An MRI study of autism : The cerebellum revisited

To the Editor: Piven et al.1 reported that in their autistic and control subjects, the midsagittal area of the cerebellar vermis lobules VI and VII was 0.31 mm (that is, 310 mm, which is less than half the cross sectional area of the cell body of a single Purkinje neuron; for instance, Ito2 reports it to be 676 mm in cats). The same report stated that the cerebellar vermis lobules I to V were 0.50 6 0.0 mm in autistic patients and 0.50 6 0.06 mm in control subjects, sizes just as impossibly small. Another cause for incredulity was the standard deviation of 0 mm. When these impossibilities were brought to the attention of Piven by one of my colleagues, his laboratory staff replied that “mm” was a typo and it should have been “cm. ” Because 1 cm 5 10 mm, and 1 cm 5 100 mm, this correction would bring the reported vermis area measures up to 31 mm for lobules VI and VII and 50 mm for lobules I to V; sizes in the rat cerebellum range. When the new concern was again voiced, Piven’s laboratory gave yet another set of numbers: 308.3 6 91.5 mm and 311.2 6 98.0 mm for lobules VI and VII and 449.5 6 71.5 mm and 457.3 6 60.7 mm for lobules I to V. This third set of numbers still does not appear to be correct. Perhaps they reported their numbers rounded off. If so, their published figures of 0.5 mm were inaccurate by 1,000 times; rescaling by this factor would bring their area size up to 500 mm, still about 11% in error of their actual numbers, 449.5 and 457.3 mm. Further, for their comparison subjects, Piven et al. reported the area of vermis lobules VI and VII to be 0.31 6 0.06 mm; but in Piven’s laboratory’s reply to my colleague’s query, the area given was 308.3 6 91.5 mm. It is not clear how the “0.06 mm” standard deviation became “91.5 mm,” as the difference in the two numbers does not appear to be a rounding or scaling error. In addition, they report that the whole volume of the autistic and control cerebellum was “141.5 mm” and “128.2 mm,” again about the size of rat cerebella. Perhaps this was another scaling or rounding off error. Although Piven has known of these significant errors for some time now, he has not yet alerted Neurology that an erratum needs to be published. Knowledgeable neuroanatomists know the correct size range of the anatomic structure they measure and report, and do not require multiple prompts to correct errors clearly out of range. Furthermore, when the entire result that makes the main point of a scientific report is pervaded by significant errors and goes undiscovered to press, one is left wondering about the care and precision used during data collection, measurement, and analysis. It is unsettling when large errors are reported that can lead to controversy, confusion, and misdirection about the neurobiologic basis of autism. The Piven et al.1 idea that the cerebellum is larger than normal in autism is inconsistent with all past and new autopsy evidence of neuron loss in the autistic cerebellum. Postmortem studies find that in nearly 90% of cases with autism reported to date, the cerebellum has a significant reduction in Purkinje neurons.3-6 Perhaps Piven et al.1 studied patients who are not typical of autism, as for patient selection they used the Diagnostic and Statistical Manual of Mental Disorders, 3rd ed., revised (DSM-III-R), which does not explicitly distinguish autism from Asperger syndrome, and in Asperger syndrome cerebellar structures may be normal or even slightly larger than normal. In an earlier paper by Piven et al,7 they also initially reported no significant difference between autistic and normal control subjects in the size of neocerebellar vermis lobules VI and VII. However, when statistical miscues were pointed out, Piven and Arndt8 reversed their position and agreed that, in reality, “in the study by Piven et al. (1992), we detected significant differences in neocerebellar [vermis lobules VI and VII] size when we compared autistic individuals with age-, sexand social class-comparable ‘normal, healthy’ volunteers. ” Piven and Arndt discounted the importance of their positive finding by dismissing it as an unimportant, general “IQ effect,” a speculation on their part not supported by any statistical correlation between IQ and vermis measures in their 15 autistic subjects. Moreover, they seem to have ignored an important point regarding the relationship between developmental cerebellar abnormalities and intellectual and affective functions. New neuroimaging and neurologic evidence demonstrates that the normal cerebellum plays an active, and probably specific, role in cognitive and language functions as well as in motor and sensory ones.9 Furthermore, cerebellar lesions lead to significant affective, cognitive, and language abnormalities, including some abnormalities similar to those following frontal lobe damage.10 Therefore, the early developmental loss of cerebellar Purkinje neurons— documented to occur in perhaps 90 to 95% of autistic postmortem cases—would be expected to impair affective, cognitive, and language development in patients with autism. Testing this prediction is extremely important as developmentally aberrant affective, cognitive, and language functions are common and debilitating phenotypic features of autism and thus are a major treatment concern for parents of autistic children and for clinicians. The brain basis of any autistic feature has yet to be definitively demonstrated. Viewing side by side the high incidence of cerebellar neuropathology in autism and the fact that the normal cerebellum plays an active role in cognitive and language operations, it is highly suggestive that cerebellar pathology may be a key factor in the development of the aberrant intellectual and affective functions of autism. It would not be surprising that autistic patients who have sustained the more severe cerebellar pathology (measurable as aberrant size) would also sustain a higher degree of abnormalities in their intellectual, cognitive, language, and affective functioning, therefore scoring lower in their IQ assessments. It should be pointed out, however, that brain-behavior relationships are unlikely to be detected via the use of IQ scores, which are at best rough measures of intellectual dysfunction. Determination of the role of early cerebellar damage in the development of the autistic phenotype will require the use of more sophisticated cognitive neuroscience concepts, tools, and experimental designs.11