Research articleLongitudinal Changes of Cerebellar Thickness in Autism Spectrum Disorder
Introduction
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impaired social and communication abilities, stereotyped behavior, and reduced interest [1]. Previous neuroimaging studies have reported a wide range of regional brain abnormalities in ASD, such as in the frontal, parietal, and limbic regions, the basal ganglia, and the cerebellum [2]. Over the years, many reports have shown that cerebellar abnormalities were associated with the onset of ASD [3]. There have been reports of cerebellar structural and functional differences in ASD, which suggests that cerebellar dysfunction may be important in the etiology of the disease [4]. In support of this, the first case of abnormal cerebellar anatomy with autism was published in 1980 [5] and described a decrease in the number of Purkinje cells in the cerebellar vermis of an autism patient. Since then, almost all postmortem analyses of ASD individuals have shown that the size and number of Purkinje cells was decreased regardless of age, sex and cognitive ability [6]. In 1987, using in vivo magnetic resonance imaging (MRI), researchers first reported the observation of an abnormality of the cerebellum in an autism patient. Since then, various studies have found significant differences in the volume of cerebellar subregions between ASD individuals and typically developing (TD) controls. Although meta-analysis-based neuroimaging studies have found that several cerebellar subregions are affected in ASD [7,8], there was no study to examine the structural differences in the brains of individuals with ASD using lobular thickness while also assessing the relationship between these subregions of the cerebellum and core ASD symptoms.
The cerebellum shows a highly regular arrangement of neurons and connections and is supposed to support a large number of parallel computing capabilities [9]. Anatomically, the cerebellum consists of twelve lobules (lobules I-X, Crus I and Crus II). There is also growing evidence supporting the idea that cerebellar subregions have functionally distinct roles in movement and in cognitive and affective functions [10]. For example, lobule VIII is found to include somatomotor networks, connected with the sensorimotor region in the cerebral cortex and involved in sensorimotor tasks [10]. Lobules VI and VII are subdivided into Crus I, Crus II and VIIB, and they receive inputs from the prefrontal cortex and parietal lobe associative regions and are involved in cognitive tasks [11]. A functional connectivity study suggested that the cerebellum is connected to association networks involved in cognitive and affective processes rather than somatomotor networks [12]. Increasingly, the cerebellum is thought to be related to nonmotor functional networks [11], and it is functionally connected to the resting-state network of the whole brain, involving higher-order cognitive networks such as the frontoparietal network (FPN) [12]. Several meta-analysis reports mapping the cerebellar activation clusters in different cognitive domains have described their involvement in a large number of tasks including attention, working memory, executive function, and other behaviors [10,13]. Clinical studies have suggested that lesions in the posterior regions of the cerebellum could result in difficulties in executive function, language, memory and emotion, while damage to the anterior cerebellum can lead to motor impairments and minimal cognitive effects [14]. Based on these findings, the role of the human cerebellum has been extended to include higher-order cognitive and affective processes [11,15]. The unique connectivity patterns of different cerebellar subregions lead to a different functional topography, from which different regions manage different types of information [11]. Taking into account the location of cerebellar subregions and the functional differences in ASD, this topography is important and may help to explain the cerebellar findings in ASD.
Various neuroimaging studies have found abnormalities in several cerebellar subregions in ASD compared with control subjects. Previous structural studies have observed hypoplasia in the posterior vermis with ASD and found that gray matter (GM) decreased in the right Crus I, lobule VIII, and lobule IX [7,8]. Fewer studies have observed decreased GM in the left Crus I, and some researchers have observed an overall increase in cerebellar GM [7,8]. Functional MRI studies show that cerebellar activation in ASD is reduced in social, language, and motor tasks. For example, compared with the TD group, Crus I was underactivated during facial and vocal stimuli processing [16] and executive functioning tasks [17]; lobule VII was abnormally activated during semantic processing [18]; and lobule IV/V was not engaged in motor tasks [19]. Clinical studies about ASD have found that deformities of the cerebellar vermis are related to social and affective disorders and these abnormalities in the cerebellar hemisphere are associated with defects in language expression and in motor and executive functions. These symptoms are linked to ASD [20]. A study showed a 40-fold increase in ASD incidence in premature infants suffering cerebellar damage compared with controls [21]. In addition, patients with tuberous sclerosis (TSC) have a high incidence of ASD symptoms [22], and TSC is specifically associated with tubers within the cerebellum [23].
Cerebellar abnormalities play an important role in ASD [24]. However, few studies have explored the role of subregions in ASD, and few studies have further examined the relationship between ASD symptoms and cerebellar subregions [25,26]. To date, most studies have examined differences at the hemispheric level, while regional differences are often not located in specific cerebellar lobules. In view of the emerging cerebellar functional topographic maps and various cerebellar regions involved in the pathophysiology of autism, it is important to study more discrete subregions in the cerebellum and consider their functional correlation. The present study investigates the thickness of cerebellar subregions in ASD and links the structural findings to the core symptoms of the disorder. In addition, because it is not easy to measure the thickness of the cerebellar cortex, no quantitative changes in thickness have been studied. In this study, we used an automated and reliable quantitative analysis tool to accurately quantify cerebellar thickness. Finally, cross-sectional studies couldn’t make a conclusive distinction between causes and consequences and there is a lack of longitudinal neuroimaging studies. Therefore, we used longitudinal neuroimaging design. The goal of this study was to longitudinally characterize developmental changes in the thickness of cerebellar subregions in ASD and to assess correlations between volume changes and clinical measures. To our knowledge, this is the first study to examine the cerebellar subregions in ASD for lobular thickness analysis. Moreover, this is the first study to correlate cerebellar lobular thickness with autistic symptoms.
Section snippets
Participants
For all analyses, the publicly available longitudinal MRI datasets from the ABIDE program (http://fcon_1000.projects.nitrc.org/indi/abide/) were used. The participants were 19 individuals with ASD (16 males; age 12.53 ± 2.34 years at baseline) and 14 TD controls (12 males; age 13.50 ± 1.77 years at baseline). Two scans were available for each participant, with a mean interval between 2.33 ± 0.70 years for ASD and 2.31 ± 0.65 years for TDC. Participants were recruited and scanned at one of two
Demographics
The demographic characteristics of the sample are summarized in Table 1. There were no differences in interscan interval or baseline age, performance IQ, verbal IQ, or full-scale IQ across groups (all p > 0.05). The χ2 test was used to analysis the gender differences on ASD and TDC, results showed there was no gender difference (χ2 = 0.014, p = 0.905).
Group differences in the development of cerebellar structures
Descriptive statistics for cerebellar thickness analysis are provided in Table 2 and Fig. 2. There was no significant effect of time point on
Discussion
In the present study, we investigated the structural differences of cerebellar subregions in ASD and the relationship between the developmental change in cerebellar lobular thickness and core autistic symptoms. To our knowledge, this is the first study to examine the lobular cortical thickness of the cerebellum in individuals with ASD. Lobular thickness was analyzed using CERES. The right lobule VIIB and VIIIA thicknesses were observed in the main group, and they showed a larger thickness in
Limitations
The strengths of the current study include the longitudinal design and the uniform segmentation approach. However, the sample size was small, and the age distribution was not centralized, therefore it is unknown if our findings will generalize to other groups. Although scanner site was included as a covariate in our analysis, conclusions may be strengthened if data were collected from the same site.
Conclusion
In this longitudinal study, we observed that decreased right Crus II and reduced right asymmetry are important biomarkers in ASD, and their developmental changes were associated with the ADOS stereotyped behavior score, offering an explanation for the behavior deficits in ASD. Future research will focus on exploring the specific contribution of this area to ASD symptomology.
Credit Author Statement
Yanpei Wang analyzed the data and wrote the draft of the paper. LeiHao and Qinfang Xu amend and proofread the draft of the paper. Qinfang Xu, Chenyi Zuo, Liying Zhao and LeiHao participated in the discussion and offered some good ideas. All authors reviewed the manuscript.
Declaration of Competing Interest
No potential conflict of interest was reported by the authors.
Acknowledgements
This research was supported by Humanities & Social Science Program of Ministry of Education in China (No. 18YJA90018) and The National Natural Science Foundation of China (No. 31662083).
References (39)
- et al.
Neuroanatomy of autism
Trends Neurosci
(2008) - et al.
The cerebellum, sensitive periods, and autism
Neuron
(2014) - et al.
Cerebellar function in autism: functional magnetic resonance image activation during a simple motor task
Biol Psychiatry
(2004) - et al.
Evidence for topographic organization in the cerebellum of motor control versus cognitive and affective processing
Cortex; a journal devoted to the study of the nervous system and behavior
(2010) - et al.
Social cognition and the cerebellum: a meta-analysis of over 350 fMRI studies
Neuroimage
(2014) - et al.
Functional topography in the human cerebellum: a meta-analysis of neuroimaging studies
Neuroimage
(2009) - et al.
The neural substrates of cognitive control deficits in autism spectrum disorders
Neuropsychologia
(2009) - et al.
Brain activation during semantic processing in autism spectrum disorders via functional magnetic resonance imaging
Brain Cogn
(2006) - et al.
CERES: A new cerebellum lobule segmentation method
Neuroimage
(2017) - et al.
Derivation of high-resolution MRI atlases of the human cerebellum at 3 T and segmentation using multiple automatically generated templates
Neuroimage
(2014)
Gender differences in anomalous subcortical morphology for children with ADHD
Neurosci Lett
Abnormal functional connectivity of default mode sub-networks in autism spectrum disorder patients
Neuroimage
Cerebellar gray matter and lobular volumes correlate with core autism symptoms
NeuroImage. Clinical
Cerebellar vermis lobules VIII-X in autism
Progress in neuro-psychopharmacology & biological psychiatry
Heterogeneity in the patterns of neural abnormality in autistic spectrum disorders: evidence from ERP and MRI
Cortex; a journal devoted to the study of the nervous system and behavior
Temporal dynamics of cerebro-cerebellar network recruitment during a cognitive task
Neuropsychologia
Diagnostic and statistical manual of mental disorders
BMC Med
Autism and mental retardation: neuropathologic studies performed in four retarded persons with autistic behavior
Arch Neurol
Cited by (11)
Postnatal baicalin ameliorates behavioral and neurochemical alterations in valproic acid-induced rodent model of autism: The possible implication of sirtuin-1/mitofusin-2/ Bcl-2 pathway
2022, Biomedicine and PharmacotherapyCitation Excerpt :Recently, substantial evidence had demonstrated that cerebellar dysfunction plays a pivotal role in the pathogenesis of autism [4]. Patients with autism were proven to have numerous cerebellar structural and functional developmental abnormalities [5]. Cerebellar hypoplasia and reduced cerebellar Purkinje cell numbers are the most consistent neuropathologic features linked to autism, along with cerebellar function disturbances including deficits in the cognitive and motor behavior, and social reward processing [6].
Cerebellar Structural Abnormality in Autism Spectrum Disorder: A Magnetic Resonance Imaging Study
2023, Psychiatry Investigation