The human cerebellum has a protracted developmental timeline compared with the neocortex, expanding the window of vulnerability to neurological disorders. As the cerebellum is critical for motor behaviour, it is not surprising that most neurodevelopmental disorders share motor deficits as a common sequela. However, evidence gathered since the late 1980s suggests that the cerebellum is involved in motor and non-motor function, including cognition and emotion. More recently, evidence indicates that major neurodevelopmental disorders such as intellectual disability, autism spectrum disorder, attention-deficit hyperactivity disorder and Down syndrome have potential links to abnormal cerebellar development. Out of recent findings from clinical and preclinical studies, the concept of the ‘cerebellar connectome’ has emerged that can be used as a framework to link the role of cerebellar development to human behaviour, disease states and the design of better therapeutic strategies.
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Stoodley, C. J., Valera, E. M. & Schmahmann, J. D. Functional topography of the cerebellum for motor and cognitive tasks: an fMRI study. Neuroimage 59, 1560–1570 (2012).
Buckner, R. L. The cerebellum and cognitive function: 25 years of insight from anatomy and neuroimaging. Neuron 80, 807–815 (2013).
Timmann, D. et al. The human cerebellum contributes to motor, emotional and cognitive associative learning. A review. Cortex 46, 845–857 (2010).
Strick, P. L., Dum, R. P. & Fiez, J. A. Cerebellum and nonmotor function. Annu. Rev. Neurosci. 32, 413–434 (2009).
Piaget, J. The Origin of Intelligence in the Child (Routledge & Kegan Paul Ltd, 1953).
Stoodley, C. J. & Limperopoulos, C. Structure-function relationships in the developing cerebellum: evidence from early-life cerebellar injury and neurodevelopmental disorders. Semin. Fetal Neonatal Med. 21, 356–364 (2016).
Schmahmann, J. D. The cerebellum and cognition. Neurosci. Lett. 688, 62–75 (2018).
Tavano, A. et al. Disorders of cognitive and affective development in cerebellar malformations. Brain 130, 2646–2660 (2007).
Levisohn, L., Cronin-Golomb, A. & Schmahmann, J. D. Neuropsychological consequences of cerebellar tumour resection in children: cerebellar cognitive affective syndrome in a paediatric population. Brain 123, 1041–1050 (2000). This study is the first to show long-term non-motor behavioural changes in children with cerebellar tumour resection.
ten Donkelaar, H. J., Lammens, M., Wesseling, P., Thijssen, H. O. & Renier, W. O. Development and developmental disorders of the human cerebellum. J. Neurol. 250, 1025–1036 (2003).
Wang, V. Y. & Zoghbi, H. Y. Genetic regulation of cerebellar development. Nat. Rev. Neurosci. 2, 484–491 (2001).
Ramnani, N. The primate cortico-cerebellar system: anatomy and function. Nat. Rev. Neurosci. 7, 511–522 (2006).
Wang, S. S., Kloth, A. D. & Badura, A. The cerebellum, sensitive periods, and autism. Neuron 83, 518–532 (2014).
Limperopoulos, C. et al. Injury to the premature cerebellum: outcome is related to remote cortical development. Cereb. Cortex 24, 728–736 (2012).
Sathyanesan, A. & Gallo, V. Cerebellar contribution to locomotor behavior: a neurodevelopmental perspective. Neurobiol. Learn. Mem. https://doi.org/10.1016/j.nlm.2018.04.016 (2018).
White, J. J. & Sillitoe, R. V. Development of the cerebellum: from gene expression patterns to circuit maps. Wiley Interdiscip. Rev. Dev. Biol. 2, 149–164 (2013).
Jayadev, S. & Bird, T. D. Hereditary ataxias: overview. Genet. Med. 15, 673–683 (2013).
Stoodley, C. J., MacMore, J. P., Makris, N., Sherman, J. C. & Schmahmann, J. D. Location of lesion determines motor versus cognitive consequences in patients with cerebellar stroke. Neuroimage Clin. 12, 765–775 (2016).
Butts, T., Green, M. J. & Wingate, R. J. Development of the cerebellum: simple steps to make a ‘little brain’. Development 141, 4031–4041 (2014).
Sillitoe, R. V. & Joyner, A. L. Morphology, molecular codes, and circuitry produce the three-dimensional complexity of the cerebellum. Annu. Rev. Cell Dev. Biol. 23, 549–577 (2007).
Rakic, P. & Sidman, R. L. Histogenesis of cortical layers in human cerebellum, particularly the lamina dissecans. J. Comp. Neurol. 139, 473–500 (1970).
Kano, M. & Watanabe, M. in Neural Circuit Development and Function in the Brain (eds Rubenstein, J. & Rakic, P.) 75–93 (Academic Press, 2013).
Zhang, L. & Goldman, J. E. Generation of cerebellar interneurons from dividing progenitors in white matter. Neuron 16, 47–54 (1996).
Altman, J. & Bayer, S. A. Embryonic development of the rat cerebellum. I. Delineation of the cerebellar primordium and early cell movements. J. Comp. Neurol. 231, 1–26 (1985).
Miale, I. L. & Sidman, R. L. An autoradiographic analysis of histogenesis in the mouse cerebellum. Exp. Neurol. 4, 277–296 (1961).
Abraham, H., Tornoczky, T., Kosztolanyi, G. & Seress, L. Cell formation in the cortical layers of the developing human cerebellum. Int. J. Dev. Neurosci. 19, 53–62 (2001).
Kiessling, M. C. et al. Cerebellar granule cells are generated postnatally in humans. Brain Struct. Funct. 219, 1271–1286 (2014).
Sussman, D., Leung, R. C., Chakravarty, M. M., Lerch, J. P. & Taylor, M. J. The developing human brain: age-related changes in cortical, subcortical, and cerebellar anatomy. Brain Behav. 6, e00457 (2016).
Tiemeier, H. et al. Cerebellum development during childhood and adolescence: a longitudinal morphometric MRI study. Neuroimage 49, 63–70 (2010).
De Luca, A. et al. Sonic hedgehog patterning during cerebellar development. Cell. Mol. Life Sci. 73, 291–303 (2016).
Lewis, P. M., Gritli-Linde, A., Smeyne, R., Kottmann, A. & McMahon, A. P. Sonic hedgehog signaling is required for expansion of granule neuron precursors and patterning of the mouse cerebellum. Dev. Biol. 270, 393–410 (2004).
Sudarov, A. & Joyner, A. L. Cerebellum morphogenesis: the foliation pattern is orchestrated by multi-cellular anchoring centers. Neural Dev. 2, 26 (2007).
Nguyen, V. et al. Sonic hedgehog agonist protects against complex neonatal cerebellar injury. Cerebellum 17, 213–227 (2018).
Haldipur, P. et al. Preterm delivery disrupts the developmental program of the cerebellum. PLOS ONE 6, e23449 (2011).
Zonouzi, M. et al. GABAergic regulation of cerebellar NG2 cell development is altered in perinatal white matter injury. Nat. Neurosci. 18, 674–682 (2015).
Rico, B., Xu, B. & Reichardt, L. F. TrkB receptor signaling is required for establishment of GABAergic synapses in the cerebellum. Nat. Neurosci. 5, 225–233 (2002).
ten Brinke, M. M. et al. Evolving models of pavlovian conditioning: cerebellar cortical dynamics in awake behaving mice. Cell Rep. 13, 1977–1988 (2015).
De Zeeuw, C. I. & Ten Brinke, M. M. Motor learning and the cerebellum. Cold Spring Harb. Perspect. Biol. 7, a021683 (2015).
Holtzman, T., Cerminara, N. L., Edgley, S. A. & Apps, R. Characterization in vivo of bilaterally branching pontocerebellar mossy fibre to Golgi cell inputs in the rat cerebellum. Eur. J. Neurosci. 29, 328–339 (2009).
Park, H. & Poo, M. M. Neurotrophin regulation of neural circuit development and function. Nat. Rev. Neurosci. 14, 7–23 (2013).
Bao, S., Chen, L., Qiao, X. & Thompson, R. F. Transgenic brain-derived neurotrophic factor modulates a developing cerebellar inhibitory synapse. Learn. Mem. 6, 276–283 (1999).
Bosman, L. W. et al. Requirement of TrkB for synapse elimination in developing cerebellar Purkinje cells. Brain Cell Biol. 35, 87–101 (2006).
Johnson, E. M., Craig, E. T. & Yeh, H. H. TrkB is necessary for pruning at the climbing fibre-Purkinje cell synapse in the developing murine cerebellum. J. Physiol. 582, 629–646 (2007).
Willson, M. L., McElnea, C., Mariani, J., Lohof, A. M. & Sherrard, R. M. BDNF increases homotypic olivocerebellar reinnervation and associated fine motor and cognitive skill. Brain 131, 1099–1112 (2008).
Sherrard, R. M. et al. Differential expression of TrkB isoforms switches climbing fiber-Purkinje cell synaptogenesis to selective synapse elimination. Dev. Neurobiol. 69, 647–662 (2009).
Choo, M. et al. Retrograde BDNF to TrkB signaling promotes synapse elimination in the developing cerebellum. Nat. Commun. 8, 195 (2017).
Hulbert, S. W. & Jiang, Y. H. Monogenic mouse models of autism spectrum disorders: common mechanisms and missing links. Neuroscience 321, 3–23 (2016).
Qin, X. Y. et al. Association of peripheral blood levels of brain-derived neurotrophic factor with autism spectrum disorder in children: a systematic review and meta-analysis. JAMA Pediatr. 170, 1079–1086 (2016).
Klein, A. B. et al. Blood BDNF concentrations reflect brain-tissue BDNF levels across species. Int. J. Neuropsychopharmacol. 14, 347–353 (2011).
Kaiser, M. Mechanisms of connectome development. Trends Cogn. Sci. 21, 703–717 (2017).
Hauser, T., Will, G.-J., Dubois, M. & Dolan, R. J. Developmental computational psychiatry. Preprint at PsyArXiv. https://doi.org/10.31234/osf.io/85prq (2018).
Thivierge, J. P. Computational developmental neuroscience: capturing developmental trajectories from genes to cognition. IEEE Trans. Autonom. Mental Dev. 2, 51–58 (2010).
Silbereis, J. C., Pochareddy, S., Zhu, Y., Li, M. & Sestan, N. The cellular and molecular landscapes of the developing human central nervous system. Neuron 89, 248–268 (2016).
Volpe, J. J. Cerebellum of the premature infant: rapidly developing, vulnerable, clinically important. J. Child Neurol. 24, 1085–1104 (2009).
Holland, D. et al. Structural growth trajectories and rates of change in the first 3 months of infant brain development. JAMA Neurol. 71, 1266–1274 (2014).
Herculano-Houzel, S. The remarkable, yet not extraordinary, human brain as a scaled-up primate brain and its associated cost. Proc. Natl Acad. Sci. USA 109 (Suppl. 1), 10661–10668 (2012).
Cole, M. W., Pathak, S. & Schneider, W. Identifying the brain’s most globally connected regions. Neuroimage 49, 3132–3148 (2010).
Limperopoulos, C. et al. Impaired trophic interactions between the cerebellum and the cerebrum among preterm infants. Pediatrics 116, 844–850 (2005). This study is one of the first to demonstrate that injury to the developing cerebellum is associated with structural changes to the cerebrum.
Cupolillo, D. et al. Autistic-like traits and cerebellar dysfunction in Purkinje cell PTEN knock-out mice. Neuropsychopharmacology 41, 1457–1466 (2016).
Tsai, P. T. et al. Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature 488, 647–651 (2012). This study provides genetic evidence demonstrating that PC-specific manipulations can result in behavioural features that resemble ASDs.
Sundberg, M. et al. Purkinje cells derived from TSC patients display hypoexcitability and synaptic deficits associated with reduced FMRP levels and reversed by rapamycin. Mol. Psychiatry 23, 2167–2183 (2018).
Watt, A. J. et al. Traveling waves in developing cerebellar cortex mediated by asymmetrical Purkinje cell connectivity. Nat. Neurosci. 12, 463–473 (2009).
Kirkby, L. A., Sack, G. S., Firl, A. & Feller, M. B. A role for correlated spontaneous activity in the assembly of neural circuits. Neuron 80, 1129–1144 (2013).
Hashimoto, K. & Kano, M. Synapse elimination in the developing cerebellum. Cell. Mol. Life Sci. 70, 4667–4680 (2013).
Piochon, C., Kano, M. & Hansel, C. LTD-like molecular pathways in developmental synaptic pruning. Nat. Neurosci. 19, 1299–1310 (2016).
Howarth, C., Gleeson, P. & Attwell, D. Updated energy budgets for neural computation in the neocortex and cerebellum. J. Cereb. Blood Flow Metab. 32, 1222–1232 (2012).
Welsh, J. P. et al. Why do Purkinje cells die so easily after global brain ischemia? Aldolase C, EAAT4, and the cerebellar contribution to posthypoxic myoclonus. Adv. Neurol. 89, 331–359 (2002).
Empson, R. M. & Knopfel, T. Functional integration of calcium regulatory mechanisms at Purkinje neuron synapses. Cerebellum 11, 640–650 (2012).
Hashimoto, K. et al. Postsynaptic P/Q-type Ca2+ channel in Purkinje cell mediates synaptic competition and elimination in developing cerebellum. Proc. Natl Acad. Sci. USA 108, 9987–9992 (2011).
Llano, I., DiPolo, R. & Marty, A. Calcium-induced calcium release in cerebellar Purkinje cells. Neuron 12, 663–673 (1994).
Bezprozvanny, I. Calcium signaling and neurodegenerative diseases. Trends Mol. Med. 15, 89–100 (2009).
Good, J. M. et al. Maturation of cerebellar purkinje cell population activity during postnatal refinement of climbing fiber network. Cell Rep. 21, 2066–2073 (2017).
Ichise, T. et al. mGluR1 in cerebellar Purkinje cells essential for long-term depression, synapse elimination, and motor coordination. Science 288, 1832–1835 (2000).
Anderson, J. S. et al. Abnormal brain synchrony in Down Syndrome. Neuroimage Clin. 2, 703–715 (2013).
Tobe, R. H. et al. Cerebellar morphology in Tourette syndrome and obsessive-compulsive disorder. Ann. Neurol. 67, 479–487 (2010).
Mackie, S. et al. Cerebellar development and clinical outcome in attention deficit hyperactivity disorder. Am. J. Psychiatry 164, 647–655 (2007).
Crippa, A. et al. Cortico-cerebellar connectivity in autism spectrum disorder: what do we know so far? Front. Psychiatry 7, 20 (2016).
D’Mello, A. M. & Stoodley, C. J. Cerebro-cerebellar circuits in autism spectrum disorder. Front. Neurosci. 9, 408 (2015).
Fatemi, S. H. et al. Consensus paper: pathological role of the cerebellum in autism. Cerebellum 11, 777–807 (2012).
Stoodley, C. J. Distinct regions of the cerebellum show gray matter decreases in autism, ADHD, and developmental dyslexia. Front. Syst. Neurosci. 8, 92 (2014).
D’Mello, A. M., Crocetti, D., Mostofsky, S. H. & Stoodley, C. J. Cerebellar gray matter and lobular volumes correlate with core autism symptoms. Neuroimage Clin. 7, 631–639 (2015).
Stanfield, A. C. et al. Towards a neuroanatomy of autism: a systematic review and meta-analysis of structural magnetic resonance imaging studies. Eur. Psychiatry 23, 289–299 (2008).
Courchesne, E. et al. Unusual brain growth patterns in early life in patients with autistic disorder: an MRI study. Neurology 57, 245–254 (2001).
Nickl-Jockschat, T. et al. Brain structure anomalies in autism spectrum disorder — a meta-analysis of VBM studies using anatomic likelihood estimation. Hum. Brain Mapp. 33, 1470–1489 (2012).
Scott, J. A., Schumann, C. M., Goodlin-Jones, B. L. & Amaral, D. G. A comprehensive volumetric analysis of the cerebellum in children and adolescents with autism spectrum disorder. Autism Res. 2, 246–257 (2009).
DeRamus, T. P. & Kana, R. K. Anatomical likelihood estimation meta-analysis of grey and white matter anomalies in autism spectrum disorders. Neuroimage Clin. 7, 525–536 (2015).
Traut, N. et al. Cerebellar volume in autism: literature meta-analysis and analysis of the autism brain imaging data exchange cohort. Biol. Psychiatry 83, 579–588 (2018).
Mostofsky, S. H. et al. Decreased connectivity and cerebellar activity in autism during motor task performance. Brain 132, 2413–2425 (2009). This first fMRI study investigates the link between motor execution in children with ASD, showing decreased cerebellar activation during the motor task in the ASD group.
Floris, D. L. et al. Atypical lateralization of motor circuit functional connectivity in children with autism is associated with motor deficits. Mol. Autism 7, 35 (2016).
Jack, A., Keifer, C. M. & Pelphrey, K. A. Cerebellar contributions to biological motion perception in autism and typical development. Hum. Brain Mapp. 38, 1914–1932 (2017).
Kana, R. K. et al. Aberrant functioning of the theory-of-mind network in children and adolescents with autism. Mol. Autism 6, 59 (2015).
Biswal, B., Yetkin, F. Z., Haughton, V. M. & Hyde, J. S. Functional connectivity in the motor cortex of resting human brain using echo-planar MRI. Magn. Reson. Med. 34, 537–541 (1995).
Buckner, R. L., Krienen, F. M., Castellanos, A., Diaz, J. C. & Yeo, B. T. The organization of the human cerebellum estimated by intrinsic functional connectivity. J. Neurophysiol. 106, 2322–2345 (2011). This seminal imaging study uses resting-state functional connectivity, suggesting, against established belief, that the majority of the human cerebellar cortex maps to association cerebral cortical areas.
O’Reilly, J. X., Beckmann, C. F., Tomassini, V., Ramnani, N. & Johansen-Berg, H. Distinct and overlapping functional zones in the cerebellum defined by resting state functional connectivity. Cereb. Cortex 20, 953–965 (2010).
Khan, A. J. et al. Cerebro-cerebellar resting-state functional connectivity in children and adolescents with autism spectrum disorder. Biol. Psychiatry 78, 625–634 (2015).
Krishnan, A. et al. Genome-wide prediction and functional characterization of the genetic basis of autism spectrum disorder. Nat. Neurosci. 19, 1454–1462 (2016).
Vorstman, J. A. S. et al. Autism genetics: opportunities and challenges for clinical translation. Nat. Rev. Genet. 18, 362–376 (2017).
Limperopoulos, C., Chilingaryan, G., Guizard, N., Robertson, R. L. & Du Plessis, A. J. Cerebellar injury in the premature infant is associated with impaired growth of specific cerebral regions. Pediatr. Res. 68, 145–150 (2010).
Fields, R. D. A new mechanism of nervous system plasticity: activity-dependent myelination. Nat. Rev. Neurosci. 16, 756–767 (2015).
Parker, S. E. et al. Updated National Birth Prevalence estimates for selected birth defects in the United States, 2004–2006. Birth Defects Res. Part A Clin. Mol. Teratol. 88, 1008–1016 (2010).
Pinter, J. D., Eliez, S., Schmitt, J. E., Capone, G. T. & Reiss, A. L. Neuroanatomy of Down’s syndrome: a high-resolution MRI study. Am. J. Psychiatry 158, 1659–1665 (2001).
Lott, I. T. Neurological phenotypes for Down syndrome across the life span. Prog. Brain Res. 197, 101–121 (2012).
Aylward, E. H. et al. Cerebellar volume in adults with Down syndrome. Arch. Neurol. 54, 209–212 (1997).
White, N. S., Alkire, M. T. & Haier, R. J. A voxel-based morphometric study of nondemented adults with Down Syndrome. Neuroimage 20, 393–403 (2003).
Gunbey, H. P. et al. Structural brain alterations of Down’s syndrome in early childhood evaluation by DTI and volumetric analyses. Eur. Radiol. 27, 3013–3021 (2017).
Carter, J. C., Capone, G. T. & Kaufmann, W. E. Neuroanatomic correlates of autism and stereotypy in children with Down syndrome. Neuroreport 19, 653–656 (2008).
Capone, G. T., Grados, M. A., Kaufmann, W. E., Bernad-Ripoll, S. & Jewell, A. Down syndrome and comorbid autism-spectrum disorder: characterization using the aberrant behavior checklist. Am. J. Med. Genet. A 134, 373–380 (2005).
Lazaro, M. T. & Golshani, P. The utility of rodent models of autism spectrum disorders. Curr. Opin. Neurol. 28, 103–109 (2015).
Banerjee-Basu, S. & Packer, A. SFARI Gene: an evolving database for the autism research community. Dis. Model. Mech. 3, 133–135 (2010).
Ellegood, J. et al. Clustering autism: using neuroanatomical differences in 26 mouse models to gain insight into the heterogeneity. Mol. Psychiatry 20, 118–125 (2015).
Herault, Y. et al. Rodent models in Down syndrome research: impact and future opportunities. Dis. Model. Mech. 10, 1165–1186 (2017).
Richtsmeier, J. T., Baxter, L. L. & Reeves, R. H. Parallels of craniofacial maldevelopment in Down syndrome and Ts65Dn mice. Dev. Dyn. 217, 137–145 (2000).
Baxter, L. L., Moran, T. H., Richtsmeier, J. T., Troncoso, J. & Reeves, R. H. Discovery and genetic localization of Down syndrome cerebellar phenotypes using the Ts65Dn mouse. Hum. Mol. Genet. 9, 195–202 (2000).
Das, I. et al. Hedgehog agonist therapy corrects structural and cognitive deficits in a Down syndrome mouse model. Sci. Transl Med. 5, 201ra120 (2013).
Roper, R. J. et al. Defective cerebellar response to mitogenic Hedgehog signaling in Down [corrected] syndrome mice. Proc. Natl Acad. Sci. USA 103, 1452–1456 (2006).
Hyde, L. A., Crnic, L. S., Pollock, A. & Bickford, P. C. Motor learning in Ts65Dn mice, a model for Down syndrome. Dev. Psychobiol. 38, 33–45 (2001).
Costa, A. C., Walsh, K. & Davisson, M. T. Motor dysfunction in a mouse model for Down syndrome. Physiol. Behav. 68, 211–220 (1999).
Costa, A. C. An assessment of the vestibulo-ocular reflex (VOR) in persons with Down syndrome. Exp. Brain Res. 214, 199–213 (2011).
Stringer, M., Goodlett, C. R. & Roper, R. J. Targeting trisomic treatments: optimizing Dyrk1a inhibition to improve Down syndrome deficits. Mol. Genet. Genom. Med. 5, 451–465 (2017).
Hampson, D. R. & Blatt, G. J. Autism spectrum disorders and neuropathology of the cerebellum. Front. Neurosci. 9, 420 (2015).
Leblond, C. S. et al. Meta-analysis of SHANK mutations in autism spectrum disorders: a gradient of severity in cognitive impairments. PLOS Genet. 10, e1004580 (2014).
Peter, S. et al. Dysfunctional cerebellar Purkinje cells contribute to autism-like behaviour in Shank2-deficient mice. Nat. Commun. 7, 12627 (2016).
Piochon, C. et al. Cerebellar plasticity and motor learning deficits in a copy-number variation mouse model of autism. Nat. Commun. 5, 5586 (2014).
Koekkoek, S. K. et al. Deletion of FMR1 in Purkinje cells enhances parallel fiber LTD, enlarges spines, and attenuates cerebellar eyelid conditioning in Fragile X syndrome. Neuron 47, 339–352 (2005). This article presents the first systematic evidence to link synaptic pathophysiology to adaptive cerebellar deficits in a mouse model of fragile X syndrome.
Baudouin, S. J. et al. Shared synaptic pathophysiology in syndromic and nonsyndromic rodent models of autism. Science 338, 128–132 (2012).
Petersen, S. E., Fox, P. T., Posner, M. I., Mintun, M. & Raichle, M. E. Positron emission tomographic studies of the processing of singe words. J. Cogn. Neurosci. 1, 153–170 (1989).
Peterburs, J., Cheng, D. T. & Desmond, J. E. The association between eye movements and cerebellar activation in a verbal working memory task. Cereb. Cortex 26, 3802–3813 (2016).
Tran, L. et al. Cerebellar-dependent associative learning is impaired in very preterm born children and young adults. Sci. Rep. 7, 18028 (2017).
Oristaglio, J. et al. Children with autism spectrum disorders show abnormal conditioned response timing on delay, but not trace, eyeblink conditioning. Neuroscience 248, 708–718 (2013).
Kloth, A. D. et al. Cerebellar associative sensory learning defects in five mouse autism models. eLife 4, e06085 (2015).
Shadmehr, R., Smith, M. A. & Krakauer, J. W. Error correction, sensory prediction, and adaptation in motor control. Annu. Rev. Neurosci. 33, 89–108 (2010).
Baumann, O. et al. Consensus paper: the role of the cerebellum in perceptual processes. Cerebellum 14, 197–220 (2015).
Deluca, C. et al. The cerebellum and visual perceptual learning: evidence from a motion extrapolation task. Cortex 58, 52–71 (2014).
Chen, Y. C. et al. Tinnitus and hyperacusis involve hyperactivity and enhanced connectivity in auditory-limbic-arousal-cerebellar network. eLife 4, e06576 (2015).
Blakemore, S. J., Wolpert, D. M. & Frith, C. D. The cerebellum contributes to somatosensory cortical activity during self-produced tactile stimulation. Neuroimage 10, 448–459 (1999).
Mainland, J. D., Johnson, B. N., Khan, R., Ivry, R. B. & Sobel, N. Olfactory impairments in patients with unilateral cerebellar lesions are selective to inputs from the contralesional nostril. J. Neurosci. 25, 6362–6371 (2005).
Proville, R. D. et al. Cerebellum involvement in cortical sensorimotor circuits for the control of voluntary movements. Nat. Neurosci. 17, 1233–1239 (2014).
Ishikawa, T., Shimuta, M. & Hausser, M. Multimodal sensory integration in single cerebellar granule cells in vivo. eLife 4, e12916 (2015).
Huang, C. C. et al. Convergence of pontine and proprioceptive streams onto multimodal cerebellar granule cells. eLife 2, e00400 (2013).
Ronconi, L. et al. When one is enough: impaired multisensory integration in cerebellar agenesis. Cereb. Cortex 27, 2041–2051 (2017).
Baumann, O. & Greenlee, M. W. Effects of attention to auditory motion on cortical activations during smooth pursuit eye tracking. PLOS ONE 4, e7110 (2009).
Hornix, B. E., Havekes, R. & Kas, M. J. H. Multisensory cortical processing and dysfunction across the neuropsychiatric spectrum. Neurosci. Biobehavioral Rev.. https://doi.org/10.1016/j.neubiorev.2018.02.010 (2018).
Smith, E. G. & Bennetto, L. Audiovisual speech integration and lipreading in autism. J. Child Psychol. Psychiatry 48, 813–821 (2007).
Brandwein, A. B. et al. The development of multisensory integration in high-functioning autism: high-density electrical mapping and psychophysical measures reveal impairments in the processing of audiovisual inputs. Cereb. Cortex 23, 1329–1341 (2013).
Stevenson, R. A. et al. Multisensory temporal integration in autism spectrum disorders. J. Neurosci. 34, 691–697 (2014).
Verly, M. et al. Altered functional connectivity of the language network in ASD: role of classical language areas and cerebellum. Neuroimage Clin. 4, 374–382 (2014).
Ruigrok, T. J. H., Sillitoe, R. V. & Voogd, J. in The Rat Nervous System (ed. Paxinos, G.) 133–205 (Elsevier, 2015).
Lu, H., Yang, B. & Jaeger, D. Cerebellar nuclei neurons show only small excitatory responses to optogenetic olivary stimulation in transgenic mice: in vivo and in vitro studies. Front. Neural Circuits 10, 21 (2016).
Beitzel, C. S., Houck, B. D., Lewis, S. M. & Person, A. L. Rubrocerebellar feedback loop isolates the interposed nucleus as an independent processor of corollary discharge information in mice. J. Neurosci. 37, 10085–10096 (2017).
Arsenio Nunes, M. L. & Sotelo, C. Development of the spinocerebellar system in the postnatal rat. J. Comp. Neurol. 237, 291–306 (1985).
Ashwell, K. W. & Zhang, L. L. Ontogeny of afferents to the fetal rat cerebellum. Acta Anat. (Basel) 145, (17–23 (1992).
Ashwell, K. W. & Zhang, L. I. Prenatal development of the vestibular ganglion and vestibulocerebellar fibres in the rat. Anat. Embryol. 198, 149–161 (1998).
Paradies, M. A. & Eisenman, L. M. Evidence of early topographic organization in the embryonic olivocerebellar projection: a model system for the study of pattern formation processes in the central nervous system. Dev. Dyn. 197, 125–145 (1993).
Ji, Z. & Hawkes, R. Topography of Purkinje cell compartments and mossy fiber terminal fields in lobules II and III of the rat cerebellar cortex: spinocerebellar and cuneocerebellar projections. Neuroscience 61, 935–954 (1994).
Dipietrantonio, H. J. & Dymecki, S. M. Zic1 levels regulate mossy fiber neuron position and axon laterality choice in the ventral brain stem. Neuroscience 162, 560–573 (2009).
Sillitoe, R. V., Vogel, M. W. & Joyner, A. L. Engrailed homeobox genes regulate establishment of the cerebellar afferent circuit map. J. Neurosci. 30, 10015–10024 (2010). This study provides evidence demonstrating that an intrinsic genetic code establishes cerebellar zonal patterning.
Wong, S. Z. H. et al. In vivo clonal analysis reveals spatiotemporal regulation of thalamic nucleogenesis. PLOS Biol. 16, e2005211 (2018).
Bayin, N. S. et al. Age-dependent dormant resident progenitors are stimulated by injury to regenerate Purkinje neurons. eLife 7, e39879 (2018).
Suzuki-Hirano, A. et al. Dynamic spatiotemporal gene expression in embryonic mouse thalamus. J. Comp. Neurol. 519, 528–543 (2011).
Legue, E., Riedel, E. & Joyner, A. L. Clonal analysis reveals granule cell behaviors and compartmentalization that determine the folded morphology of the cerebellum. Development 142, 1661–1671 (2015).
Legue, E. et al. Differential timing of granule cell production during cerebellum development underlies generation of the foliation pattern. Neural Dev. 11, 17 (2016).
Kuemerle, B., Gulden, F., Cherosky, N., Williams, E. & Herrup, K. The mouse Engrailed genes: a window into autism. Behav. Brain Res. 176, 121–132 (2007).
Genestine, M. et al. Engrailed-2 (En2) deletion produces multiple neurodevelopmental defects in monoamine systems, forebrain structures and neurogenesis and behavior. Hum. Mol. Genet. 24, 5805–5827 (2015).
Allegra, M. et al. Altered GABAergic markers, increased binocularity and reduced plasticity in the visual cortex of Engrailed-2 knockout mice. Front. Cell. Neurosci. 8, 163 (2014).
Gerlai, R. et al. Impaired motor learning performance in cerebellar En-2 mutant mice. Behav. Neurosci. 110, 126–133 (1996).
Brielmaier, J. et al. Autism-relevant social abnormalities and cognitive deficits in engrailed-2 knockout mice. PLOS ONE 7, e40914 (2012).
Wilson, S. L., Kalinovsky, A., Orvis, G. D. & Joyner, A. L. Spatially restricted and developmentally dynamic expression of engrailed genes in multiple cerebellar cell types. Cerebellum 10, 356–372 (2011).
Panneton, W. M. The persistence of a normally transient cerebrocerebellar pathway in the cat. Brain Res. 395, 133–139 (1986).
Wild, J. M. & Williams, M. N. A direct cerebrocerebellar projection in adult birds and rats. Neuroscience 96, 333–339 (2000).
Chedotal, A., Bloch-Gallego, E. & Sotelo, C. The embryonic cerebellum contains topographic cues that guide developing inferior olivary axons. Development 124, 861–870 (1997). This study provides crucial experimental evidence for a molecular matching code that plays a role in cerebellar topographic patterning.
Sotelo, C. Cellular and genetic regulation of the development of the cerebellar system. Prog. Neurobiol. 72, 295–339 (2004).
Nishida, K., Flanagan, J. G. & Nakamoto, M. Domain-specific olivocerebellar projection regulated by the EphA-ephrin-A interaction. Development 129, 5647–5658 (2002). This study identifies EPH–ephrin signalling as a possible mechanism for orchestrating cerebellar topographic patterning.
Suzuki-Hirano, A., Harada, H., Sato, T. & Nakamura, H. Activation of Ras-ERK pathway by Fgf8 and its downregulation by Sprouty2 for the isthmus organizing activity. Dev. Biol. 337, 284–293 (2010).
Yuge, K. et al. Region-specific gene expression in early postnatal mouse thalamus. J. Comp. Neurol. 519, 544–561 (2011).
Grimaldi, G. et al. Cerebellar transcranial direct current stimulation (ctDCS): a novel approach to understanding cerebellar function in health and disease. Neuroscientist 22, 83–97 (2016).
Nitsche, M. A. & Paulus, W. Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. J. Physiol. 527 (Pt. 3), 633–639 (2000).
Gupta, T. et al. Cerebellar transcranial direct current stimulation improves procedural learning in nonclinical psychosis: a double-blind crossover study. Schizophr. Bull. 44, 1373–1380 (2017).
Poortvliet, P., Hsieh, B., Cresswell, A., Au, J. & Meinzer, M. Cerebellar transcranial direct current stimulation improves adaptive postural control. Clin. Neurophysiol. 129, 33–41 (2018).
Pope, P. A. & Miall, R. C. Restoring cognitive functions using non-invasive brain stimulation techniques in patients with cerebellar disorders. Front. Psychiatry 5, 33 (2014).
Grimaldi, G. & Manto, M. Anodal transcranial direct current stimulation (tDCS) decreases the amplitudes of long-latency stretch reflexes in cerebellar ataxia. Ann. Biomed. Eng. 41, 2437–2447 (2013).
Benussi, A., Koch, G., Cotelli, M., Padovani, A. & Borroni, B. Cerebellar transcranial direct current stimulation in patients with ataxia: A double-blind, randomized, sham-controlled study. Mov. Disord. 30, 1701–1705 (2015).
Bradnam, L. V., Graetz, L. J., McDonnell, M. N. & Ridding, M. C. Anodal transcranial direct current stimulation to the cerebellum improves handwriting and cyclic drawing kinematics in focal hand dystonia. Front. Hum. Neurosci. 9, 286 (2015).
Helvaci Yilmaz, N., Polat, B. & Hanoglu, L. Transcranial direct current stimulation in the treatment of essential tremor: an open-label study. Neurologist 21, 28–29 (2016).
Helvaci Yilmaz, N., Polat, B. & Hanoglu, L. Transcranial direct current stimulation in the treatment of essential tremor. Parkinsonism Relat. Disord. 22, e130 (2016).
Wessel, M. J., Zimerman, M. & Hummel, F. C. Non-invasive brain stimulation: an interventional tool for enhancing behavioral training after stroke. Front. Hum. Neurosci. 9, 265 (2015).
Demirtas-Tatlidede, A. et al. Safety and proof of principle study of cerebellar vermal theta burst stimulation in refractory schizophrenia. Schizophr. Res. 124, 91–100 (2010).
Aum, D. J. & Tierney, T. S. Deep brain stimulation: foundations and future trends. Front. Biosci. (Landmark Ed) 23, 162–182 (2018).
Herrington, T. M., Cheng, J. J. & Eskandar, E. N. Mechanisms of deep brain stimulation. J. Neurophysiol. 115, 19–38 (2016).
Chiken, S. & Nambu, A. Mechanism of deep brain stimulation: inhibition, excitation, or disruption? Neuroscientist 22, 313–322 (2016).
Budman, E. et al. Potential indications for deep brain stimulation in neurological disorders: an evolving field. Eur. J. Neurol. 25, 434 (2018).
Reeber, S. L., Otis, T. S. & Sillitoe, R. V. New roles for the cerebellum in health and disease. Front. Syst. Neurosci. 7, 83 (2013).
White, J. J. & Sillitoe, R. V. Genetic silencing of olivocerebellar synapses causes dystonia-like behaviour in mice. Nat. Commun. 8, 14912 (2017).
Heath, R. G. Modulation of emotion with a brain pacemamer. Treatment for intractable psychiatric illness. J. Nerv. Ment. Dis. 165, 300–317 (1977).
Cooper, I. S. & Upton, A. R. Use of chronic cerebellar stimulation for disorders of disinhibition. Lancet 1, 595–600 (1978).
Penn, R. D., Gottlieb, G. L. & Agarwal, G. C. Cerebellar stimulation in man. Quantitative changes in spasticity. J. Neurosurg. 48, 779–786 (1978).
Correa, A. J. et al. Chronic cerebellar stimulation in the modulation of behavior. Acta Neurol. 26, 143–153 (1980).
Cooperrider, J. et al. Chronic deep cerebellar stimulation promotes long-term potentiation, microstructural plasticity, and reorganization of perilesional cortical representation in a rodent model. J. Neurosci. 34, 9040–9050 (2014).
Agnesi, F., Johnson, M. D. & Vitek, J. L. Deep brain stimulation: how does it work? Handb. Clin. Neurol. 116, 39–54 (2013).
Creed, M., Pascoli, V. J. & Luscher, C. Addiction therapy. Refining deep brain stimulation to emulate optogenetic treatment of synaptic pathology. Science 347, 659–664 (2015).
Shah, A. M. et al. Optogenetic neuronal stimulation of the lateral cerebellar nucleus promotes persistent functional recovery after stroke. Sci. Rep. 7, 46612 (2017).
Ebert, D. H. & Greenberg, M. E. Activity-dependent neuronal signalling and autism spectrum disorder. Nature 493, 327–337 (2013).
Subramanian, M., Timmerman, C. K., Schwartz, J. L., Pham, D. L. & Meffert, M. K. Characterizing autism spectrum disorders by key biochemical pathways. Front. Neurosci. 9, 313 (2015).
Braat, S. & Kooy, R. F. The GABAA receptor as a therapeutic target for neurodevelopmental disorders. Neuron 86, 1119–1130 (2015).
Ajram, L. A. et al. Shifting brain inhibitory balance and connectivity of the prefrontal cortex of adults with autism spectrum disorder. Transl Psychiatry 7, e1137 (2017).
Canitano, R. New experimental treatments for core social domain in autism spectrum disorders. Front. Pediatr. 2, 61 (2014).
Lemonnier, E. et al. A randomised controlled trial of bumetanide in the treatment of autism in children. Transl Psychiatry 2, e202 (2012).
Sathyanesan, A., Kundu, S., Abbah, J. & Gallo, V. Neonatal brain injury causes cerebellar learning deficits and Purkinje cell dysfunction. Nat. Commun. 9, 3235 (2018).
Ben-Ari, Y., Khalilov, I., Kahle, K. T. & Cherubini, E. The GABA excitatory/inhibitory shift in brain maturation and neurological disorders. Neuroscientist 18, 467–486 (2012).
Kaila, K., Price, T. J., Payne, J. A., Puskarjov, M. & Voipio, J. Cation-chloride cotransporters in neuronal development, plasticity and disease. Nat. Rev. Neurosci. 15, 637–654 (2014).
Paulson, H. L., Shakkottai, V. G., Clark, H. B. & Orr, H. T. Polyglutamine spinocerebellar ataxias - from genes to potential treatments. Nat. Rev. Neurosci. 18, 613–626 (2017).
Jayabal, S., Chang, H. H., Cullen, K. E. & Watt, A. J. 4-Aminopyridine reverses ataxia and cerebellar firing deficiency in a mouse model of spinocerebellar ataxia type 6. Sci. Rep. 6, 29489 (2016).
White, J. J. et al. Pathogenesis of severe ataxia and tremor without the typical signs of neurodegeneration. Neurobiol. Dis. 86, 86–98 (2016).
Alvina, K. & Khodakhah, K. KCa channels as therapeutic targets in episodic ataxia type-2. J. Neurosci. 30, 7249–7257 (2010).
Dell’Orco, J. M., Pulst, S. M. & Shakkottai, V. G. Potassium channel dysfunction underlies Purkinje neuron spiking abnormalities in spinocerebellar ataxia type 2. Hum. Mol. Genet. 26, 3935–3945 (2017).
Power, E. M., Morales, A. & Empson, R. M. Prolonged type 1 metabotropic glutamate receptor dependent synaptic signaling contributes to spino-cerebellar ataxia type 1. J. Neurosci. 36, 4910–4916 (2016).
Krishnan, N. et al. PTP1B inhibition suggests a therapeutic strategy for Rett syndrome. J. Clin. Invest. 125, 3163–3177 (2015).
Castren, E. & Antila, H. Neuronal plasticity and neurotrophic factors in drug responses. Mol. Psychiatry 22, 1085–1095 (2017).
Jeanneteau, F., Garabedian, M. J. & Chao, M. V. Activation of Trk neurotrophin receptors by glucocorticoids provides a neuroprotective effect. Proc. Natl Acad. Sci. USA 105, 4862–4867 (2008).
Jha, S., Dong, B. & Sakata, K. Enriched environment treatment reverses depression-like behavior and restores reduced hippocampal neurogenesis and protein levels of brain-derived neurotrophic factor in mice lacking its expression through promoter IV. Transl Psychiatry 1, e40 (2011).
Zeng, L. et al. Corticosteroids for the prevention of bronchopulmonary dysplasia in preterm infants: a network meta-analysis. Arch. Dis. Child Fetal Neonatal Ed. 103, F506–F511 (2018).
Morgan, C., Novak, I. & Badawi, N. Enriched environments and motor outcomes in cerebral palsy: systematic review and meta-analysis. Pediatrics 132, e735–e746 (2013).
Massaro, A. N. et al. Plasma biomarkers of brain injury in neonatal hypoxic-ischemic encephalopathy. J. Pediatr. 194, 67–75 (2018).
Carta, I., Chen, C. H., Schott, A. L., Dorizan, S. & Khodakhah, K. Cerebellar modulation of the reward circuitry and social behavior. Science 363, eaav0581 (2019).
Woo, J. et al. Control of motor coordination by astrocytic tonic GABA release through modulation of excitation/inhibition balance in cerebellum. Proc. Natl Acad. Sci. USA 115, 5004–5009 (2018).
Jelitai, M., Puggioni, P., Ishikawa, T., Rinaldi, A. & Duguid, I. Dendritic excitation-inhibition balance shapes cerebellar output during motor behaviour. Nat. Commun. 7, 13722 (2016).
Grangeray-Vilmint, A., Valera, A. M., Kumar, A. & Isope, P. Short-term plasticity combines with excitation-inhibition balance to expand cerebellar purkinje cell dynamic range. J. Neurosci. 38, 5153–5167 (2018).
Usowicz, M. M. & Garden, C. L. Increased excitability and altered action potential waveform in cerebellar granule neurons of the Ts65Dn mouse model of Down syndrome. Brain Res. 1465, 10–17 (2012).
Nelson, S. B. & Valakh, V. Excitatory/inhibitory balance and circuit homeostasis in autism spectrum disorders. Neuron 87, 684–698 (2015).
Braitenberg, V. & Schüz, A. Anatomy of the Cortex: Statistics and Geometry (Springer-Verlag Publishing, 1991).
Marr, D. A theory of cerebellar cortex. J. Physiol. 202, 437–470 (1969).
Hansel, C., Linden, D. J. & D’Angelo, E. Beyond parallel fiber LTD: the diversity of synaptic and non-synaptic plasticity in the cerebellum. Nat. Neurosci. 4, 467–475 (2001).
Zoghbi, H. Y. & Bear, M. F. Synaptic dysfunction in neurodevelopmental disorders associated with autism and intellectual disabilities. Cold Spring Harb. Perspect. Biol. 4, a009886 (2012).
Giovannucci, A. et al. Cerebellar granule cells acquire a widespread predictive feedback signal during motor learning. Nat. Neurosci. 20, 727–734 (2017).
Wagner, M. J., Kim, T. H., Savall, J., Schnitzer, M. J. & Luo, L. Cerebellar granule cells encode the expectation of reward. Nature 544, 96–100 (2017).
Habas, C. et al. Distinct cerebellar contributions to intrinsic connectivity networks. J. Neurosci. 29, 8586–8594 (2009).
Marek, S. et al. Spatial and temporal organization of the individual human cerebellum. Neuron 100, 977–993.e7 (2018).
Halko, M. A., Farzan, F., Eldaief, M. C., Schmahmann, J. D. & Pascual-Leone, A. Intermittent theta-burst stimulation of the lateral cerebellum increases functional connectivity of the default network. J. Neurosci. 34, 12049–12056 (2014).
Buckner, R. L., Krienen, F. M. & Yeo, B. T. Opportunities and limitations of intrinsic functional connectivity MRI. Nat. Neurosci. 16, 832–837 (2013).
Rastogi, A., Ghahremani, A. & Cash, R. Modulation of cerebello-cerebral resting state networks by site-specific stimulation. J. Neurophysiol. 114, 2084–2086 (2015).
Cerminara, N. L., Lang, E. J., Sillitoe, R. V. & Apps, R. Redefining the cerebellar cortex as an assembly of non-uniform Purkinje cell microcircuits. Nat. Rev. Neurosci. 16, 79–93 (2015).
Apps, R. & Garwicz, M. Anatomical and physiological foundations of cerebellar information processing. Nat. Rev. Neurosci. 6, 297–311 (2005).
Becker, E. B. & Stoodley, C. J. Autism spectrum disorder and the cerebellum. Int. Rev. Neurobiol. 113, 1–34 (2013).
Andreasen, N. C. & Pierson, R. The role of the cerebellum in schizophrenia. Biol. Psychiatry 64, 81–88 (2008).
Zhuo, C. et al. Altered resting-state functional connectivity of the cerebellum in schizophrenia. Brain Imaging Behav. 12, 383–389 (2018).
Collin, G. et al. Impaired cerebellar functional connectivity in schizophrenia patients and their healthy siblings. Front. Psychiatry 2, 73 (2011).
Ozonoff, S., Heung, K., Byrd, R., Hansen, R. & Hertz-Picciotto, I. The onset of autism: patterns of symptom emergence in the first years of life. Autism Res. 1, 320–328 (2008).
Zhang, C. et al. Differential cortical gray matter deficits in adolescent- and adult-onset first-episode treatment-naive patients with schizophrenia. Sci. Rep. 7, 10267 (2017).
Knogler, L. D., Markov, D. A., Dragomir, E. I., Stih, V. & Portugues, R. Sensorimotor representations in cerebellar granule cells in larval zebrafish are dense, spatially organized, and non-temporally patterned. Curr. Biol. 27, 1288–1302 (2017).
Apps, R. & Hawkes, R. Cerebellar cortical organization: a one-map hypothesis. Nat. Rev. Neurosci. 10, 670–681 (2009).
Miterko, L. N. & Sillitoe, R. V. Climbing fiber development is impaired in postnatal Car8 (wdl) mice. Cerebellum 17, 56–61 (2018).
Xiao, J. et al. Systematic regional variations in Purkinje cell spiking patterns. PLOS ONE 9, e105633 (2014).
Zhou, H. et al. Cerebellar modules operate at different frequencies. eLife 3, e02536 (2014). This study provides one of the first demonstrations that PCs in different zebrin stripes have different firing properties in vivo.
Beckinghausen, J. & Sillitoe, R. V. Insights into cerebellar development and connectivity. Neurosci. Lett. 688, 2–13 (2018).
Biran, V., Verney, C. & Ferriero, D. M. Perinatal cerebellar injury in human and animal models. Neurol. Res. Int. 2012, 858929 (2012).
J.S. was supported by the US National Institute of Neurological Disorders and Stroke (NINDS) grant 5R01NS099461. R.V.S. received support from the Hamill Foundation, the Baylor College of Medicine Intellectual and Developmental Disabilities Research Center grant U54HD083092 and NINDS grants R01NS089664 and R01NS100874. D.H.H. received support from the University of Tennessee Health Science Center (UTHSC) Neuroscience Institute and the UTHSC Cornet Award. R.V.S. and D.H.H. were also supported by the US National Institute of Mental Health grant R01MH112143. V.G. was supported by the District of Columbia Intellectual and Developmental Disabilities Research Center grant U54 HD090257 and NINDS grants R01NS105138 and R37NS109478 (Javits Award).
Nature Reviews Neuroscience thanks J. Fernandez-Ruiz and A. Watt, and the other anonymous reviewer, for their contribution to the peer review of this work.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- Complex developmental brain disorders
Neurodevelopmental disorders that affect multiple brain regions, gene loci and behavioural domains. These disorders do not have a clearly defined hereditary basis.
- Neurodevelopmental disorders
(NDDs). Disorders that emerge during the course of CNS development, often having long-term effects on behaviour.
- Cerebellar connectome
A map of neuronal connections within the cerebellum as well as that between the cerebellum and other CNS regions, including the cerebral cortex and subcortical regions.
- Autism spectrum disorder
(ASD). A broad range of neurodevelopmental conditions characterized by social skill deficits, repetitive motor behaviour and communication deficits.
- Down syndrome
(DS). A neurodevelopmental disorder wherein persons have abnormalities associated with chromosome 21. Persons with DS have reduced muscle tone (hypotonia) during infancy, characteristic facial features and mild to moderate intellectual disability and experience developmental delay, among other symptoms.
- Attention deficit hyperactivity disorder
(ADHD). A complex developmental brain disorder that is characterized by deficits in attentional processes and increased frequency, intensity and variability of motor behaviour.
- Intellectual disability
(ID). A neurodevelopmental disorder and/or condition that often co-occurs with other disorders and is characterized by reduced intellectual functioning (such as learning and abstract reasoning) and deficits in flexible or adaptive behaviours (such as social and motor behaviour).
The selective reporting of statistically significant results on the basis of inappropriate, faulty or loosely defined data analysis schemes.
- Finger-sequencing task
A behavioural task to assess motor function wherein subjects are directed to tap their fingers, on either hand, in a particular sequence. This task is commonly used to identify motor-related regional activation during functional brain imaging.
A statistical method used to measure how strong a given grouping or cluster is supported by the data.
- Vestibulo-ocular reflex
(VOR). A reflex that generates eye movement in the opposite direction to head movement in order to stabilize vision. The cerebellar flocculus is an integral part of VOR circuitry, contributing to adaptive control of the VOR during trial-based learning.
- Eyeblink conditioning paradigm
An associative conditioned-learning paradigm wherein an acoustic or light stimulus (conditioning stimulus (CS)) is paired with an air-puff stimulus (unconditioned stimulus (US)) over multiple trials to eventually yield anticipatory eyelid closure (conditioned response (CR)) as soon as the CS is presented, before US onset. Whereas delay eyeblink conditioning involves co-terminous CS and US and is primarily cerebellar-dependent, trace eyeblink conditioning involves non-overlapping CS and US and requires multiple brain regions including the hippocampus.
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Current Opinion in Genetics & Development (2019)
Journal of Pediatric Neuropsychology (2019)