Abstract
Neuropathological studies have demonstrated decreased Purkinje cells in cerebellar cortex and changes in the dentate nucleus of the cerebellum, the projection target for the Purkinje cells, in autistic spectrum disorders (ASD). The dentatorubrothalamic tract is formed by efferents from the dentate nucleus projecting toward the red nucleus with axon collaterals to this nucleus and continuing to innervate the ventral lateral and ventral anterior nuclei of the thalamus. In the current study, we assessed whether the dentatorubrothalamic tract is altered in ASD using Q-ball imaging (QBI). The QBI tractography was performed in 13 children with high functioning ASD (HFA), 11 children with low functioning ASD (LFA), and 14 typically developing children (TD). Regions of interest in dentate nucleus and red nucleus in both hemispheres were objectively placed to sort bilateral dorsal–rostral (DR), dorsal–caudal (DC), ventral–rostral (VR), and ventral–caudal (VC) portions of the dentatorubrothalamic pathway. Group differences in fractional anisotropy (FA), axial diffusivity, radial diffusivity, and fiber volume of individual pathways were analyzed. Significantly reduced FA was found in children with LFA and HFA, compared to the TD group in tracts originating in all four subdivisions of the right dentate nucleus. Tract-based morphometry (TBM) analysis demonstrated significant reductions of FA in caudal midbrain (p < 0.0001), dorsal–caudal dentate (p = 0.0013), and ventral–caudal dentate (p = 0.0061) on the right in the LFA group. The FA values in TBM segments of right VR and VC pathways were significantly correlated with communication skills in the combined HFA/LFA group, while there was a significant correlation found between TBM segments of right DR pathway and daily living skills (r = 0.76; p = 0.004). Decreased white matter integrity in dorsal portions of the dentatorubrothalamic tract may be related to motor features in ASD, while changes in the ventral portions are related more to communication behavior.
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References
Bauman ML, Kemper TL. Histoanatomic observations of the brain in early infantile autism. Neurology. 1985;35(6):866–74.
Ritvo ER, Freeman BJ, Scheibel AB, Duong T, Robinson H, Guthrie D, et al. Lower Purkinje cell counts in the cerebella of four autistic subjects: initial findings of the UCLA-NSAC autopsy research report. Am J Psychiatry. 1986;143(7):862–6.
Bailey A, Luthert P, Dean A, Harding B, Janota I, Montgomery M, et al. A clinicopathological study of autism. Brain. 1998;121(Pt 5):889–905.
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.
Whitney ER, Kemper TL, Rosens DL, Bauman ML, Blatt GJ. Density of cerebellar basket and stellate cells in autism: evidence for a late developmental loss of Purkinje cells. J Neurosci Res. 2009;87(10):2245–54.
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):171–5.
Batini C, Compoint C, Buisseret-Delmas H, Danile M, Guegan M. Cerebellar nuclei and the nucleocrotical projections in the rat: retrograde tracking coupled to GABA and glutatame immunohistochemistry. J Comp Neurol. 1992;315(1):74–84.
Yip J, Soghomonian JJ, Blatt GJ. Decreased GAD65 mRNA levels in select subpopulations in the cerebellar dentate nuclei in autism: an in situ hybridization study. Autism Res. 2009;2(1):50–9.
Yip J, Soghomonian JJ, Blatt GJ. Decreased GAD67 mRNA levels in cerebellar Punkinje cells in autism: pathophysiological implications. Acta Neuropathol. 2007;113(5):559–68.
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(8):1647–51.
McAlonan GM, Daly E, Kumari V, Critchley HD, van Amlsvoort T, Suckling J, et al. Brain anatomy and sensorimotor gating in Asperger's syndrome. Brain. 2002;125(Pt 7):1584–606.
Allen G, Courchesne E. Differential effects of developmental cerebellar abnormality on cognition and motor functions in the cerebellum: an fMRI study of autism. Am J Psychiatry. 2003;160(2):262–73.
Akshoomoff N, Lord C, Lincoln AJ, Courchesne RY, Carper RA, Townsend J, et al. Outcome classification of preschool children with autism spectrum disorders using MRI brain measures. J Am Acad Child Adolesc Psychiatry. 2004;43(3):349–57.
Takarae Y, Minshew NJ, Luna B, Sweeney JA. Atypical involvement of frontostriatal systems during sensorimotor control in autism. Psychiatry Res. 2007;156(2):117–27.
Scott JA, Schumann CM, Goodlin-Jones BL, Amaral DG. A comprehensive volumetric analysis of the cerebellum in children and adolescents with autism spectrum disorder. Autism Res. 2009;2(5):246–57.
Mostofsky SH, Powel SK, Simmonds DJ, Goldberg MC, Caffo B, Pekar JJ. Decreased connectivity and cerebellar activity in autism during motor task performance. Brain. 2009;132(Pt 9):2413–25.
Hodge SM, Makris S, Kennedy DN, Caviness Jr VS, Howard J, McGrath L, et al. Cerebellum, language, and cognition in autism and specific language impairment. J Autism Dev Disord. 2010;40(3):300–16.
Dum RP, Strick PL. An unfolded map of the cerebellar dentate nucleus and its projections to the cerebral cortex. J Neurophysiol. 2003;89(1):634–9.
Küper M, Dimitrova A, Thürling M, Maderwald S, Roths J, Elles HG, et al. Evidence for a motor and a non-motor domain in the human dentate nucleus—an fMRI study. Neuroimage. 2011;54(4):2612–22.
Barnea-Goraly N, Kwon H, Menon V, Eliez S, Lotspeich L, Reiss AL. White matter structure in autism: preliminary evidence from diffusion tensor imaging. Biol Psychiatry. 2004;55(3):323–6.
Ben Bashat D, Kronfeld-Duenias V, Zachor DA, Ekstein PM, Hendler T, Tarrasch R, et al. Accelerated maturation of white matter in young children with autism: a high b value DWI study. Neuroimage. 2007;37(1):40–7.
Keller TA, Kana RK, Just MA. A developmental study of the structural integrity of white matter in autism. Neuroreport. 2007;18(1):23–7.
Lee JE, Bigler ED, Alexander AL, Lazar M, BuBray MB, Chung MK, et al. Diffusion tensor imaging of white matter in the superior temporal gyrus and temporal stem in autism. Neurosci Lett. 2007;424(2):127–32.
Sundaram SK, Kumar A, Makki MI, Behen ME, Chugani HT, Chugani DC. Diffusion tensor imaging of frontal lobe in autism spectrum disorder. Cereb Cortex. 2008;18(11):2659–65.
Kumar A, Sundaram SK, Sivaswamy L, Behen ME, Makki MI, Ager J, et al. Alterations in frontal lobe tracts and corpus callosum in young children with autism spectrum disorder. Cereb Cortex. 2010;20(9):2103–13.
Cheng Y, Chou KH, Chen IY, Fan YT, Decety J, Lin CP. Atypical development of white matter microstructure in adolescents with autism spectrum disorders. Neuroimage. 2010;50(3):873–82.
Mori S, Crain BJ, Chacko VP, van Zijl PC. Three-dimensional tracking of axonal projections in the brain by magnetic resonance imaging. Ann Neurol. 1999;45(2):265–9.
Basser PJ, Pajevic S, Pierpaoli C, Duda J, Aldroubi A. In vivo fiber tractography using DT-MRI data. Magn Reson Med. 2000;44(4):625–32.
Koch MA, Glauche V, Finsterbusch J, Nolte UG, Frahm J, Weiller C, et al. Distortion-free diffusion tensor imaging of cranial nerves and of inferior temporal and orbitofrontal white matter. Neuroimage. 2002;17(1):497–506.
Tuch DS. Q-ball imaging. Magn Reson Med. 2004;52(6):1358–71.
Tuch DS, Resse TG, Wiegell MR, Wedeen VJ. Diffusion MRI of complex neural architecture. Neuron. 2003;40(5):885–95.
Hess CP, Mukherjee P, Han ET, Xu D, Vigneron DB. Q-ball reconstruction of multimodal fiber orientations using the spherical harmonic basis. Magn Reson Med. 2006;56(1):104–17.
Descoteaux M, Angelino E, Fitzgibbons S, Deriche R. Apparent diffusion coefficients from high angular resolution diffusion imaging: estimation and applications. Magn Reson Med. 2006;56(2):395–410.
Kuo L, Chen J, Wedeen VJ, Tseng WI. Optimization of diffusion spectrum imaging and q-ball imaging on clinical MRI system. Neuroimage. 2008;41(11):7–18.
Deriche R, Calder J, Descoteaux M. Optimal real-time Q-ball imaging using regularized Kalman filtering with incremental orientation sets. Med Image Anal. 2009;13(4):564–79.
Diedrichsen J. A spatially unbiased atlas template of the human cerebellum. Neuroimage. 2006;33(1):127–38.
Diedrichsen J, Maderwald S, Küper M, Thürling M, Rabe K, Gizweski ER, et al. Imaging the deep cerebellar nuclei: a probabilistic atlas and normalization procedure. Neuroimage. 2010;54(3):1786–94.
O’Donnell LJ, Westin CF, Golby AJ. Tract-based morphometry for white matter group analysis. Neuroimage. 2009;45(3):832–44.
Jeong JW, Kumar A, Sundaram SK, Chugani HT, Chugani DC. Aberrant diffusion and geometric properties in the left arcuate fasciculus of developmentally delayed children: a diffusion tensor imaging study. Am J Neuroradiol. 2011;32(2):323–30.
Smith SM, Jenkinson M, Johansen-Berg H, Rueckert D, Nichols TE, Mackay CE, et al. Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. Neuroimage. 2006;31(4):1487–505.
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.
Constantino JN, Przybeck T, Friesen D, Todd RD. Reciprocal social behavior in children with and without pervasive developmental disorders. J Dev Behav Pediatr. 2000;21(1):2–11.
Constantino JN, Davis SA, Todd RD, Schindler MK, Gross MM, Brophy SL, et al. Validation of a brief quantitative measure of autistic traits: comparison of the social responsiveness scale with the autism diagnostic interview-revised. J Autism Dev Disord. 2003;33(4):427–33.
Wechsler D. Wechsler preschool and primary scale of intelligence, 3rd edition (WPPSI-III). San Antonio: The Psychological Corporation; 2002.
Wechsler D. Wechsler intelligence scale for children—fourth edition: administrative and scoring manual. San Antonio: The Psychological Corporation; 2003.
Sattler JM, Dumont R. Assessment of children: WISC-IV and WISC-III supplement. San Diego, CA: Author; 2004.
Mullen EM, editor. Mullen scales of early learning. Circle Pines: American Guidance Service Inc.; 1995.
Sparrow SS, Balla DA, Cicchetti DV, Doll EA. Vineland adaptive behavior scales. Circle Pines: American Guidance Service; 1984.
Perry A, Factor DC. Psychometric validity and clinical usefulness of the Vineland Adaptive Behavior Scales and the AAMD Adaptive Behavior Scale for an autistic sample. J Autism Dev Disord. 1989;19(1):41–55.
Descoteaux M, Angelino E, Fitzgibbons S, Deriche R. Regularized, fast, and robust analytical Q-ball imaging. Magn Reson Med. 2007;58(3):497–510.
Wedeen VJ, Wang RP, Schmahmann JD, Benner T, Tseng WY, Dai G, et al. Diffusion spectrum magnetic resonance imaging (DSI) tractography of crossing fibers. Neuroimage. 2008;41(4):1267–77.
Holm S. A simple sequentially rejective multiple test procedure. Scand J Stat. 1979;6(2):65–70.
Zikopoulos B, Barbas H. Changes in prefrontal axons may disrupt the network in autism. J Neurosci. 2010;30(44):14595–609.
Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005;57(1):67–81.
Singh VK, Warren RP, Odell JD, Warren WL, Cole P. Antibodies to myelin basic protein in children with autistic behavior. Brain Behav Immun. 1993;7(1):97–103.
Singer HS, Morris CM, Gause CD, Gillin PK, Crawford S, Zimmerman AW. Antibodies against fetal brain in sera of mothers with autistic children. J Neuroimmunol. 2008;194(1–2):165–72. Epub 2008 Feb 21.
Frank LR. Anisotropy in high angular resolution diffusion-weighted MRI. Magn Reson Med. 2001;45(6):935–9.
Strick PL, Dum RP, Fiez JA. Cerebellum and nonmotor function. Annu Rev Neurosci. 2009;32:413–34.
Chugani D, Muzik O, Rothermel R, Behen M, Chakraborty P, Mangner T, et al. Altered serotonin synthesis in the dentatothalamocortical pathway in autistic boys. Ann Neurol. 1997;42(4):666–9.
Palmen SJ, van Engeland H, Hof PR, Schmitz C. Neuropathological findings in autism. Brain. 2004;127(Pt 12):2572–83.
Guptill JT, Booker AB, Gibbs TT, Kemper TL, Bauman ML, Blatt GJ. [3H]-flunitrazepam-labeled benzodiazepine binding sites in the hippocampal formation in autism: a multiple concentration autoradiographic study. J Autism Dev Disord. 2007;37(5):911–20.
Courchesne E, Karns CM, Davis HR, Ziccardi R, Carper RA, Tigue ZD, et al. Unusual brain growth patterns in early life in patients with autistic disorder: an MRI study. Neurology. 2001;57(2):245–54.
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 difference and intercorrelations in autism. Brain. 2005;128(Pt2):268–76.
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Jeong, JW., Chugani, D.C., Behen, M.E. et al. Altered White Matter Structure of the Dentatorubrothalamic Pathway in Children with Autistic Spectrum Disorders. Cerebellum 11, 957–971 (2012). https://doi.org/10.1007/s12311-012-0369-3
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DOI: https://doi.org/10.1007/s12311-012-0369-3