321707947.
    1. Dale AM, Fischl B, Sereno MI. Cortical surface-based analysis—I. Segmentation and surface reconstruction. NeuroImage. 1999;9:179–194. doi: 10.1006/nimg.1998.0395.
    1. Davis M. The role of the amygdala in fear and anxiety. Annu Rev Neurosci. 1992;15:353–75. doi: 10.1146/annurev.ne.15.030192.002033.
    1. Delmonte S, Gallagher L, O’Hanlon E, McGrath J, Balsters JH. Functional and structural connectivity of frontostriatal circuitry in Autism Spectrum Disorder. Front Hum Neurosci. 2013;7:430. doi: 10.3389/fnhum.2013.00430.
    1. Desikan RS, Ségonne F, Fischl B, Quinn BT, Dickerson BC, Blacker D, et al. An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. NeuroImage. 2006;31(3):968–80. doi: 10.1016/j.neuroimage.2006.01.021.
    1. Di Martino A, Kelly C, Grzadzinski R, Zuo X-N, Mennes M, Mairena MA, et al. Aberrant striatal functional connectivity in children with autism. Biol Psychiatry. 2011;69(9):847–56. doi: 10.1016/j.biopsych.2010.10.029.
    1. Di Martino A, Yan C-G, Li Q, Denio E, Castellanos FX, Alaerts K, et al. The autism brain imaging data exchange: towards a large-scale evaluation of the intrinsic brain architecture in autism. Mol Psychiatry. 2014;19:659–67. doi: 10.1038/mp.2013.78.
    1. Dziobek I, Fleck S, Rogers K, Wolf OT, Convit A. The “amygdala theory of autism” revisited: linking structure to behavior. Neuropsychologia. 2006;44(10):1891–9. doi: 10.1016/j.neuropsychologia.2006.02.005.
    1. Estes A, Shaw DWW, Sparks BF, Friedman S, Giedd JN, Dawson G, et al. Basal ganglia morphometry and repetitive behavior in young children with autism spectrum disorder. Autism Res. 2011;4(3):212–20. doi: 10.1002/aur.193.
    1. Evans AC. Networks of anatomical covariance. NeuroImage. 2013;80:489–504. doi: 10.1016/j.neuroimage.2013.05.054.
    1. Fischl B, Sereno MI, Dale AM. Cortical surface-based analysis—II: inflation, flattening, and a surface-based coordinate system. NeuroImage. 1999;9:195–207. doi: 10.1006/nimg.1998.0396.
    1. Fischl B, van der Kouwe A, Destrieux C, Halgren E, Segonne F, Salat DH, et al. Automatically parcellating the human cerebral cortex. Cereb Cortex. 2004;14:11–22. doi: 10.1093/cercor/bhg087.
    1. Fisher RA. Frequency distribution of the values of the correlation coefficient in samples from an indefinitely large population. Biometrika. 1915;10(4):507–521.
    1. Gaffney GR, Kuperman S, Tsai LY, Minchin S. Forebrain structure in infantile autism. J Am Acad Child Adolesc Psychiatry. 1989;28(4):534–7. doi: 10.1097/00004583-198907000-00011.
    1. Gotts SJ, Simmons WK, Milbury LA, Wallace GL, Cox RW, Martin A. Fractionation of social brain circuits in autism spectrum disorders. Brain. 2012;135(9):2711–25. doi: 10.1093/brain/aws160.
    1. Happé F, Ronald A, Plomin R. Time to give up on a single explanation for autism. Nat Neurosci. 2006;9(10):1218–20. doi: 10.1038/nn1770.
    1. Hartley SL, Sikora DM. Sex differences in autism spectrum disorder: an examination of developmental functioning, Autistic symptoms, and coexisting behavior problems in toddlers. J Autism Dev Disord. 2009;39(12):1715–1722. doi: 10.1007/s10803-009-0810-8.
    1. Haznedar MM, Buchsbaum MS, Hazlett EA, LiCalzi EM, Cartwright C, Hollander E. Volumetric analysis and three-dimensional glucose metabolic mapping of the striatum and thalamus in patients with autism spectrum disorders. Am J Psychiatry. 2006;163(7):1252–63. doi: 10.1176/appi.ajp.163.7.1252.
    1. Herbert MR, Ziegler DA, Deutsch CK, O’Brien LM, Lange N, Bakardjiev A, et al. Dissociations of cerebral cortex, subcortical and cerebral white matter volumes in autistic boys. Brain. 2003;126(5):1182–1192. doi: 10.1093/brain/awg110.
    1. Hollander E, Anagnostou E, Chaplin W, Esposito K, Haznedar MM, Licalzi E, et al. Striatal volume on magnetic resonance imaging and repetitive behaviors in autism. Biol Psychiatry. 2005;58:226–232. doi: 10.1016/j.biopsych.2005.03.040.
    1. Honey CJ, Sporns O, Cammoun L, Gigandet X, Thiran JP, Meuli R, et al. Predicting human resting-state functional connectivity from structural connectivity. Proc Natl Acad Sci. 2009;106(6):2035–40. doi: 10.1073/pnas.0811168106.
    1. Hus V, Pickles A, Cook EH, Risi S, Lord C. Using the autism diagnostic interview–revised to increase phenotypic homogeneity in genetic studies of autism. Biol Psychiatry. 2007;61(4):438–48. doi: 10.1016/j.biopsych.2006.08.044.
    1. Kim MJ, Loucks RA, Palmer AL, Brown AC, Solomon KM, Marchante AN, et al. The structural and functional connectivity of the amygdala: from normal emotion to pathological anxiety. Behav Brain Res. 2011;223(2):403–10. doi: 10.1016/j.bbr.2011.04.025.
    1. Lainhart JE, Bigler ED, Bocian M, Coon H, Dinh E, Dawson G, et al. Head circumference and height in autism: a study by the Collaborative Program of Excellence in Autism. Am J Med Genet A. 2006;140(21):2257–2274. doi: 10.1002/ajmg.a.31465.
    1. Lam KSL, Aman MG. The repetitive behavior scale-revised: independent validation in individuals with autism spectrum disorders. J Autism Dev Disord. 2007;37(5):855–866. doi: 10.1007/s10803-006-0213-z.
    1. Lam KSL, Bodfish JW, Piven J. Evidence for three subtypes of repetitive behavior in autism that differ in familiality and association with other symptoms. J Child Psychol Psychiatry. 2008;49(11):1193–200. doi: 10.1111/j.1469-7610.2008.01944.x.
    1. Langen M, Bos D, Noordermeer SDS, Nederveen H, van Engeland H, Durston S. Changes in the development of striatum are involved in repetitive behavior in autism. Biol Psychiatry. 2014;76(5):405–11. doi: 10.1016/j.biopsych.2013.08.013.
    1. Langen M, Durston S, Kas MJH, van Engeland H, Staal WG. The neurobiology of repetitive behavior: …and men. Neurosci Biobehav Rev. 2011;35(3):356–65. doi: 10.1016/j.neubiorev.2010.02.005.
    1. Langen M, Durston S, Staal WG, Palmen SJMC, Van Engeland H. Caudate nucleus is enlarged in high-functioning medication-naive subjects with autism. Biol Psychiatry. 2007;62(3):262–6. doi: 10.1016/j.biopsych.2006.09.040.
    1. Langen M, Schnack HG, Nederveen H, Bos D, Lahuis BE, De Jonge MV, et al. Changes in the developmental trajectories of striatum in autism. Biol Psychiatry. 2009;66(4):327–33. doi: 10.1016/j.biopsych.2009.03.017.
    1. Leekam SR, Prior MR, Uljarevic M. Restricted and repetitive behaviors in autism spectrum disorders: a review of research in the last decade. Psychol Bull. 2011;137(4):562–93. doi: 10.1037/a0023341.
    1. Lenroot RK, Yeung PK. Heterogeneity within autism spectrum disorders: what have we learned from neuroimaging studies? Front Hum Neurosci. 2013;7(October):733.
    1. Lingawi NW, Balleine BW. Amygdala central nucleus interacts with dorsolateral striatum to regulate the acquisition of habits. J Neurosci. 2012;32(3):1073–81. doi: 10.1523/JNEUROSCI.4806-11.2012.
    1. Lord C, Jones RM. Annual research review: re-thinking the classification of autism spectrum disorders. J Child Psychol Psychiatry. 2012;53(5):490–509. doi: 10.1111/j.1469-7610.2012.02547.x.
    1. Lord C, Risi S, Lambrecht L, Cook EH, Leventhal BL, DiLavore PC, et al. The autism diagnostic observation schedule-generic: a standard measure of social and communication deficits associated with the spectrum of autism. J Autism Dev Disord. 2000;30(3):205–23. doi: 10.1023/A:1005592401947.
    1. 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(5):659–85. doi: 10.1007/BF02172145.
    1. MacCallum RC, Zhang S, Preacher KJ, Rucker DD. On the practice of dichotomization of quantitative variables. Psychol Methods. 2002;7(1):19–40. doi: 10.1037/1082-989X.7.1.19.
    1. McLennan JD, Lord C, Schopler E. Sex differences in higher functioning people with autism. J Autism Dev Disord. 1993;23(2):217–227. doi: 10.1007/BF01046216.
    1. Olkin I, Pratt JW. Unbiased estimation of certan correlation coefficients. Ann Math Stat. 1958;29:201–211. doi: 10.1214/aoms/1177706717.
    1. Padmanabhan A, Lynn A, Foran W, Luna B, O’Hearn K. Age related changes in striatal resting state functional connectivity in autism. Front Hum Neurosci. 2013;7(November):814.
    1. Richler J, Bishop SL, Kleinke JR, Lord C. Restricted and repetitive behaviors in young children with autism spectrum disorders. J Autism Dev Disord. 2007;37(1):73–85. doi: 10.1007/s10803-006-0332-6.
    1. Richler J, Huerta M, Bishop SL, Lord C. Developmental trajectories of restricted and repetitive behaviors and interests in children with autism spectrum disorders. Dev Psychopathol. 2010;22(1):55–69. doi: 10.1017/S0954579409990265.
    1. Rodgers J, Glod M, Connolly B, McConachie H. The relationship between anxiety and repetitive behaviours in autism spectrum disorder. J Autism Dev Disord. 2012;42(11):2404–9. doi: 10.1007/s10803-012-1531-y.
    1. Rojas DC, Peterson E, Winterrowd E, Reite ML, Rogers SJ, Tregellas JR. Regional gray matter volumetric changes in autism associated with social and repetitive behavior symptoms. BMC Psychiatry. 2006;6:56. doi: 10.1186/1471-244X-6-56.
    1. Schumann CM, Bauman MD, Amaral DG. Abnormal structure or function of the amygdala is a common component of neurodevelopmental disorders. Neuropsychologia. 2011;49(4):745–59. doi: 10.1016/j.neuropsychologia.2010.09.028.
    1. Schumann CM, Hamstra J, Goodlin-Jones BL, Lotspeich LJ, Kwon H, Buonocore MH, et al. The amygdala is enlarged in children but not adolescents with autism; the hippocampus is enlarged at all ages. J Neurosci. 2004;24(28):6392–401. doi: 10.1523/JNEUROSCI.1297-04.2004.
    1. Shao Y, Cuccaro ML, Hauser ER, Raiford KL, Menold MM, Wolpert CM, et al. Fine mapping of autistic disorder to chromosome 15q11-q13 by use of phenotypic subtypes. Am J Hum Genet. 2003;72(3):539–48. doi: 10.1086/367846.
    1. Sharda M, Khundrakpam BS, Evans AC, Singh NC. Disruption of structural covariance networks for language in autism is modulated by verbal ability. Brain Struct Funct. 2014
    1. Sweeten TL, Posey DJ, Shekhar A, McDougle CJ. The amygdala and related structures in the pathophysiology of autism. Pharmacol Biochem Behav. 2002;71(3):449–55. doi: 10.1016/S0091-3057(01)00697-9.
    1. Szatmari P, Georgiades S, Bryson S, Zwaigenbaum L, Roberts W, Mahoney W, et al. Investigating the structure of the restricted, repetitive behaviours and interests domain of autism. J Child Psychol Psychiatry. 2006;47(6):582–90. doi: 10.1111/j.1469-7610.2005.01537.x.
    1. Tsatsanis KD, Rourke BP, Klin A, Volkmar FR, Cicchetti D, Schultz RT. Reduced thalamic volume in high-functioning individuals with autism. Biol Psychiatry. 2003;53(2):121–129. doi: 10.1016/S0006-3223(02)01530-5.
    1. Uddin LQ, Supekar K, Lynch CJ, Cheng KM, Odriozola P, Barth ME, et al. Brain state differentiation and behavioral inflexibility in autism. Cereb Cortex. 2014;1–8. doi:10.1093/cercor/bhu161.
    1. Vissers ME, Cohen MX, Geurts HM. Brain connectivity and high functioning autism: a promising path of research that needs refined models, methodological convergence, and stronger behavioral links. Neurosci Biobehav Rev. 2012;36(1):604–25. doi: 10.1016/j.neubiorev.2011.09.003.
    1. Wallace GL, Eisenberg IW, Robustelli B, Dankner N, Kenworthy L, Giedd JN, et al. Longitudinal cortical development during adolescence and young adulthood in autism spectrum disorders: increased cortical thinning but comparable surface area changes. J Am Acad Child Adolesc Psychiatry. 2015;54(6):464–469. doi: 10.1016/j.jaac.2015.03.007.
    1. Yerys BE, Antezana L, Weinblatt R, Jankowski KF, Strang J, Vaidya CJ, et al. Neural correlates of set-shifting in children with autism, 1–12. Autism Res. 2015. doi:10.1002/aur.1454.
    1. Zielinski BA, Anderson JS, Froehlich AL, Prigge MBD, Nielsen JA, Cooperrider JR, et al. scMRI reveals large-scale brain network abnormalities in Autism. PLoS ONE. 2012;7(11). doi:10.1371/journal.pone.0049172.
    1. Zielinski BA, Prigge MB, Nielsen JA, Froehlich AL, Abildskov TJ, Anderson JS, et al. Longitudinal changes in cortical thickness in autism and typical development. Brain. 2014;137(Pt 6):1799–1812. doi: 10.1093/brain/awu083.
    1. Zhang Z, Liao W, Zuo X-N, Wang Z, Yuan C, Jiao Q, et al. Resting-state brain organization revealed by functional covariance networks. PLoS One. 2011;6(12):e28817. doi: 10.1371/journal.pone.0028817.

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