Abstract
Atypical functional connectivity (FC) and an imbalance of excitation-to-inhibition (E/I) have been previously reported in cerebro-cerebellar circuits in autism spectrum disorder (ASD). The current investigation used resting state fMRI and proton magnetic resonance spectroscopy (1H-MRS) to examine the relationships between E/I (glutamate + glutamine/GABA) and FC of the dorsolateral prefrontal cortex and posterolateral cerebellar hemisphere from 14 adolescents/adults with ASD and 12 age/sex/IQ-matched controls. In this pilot sample, cerebro-cerebellar FC was positively associated with cerebellar E/I and listening comprehension abilities in individuals with ASD but not controls. Additionally, a subgroup of individuals with ASD and low FC (n = 5) exhibited reduced E/I and impaired listening comprehension. Thus, altered functional coherence of cerebro-cerebellar circuits in ASD may be related with a cerebellar E/I imbalance.
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References
Allen, G., & Courchesne, E. (2003). Differential effects of developmental cerebellar abnormality on cognitive and motor functions in the cerebellum: An fMRI study of autism. American Journal of Psychiatry, 160(2), 262–273. https://doi.org/10.1176/appi.ajp.160.2.262.
Aman, M. G., Singh, N. N., Stewart, A. W., & Field, C. J. (1985). The aberrant behavior checklist: A behavior rating scale for the assessment of treatment effects. American Journal of Mental Deficiency, 89(5), 485–491.
Amaral, D. G., Schumann, C. M., & Nordahl, C. W. (2008). Neuroanatomy of autism. Trends in Neurosciences, 31(3), 137–145. https://doi.org/10.1016/j.tins.2007.12.005.
APA. (2013). Diagnostic and statistical manual of mental disorders: DSM-V. Arlington, VA: APA.
Arin, D. M., Bauman, M. L., & Kemper, T. L. (1991). The distribution of Purkinje cell loss in the cerebellum in autism. Neurology, 41(Suppl), 307.
Bailey, A., Luthert, P., Dean, A., Harding, B., Janota, I., Montgomery, M., … Lantos, P. (1998). A clinicopathological study of autism. Brain, 121, 889–905.
Baron-Cohen, S., Ring, H., Wheelwright, S., Bullmore, E., Brammer, M., Simmons, A., & Williams, S. (1999). Social intelligence in the normal and autistic brain: An fMRI study. European Journal of Neuroscience, 11(6), 1891–1898.
Bauman, M. L., & Kemper, T. L. (1985). Histoanatomic observations of the brain in early infantile autism. Neurology, 35, 866–874.
Benjamini, Y., & Hochberg, Y. (1995). Controlling the false discovery rate: A practical and powerful approach to multiple testing. Journal of the Royal Statistical Society, 57(1), 289–300.
Bottomley, P. A. (1987). Spatial localization in NMR spectroscopy in vivo. Annals of the New York Academy of Sciences, 508(1), 333–348.
Constantino, J. N., & Gruber, C. P. (2007). Social responsiveness scale (SRS). CA: Western Psychological Services Los Angeles.
D’Angelo, E., & Casali, S. (2012). Seeking a unified framework for cerebellar function and dysfunction: From circuit operations to cognition. Front Neural Circuits, 6, 116. https://doi.org/10.3389/fncir.2012.00116.
DeVito, T. J., Drost, D. J., Neufeld, R. W., Rajakumar, N., Pavlosky, W., Williamson, P., & Nicolson, R. (2007). Evidence for cortical dysfunction in autism: A proton magnetic resonance spectroscopic imaging study. Biol Psychiatry, 61(4), 465–473. https://doi.org/10.1016/j.biopsych.2006.07.022.
Fatemi, S. H., Aldinger, K. A., Ashwood, P., Bauman, M. L., Blaha, C. D., Blatt, G. J., … Welsh, J. P. (2012). Consensus paper: Pathological role of the cerebellum in autism. Cerebellum, 11(3), 777–807. https://doi.org/10.1007/s12311-012-0355-9.
Fatemi, S. H., Halt, A. R., Stary, J. M., Kanodia, R., Schulz, S. C., & Realmuto, G. R. (2002). Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices. Biol Psychiatry, 52(8), 805–810.
Fatemi, S. H., Reutiman, T. J., Folsom, T. D., & Thuras, P. D. (2009). GABA(A) receptor downregulation in brains of subjects with autism. Journal of Autism and Developmental Disorders, 39(2), 223–230. https://doi.org/10.1007/s10803-008-0646-7.
Fatemi, S. H., Stary, J. M., Halt, A. R., & Realmuto, G. R. (2001). Dysregulation of Reelin and Bcl-2 proteins in autistic cerebellum. Journal of Autism and Developmental Disorders, 31(6), 529–535.
Fox, M. D., & Raichle, M. E. (2007). Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging. Nature Reviews, 8, 700–711.
Friedman, S. D., Shaw, D. W., Artru, A. A., Richards, T. L., Gardner, J., Dawson, G., … Dager, S. R. (2003). Regional brain chemical alterations in young children with autism spectrum disorder. Neurology, 60, 100–107.
Gasparovic, C., Song, T., Devier, D., Bockholt, H. J., Caprihan, A., Mullins, P. G., … Morrison, L. A. (2006). Use of tissue water as a concentration reference for proton spectroscopic imaging. Magnetic Resonance in Medicine, 55(6), 1219–1226.
Guell, X., Hoche, F., & Schmahmann, J. D. (2015). Metalinguistic deficits in patients with cerebellar dysfunction: Empirical support for the dysmetria of though theory. Cerebellum, 14, 50–58.
Guerrini, L., Belli, G., Mazzoni, L., Foresti, S., Ginestroni, A., Della Nave, R., … Mascalchi, M. (2009). Impact of cerebrospinal fluid contamination on brain metabolites evaluation with 1H-MR spectroscopy: A single voxel study of the cerebellar vermis in patients with degenerative ataxias. Journal of Magnetic Resonance Imaging, 30(1), 11–17. https://doi.org/10.1002/jmri.21804.
Hartigan, J. A., & Hartigan, P. M. (1985). The dip test of unimodality. The Annals of Statistics, 13, 70–84.
Hassan, T. H., Abdelrahman, H. M., Abdel Fattah, N. R., El-Masry, N. M., Hashim, H. M., El-Gerby, K. M., & Abdel Fattah, N. R. (2013). Blood and brain glutamate levels in children with autistic disorder. Research in Autism Spectrum Disorders, 7(4), 541–548. https://doi.org/10.1016/j.rasd.2012.12.005.
IBM. (2013). IBM SPSS statistics for Macintosh (version 22). Armonk, NY: IBM Corp.
Ito, H., Mori, K., Harada, M., Hisaoka, S., Toda, Y., Mori, T., … Kagami, S. (2017). A proton magnetic resonance spectroscopic study in autism spectrum disorder using a 3-Tesla clinical magnetic resonance imaging (MRI) system: The anterior cingulate cortex and the left cerebellum. Journal of Child Neurology. https://doi.org/10.1177/0883073817702981.
Jansen, J. F. A., Backes, W. H., Nicolay, K., & Kooi, M. E. (2006). H MR spectroscopy of the brain: Absolute quantification of metabolites. Radiology, 240(2), 15.
Jenkinson, M., Beckman, C. F., Behrens, T. E., Woolrich, M. W., & Smith, S. M. (2012). FSL. NeuroImage, 62, 782–790.
Jensen, J. E., deB. Frederick, B., & Renshaw, P. F. (2005). Grey and white matter GABA level differences in the human brain using two-dimensional, J-resolved spectroscopic imaging. NMR in Biomedicine, 18(8), 570–576.
Khan, A. J., Nair, A., Keown, C. L., Datko, M. C., Lincoln, A. J., & Muller, R. A. (2015). Cerebro-cerebellar resting state functional connectivity in children and adolscents with autism spectrum disorder. Biological Psychiatry. https://doi.org/10.1016/j.biopsych.2015.03.024.
Kingma, A., Mooij, J. J. A., Metzemaekers, J. D. M., & Leeuw, J. A. (1994). Transient mutism and speech disorders after posterior fossa surgery in children with brain tumours. Acta Neurochirurgica, 131(1–2), 74–79.
Kreis, R. (2004). Issues of spectral quality in clinical 1 H-magnetic resonance spectroscopy and a gallery of artefacts. NMR in Biomedicine, 17, 361–381.
Le Couteur, A., Lord, C., & Rutter, M. (2003). The autism diagnostic interview-revised (ADI-R). Los Angeles, CA: Western Psychological Services.
Lord, C., Risi, S., Lambrecht, L., Cook, E. H. Jr., Leventhal, B. L., DiLavore, P. C., … Rutter, M. (2000). The autism diagnostic observation schedule-generic: A standard measure of social and communication deficits associated with the spectrum of autism. Journal of Autism and Developmental Disorders, 30(3), 205–223.
Lowe, M. J., Mock, B. J., & Sorenson, J. A. (1998). Functional connectivity in single and multislice echoplanar imaging using resting-state fluctuations. NeuroImage, 7, 119–132.
Lynch, J., Peeling, J., Auty, A., & Sutherland, G. R. (1993). Nuclear magnetic resonance study of cerebrospinal fluid from patients with multiple sclerosis. Canadian Journal of Neurological Sciences/Journal Canadien des Sciences Neurologiques, 20(3), 194–198. https://doi.org/10.1017/S0317167100047922.
Martin, L. A., Goldowitz, D., & Mittleman, G. (2010). Repetitive behavior and increased activity in mice with Purkinje cell loss: A model for understanding the role of cerebellar pathology in autism. The European Journal of Neuroscience, 31(3), 544–555. https://doi.org/10.1111/j.1460-9568.2009.07073.x.
Mazziotta, J., Toga, A., Evans, A. C., Fox, P., Lancaster, J., Zilles, K., … Mazoyer, B. (2001). A probabilistic atlas and reference system for the human brain: International consortium for brain mapping (ICBM). Philosophical Transactions of the Royal Society B, 356, 1293–1322.
McKimm, E., Corkill, B., Goldowitz, D., Albritton, L., Homayouni, R., Blaha, C., & Mittleman, G. (2014). Glutamate dysfunction associated with developmental cerebellar damage: Relevance to autism spectrum disorders. The Cerebellum, 13(3), 346–353. https://doi.org/10.1007/s12311-013-0541-4.
Mescher, M., Merkle, H., Kirsch, J., Garwood, M., & Gruetter, R. (1998). Simultaneous in vivo spectral editing and water suppression. NMR in Biomedicine, 11, 266–272.
Mostofsky, S. H., Powell, S. K., Simmonds, D. J., Goldberg, M. C., Caffo, B., & Pekar, J. J. (2009). Decreased connectivity and cerebellar activity in autism during motor task performance. Brain, 132, 2413–2425.
Mullins, P. G., McGonigle, D. J., O’Gorman, R. L., Puts, N. A. J., Vidyasagar, R., Evans, C. J., … Edden, R. A. E. (2014). Current practice in the use of MEGA-PRESS spectroscopy for the detection of GABA. NeuroImage, 86, 43–52. https://doi.org/10.1016/j.neuroimage.2012.12.004.
Murphy, K., Birn, R. M., Handwerker, D. A., Jones, T. B., & Bandettini, P. A. (2009). The impact of global signal regression on resting state correlations: Are anti-correlated networks introduced? NeuroImage, 44(3), 893–905. https://doi.org/10.1016/j.neuroimage.2008.09.036.
Near, J., Simpson, R., Cowen, P., & Jezzard, P. (2011). Efficient γ-aminobutyric acid editing at 3T without macromolecule contamination: MEGA-SPECIAL. NMR in Biomedicine, 24(10), 1277–1285.
Nicoletti, F., Wroblewski, J. T., Novelli, A., Alho, H., Guidotti, A., & Costa, E. (1986). The activation of inositol phospholipid metabolism as a signal- transducing system for excitatory amino acids in primary cultures of cerebellar granule cells. The Journal of Neuroscience, 6(7), 1905.
Ohyama, T., Nores, W. L., Murphy, M., & Mauk, M. D. (2003). What the cerebellum computes. Trends in Neurosciences, 26(4), 222–227. https://doi.org/10.1016/S0166-2236(03)00054-7.
Pearce, B., Cambray-Deakin, M., Morrow, C., Grimble, J., & Murphy, S. (1985). Activation of muscarinic and of α1-adrenergic receptors on astrocytes results in the accumulation of inositol phosphates. Journal of Neurochemistry, 45(5), 1534–1540. https://doi.org/10.1111/j.1471-4159.1985.tb07224.x.
Pizzarelli, R., & Cherubini, E. (2011). Alterations of GABAergic signaling in autism spectrum disorders. Neural Plasticity, 2011, 297153. https://doi.org/10.1155/2011/297153.
Provencher, S. W. (2001). Automatic quantitation of localized in vivo 1H spectra with LCModel. NMR in Biomedicine, 14(4), 260–264.
Purcell, A. E., Jeon, O. H., Zimmerman, A. W., Blue, M. E., & Pevsner, J. (2001). Postmortem brain abnormalities of the glutamate neurotransmitter system in autism. Neurology, 57, 1618–1628.
R_Core_Team. (2012). R: A language and environment for statistical computing. Vienna: R Foundation for Statistical Computing. http://www.r-project.org/.
Ritvo, E. R., Freeman, B. J., Scheibel, A. B., Duong, T., Robinson, H., Guthrie, D., & Ritvo, A. (1986). Lower Purkinje cell counts in the cerebella of four autitic subjects: Initial findings of the UCLA-NSAC autopsy research report. American Journal of Psychiatry, 143, 862–866.
Rothman, D. L., Petroff, O. A., Behar, K. L., & Mattson, R. H. (1993). Localized 1H NMR measurements of gamma-aminobutyric acid in human brain in vivo. Proceedings of the National Academy of Sciences of the United States of America 90(12), 5662–5666.
Rubenstein, J. L. R., & Merzenich, M. M. (2003). Model of autism: Increased ratio of excitation/inhibition in key neural systems. Genes, Brain and Behavior, 2, 255–267. https://doi.org/10.1046/j.1601-183X.2003.00037.x.
Schmahmann, J. D., & Sherman, J. C. (1998). The cerebellar cognitive affective syndrome. Brain, 121, 561–579.
Segovia, G., Del Arco, A., Prieto, L., & Mora, F. (2001). Glutamate-glutamine cycle and aging in striatum of the awake rat: Effects of a glutamate transporter blocker. Neurochemical Research, 26(1), 37–41.
Shibuya-Tayoshi, S., Tayoshi, S. Y., Sumitani, S., Ueno, S., Harada, M., & Ohmori, T. (2008). Lithium effects on brain glutamatergic and GABAergic systems of healthy volunteers as measured by proton magnetic resonance spectroscopy. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 32(1), 249–256. https://doi.org/10.1016/j.pnpbp.2007.08.015.
Shimmura, C., Suzuki, K., Iwata, Y., Tsuchiya, K. J., Ohno, K., Matsuzaki, H., … Mori, N. (2013). Enzymes in the glutamate-glutamine cycle in the anterior cingulate cortex in postmortem brain of subjects with autism. Molecular Autism, 4(1), 6. https://doi.org/10.1186/2040-2392-4-6.
Smith, S. M., Jenkinson, M., Woolrich, M. W., Beckman, C. F., Behrens, T. E., Johansen-Berg, H., … Matthews, P. M. (2004). Advances in functional and structural MR image analysis and implementation as FSL. NeuroImage, 23(Supplement 1), S208–S219.
Song, X.-W., Dong, Z.-Y., Long, X.-Y., Li, S.-F., Zuo, X.-N., Zhu, C.-Z., … Zang, Y.-F. (2011). REST: A toolkit for resting-state functional magnetic resonance imaging data processing. PLoS ONE, 6(9), E25031.
Stichter, J. P., Herzog, M. J., O’Connor, K. V., & Schmidt, C. (2012). A preliminary examination of a general social outcome measure. Assessment for Effective Intervention, 38(1), 40–52. https://doi.org/10.1177/1534508412455213.
Stoodley, C. J., D’Mello, A. M., Ellegood, J., Jakkamsetti, V., Liu, P., Nebel, M. B., … Tsai, P. T. (2017). Altered cerebellar connectivity in autism and cerebellar-mediated rescue of autism-related behaviors in mice. Nature Neuroscience, 20(12), 1744–1751. https://doi.org/10.1038/s41593-017-0004-1.
Stoodley, C. J., & Schmahmann, J. D. (2010). Evidence for topographic organization in the cerebellum of motor control versus cognitive and affective processing. Cortex, 46(7), 831–844. https://doi.org/10.1016/j.cortex.2009.11.008.
Stoodley, C. J., Valera, E. M., & Schmahmann, J. D. (2012). Functional topography of the cerebellum for motor and cognitive tasks: An fMRI study. NeuroImage, 59(2), 1560–1570.
Talairach, J., & Tournoux, P. (1988). Co-planar stereotaxic atlas of the human brain. New York: Thieme.
Tedesco, A. M., Chiricozzi, F. R., Clausi, S., Lupo, M., Molinari, M., & Leggio, M. G. (2011). The cerebellar cognitive profile. Brain, 134(12), 3672–3686.
Thurston, J. H., Sherman, W. R., Hauhart, R. E., & Kloepper, R. F. (1989). myo-Inositol: A newly identified nonnitrogenous osmoregulatory molecule in mammalian brain. Pediatric Research, 26, 482. https://doi.org/10.1203/00006450-198911000-00024.
Tsai, S.-Y., Fang, C.-H., Wu, T.-Y., & Lin, Y.-R. (2016). Effects of frequency drift on the quantification of gamma-aminobutyric acid using MEGA-PRESS. Scientific Reports, 6, 24564.
Verly, M., Verhoeven, J., Zink, I., Mantini, D., Peeters, R., Deprez, S., … Sunaert, S. (2014). Altered functional connectivity of the language network in ASD: Role of classical language areas and cerebellum. NeuroImage: Clinical, 4, 374–382. https://doi.org/10.1016/j.nicl.2014.01.008.
Vogel, M. W., Caston, J., Yuzaki, M., & Mariani, J. (2007). The Lurcher mouse: Fresh insights from an old mutant. Brain Research, 1140, 4–18. https://doi.org/10.1016/j.brainres.2005.11.086.
Wechsler, D. (1999). WASI manual. San Antonio: Psychological Corporation.
Whitney, E. R., Kemper, T. L., Bauman, M. L., Rosene, D. L., & Blatt, G. J. (2008). Cerebellar Purkinje cells are reduced in a subpopulation of autistic brains: A stereological experiment using calbindin-D28k. Cerebellum, 7(3), 406–416. https://doi.org/10.1007/s12311-008-0043-y.
Wiig, E. H., & Secord, W. (1989). Test of language competence (TLC): Expanded edition. San Antonio: Psychological Corporation.
Yip, J., Soghomonian, J. J., & Blatt, G. J. (2007). Decreased GAD67 mRNA levels in cerebellar Purkinje cells in autism: Pathophysiological implications. Acta Neuropathologica, 113(5), 559–568. https://doi.org/10.1007/s00401-006-0176-3.
Yip, J., Soghomonian, J. J., & Blatt, G. J. (2009). Decreased GAD65 mRNA levels in select subpopulations of neurons in the cerebellar dentate nuclei in autism: An in situ hybridization study. Autism Research, 2(1), 50–59. https://doi.org/10.1002/aur.62.
Zhang, Y., Brady, M., & Smith, S. (2001). Segmentation of brain MR images through a hidden Markov random field model and the expectation-maximization algorithm. IEEE Transactions on Medical Imaging, 20(1), 45–57.
Acknowledgments
This investigation was supported by a pilot grant from the University of Missouri Brain Imaging Center, the University of Missouri School of Medicine Mission Enhancement Fund, and crowdsourced funding from the community. We would like to thank Dr. Lori Thombs for her statistical consultation and the many research assistants that were integral to the completion of this work. We would like to especially thank the participants and their families that contributed to this investigation and the support from the University of Missouri Brain Imaging Center and Thompson Center for Autism and Neurodevelopmental Disorders.
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JH conceived of the study, participated in its design and coordination and drafted the manuscript; DW participated in the coordination of the study and performed the outlined measurements; CS participated in the design and analysis/interpretation of the neuroimaging data and helped draft the manuscript; and DB participated in the study design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.
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Hegarty, J.P., Weber, D.J., Cirstea, C.M. et al. Cerebro-Cerebellar Functional Connectivity is Associated with Cerebellar Excitation–Inhibition Balance in Autism Spectrum Disorder. J Autism Dev Disord 48, 3460–3473 (2018). https://doi.org/10.1007/s10803-018-3613-y
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DOI: https://doi.org/10.1007/s10803-018-3613-y