Chapter 4 - Cerebellar involvement in autism and ADHD

https://doi.org/10.1016/B978-0-444-64189-2.00004-4Get rights and content

Abstract

The cerebellum has long been known for its importance in motor learning and coordination. However, increasing evidence supports a role for the cerebellum in cognition and emotion. Consistent with a role in cognitive functions, the cerebellum has emerged as one of the key brain regions affected in nonmotor disorders, including autism spectrum disorder and attention deficit-hyperactivity disorder. Here, we discuss behavioral, postmortem, genetic, and neuroimaging studies in humans in order to understand the cerebellar contributions to the pathogenesis of both disorders. We also review relevant animal model findings.

Introduction

Early lesion studies by Rolando and Flourens (Flourens, 1822) in the 19th century revealed the importance of the cerebellum in motor action and movement coordination, leading Flourens to suggest the cerebellum as a seat for motor learning. Since then, recent findings have shown that the cerebellum expresses a range of different functions in addition to motor action, including working memory, emotion regulation, response timing, action planning, and attentional control (for review, see Ito, 2012). Interestingly, a disruption of these functions and dysfunctional cerebellar neuroanatomy has been shown in several neurodevelopmental disorders, including autism spectrum disorder (ASD) and attention deficit-hyperactivity disorder (ADHD) (Stoodley, 2016). Both disorders are highly comorbid with each other (Sinzig et al., 2009), overlap in genetic vulnerability (Ronald et al., 2008), and share similar patterns of social impairment and increased nonsocial behavior such as repetitive behavior (Nijmeijer et al., 2009).

ASD is a lifelong neurodevelopmental condition characterized by deficits in social communication and social interaction, as well as increased repetitive behaviors (American Psychiatric Association, 2013), all functions where cerebellar involvement has been well described (Stoodley and Schmahmann, 2009). While it is highly heritable, ASD is also very heterogeneous and current estimates suggest that up to 1000 risk genes carry de novo coding mutations (Willsey and State, 2015). Furthermore, autism-like behavior is highly present in a number of genetic syndromes including tuberous sclerosis (TSC), Rett syndrome (RTT), and fragile X syndrome (FXS) (Hampson and Blatt, 2015).

ADHD is one of the most common neurodevelopmental disorders (Faraone et al., 2003), defined by age-inappropriate inattention, impulsiveness, and hyperactivity (American Psychiatric Association, 2013), and is associated with deficits in attention, working memory, and timing (Rubia et al., 2014), all functions of cerebellar contribution (Ito, 2012). ADHD is also highly heterogeneous, but in contrast to ASD, its symptoms are treatable. However, when left untreated, it can lead to adverse consequences in adult life, including depression and drug dependency (Leo and Gainetdinov, 2013), underlining the importance of early diagnosis and treatment of ADHD.

In this chapter, we aim to review recent literature from behavioral, postmortem, genetic, and neuroimaging studies in order to understand the underlying cerebellar involvement in the pathophysiology of both disorders, ASD and ADHD.

Section snippets

Motor impairment in autism spectrum disorder

One of the main characteristics of ASD is increased stereotypic and repetitive behavior, which can be expressed through hand flapping, rhythmic rocking, and twirling objects. In children with ASD, repetitive behavior occurs more often and in longer bouts than in typical developing (TD) children, but is maintained with age, making it a pervasive feature of ASD (for review, see Leekam et al., 2011). In addition, patients without a cerebellar vermis (vermal agenesis) or diffuse cerebellar volume

Cerebellar abnormalities in ASD postmortem studies

Histopathologic changes in the cerebellum have been frequently observed in postmortem studies of ASD brains (for review, see Becker and Stoodley, 2013; Hampson and Blatt, 2015). In particular, the loss of cerebellar Purkinje cells has been consistently described in ASD brains compared to controls. This is widely distributed throughout the cerebellar folia and mainly observed in lateral hemispheres, with fewer studies reporting Purkinje cell loss in the vermis. Because of the absence of glial

Cerebellar deficits in mouse models of ASD

Over the past several years and accelerated by recent genetic findings in ASD, an increasing number of rodent models of autism have been developed (for review, see Ellegood and Crawley, 2015; Hulbert and Jiang, 2017). In general, good animal models for ASD and other human disorders should possess three main attributes: (1) face validity, i.e., strong analogies to the endophenotypes of the human syndrome; (2) construct validity, i.e., the same underlying biologic dysfunction that causes the

Conclusions

Findings from human behavioral studies, neuropathology, neuroimaging and rodent models suggest a critical role for the cerebellum in the pathophysiology of ASD and ADHD. Early disruption of the cerebellum due to various genetic and/or environmental insults is likely to cause significant changes in the structure and function of closed-loop cerebrocerebellar circuitry, resulting in both sensorimotor and cognitive dysfunction, a concept described as developmental diaschisis (Wang et al., 2014).

Acknowledgments

M.M.K. Bruchhage has received funding from the European Community's Seventh Framework Program (FP7/2007-2013) TACTICS under grant agreement no. 278948. M.P. Bucci was supported by the Académie des Sciences, Institut de France / Fondation NRJ. E.B.E. Becker was supported by the Royal Society.

References (144)

  • F. Chen et al.

    A light fingertip touch reduces postural sway in children with autism spectrum disorders

    Gait Posture

    (2015)
  • E. Courchesne et al.

    Brain growth across the life span in autism: age-specific changes in anatomical pathology

    Brain Res

    (2011)
  • A.M. D'Mello et al.

    Cerebellar gray matter and lobular volumes correlate with core autism symptoms

    Neuroimage Clin

    (2015)
  • J. Ellegood et al.

    Behavioral and neuroanatomical phenotypes in mouse models of autism

    Neurotherapeutics

    (2015)
  • J. Ellegood et al.

    Anatomical phenotyping in a mouse model of fragile X syndrome with magnetic resonance imaging

    NeuroImage

    (2010)
  • S.A. Ferguson

    Neuroanatomical and functional alterations resulting from early postnatal cerebellar insults in rodents

    Pharmacol Biochem Behav

    (1996)
  • K.A. Fournier et al.

    Decreased static and dynamic postural control in children with autism spectrum disorders

    Gait Posture

    (2010)
  • K.A. Fournier et al.

    Decreased dynamical complexity during quiet stance in children with autism spectrum disorders

    Gait Posture

    (2014)
  • N. Goulème et al.

    Spatial and temporal analysis of postural control in children with high functioning autism spectrum disorder

    Res Autism Spectr Disord

    (2017)
  • H. Hart et al.

    Meta-analysis of fMRI studies of timing in attention-deficit hyperactivity disorder (ADHD)

    Neurosci Biobehav Rev

    (2012)
  • C.J. Heyser et al.

    Coloboma hyperactive mutant exhibits delayed neurobehavioral developmental milestones

    Brain Res Dev Brain Res

    (1995)
  • J.R. Homberg et al.

    Understanding autism and other neurodevelopmental disorders through experimental translational neurobehavioral models

    Neurosci Biobehav Rev

    (2016)
  • M.J. Hove et al.

    Postural sway and regional cerebellar volume in adults with attention-deficit/hyperactivity disorder

    Neuroimage Clin

    (2015)
  • C. Hutt

    Specific and diversive exploration

  • T. Jacobi-Polishook et al.

    The effect of methylphenidate on postural stability under single and dual task conditions in children with attention deficit hyperactivity disorder – a double blind randomized control trial

    J Neurol Sci

    (2009)
  • A. Karmiloff-Smith

    Development itself is the key to understanding developmental disorders

    Trends Cogn Sci

    (1998)
  • A.J. Khan et al.

    Cerebro-cerebellar resting-state functional connectivity in children and adolescents with autism spectrum disorder

    Biol Psychiatry

    (2015)
  • M. Kobel et al.

    Effects of methylphenidate on working memory functioning in children with attention deficit/hyperactivity disorder

    Eur J Paediatr Neurol

    (2009)
  • S.K.E. Koekkoek et al.

    Deletion of FMR1 in Purkinje cells enhances parallel fiber LTD, enlarges spines, and attenuates cerebellar eyelid conditioning in fragile X syndrome

    Neuron

    (2005)
  • L. Kooistra et al.

    Can attention deficit hyperactivity disorder and fetal alcohol spectrum disorder be differentiated by motor and balance deficits?

    Hum Mov Sci

    (2009)
  • S.L. Morris et al.

    Differences in the use of vision and proprioception for postural control in autism spectrum disorder

    Neuroscience

    (2015)
  • K. Pierce et al.

    Evidence for a cerebellar role in reduced exploration and stereotyped behavior in autism

    Biol Psychiatry

    (2001)
  • G. Allen

    The cerebellum in autism

    Clinical Neuropsychiatry

    (2005)
  • American Psychiatric Association

    Diagnostic and statistical manual of mental disorders (DSM-5)

    (2013)
  • R. Apps et al.

    Cerebellar cortical organization: a one-map hypothesis

    Nat Rev Neurosci

    (2009)
  • A. Bari et al.

    Animal models of ADHD

  • S.J. Baudouin et al.

    Shared synaptic pathophysiology in syndromic and nonsyndromic rodent models of autism

    Science

    (2012)
  • M.L. Bauman

    Microscopic neuroanatomic abnormalities in autism

    Pediatrics

    (1991)
  • N.P. Belichenko et al.

    Comparative study of brain morphology in Mecp2 mutant mouse models of Rett syndrome

    J Comp Neurol

    (2008)
  • S. Ben-Shachar et al.

    Mouse models of MeCP2 disorders share gene expression changes in the cerebellum and hypothalamus

    Hum Mol Genet

    (2009)
  • P.C. Berquin et al.

    Cerebellum in attention-deficit hyperactivity disorder: a morphometric MRI study

    Neurology

    (1998)
  • T. Bourgeron

    From the genetic architecture to synaptic plasticity in autism spectrum disorder

    Nat Rev Neurosci

    (2015)
  • M.M.K. Bruchhage et al.

    The cerebellum and brainstem reshape with compulsive behaviour and symptom severity in autism spectrum disorder and obsessive compulsive disorder

    Front Cell Neurosci. Conference Abstract: The cerebellum inside out: cells, circuits and functions

    (2017)
  • M.P. Bucci et al.

    The effect of performing a dual task on postural control in children with autism

    ISRN Neurosci

    (2013)
  • M.P. Bucci et al.

    Postural instability in children with ADHD is improved by methylphenidate

    Front Neurosci

    (2016)
  • R.A. Carper et al.

    Inverse correlation between frontal lobe and cerebellum sizes in children with autism

    Brain

    (2000)
  • F.X. Castellanos et al.

    Developmental trajectories of brain volume abnormalities in children and adolescents with attention-deficit/hyperactivity disorder

    JAMA

    (2002)
  • R.Z. Chen et al.

    Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice

    Nat Genet

    (2001)
  • A. Cubillo et al.

    Shared and drug-specific effects of atomoxetine and methylphenidate on inhibitory brain dysfunction in medication-naive ADHD boys

    Cereb Cortex

    (2014)
  • D. Cupolillo et al.

    Autistic-like traits and cerebellar dysfunction in Purkinje cell PTEN knock-out mice

    Neuropsychopharmacology

    (2016)
  • Cited by (0)

    View full text