Abstract
Voxel-based morphometry (VBM) studies have reported abnormalities in brain regions involved in functions that are commonly impaired in autism spectrum disorders (ASD). However, little is known about brain structure anomalies in low-functioning (LF) young children with ASD. A VBM analysis was carried out to assess brain regions involved in ASD LF children, and a multiple regression analysis was used to examine the relationship between regional volume changes and autism symptom measures. Twenty-six LF ASD children (2–10 years) were compared with 21 controls. A VBM-Diffeomorphic Anatomical Registration analysis using Exponentiated Lie algebra (DARTEL) was used to evaluate gray matter (GM) and white matter alterations, covaried with Intelligence Quotient, age, and total brain volume. The resulting altered regions were correlated with Autism Diagnostic Interview (ADI)-Revised and Autism Diagnostic Observation Schedule (ADOS)-Generic scores. GM bilateral reduction was noted in the cerebellum (Crus II and vermis) and in the hippocampi in ASD group. GM reduction was also detected in the inferior and superior frontal gyri, in the occipital medial and superior gyri, and in the inferior temporal gyrus of the left cerebral hemisphere. In the right hemisphere, GM reduction was found in the post-central cortex and in the occipital inferior gyrus. Multiple regression analysis showed a correlation between alterations in GM volume in the cerebellum (Crus II and vermis) and ADI-communication and ADOS-total (communication and interaction) scores. These findings seem to confirm that the cerebellum is involved in integrating and regulating emotional and cognitive functions which are impaired in ASD.
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References
Bauman M, Kemper TL. Histoanatomic observations of the brain in early infantile autism. Neurology. 1985;35(6):866–74.
Amaral DG, Schumann CM, Nordahl CW. Neuroanatomy of autism. Trends Neurosci. 2008;3(31):137–45.
Dapretto M, Davies MS, Pfeifer JH. Understanding emotions in others: mirror neuron dysfunction in children with autism spectrum disorders. Nat Neurosci. 2006;9:29–30.
Bauman ML, Kemper TL. Neuroanatomic observations of the brain in autism: a review and future directions. Int J Dev Neurosci. 2005;23(2–3):183–7.
Courchesne E, Redcay E, Kennedy DP. The autistic brain: birth through adulthood. Curr Opin Neurol. 2004;17:489–96.
Courchesne E, Müller RA, Saitoh O. Brain weight in autism: normal in the majority of cases, megalencephalic in rare cases. Neurology. 1999;52:1057–59.
Redcay E, Courchesne E. When is the brain enlarged in autism? A meta-analysis of all brain size reports. Biol Psychiatry. 2005;58(1):1–9.
Langen M, Durston S, Staal WG, Palmen SJ, van Engeland H. Caudate nucleus is enlarged in high-functioning medication-naive subjects with autism. Biol Psychiatry. 2007;62(3):262–66.
McAlonan GM, Daly E, Kumari V, Critchley HD, van Amelsvoort T, Suckling J, et al. Brain anatomy and sensorimotor gating in Asperger’s syndrome. Brain. 2002;125:1594–606.
Boddaert N, Chabane N, Gervais H, Good CD, Bourgeois M, Plumet MH, et al. Superior temporal sulcus anatomical abnormalities in childhood autism: a voxel-based morphometry MRI study. NeuroImage. 2004;23:364–69.
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;6:56–68.
Ke X, Hong S, Tang T, Zou B, Li H, Hang Y, et al. Voxel-based morphometry study on brain structure in children with high-functioning autism. NeuroReport. 2008;9(19):921–25.
Palmen SJ, van Engeland H. Review on structural neuroimaging findings in autism. J Neural Transm. 2004;111:903–29.
Piven J, Arndt S. The cerebellum and autism. Neurology. 1995;45:398–402.
Kosaka H, Omori M, Munesue T, Ishitobi M, Matsumura Y, Takahashi T, et al. Smaller insula and inferior frontal volumes in young adults with pervasive developmental disorders. NeuroImage. 2010;4(50):1357–63.
Fombonne E. Epidemiology of pervasive developmental disorders. Pediatr Res. 2009;65(6):591–98.
Spencer MD, Moorhead TW, Lymer GK, Job DE, Muir WJ, Hoare P, et al. Structural correlates of intellectual impairment and autistic features in adolescents. NeuroImage. 2006;4(33):1136–44.
Bonilha L, Cendes F, Rorden C, Eckert M, Dalgalarrondo P, Li LM, et al. Gray and white matter imbalance—typical structural abnormality underlying classic autism? Brain Dev. 2008;6(30):396–401.
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.
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.
Huerta M, Lord C. Diagnostic evaluation of autism spectrum disorders. Pediatr Clin North Am. 2012;59(1):103–11.
Yassa MA, Stark CE. A quantitative evaluation of cross-participant registration techniques for MRI studies of the medial temporal lobe. NeuroImage. 2009;44(2):319–27.
Ashburner J. A fast diffeomorphic image registration algorithm. NeuroImage. 2007;38(1):95–113.
Good CD, Johnsrude IS, Ashburner J, Henson RN, Friston KJ, Frackowiak RS. A voxel-based morphometric study of ageing in 465 normal adult human brains. NeuroImage. 2011;14:21–36.
Ashburner J, Friston KJ. Voxel-based morphometry: the methods. NeuroImage. 2000;11:805–21.
Radua J, Via E, Catani M, Mataix-Cols D. Voxel-based meta-analysis of regional white-matter volume differences in autism spectrum disorder versus healthy controls. Psychol Med. 2011;41(7):1539–50.
Waiter GD, Williams JH, Murray AD, Gilchrist A, Perrett DI, Whiten A. A voxel-based investigation of brain structure in male adolescents with autistic spectrum disorder. NeuroImage. 2004;2(22):619–25.
Bode MK, Mattila ML, Kiviniemi V, Rahko J, Moilanen I, Ebeling H, et al. White matter in autism spectrum disorders—evidence of impaired fiber formation. Acta Radiol. 2011;52(10):1169–74.
Strick PL, Dum RP, Fiez JA. Cerebellum and nonmotor function. Annu Rev Neurosci. 2009;32:413–34.
Leiner H, Leiner A, Dow R. Does the cerebellum contribute to mental skills? Behav Neurosci. 1986;100:443–54.
Schmahmann JD. Disorders of the cerebellum: ataxia, dysmetria of thought, and the cerebellar cognitive affective syndrome. J Neuropsychiat Clin Neurosci. 2004;16(3):367–78.
Courchesne E, Pierce K, Schumann CM, Redcay E, Buckwalter JA, Kennedy DP, et al. Mapping early brain development in autism. Neuron. 2007;56(2):399–13.
Fatemi SH, Halt AR, Realmuto G, Earle J, Kist DA, Thuras P, et al. Purkinje cell size is reduced in cerebellum of patients with autism. Cell Mol Neurobiol. 2002;22(2):171–75.
Fatemi SH, Stary JM, Halt AR, Realmuto GR. Dysregulation of Reelin and Bcl-2 proteins in autistic cerebellum. J Autism Dev Disord. 2001;31(6):529–35.
Verhoeven JS, De Cock P, Lagae L, Sunaert S. Neuroimaging of autism. Neuroradiology. 2010;1(52):3–14.
Dalton P, Deacon R, Blamire A, Pike M, McKinlay I, Stein J, et al. Maternal neuronal antibodies associated with autism and a language disorder. Ann Neurol. 2003;53(4):533–37.
Singer HS, Morris CM, Williams PN, Yoon DY, Hong JJ, Zimmerman AW. Antibrain antibodies in children with autism and their unaffected siblings. J Neuroimmunol. 2006;178(1–2):149–55.
Wills S, Cabanlit M, Bennett J, Ashwood P, Amaral DG, Van de Water J. Detection of autoantibodies to neural cells of the cerebellum in the plasma of subjects with autism spectrum disorders. Brain Behav Immun. 2009;23(1):64–74.
Steinlein M. Cerebellar disorders in childhood: cognitive problems. Cerebellum. 2008;7(4):607–10.
Goines P, Haapanen L, Boyce R, Duncanson P, Braunschweig D, Delwiche L, et al. Autoantibodies to cerebellum in children with autism associate with behavior. Brain Behav Immun. 2011;25(3):514–23.
Levisohn L, Cronin-Golomb A, Schmahmann JD. Neuropsychological consequences of cerebellar tumour resection in children: cerebellar cognitive affective syndrome in a paediatric population. Brain. 2000;123:1041–50.
Riva D, Giorgi C. The cerebellum contributes to higher functions during development: evidence from a series of children surgically treated for posterior fossa tumours. Brain. 2000;123:1051–61.
Schmahmann JD, Weilburg JB, Sherman JC. The neuropsychiatry of the cerebellum—insights from the clinic. Cerebellum. 2007;6(3):254–67.
Stanfield AC, McIntosh AM, Spencer M, Philip R, Gaur S, Lawrie SM. Towards a neuroanatomy of autism: a systematic review and meta-analysis of structural magnetic resonance imaging studies. Eur Psychiatry. 2008;4(23):289–99.
Schmahmann JD. An emerging concept. The cerebellar contribution to higher function. Arch Neurol. 1991;48(11):1178–87.
Schmahmann JD. The role of the cerebellum in affect and psychosis. J Neurolinguistics. 2000;13:189–214.
Bobée S, Mariette E, Tremblay-Leveau H, Caston J. Effects of early midline cerebellar lesion on cognitive and emotional functions in the rat. Behav Brain Res. 2000;112(1–2):107–17.
Krienen FM, Buckner RL. Segregated fronto-cerebellar circuits revealed by intrinsic functional connectivity. Cereb Cortex. 2009;19(10):2485–97.
Habas C, Kamdar N, Nguyen D, Prater K, Beckmann CF, Menon V, et al. Distinct cerebellar contributions to intrinsic connectivity networks. J Neurosci. 2009;29(26):8586–94.
Stoodley CJ, Schmahmann JD. Evidence for topographic organization in the cerebellum of motor control versus cognitive and affective processing. Cortex. 2010;46(7):831–44.
Sang L, Qin W, Liu Y, Han W, Zhang Y, Jiang T, et al. Resting-state functional connectivity of the vermal and hemispheric subregions of the cerebellum with both the cerebral cortical networks and subcortical structures. NeuroImage. 2012;61(4):1213–25.
Calarge C, Andreasen NC, O’Leary DS. Visualizing how one brain understands another: a PET study of theory of mind. Am J Psychiatry. 2003;160(11):1954–64.
Scott RB, Stoodley CJ, Anslow P, Paul C, Stein JF, Sugden EM, et al. Lateralized cognitive deficits in children following cerebellar lesions. Dev Med Child Neurol. 2001;43(10):685–91.
Schmahmann JD, Sherman JC. The cerebellar cognitive affective syndrome. Brain. 1998;121:561–79.
McAlonan GM, Cheung V, Cheung C, Suckling J, Lam GY, Tai KS, et al. Mapping the brain in autism. A voxel-based MRI study of volumetric differences and intercorrelations in autism. Brain. 2005;128:268–76.
Toal F, Daly EM, Page L, Dee ley Q, Hallahan B, Bloemen O, et al. Clinical and anatomical heterogeneity in autistic spectrum disorder: a structural MRI study. Psychol Med. 2010;7(40):1171–81.
Abell F, Krams M, Ashburner J, Passingham R, Friston K, Frackowiak R, et al. The neuroanatomy of autism: a voxel-based whole brain analysis of structural scans. NeuroReport. 1999;10:1647–51.
Salmond CH, Vargha-Khadem F, Gadian DG, de Haan M, Baldeweg T. Heterogeneity in the patterns of neural abnormality in autistic spectrum disorders: evidence from ERP and MRI. Cortex. 2007;6(43):686–99.
Dow R. The evolution and anatomy of the cerebellum. Biol Rev. 1942;17:179–20.
Schmahmann JD. From movement to thought: anatomic substrates of the cerebellar contribution to cognitive processing. Hum Brain Mapp. 1996;4(3):174–98.
O’Reilly JX, Beckmann CF, Tomassini V, Ramnani N, Johansen-Berg H. Distinct and overlapping functional zones in the cerebellum defined by resting state functional connectivity. Cereb Cortex. 2010;20(4):953–65.
Salmi J, Pallesen KJ, Neuvonen T, Brattico E, Korvenoja A, Salonen O, et al. Cognitive and motor loops of the human cerebro-cerebellar system. J Cogn Neurosci. 2010;22(11):2663–76.
Teffer K, Semendeferi K. Human prefrontal cortex: evolution, development, and pathology. Prog Brain Res. 2012;195:191–218.
Rojas DC, Smith JA, Benkers TL, Camou SL, Reite ML, Rogers SJ. Hippocampus and amygdala volumes in parents of children with autistic disorder. Am J Psychiatry. 2004;161:2038–44.
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;28(24):6392–01.
McAlonan GM, Suckling J, Wong N, Cheung V, Lienenkaemper N, Cheung C, et al. Distinct patterns of grey matter abnormality in high-functioning autism and Asperger’s syndrome. J Child Psychol Psychiatry. 2008;49(12):1287–95.
Hyde KL, Samson F, Evans AC, Mottron L. Neuroanatomical differences in brain areas implicated in perceptual and other core features of autism revealed by cortical thickness analysis and voxel-based morphometry. Hum Brain Mapp. 2010;4(31):556–66.
Riva D, Bulgheroni S, Aquino D, Di Salle F, Savoiardo M, Erbetta A. Basal forebrain involvement in low functioning autistic children: a voxel-based morphometry study. AJNR Am J Neuroradiol. 2011;32(8):1430–35.
Rizzolatti G, Craighero L. The mirror-neuron system. Annu Rev Neurosci. 2004;27:169–92.
Iacoboni M, Dapretto M. The mirror neuron system and the consequences of its dysfunction. Nat Rev Neurosci. 2006;7(12):942–51.
Frith CD, Frith U. Interacting minds—a biological basis. Science. 1999;286:1692–95.
Williams JH, Whiten A, Suddendorf T, Perrett DI. Imitation, mirror neurons and autism. Neurosci Biobehav Rev. 2001;25(4):287–95.
Adolphs R. The social brain: neural basis of social knowledge. Ann Rev Psychol. 2009;60:693–16.
Sugiura M, Kawashima R, Nakamura K, Okada K, Kato T, Nakamura A, et al. Passive and active recognition of one’s own face. Neuroimag. 2000;11(1):36–48.
Sui J, Chechlacz M, Humphreys GW. Dividing the self: distinct neural substrates of task-based and automatic self-prioritization after brain damage. Cognition. 2012;122(2):150–62.
Li HJ, Chan RC, Gong QY, Liu Y, Liu SM, Shum D, et al. Facial emotion processing in patients with schizophrenia and their non-psychotic siblings: a functional magnetic resonance imaging study. Schizophr Res. 2012;134(2–3):143–50.
Schultz RT, Gauthier I, Klin A, Fulbright RK, Anderson AW, Volkmar F, et al. Abnormal ventral temporal cortical activity during face discrimination among individuals with autism and Asperger syndrome. Arch Gen Psychiatry. 2000;4(57):331–40.
Adolphs R, Damasco H, Tranel D, Damasco AR. Cortical systems for the recognition of emotion in facial expressions. J Neurosci. 1996;23(16):7678–87.
Hadjikhanim N, Joseph RM, Snyder J, Tager-Flusberg H. Abnormal activation of the social brain during face perception in autism. Hum Brain Mapp. 2007;5(28):441–49.
Pierce K, Courchesne E. Evidence for a cerebellar role in reduced exploration and stereotyped behavior in autism. Biol Psychiatry. 2001;49(8):655–64.
Webb SJ, Sparks BF, Friedman SD, Shaw DW, Giedd J, Dawson G, et al. Cerebellar vermal volumes and behavioral correlates in children with autism spectrum disorder. Psychiatry Res. 2009;172(1):61–7.
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Riva, D., Annunziata, S., Contarino, V. et al. Gray Matter Reduction in the Vermis and CRUS-II Is Associated with Social and Interaction Deficits in Low-Functioning Children with Autistic Spectrum Disorders: a VBM-DARTEL Study. Cerebellum 12, 676–685 (2013). https://doi.org/10.1007/s12311-013-0469-8
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DOI: https://doi.org/10.1007/s12311-013-0469-8