Chapter 4 - Cerebellar involvement in autism and ADHD
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.
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