Cerebellar vermis lobules VIII — X in autism

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CEBBBELLAR

VERIUIS LOBULES VIII - X IN AUTISM

JENNIFER G. LEVITT’.‘, REBECCA BLANTON’, LINDA CAPETILLO-CUNLIWE’, DONALD GUTBRIE’, ARTHUR TOGA* and JAMES T. MCCRACKEN’*’

‘Department of Psychiatry and *Laboratory of Neuroimaging, ‘UCLA Neuropsychiatric Institute, Los Angeles, CA, USA

(Final form, February,

1999)

Levitt, Jennifer G., Rebecca Blanton, Linda Capetillo-Cunliffe, Donald Guthrie, Arthur Toga and James T. McCracken: 1999,2;t

Cerebellar Vermis Lobules VIII-X in Autism. Prog. Nemo-Psychopharmacol.

pp. 625633.81999

& Biol. Psychiatry

Elaevier Science Inc.

1. The aim was to investigate cerebellar vennis cross-sectional area in a group of high-functioning autistic children and normal control children. 2. Cerebellar vermis area measurements were completed on MRI scans from 8 autistic children (mean age 12.5 f 2.2, mean IQ 83.3 f 11.9) and 21 normal children (mean age 12.0 f 2.8, mean IQ 115 f 11). 3. The area of cerebellar vermis lobules VIII-X was significantly smaller in the autistic children than in the normal control subjects. ANCOVA demonstrated a confounding effect of IQ on these results. 4. Larger studies of autistic and normal subjects will be needed to assess the relationship between cerebellar abnormalities, autistic symptoms and IQ.

l&y~&:

m:

autism, cerebellum, IQ, MRI, vennis

analyses of covariance (ANCOVA), analysis of variance (ANOVA), Diagnostic and Statistical

Manual of Mental Disorder, 4u edition (DSM-IV), magnetic resonance imaging (MRI), positron emission tomography (PET), spoiled grass (SPGR).

625

626

J.G. Levitt et

al.

Autism is a severe developmental disorder of communication and reciprocal social interaction with repetitive, odd behaviors (American Psychiatric Association, 1994). While the underlying neurobiology of autism remains unknown (Smalley et al., 1998), histoanatomic investigations have demonstrated cellular abnormalities in the limbic system (Bauman and Kemper, 1995) and cerebella (Bauman and Kemp, 1995; Ritvo et al., 1986) of autistic subjects. A variety of magnetic resonance imaging (MRI) studies have also demonstrated neuroanatomic abnormalities in autistic subjects such as increased brain size (Piven et al., 1995, 1996), irregularities of the cerebral cortical surface (Piven et al., 1990) and posterior fossa abnormalities in areas including the pans, fourth ventricle and cerebellar vermal lobules VI and VII (Gaffney et al., 1987; Courchesne et al., 1988, 1994; Murakami et al., 1989; Hashimoto et al., 1992).

Although several studies have not replicated the cerebellar findings in autistic subjects (Garber et al., 1989; Filipek et al., 1992; Garber and Ritvo, 1992; Kleimen et al., 1992; Holttum et al., 1992; Piven et al., 1992, 1997), recent work continues to implicate the cerebellum in symptoms associated with the autistic syndrome. In a study of monozygotic twins discordant for autism, Kates et al. (1998) demonstrated a variety of neuroanatomic differences in the affected twin compared to the unaffected twin, including a significant decrease in the ama of cerebellar vermis lobules VI and VII. Mazzocco et al. (1997) evaluated girls with fragile X syndrome, and found that the area of cerebellar vermis lobule VI-VII was negatively correlated with stereotypic/repetitive behaviors and communication abnormalities in the study subjects. In a study of Ll knockout mice, Fransen et al. (1998) suggested that vermal hypoplasia was associated with stereotypic circling behaviors and impaired spatial exploration observed in the affected animals.

These findings of an association between cerebellar vermis size and autistic symptoms, and the conflicting MRI evidence regarding cerebellar abnormalities in autistic subjects, underscore the importance of further exploration of cerebellar structure and function in autism. In the present study, the authors examined the cross-sectional surface area of the cerebellar vermis in a group of children with autism and a group of normal children. We recruited ‘high-functioning” autistic children (IQ > 65) for this study, in order to address the issues concerning an association between IQ and cerebellar vermis area.

This pilot study was performed on 8 children with autism and 21 normal subjects. Informed consent for participation in this study was obtained from the children and their parents. The 8 autistic children were recruited from a pool of 45 non-retarded autistic subjects who participated in a previous family-genetic study of autism (Smalley et al., 1992). All children in the autistic group met Diagnostic and Statistical Manual of Mental

Cerebellar vermis lobules VIII-X in autism Disorder, 4& edition @M-IV),

627

(American Psychiatric Association, 1994) criteria for autism based on the Autism

Diagnostic Interview (Lord et al., 1989). The age range of the autistic children was 9.8 to 16 years with a mean age of 12.5 years (sd = 2.2). The mean full-scale IQ of the patients was 83.3 (sd = 11.9). The authors recruited normal control children from public and private schools in the community. Potential normal control children were screened for neurological, psychiatric, language, or hearing disorders by clinical interview and structured interview using the Schedule for Aifective Disorders and Schizophrenia for School-Age Children-Epidemiologic Version (Orvaschel and Puig-Antich, 1987). We excluded children from the normal sample if they manifested symptoms of these disorders either at the time of the study or in the past. The age range of the normal children was 7.9 - 16.8 with a mean age of 12.0 (sd = 2.8). The mean full-scale IQ of the control group was 115 (sd = 11).

Procedures

All subjects completed MRI scam performed on a 1.5 Tesla Sigoa magnetic resonance scanner (GE Medical Systems, Milwaukee, WI) using a coronal SPGR (spoiled grass) sequence of 42/5/l or 43/6/l (repetition time/echo time/excitations).

A slice thickness of 1.4 mm, flip angle = 35, and matrix 256 x 192 were used in all

scans.

The image data were digitally transformed into the Talaimch coordinate system (Talairach et al., 1967) using the anterior and posterior commissures as the center of origin, then resliced into 1 mm sections. One rater, blind to the diagnosis of the children, outlined the vermis of the cerebellum on the most midsagittal slice using a clear separation of the lingula from the medullary vehun as one of the intravennian landmarks. Manual tracing of the vermis was subdivided into three regions: lobules I-V (lingula, centralis, and culmen), lobules VI-VII (declive, folium, and tuber), and VIII-X (pyramis, uvula, and nodulus). Inferior boundaries of vermian lobules I-V and VIVII were defined by using a straight line from the most posterior aspect of the fourth ventricle to the primary and prepyramidal fissures respectively. Lobules VIII-X constituted the remaining portion of the vermis. Six redrawings of the brain of one subject revealed excellent it&a-rater reliability with a coefficient of variation of 1.2%.

Statistical

Analysis

Data analysis was performed with analysis of variance (ANOVA) using cerebellar vermis area of lobules I-V, VI-VII and VIII-X as the dependent variables and group (normal vs. autistic) as the between groups variable. Additionally, effect size was calculated as an indication of the magnitude of the differences found by ANOVA. Two analyses of covariauce (ANCOVA) were run, one using IQ as the covariate, the other using age as the covariate.

J.G. Levitt et al.

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ANOVA revealed a significant difference in the area of vermis lobules VIII-X (F (1, 28) = 9.26, p = ,005) with the normal group having a significantly larger area of lobules VIII-X than the autistic group. There were no statistically significant differences between groups in area of lobules I-V or VI-VII (Table 1). The effect size (d = 1.13) revealed a discrepancy between the values of the two means that was greater than one standard deviation. Figure 1 shows the shape analysis averages of autistic and normal groups.

Table 1

Sample Characteristics and Cerebellar Vermis Lobules VIII-X Area Measure

Group

n

Range(-‘I

Mean (mm’)

Mean Age

Normals

21

218.6 - 352.9

281.8 +31.7

12.0 f 2.8

164.6 - 298.9

234.0 f 51.5

12.5 f 2.2

Autistics

3nly 19 IQ

-

easu ments were availa le for the normal group

1Mean IQ*

I

114.9 Zk11

Fig 1. Shape analyses of autistic and normal subject groups.

83.3 + 11.9

Cerebellar vermis lobules VIII-X in autism

629

ANCOVA illustrated by Figure 2 showed IQ to be a significant covariate (F&26)=8.63, p=O.O07),with the difference between autistic and normal groups no longer significant. Age was not a statistically significant covariate (F( 1,28)=3.54, p=O.O7).

Autidic vs. Normal InferiorPosteriorCembellumArea

A AN

65

NNNANN

A

NNNNN N N

N

N

N NN

AN

88

108

114

121

127

IQ

Fig 2. Cerebellar ama versus IQ for autistic and normal subject groups.

In this pilot study of autistic children and normal controls, the authors found a significant decrease in the crosssectional area of cerebellar vermis lobules VIII-X in the autistic group when compared to the normal children. We did not replicate previous findings by Courchesne et al. (1988, 1994) and Murakami et al. (1989) of cerebellar hypoplasia or hyperplasia in vermis lobules VI-VII. Although our effect size of 1.13 was quite large, the analysis of covariance of IQ and vcrmis area revealed a significant confounding effect of IQ upon the results. These results are similar to those of Piven et al. (1992, 1997) and Filipek et al (1995) demonstrating a strong association between IQ and the area of cerebellar vermis lobules VI-VII across several studies of autistic subjects and normal controls.

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There is a growing body of data that indicates that the cerebellum is involved in cognitive function (BrackeTolkmitt et al., 1989; Petersen et al., 1989; Fiez et al., 1992). In a 1989 positron emission tomography (PET) study, Petersen et al. (1989) found increased activation in the right lateral cerebellum when subjects performed a verb generation task. Fiez et al. (1992) found a significant deficit in error detection and practice-related learning in a subject with right cerebellar damage and suggested that the cerebellum may be essential for aspects of learning which involve non-hippocampal memory circuits. Studies of episodic memory indicate that the cerebellum may participate in the pathways involved in the retrieval of personally experienced events (Nyberg et al., 1996; Tulving et al., 1997). There is also growing evidence for cerebellar (dentate nucleus) involvement in sensory discrimination and acquisition (Gao et al., 1996).

Vermal hypoplasia is not unique to the autistic syndrome (Ciesielski and Knight, 1994) and has been associated with deficits in visual-spatial-motor coordination and memory tests in children treated for acute lymphoblastic leukemia (Ciesielski et al., 1994). Therefore, damage to the cerebellum may affect IQ, sensory functioning and memory, all of which may contribute to symptoms seen in autism. However, findings of abnormalities in a variety of other brain areas in autistic subjects (Bauman and Kemperl995; Minshew et al., 1993; Piven et al., 1990,1995, 1996), strongly suggest that the etiology of autism is not localized to any one brain area.

The findings of Kates et al. (1998) and Mazzucco et al. (1997) suggest an association between cerebellar hypoplasia and autistic symptoms, and possibly with specific symptoms such as stereotypies and other repetitive behaviors. In this pilot study, it was not possible to examine the association of vermal area with repetitive behaviors and stereotypies because of the small number of subjects. Further studies of large samples of highfunctioning autistic subjects with ratings for symptom domains may contribute to a greater understanding of this issue. We are currently pursuing this line of research in a larger group of high-functioning autistic subjects and normal controls.

In this pilot study, we found a significant difference in the size of cerebellar vermis lobules VIII-X between autistic subjects and normal control subjects. The analysis of covariance demonstrated a confounding effect of IQ upon these results. These findings, although preliminary, support those of other studies suggesting that IQ might play a role in the association between autism and vermal hypoplasia.

AMERICAN PSYCHIATRIC ASSOCIATION (1994) Diagnostic and Statistical Manual of Mental Disorders, 4th ed. American Psychiatric Association, Washington DC, pp 886.

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Inquiries and reprint requests should be addressed to:

Jennifer Levitt, M.D., Department of Psychiatry and Biobehavioral Sciences UCLA School of Medicine 760 Westwood Plaza NPI 47 - 4 17 Los Angeles, CA 90024, USA