Reduced cerebellar hemisphere size and its relationship to vermal hypoplasia in autism

Cerebellar hemisphere size was calculated in 10 autistic and 8 normal control subjects by summing the cross-sectional areas of cerebellar hemisphere tissue measured on paramidline sagittal magnetic resonance images. The areas of two cerebellar vermal regions (lobules I through V and lobules VI through VII) were also measured using the midsagittal image. Our cumulative slice area measure of cerebellar hemisphere size was significantly smaller in the autistic subjects than in the control group. The cumulative slice area correlated positively with the area of vermal lobules VI through VII only in the autistic subjects. Our results indicated that the decreased size of the cerebellar hemispheres and vermal lobules VI through VII was associated with autism.     

Positron emission tomography of the cerebellum in autism

On the basis of neurological evidence that autistic patients have fewer Purkinje and granule cells in the cerebellum as well as vermal cerebellar hypoplasia, the authors tested the hypothesis that autistic patients have cerebellar hypofunctioning. They used positron emission tomography of the cerebellum with 18F-labeled 2-deoxyglucose to study seven autistic patients and eight age-matched control subjects. The results showed no significant difference in mean cerebellar glucose metabolism between the two groups, but all mean glucose rates of the autistic patients were either equal to or greater than those of the control subjects. The implications of these findings are discussed.     

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

BACKGROUND: Although limited environmental exploration in autism is an obvious behavioral feature and may be a manifestation of "restricted interests" as described in DSM-IV criteria, there have been no behavioral or neurobiological studies of this important aspect of the disorder. Given consistent reports of cerebellar abnormality in autism, combined with animal research showing a relationship between exploration and the cerebellum, this study aimed to test the possible link between cerebellar abnormality and exploration in autism. METHODS: The relationship between visuospatial exploration, stereotyped motor movements, and magnetic resonance imaging measures of the cerebellar vermis, whole brain volume, and frontal lobes in 14 autistic and 14 normal children was investigated. Children were exposed to a large room with several exploration containers and instructed to play. Exploration behavior was videotaped and scored for percentage of time engaged in exploration, number of containers explored, as well as stereotyped movements. RESULTS: Children with autism spent significantly less time in active exploration and explored fewer containers overall than normal children. Measures of decreased exploration were significantly correlated with the magnitude of cerebellar hypoplasia of vermal lobules VI-VII in the autistic children, but no relationship to vermis size was found with normal control children. Further, measures of rates of stereotyped behavior were significantly negatively correlated with area measures of cerebellar vermis lobules VI-VII and positively correlated with frontal lobe volume in the autism sample. CONCLUSIONS: Reduced environmental exploration and repetitive behavior may have particularly important developmental consequences for children with autism because it may lead them to miss learning opportunities that fall outside their scope of interest. Our findings represent the first documented link between the restricted range of interests and stereotyped behaviors pathognomonic of autism and particular neuroanatomic sites.     

Oculomotor evidence for neocortical systems but not cerebellar dysfunction in autism

OBJECTIVE: To investigate the functional integrity of cerebellar and frontal systems in autism using oculomotor paradigms. BACKGROUND: Cerebellar and neocortical systems models of autism have been proposed. Courchesne and colleagues have argued that cognitive deficits such as shifting attention disturbances result from dysfunction of vermal lobules VI and VII. Such a vermal deficit should be associated with dysmetric saccadic eye movements because of the major role these areas play in guiding the motor precision of saccades. In contrast, neocortical models of autism predict intact saccade metrics, but impairments on tasks requiring the higher cognitive control of saccades. METHODS: A total of 26 rigorously diagnosed nonmentally retarded autistic subjects and 26 matched healthy control subjects were assessed with a visually guided saccade task and two volitional saccade tasks, the oculomotor delayed-response task and the antisaccade task. RESULTS: Metrics and dynamics of the visually guided saccades were normal in autistic subjects, documenting the absence of disturbances in cerebellar vermal lobules VI and VII and in automatic shifts of visual attention. Deficits were demonstrated on both volitional saccade tasks, indicating dysfunction in the circuitry of prefrontal cortex and its connections with the parietal cortex, and associated cognitive impairments in spatial working memory and in the ability to voluntarily suppress context-inappropriate responses. CONCLUSIONS: These findings demonstrate intrinsic neocortical, not cerebellar, dysfunction in autism, and parallel deficits in higher order cognitive mechanisms and not in elementary attentional and sensorimotor systems in autism.     

Consensus Paper: Pathological Role of the Cerebellum in Autism

There has been significant advancement in various aspects of scientific knowledge concerning the role of cerebellum in the etiopathogenesis of autism. In the current consensus paper, we will observe the diversity of opinions regarding the involvement of this important site in the pathology of autism. Recent emergent findings in literature related to cerebellar involvement in autism are discussed, including: cerebellar pathology, cerebellar imaging and symptom expression in autism, cerebellar genetics, cerebellar immune function, oxidative stress and mitochondrial dysfunction, GABAergic and glutamatergic systems, cholinergic, dopaminergic, serotonergic, and oxytocin-related changes in autism, motor control and cognitive deficits, cerebellar coordination of movements and cognition, gene-environment interactions, therapeutics in autism, and relevant animal models of autism. Points of consensus include presence of abnormal cerebellar anatomy, abnormal neurotransmitter systems, oxidative stress, cerebellar motor and cognitive deficits, and neuroinflammation in subjects with autism. Undefined areas or areas requiring further investigation include lack of treatment options for core symptoms of autism, vermal hypoplasia, and other vermal abnormalities as a consistent feature of autism, mechanisms underlying cerebellar contributions to cognition, and unknown mechanisms underlying neuroinflammation.     

Neuroanatomic contributions to slowed orienting of attention in children with autism

Previous research has demonstrated that adult autistic patients are abnormally slow to orient attention, with degree of slowed orienting associated with severity of cerebellar hypoplasia. This research was extended to children who, at ages two through six, met diagnostic criteria for autism and underwent magnetic resonance imaging (MRI). An average of 3 years later, when old enough to participate in behavioral experiments, the children returned to the laboratory and completed a spatial attention paradigm. Degree of slowed attentional orienting to visual cues was significantly correlated with degree of cerebellar hypoplasia, but not with size of other neuroanatomic regions. Additionally, there was a trend for orienting speed to differ between diagnostic outcome subgroups; children with confirmed diagnoses of autism at time of behavioral testing had larger orienting deficits than those who no longer met diagnostic criteria for autism. This research is among the first to establish a specific brain-behavior link in autistic children.     

Perinatal brain injury and cerebellar vermal lobules I-X in schizophrenia

Several studies, including our own, have reported atrophy of the cerebellar vermis in some schizophrenic patients. A recent report by Courchesne et al (1988) of hypoplasia of a developmentally specific region of the cerebellar vermis in autism prompted us to hypothesize that the cerebellar "atrophy" in some schizophrenic patients may also have developmental origins. We measured the area of the vermal lobules in 30 male schizophrenics. Contrary to expectation, the patients as a group had consistently larger cerebellar structures than the controls. Patients with perinatal injury had smaller structures than the nonperinatally injured group, but these measures were still larger than in the control subjects. Patients without perinatal injury differed from controls, having larger lobules VI-VII (p less than 0.03). These preliminary findings tentatively suggest a role for developmental factors for cerebellar structures in schizophrenia. Further research is needed to clarify the cerebellar vermal changes observed in some schizophrenic patients.     

Magnetic resonance imaging of the posterior fossa in autism.

The brainstem-cerebellar circuitry has been implicated in the pathophysiology of autism for several decades. Recent magnetic resonance imaging (MRI) studies of the posterior fossa have reported various abnormalities, the most noteworthy of which has been selective hypoplasia of the neocerebellar vermis. However, these initial MRI studies are limited by problems in both subject and control selection. The present study was undertaken to further investigate these MRI findings and the role of the cerebellum in autism, taking into consideration these methodologic issues. Eighteen high-functioning autistic subjects were recruited and matched with 18 normal controls on the basis of age, gender, IQ, race and socioeconomic status (SES). The midsagittal areas of the cerebellar vermis, vermal lobes, and the fourth ventricle were measured on 3 mm contiguous magnetic resonance images. Mean areas and standard deviations were comparable for all regions of interest and no statistically significant between-group differences were found. These negative findings argue against theories of autism based on gross structural abnormalities of the cerebellum. Previous reports of posterior fossa abnormalities may be related to technical and methodological factors, based on comparison of extant literature and recently available normative data.     

Event-related brain response abnormalities in autism: evidence for impaired cerebello-frontal spatial attention networks

Although under some conditions the attention-related late positive event-related potential (ERP) response (LPC) is apparently normal in autism during visual processing, the LPC elicited by visuospatial processing may be compromised. Results from this study provide evidence for abnormalities in autism in two components of the LPC generated during spatial processing. The early frontal distribution of the LPC which may reflect attention orienting was delayed or missing in autistic subjects during conditions in which attention was to peripheral visual fields. The later parietal distribution of the LPC which may be associated with context updating was smaller in amplitude in autistic subjects regardless of attention location. Both abnormalities suggest disruption of function in spatial attention networks in autism. Evidence that the cerebellar abnormalities in autism may underlie these deficits comes from: (1) similar results in ERP responses and spatial attention deficits in patients with cerebellar lesions; (2) brain-behavior correlations in normally functioning individuals associating the size of the posterior cerebellar vermis and the latency of the frontal LPC; and (3) a previously reported complementary correlation between the size of the posterior vermal lobules and spatial orienting speed. Although the scalp-recorded LPC is thought to be cortically generated, it may be modulated by subcortical neural activity. The cerebellum may serve as a modulating influence by affecting the task-related antecedent attentional process. The electrophysiological abnormalities reported here index spatial attention deficits in autism that may reflect cerebellar influence on both frontal and parietal spatial attention function.     

Effects of early midline cerebellar lesion on cognitive and emotional functions in the rat

Midline lesion of the cerebellum was performed in young 10-day-old DA/HAN strained (pigmented) rats. Once adults, the lesioned animals were subjected to a series of behavioral tests and their performances were compared with those of control (nonlesioned) rats. Compared with controls, the spontaneous motor activity of the lesioned rats was higher, they showed persevering behavior and did not pay attention to environmental distractors. In anxiety and social discrimination tests, disinhibition tendencies were obvious, which suggested that the animals were less dependent on the context. These abnormalities were most likely due to early midline lesion of the cerebellum and not to a deficit in maternal care before weaning, since the dams took care of the lesioned and control pups similarly. From these results, it can be concluded that the cerebellar vermis is involved in motor control, attentional capabilities and emotional behavior. Given that the lesioned rats observed in this study presented obvious autistic-like symptoms, and since a number of autistic subjects have cerebellar deficits and, particularly, a hypoplasia of vermal lobules, our results may strengthen the idea that the cerebellar vermis is involved in autism, as already suggested in the guinea pig (Caston J, et al. Eur J Neurosci 1998;10:2677-2684).     

Absence of magnetic resonance imaging evidence of pontine abnormality in infantile autism

In vivo studies involving magnetic resonance imaging and studies of neuropathologic specimens have shown that autism is most consistently associated with developmental hypoplasia of the neocerebellum. We investigated whether the cerebellar hypoplasia was accompanied by gross structural abnormalities in the major input (cerebrocerebellar) and output (cerebrorubral) pathways to the cerebellum by measuring the area of the ventral pons (including the pontine nuclei and the transverse fibers) and the midbrain on midsagittal magnetic resonance images in 34 autistic and 44 subjects. The area of the entire pons and several regions of interest within the midbrain (including the superior and inferior colliculi) were also determined with midsagittal magnetic resonance images. We found no significant difference between measurements of the pons and midbrain in autistic and control subjects. Our data show no evidence of gross anatomic abnormalities in the input and output pathways to the cerebellum in autism, a finding that is consistent with previous studies of neuropathologic specimens; rather, the reduced size of the neocerebellum in autism appears to be the result of maldevelopment within the cerebellum itself.     

Abnormal neuroanatomy in a nonretarded person with autism. Unusual findings with magnetic resonance imaging

Recent studies of infantile autism using computed tomographic scanning emphasized the importance of studying cases of classic autism (Kanner's syndrome) without complicating conditions such as mental retardation. Computed tomographic scan studies of such patients reported no evidence of anatomical abnormalities of cerebral hemispheres or of subcortical structures, which are defined by landmarks such as the lateral ventricles and lentiform nuclei. Examination of the cerebellum was not mentioned. The most recent postmortem neuropathologic study reported significant cerebellar abnormality, but the study was of a severely retarded autistic individual. Using magnetic resonance imaging, we have found in vivo evidence of a significant and unusual cerebellar malformation in a person with the classic form of autism uncomplicated by mental retardation (current nonverbal IQ = 112), epilepsy, history of drug use, postnatal trauma, or disease. The finding showed hypoplasia of the declive, folium, and tuber in posterior vermis, but not of the anterior vermis, and hypoplasia of only the medial aspect of each cerebellar hemisphere. The right posterior cerebral hemisphere also showed pathologic findings.     

Dominantly inherited hypoplasia of the vermis.

A mother and her two daughters with presumed dominantly inherited, non-progressive, congenital cerebellar ataxia are reported. Magnetic resonance imaging revealed vermal hypoplasia in one case, and generalized hypoplasia of the cerebellum, predominating at the vermal level, in another case. These patients are identical to those previously published, except for a slowly progressive improvement of motor abilities observed during evolution.     

The brain in infantile autism: are posterior fossa structures abnormal?

We conducted a detailed MRI study of posterior fossa structures in 13 autistic children, 10 without seizures and three with seizures, and 28 controls, 17 without seizures and 11 with seizures, using computer-assisted planimetry, and measured midsagittal areas of cerebellar vermal lobule group I-V, vermal lobule group VI-VII, the pons, and fourth ventricle height. There were no significant differences between autistic and control subjects in any of the four regions measured, or in the ratio of areas of vermal lobules VI-VII to I-V.     

Clinical spectrum associated with cerebellar hypoplasia

We reviewed 45 children with cerebellar hypoplasia on magnetic resonance imaging to identify clinical features associated with cerebellar hypoplasia. We then studied children presenting with any likely associated clinical feature of cerebellar hypoplasia previously observed or reported. Two hundred fifty-one children, with one or more of these features, exhibited no cerebellar hypoplasia on imaging. We compared the children with cerebellar hypoplasia with those without cerebellar hypoplasia. Logistic regression and Pearson’s χ² test were used.

Of the 45 children with cerebellar hypoplasia, 39 exhibited developmental delay; 24, speech delay; 25, seizures; nine, microcephaly; 22, hypotonia; 22, ataxia and impaired coordination; four, abnormal movements (tremor or titubation); 13, hypertonia; eight, autistic features; and 18, ocular signs (nystagmus, strabismus, and abnormal ocular movements). Statistically significant clinical features of children with cerebellar hypoplasia compared with those without were development and speech delay, microcephaly, abnormal movements, ataxia and impaired coordination, autistic features, hypotonia, and ocular signs. The regression combination of speech delay, ataxia, hypotonia, autistic features, and ocular signs correctly predicted 86% of those with cerebellar hypoplasia.

Main clinical features of cerebellar hypoplasia are developmental or speech delay, autistic features, ataxia, hypotonia, and ocular signs.     

Development of the brainstem and cerebellum in autistic patients

Studies of magnetic resonance images have revealed morphological disorders of the brainstem and cerebellum in autistic children and adults. When we studied development of the brainstem and cerebellum in autistic patients, we found that although the brainstem and cerebellum significantly increased in size with age in both autistic patients and controls, these structures were significantly smaller in autistic patients than in controls. The speed of development of the pons, the cerebellar vermis I–V and the cerebellar vermis VI–VII was significantly more rapid in autistic patients than in the controls. However, the speed of development of the other brain structures in the posterior fossa did not differ between autistic patients and controls. The regression intercepts of the brainstem and cerebellum as well as those of their components were significantly smaller in autistic patients than in controls. Results suggest that brainstem and vermian abnormalities in autism were due to an early insult and hypoplasia rather than to a progressive degenerative process.We thank Professor Hiromu Nishitani; without his help and joint effort this study would have been impossible.     

An animal model of autism: behavioural studies in the GS guinea-pig

Autism is a human behavioural pathology marked by major difficulties in abnormal socialization, language comprehension and stereotypic motor patterns. These behavioural abnormalities have been associated with corticocerebral and cerebellar abnormalities in autistic patients, particularly in vermal folia VI and VII. Progress in understanding this disease has been hindered by the absence of a non-primate animal model. GS guinea-pigs are a partially inbred, non-ataxic guinea-pig strain with cerebellar and corticocerebral abnormalities similar to those reported to exist in human patients with autism. In order to determine if GS guinea-pigs represent an animal model of autism, their behaviour was compared with that of Hartley strain guinea-pigs. GS animals learned a motor task significantly more rapidly than Hartley guinea-pigs, but performed it in a more stereotypic manner and were less influenced by environmental stimuli than Hartleys. GS animals exhibited significantly less exploratory behaviour in a novel environment and were significantly less responsive to 50–95 dBA pure tones than Hartley guinea-pigs. In a social interaction assay, GS guinea-pigs interacted significantly less frequently with each other or with Hartley guinea-pigs than Hartleys did under the same conditions. GS behaviour thus exhibits autistic-like behaviour patterns: motor stereotypy, lack of exploration and response to environment and poor social interaction. Coupled with the neuropathological findings, this abnormal behaviour suggests that GS guinea-pigs could be a useful animal model of autism.     

The neuropathology of autism: defects of neurogenesis and neuronal migration, and dysplastic changes

Autism is characterized by a broad spectrum of clinical manifestations including qualitative impairments in social interactions and communication, and repetitive and stereotyped patterns of behavior. Abnormal acceleration of brain growth in early childhood, signs of slower growth of neurons, and minicolumn developmental abnormalities suggest multiregional alterations. The aim of this study was to detect the patterns of focal qualitative developmental defects and to identify brain regions that are prone to developmental alterations in autism. Formalin-fixed brain hemispheres of 13 autistic (4–60 years of age) and 14 age-matched control subjects were embedded in celloidin and cut into 200-μm-thick coronal sections, which were stained with cresyl violet and used for neuropathological evaluation. Thickening of the subependymal cell layer in two brains and subependymal nodular dysplasia in one brain is indicative of active neurogenesis in two autistic children. Subcortical, periventricular, hippocampal and cerebellar heterotopias detected in the brains of four autistic subjects (31%) reflect abnormal neuronal migration. Multifocal cerebral dysplasia resulted in local distortion of the cytoarchitecture of the neocortex in four brains (31%), of the entorhinal cortex in two brains (15%), of the cornu Ammonis in four brains and of the dentate gyrus in two brains. Cerebellar flocculonodular dysplasia detected in six subjects (46%), focal dysplasia in the vermis in one case, and hypoplasia in one subject indicate local failure of cerebellar development in 62% of autistic subjects. Detection of flocculonodular dysplasia in only one control subject and of a broad spectrum of focal qualitative neuropathological developmental changes in 12 of 13 examined brains of autistic subjects (92%) reflects multiregional dysregulation of neurogenesis, neuronal migration and maturation in autism, which may contribute to the heterogeneity of the clinical phenotype.     

Unusual brain growth patterns in early life in patients with autistic disorder: an MRI study

OBJECTIVE: To quantify developmental abnormalities in cerebral and cerebellar volume in autism. METHODS: The authors studied 60 autistic and 52 normal boys (age, 2 to 16 years) using MRI. Thirty autistic boys were diagnosed and scanned when 5 years or older. The other 30 were scanned when 2 through 4 years of age and then diagnosed with autism at least 2.5 years later, at an age when the diagnosis of autism is more reliable. RESULTS: Neonatal head circumferences from clinical records were available for 14 of 15 autistic 2- to 5-year-olds and, on average, were normal (35.1 +/- 1.3 cm versus clinical norms: 34.6 +/- 1.6 cm), indicative of normal overall brain volume at birth; one measure was above the 95th percentile. By ages 2 to 4 years, 90% of autistic boys had a brain volume larger than normal average, and 37% met criteria for developmental macrencephaly. Autistic 2- to 3-year-olds had more cerebral (18%) and cerebellar (39%) white matter, and more cerebral cortical gray matter (12%) than normal, whereas older autistic children and adolescents did not have such enlarged gray and white matter volumes. In the cerebellum, autistic boys had less gray matter, smaller ratio of gray to white matter, and smaller vermis lobules VI-VII than normal controls. CONCLUSIONS: Abnormal regulation of brain growth in autism results in early overgrowth followed by abnormally slowed growth. Hyperplasia was present in cerebral gray matter and cerebral and cerebellar white matter in early life in patients with autism.