Rachel Yeung-Courchesne

Hypoplasia of Cerebellar Vermal Lobules VI and VII in Autism

Autism is a neurologic disorder that severely impairs social, language, and cognitive development. Whether autism involves maldevelopment of neuroanatomical structures is not known. The size of the cerebellar vermis in patients with autism was measured on magnetic resonance scans and compared with its size in controls. The neocerebellar vermal lobules VI and VII were found to be significantly smaller in the patients. This appeared to be a result of developmental hypoplasia rather than shrinkage or deterioration after full development had been achieved. In contrast, the adjacent vermal lobules I to V, which are ontogenetically, developmentally, and anatomically distinct from lobules VI and VII, were found to be of normal size. Maldevelopment of the vermal neocerebellum had occurred in both retarded and nonretarded patients with autism. This localized maldevelopment may serve as a temporal marker to identify the events that damage the brain in autism, as well as other neural structures that may be concomitantly damaged. Our findings suggest that in patients with autism, neocerebellar abnormality may directly impair cognitive functions that some investigators have attributed to the neocerebellum; may indirectly affect, through its connections to the brain stem, hypothalamus, and thalamus, the development and functioning of one or more systems involved in cognitive, sensory, autonomic, and motor activities; or may occur concomitantly with damage to other neural sites whose dysfunction directly underlies the cognitive deficits in autism.

Impairment in shifting attention in autistic and cerebellar patients

MRI and autopsy evidence of early maldevelopment of cerebellar vermis and hemispheres in autism raise the question of how cerebellar maldevelopment contributes to the cognitive and social deficits characteristic of autism. Compared with normal controls, autistic patients and patients with acquired cerebellar lesions were similarly impaired in a task requiring rapid and accurate shifts of attention between auditory and visual stimuli. Neurophysiologic and behavioral evidence rules out motor dysfunction as the cause of this deficit. These findings are consistent with the proposal that in autism cerebellar maldevelopment may contribute to an inability to execute rapid attention shifts, which in turn undermines social and cognitive development, and also with the proposal that the human cerebellum is involved in the coordination of rapid attention shifts in a fashion analogous to its role in the coordination of movement.

Pathophysiologic findings in nonretarded autism and receptive developmental language disorder.

In nonretarded autistic, receptive developmental language disordered, and normal subject groups, we recorded in auditory and visual target detection tasks two neurophysiological components of the event-related brain potential, Nc and P3b. Existent research shows that, in normals, Nc and P3b appear early in development, are associated with attention and memory processes, and are endogenous which means that they are triggered by internal, consciously initiated attentional and cognitive mechanisms and that they can be triggered even by theomission of sensory stimulation so long as it has meaning or importance for the subject. In this report, Nc and P3b were recorded in response to auditory and visual stimulation and to the omission of auditory and visual stimulation. Consistent with the hypothesis that nonretarded autism involves abnormal attentional and cognitive responses to important information, P3b was found to be smaller than normal and Nc was small and often absent in the nonretarded autistic group even under the condition when no auditory language or sensory processing was required. Receptive developmental language disorder has been linked with difficulties in processing sequences of auditory stimuli, and in this study P3b was found to be somewhat enlarged in this group even under the conditions when P3b was elicited by stimuli separated by 1 sec and also when P3b was elicited by the omission of stimulation.

Neurologic abnormalities in infantile autism.

Neuroanatomic, pathologic, and neurobehavioral studies point to a cerebellar and parietal abnormality in autism. We used a standardized protocol to examine neurologic function in 28 pediatric autistic subjects and 24 pediatric normal healthy volunteer controls. As a group, the autistic subjects had quantitative measures from magnetic resonance imaging suggesting hypoplasia or hyperplasia of the cerebellar vermis, as well as measurements of posterior corpus callosum suggesting abnormalities of posterior cortex. In groups of tests that reflect cerebellar and parietal function, the neurologic abnormalities detectable by clinical examination were significantly greater for autistic subjects than for normal controls. These studies confirm that the structural and behavioral deficit in autism does lead to abnormalities that can be detected on the clinical neurologic examination. (J Child Neurol 1996; 11:84-92).

Methodology in neuroanatomic measurement

Magnetic resonance imaging (MRI) is a powerful tool for investigating neurologic disorders for which etiology is not yet resolved. Macroscopic neuroanatomic differences detectable by MRI complement microscopic findings from autopsy. One disorder for which this is true is infantile autism. Several researchers have used MRI to investigate the neuroanatomy of autistic subjects in search of abnormalities that may underlie the social, language, and cognitive dysfunction characteristic of the disorder. To date, substantial evidence from MRI and autopsy shows abnormalities in the cerebellum.l-ll However, a few studies have reported negative r e s ~ l t s . l ~ ~ ~ In this issue of Neurology, we present a metaanalysis of MRI measurements of the cerebellar vermis in autism from recent studies, including those reporting negative findings.’6J7 This meta-analysis combines data from separate laboratories to reveal a bimodal distribution in cerebellar vermis measures, which supports the hypothesis that there are at least two distinct subtypes of abnormality and provides a possible explanation for the conflicting results. The process of reconciling discrepancies among studies forced us to carefully consider the methodologic features employed in MRI studies of autism. In part to explain the contradictory results, and, more importantly, to offer guidelines for future studies, we have identified several critical issues that must enter decisions when planning research designs to accomplish specific goals in any MRI studies of neurologic disorders. Shrewdly made design choices greatly increase the probability of obtaining results consistent with these goals.

Brainstem auditory evoked potentials in receptive developmental language disorder

It has been hypothesized that receptive developmental language disorder (RDLD) may be explained by an auditory processing deficit. The neuroanatomical locus of this deficit is unknown. Brainstem auditory evoked potentials (BAEPs) reflect the functioning of the auditory nerve and auditory brainstem pathways to high-frequency acoustical stimulation in humans and reflect the first stages of auditory processing. These were studied in 12 subjects with RDLD (four females and eight males, ages 12 to 19) and twelve control subjects (three females and nine males, ages 14 to 24). Click intensity and rate of stimulation were varied. The BAEPs for the RDLD group were comparable to the control group as well as to hospital norms across intensity levels and stimulation rates. The evidence obtained suggests that a disorder in the neurophysiological systems underlying the BAEPs and reflecting initial stages of auditory processing is not essential for RDLD.