Maurizio Elia, Raffaele Ferri, Sebastiano A. Musumeci, Simonetta Paneral', Maria Bottitta, Carínela Scuderi, Stefano Del Gracco, Maria C. Stefanini
Department of Neurology and 'Psychology, Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), Troina, Italy
Running Title: Brain morphometry and autism
Key Words: Autism, IM, Psychoeducational Profile Revised, Childhood Autism Rating Scale, Nfldbrain, Corpus Callosum
Introduction
In the last two decades neurological research has significantly contributed to increase the knowledge on the neuroanatomic bases of autism. Several autopsy and quantitative magnetic resonance imaging ~) studies have reported central nervous system (CNS) abnormalities which may underlie the social, language and cognitive dysfunction typical of the autistic disorder [Bauman, 1991; Courchesne, 1991]. In particular, neuropathological abnonnalities of the cerebellum (loss of Purkinje and granule cells in both vermis and heniispheres) were found in 15 autistic subjects [Williams et al., 1980; Bauman and Kemper, 1985, 1986, 1990; Ritvo et al., 1986; Bauman, 1991; Arin et al., 199 11 and in vivo evidence of hypoplasia, mainly affecting the vermian lobules VI and VII in more than 200 patients with autism [Gaffney et al., 1987b; Courchesne et al., 1988; Murakami et al., 1989; Courchesne, 1991; Ciesielski and Knight., 1994; Piven et al., 1992; Kleiman et al., 1992; Courchesne et al., 1994a, b; Hashimoto et al., 1995; Courchesne et al., 1995; Saitoh et al., 1995].
However, the cerebellum probably is not the only site of the brain to be impaired in autism because other anatomic studies have shown abnormalities of the brainstem [Gaffhey et al., 1988; Hashimoto et al., 1988; Bauman, 1991; Hashimoto et al., 19951, of the posterior portion of the corpus callosum, and of the parietal lobes (Saitoh et al., 1995).
Despite the great amount of evidence that the 'autistic brain' is different from normal in a number of structures, the relationship between the severity of the developmental impairrnent in autism and the degree of the brain abnormality remains unknown. Moreover, it should be also considered that other authors have failed to demonstrate euroanatomic differences between autistic and normal subjects [Garber et al., 1989; Hsu et al., 1991; Garber and Ritvo, 1992; Kleiman et al., 1992; Holttum et al., 1992; Piven et al., 1992]. If there exists a causative correlation between the neuroradiological and the clinical characteíistics of autism, one rnight expect to find different degrees of clinical expression of autism as consequence of different degrees of neuroanatomic involvement.
The aim of the present study is to correlate the areas of some brain regions, as calculated on the basis of @ morphometry, with the Childhood Autism Rating Scale (CARS) and with the Psychoeducational Profile Revised (PEP-R ) scores in a group of 22 autistic mentally retarded male subjects.
Subjects and Methods
Twenty-two male subjects (age range 4.67-16.58 years, mean age 10.92 years, SD 4.017), all affected by autistic disorder, according to the DSM-IV (American Psychiatric Association, 1994) criteria, and by mental retardation, were admitted to this study.
Sixteen patients were right-handed, 1 was left-handed, 5 were mixed-handed. None of the patients presentes seizures, paroxysmal EEG abnormalities during wakefulness or sleep, neurological focal signs or symptoms, or other medical conditions associated with autism. Eight subjects were taking neuroleptics during the study.
Brain @ scans were obtained on all the 22 subjects, and qualitatively evaluated by one investigator (M.E.). None of the patients presentes major structural abnormalities on @. The @ scans were obtained from a 0.5 Tesla superconducting magnet, Philips Gyroscan MR. A multisection spin-echo sequence (proton density, TR 1850 msec, TE 30 msec and T2-weighted, TR 1850 msec, TE 90 msec) was performed in the axial and coronas planes, and a multisection Tiweighted sequence (TR 520 msec, TE 30 msec) in the sagittal plane centered at the @dune. The section thickness was 5 mm, with a gap of 1 mm between adjacent sections. The midsagittal image was identified as the image including the cerebral aqueduct, the foramen of Magendie, the apex of the 4th ventricle, and the infundibulum. Scans were recorded on trasparent film together with a calibration bar. The irnages were then stored on a bitmap computer file (.TIF) by means of a scanner. Measurement of the area of the cerebrum, corpus callosum, midbrain, pons, cerebellar vermis, and vermal lobules VI-VI[[ was done by computer-aided design software. The investigator who quantified the areas (R.F.) was blind to clinical characteristics of the subjects.
The boundaries of the different structures are shown in Fig. 1. The cerebrum comprised the medias surface of the right hen-fisphere, excluding the corpus callosum. The corpus callosum was entirely measured. The n-údbrain included the collicula and was bounded by the thalamus and the mammillary body rostrally and by a line joining the superior pontine notch to the aqueduct caudally. The pons was bounded by the midbrain rostrally, and by a line going from the inferior pontine notch to the 4th ventricle.
Total vermal area was measured (lobules I-IX). The boundary between the lobules I-V and lobules VI and VII was defined as the line joining the anterior aspect of the primary fissure to the 4th ventricle. Lobules VIII and IX were bounded by a line joining the anterior aspect of the prepyranudal fissure rostrally. The patients were assessed by an expert psychologist (S.P.) by means of the CARS [Schopler et al., 19801 and the PEP-R [Schopler et al, 1990]. Only the total score of the CARS was taken into account. Only the developmental subscales of PEP-R were considered, items were scored as successful (PEP-S) emerging (PEP-E), or failing (PEP-F), and summed up in subscale and total scores. A multiple regression analysis was then performed between morphometric measures and psychologicavbehavioral scores.
Results
Table 1 shows the mean values of age and of the different scores obtained at CARS and PEPR testing in the whole group of autistic patients. A low average developmental age (19.95 months) was obtained from the items scored as passing (PEP-S); a mean developmental age of approximately 27.14 months was found when also items scored as emerging were considered (PEP-S + PEP-E).
Table 2 shows the mean values of the areas of the different structures measured in the 22 autistic patients.
Tables 3 and 4 illustrate the correlation coefficients and statistical significance between morphometric findings and CARS and PEP-R scores.
The area of the cerebrum was significantly negatively correlated with chronological age, while corpus callosum showed a positive correlation. A direct significant correlation was found between midbrain and number of successfully performed PEP-R tasks (PEP-S), with the mental age obtained from the PEP-S and from the PEP-S + PEP-E. On the contrary, a negative correlation was found between the midbrain area and the number of unsuccessfully perforined PEP-R items (PEP-F). When the single developmental subscales were considered separately (Tab. 4), a significant positive correlation of the corpus callosum with irnitation and verbal tasks. lvfldbrain significantly correlated with all the subscales. The areas of cerebrum, cerebellar vermis in toto, VI-VH lobules, pons did not significantly correlate with CARS and PEP-R scores.
Discussion
The subjects included in this study were all male low-functioning autistic patients (Tab. l), free from other medical conditions such as seizures, neurological diseases or malforrnative syndromes. This makes our group of autistic subjects more homogeneous than the groups previously examined by other authors [Gaffney et al., 1987a; Gaffhey et al., 1988; Hashimoto et al., 1988; Garber et al., 1989; Murakami et al., 1989; Hsu et al., 1991; Kleiman et al., 1992; Saitoh et al., 1995; Hashimoto et al., 1995] in which male and female high-and low- functioning -subjects, in different proportions, were included; additionally, in the same studies other clinical conditions were reported associated with autism such as seizures of different type [Gaffney et al., 1987a, 1988; Garber et al., 1989; Kleiman et al., 1992; Saitoh et al., 19951, neurofibromatosis [Gaffney et al., 1987b, 1988], congenital cytomegalovirus infection [Garber et al., 19891, paroxysmal EEG abnormalities [Garber et al., 1989; Hashimoto et al., 1995].
In our group of subjects the midsagittal area of the cerebrum Recreases with increasing chronological age; this finding seems to indicate that regressive processes might be active in our group affecting brain volume.
On the other hand, corpus callosum area increases with chronological age similarly to the trend already observed in normal individuals in whom corpus callosum grows during childhood up to adulthood [Pujol et al., 1993].
Moreover, the area of corpus callosum is correlated with some specific PEP-R subscales such as imitation and verbal perfonnances. The corpus callosum interconnects homologous regions of the cortex and, therefore, is important in the transfer of information between high-level associative areas [Lassonde, 1985]. Transcallosal connections may be related to lateralized speech donúnance [O'Kusky et al., 19881 and play a role in lexical and semantic processing [Mohr et al., 1994; Gazzaniga et al., 1989]. Furthennore, the posterior part of the corpus callosum, where the parietal lobe fibers are known to project, has been found to be reduced in size in autistic subjects [Egaas et al., 1995].
Corpus callosum and parietal abnormalities in autism may contribute together with those of the midbrain to the deficits in specific attentional tasks in autism [Courchesne et al., 1995]. As directed attention and cross-modal associations are required for imitation, corpus callosum may be an important neuroanatonúc substrate for this task.
In our group of subjects, n-ddbrain is the structure which seems to be significantly correlated with PEP-R scores and consistently involved in aU the tasks, because its mean area correlates with all the PEP-R subscales. It is well-known that reticular fonnation is connected by different input/output pathways with the rostral and the caudal regions of the neuraxis [Role and Kelly, 1991]. The cholinergic pedunculopontine tegmental nucleus, partially located in the midbrain, is also involved in some aspects of behavior such as motivation, mnemonic and learning processes [Steckler et al., 1994) which are disrupted in autism. The reticular formation plays a critical role in consciousness and in the integration of acoustic, visual and other sensory perceptions (Omitz, 1983); this supports the hypothesis that midbrain is involved together with other sites of an interconnected network which modulases directed attention, a function which is disturbed in autism [Omitz, 1988). Moreover, núdbrain dopaminergic cell groups as substancia nigra, ventral tegmental area, and retrorubral nucleus connected with the neostriatum and mesocortex, have been suggested to be implicated in some autistic manifestations such as disturbances of motility, communication, attention and perception, and ritualistic and compulsivo behaviors [Damasio and Maurer, 1978].
In conclusion, even if a morphometric intra-group analysis is unable to provide information on the underlying neuropathologic alterations, our study clearly demonstrates that two different CNS structures, midbrain and corpus callosum, correlate with the results of psychological and behavioral tests. It is important underline that this is the first study which statistically evaluates the correlation between morphometric and psychological/behavioral data. Although the aim of this approach is ambitious and needs to be confirmed by other studies, our results are promising and deserve further insights.
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Corresponding Author:
Maurizio Elia, MD. Dept. of Neurology. OASI Institute. Via Conte Ruggero, 73 94018 Troina (Italy) tel +39-935-936111 fax + 39-935-653327