BRAIN ANATOMY and SENSORIMOTOR GATING in ASPERGER’S SYNDROME
Brain, Volume 125, Issue 7, July 2002, Pages 1594–1606
Abstract
The neurobiological basis of Asperger’s syndrome is poorly understood.
There are few studies on brain anatomy of Asperger’s syndrome, and no focal anatomical abnormality has been reliably reported from brain imaging studies of autism. Limbic circuits are important in sensorimotor gating, and impaired ‘gating’ may partly explain the failure of people with autistic disorders to inhibit repetitive thoughts and actions.
Thus, we compared brain anatomy and sensorimotor gating in healthy people with Asperger’s syndrome and controls. We included 21 adults with Asperger’s syndrome and 24 controls. All had normal IQ and were aged 18–49 years.
We studied brain anatomy using quantitative MRI, and sensorimotor gating using prepulse inhibition of startle in a subset of 12 individuals with Asperger’s syndrome and 14 controls.
We found significant age‐related differences in the volume of cerebral hemispheres and caudate nuclei (controls, but not people with Asperger’s syndrome, had age‐related reductions in volume).
Also, people with Asperger’s syndrome had significantly less grey matter in fronto‐striatal and cerebellar regions than controls and widespread differences in white matter. Sensorimotor gating was significantly impaired in Asperger’s syndrome. They have generalized alterations in brain development.
We hypothesize that Asperger’s syndrome is associated with abnormalities in frontostriatal pathways resulting in defective sensorimotor gating, and consequently, characteristic difficulties inhibiting repetitive thoughts, speech and actions.
Individuals with classical autism have delayed language development, and most have mental retardation (learning disability). Individuals with Asperger’s syndrome have no history of language delay and have normal or superior intellectual abilities, but still show characteristic impairments in reciprocal social interaction. Thus, in Asperger’s syndrome there is dissociation between cognitive and social skills. However, the neurobiological determinants of the behavioural phenotype of Asperger’s syndrome are poorly understood.
The limbic circuitry, proposed by some as the biological substrate of autism, plays an important role in sensorimotor gating. We use this mechanism to supress motor responses to irrelevant stimuli, and it is possible that similar processes underlie cognitive gating. A measure of sensorimotor gating is prepulse inhibition of startle (PPI), in which the startle response to a strong stimulus is muted or inhibited when momentarily preceded by a weak stimulus (the prepulse). We hypothesized that people with an autistic spectrum disorder may have defective sensorimotor gating, reflecting their characteristic inability to inhibit or ‘gate’ repetitive thoughts, speech and actions. However, to date, there have been no studies using PPI in adults with Asperger’s syndrome.
Thus there is evidence that people with an autistic spectrum disorder may have abnormalities in brain anatomy, including regions responsible for sensorimotor gating. However, there are relatively few studies of healthy, non‐learning disabled people who lie on this spectrum. We therefore used quantitative MRI in what we believe to be the first comprehensive study of brain anatomy in unmedicated, intellectually able adults with Asperger’s syndrome and healthy controls of comparable age, IQ, gender and handedness. We also carried out a pilot study of sensorimotor gating using PPI. We hypothesized that people with Asperger’s syndrome would have differences in the anatomy and function of limbic circuitry.
Discussion
We believe that this is the first study to quantify MRI differences in both regional brain volumes and grey and white matter volumes in Asperger’s syndrome, and to investigate age related differences in these parameters. Similar to others (Courchesne et al., 1999), we found that megaloencephaly is not a universal feature of autistic spectrum disorders, and we detected no bulk regional brain volume differences between Asperger’s syndrome and controls using manual tracing. Past reports of megaloencephaly in autism (Bailey et al., 1998) may therefore reflect an effect of disease severity (e.g. mental retardation) that is not evident in the Asperger’s sample we studied. We also found that age‐related differences in whole brain and grey matter volume in the controls were not evident in people with Asperger’s syndrome. The reason for this is unknown, but may include neurodevelopmental differences in neurogenesis and programmed cell death.
Our main findings were that people with Asperger’s syndrome had significant reductions in grey matter volume of frontostriatal and cerebellar regions. In addition, people with Asperger’s syndrome had white matter excesses bilaterally around the basal ganglia, whereas they had deficits mainly in left hemisphere. The concentration of abnormalities in frontostriatal circuitry we observed most likely has functional consequences. PPI is thought to depend in part on intact fronto‐striatal pathways, and we report for the first time a significant impairment in sensorimotor gating in Asperger’s syndrome.
Fronto‐striatal systems in Asperger’s syndrome
Our finding of reduced grey matter in the medial frontal lobe of people with Asperger’s syndrome is in agreement with other neuroanatomical studies of autism (Haznedar et al., 1997; Abell et al., 1999). In contrast, a recent MRI study of basal ganglia size in autism found that volume of the caudate nucleus was increased in subjects with autism and this increase was proportional to an increase in total brain volume (Sears et al., 1999). However, we observed a reduction in grey matter in the basal ganglia in people with Asperger’s syndrome and no increase in caudate or whole brain volume. Important differences between our studies may explain these disparate findings. The Sears et al. (1999) study included children and adults with performance IQs ranging from 52 to 136; the control group had IQs >70. We only studied adults with an IQ >75, and we also identified significant age‐related differences in brain anatomy between people with Asperger’s and controls. Thus our results may differ due to the specific population we studied, in addition to confounds introduced by age and IQ.
Frontal and striatal brain regions are reciprocally connected to each other and the thalamus proposed that dysfunction in a system incorporating the basal ganglia and mesial frontal lobe is responsible for the clinical symptoms of autism, including motor disturbances such as dystonia, bradykinesia and hyperkinesias, and impaired social communication. Their model also predicted temporal lobe abnormalities in autism. Although we did not identify grey matter deficits in the temporal lobe at the level of significance we adopted, we did observe extensive white matter deficits in left temporal lobe. Ours is the first study to report abnormalities in anatomy of this entire neural system in people with an autistic spectrum disorder, and we suggest that our anatomical findings are consistent with Damasio and Maurer’s model.
The fronto‐striatal regions we identified as abnormal are known to have intimate and reciprocal links with cerebellum, and the cerebellum has been implicated in higher order cognitive functions, including executive functions such as planning and shifting attention. Thus, the anomalies we found within the cerebellum, a region anatomically and functionally related to the basal ganglia and frontal cortex, are not surprising. Our study therefore lends tentative support for the hypothesis that abnormalities in the cerebellum may be related to the behavioural phenotype of people with an autistic spectrum disorder, but in our view cerebellar pathology may best be viewed in the context of system‐wide pathology, rather than in isolation.
Sensorimotor gating in Asperger’s syndrome
There is consensus that alterations in fronto‐striatal regions (as found in our study of people with Asperger’s syndrome) underlie impaired sensorimotor gating in a range of neuropsychiatric conditions such as obsessive compulsive disorder, Huntington’s disease Tourette’s syndrome, and schizophrenia spectrum disorders. The argument is perhaps most persuasive for Huntington’s disease, as this is associated with significant damage to caudate nucleus. Recent functional imaging data support this position, with activation in prefrontal cortex and caudate nuclei being observed during PPI in healthy individuals. We suggest that the reduction in grey matter volume of fronto‐striatal regions we identified in people with Asperger’s may also explain our finding of impaired PPI in this group. Our findings are unlikely to be explained by differences in schizotypal traits, as the control and Asperger’s groups were comparable in this regard.
A previous study of sensorimotor gating in autism (Ornitz et al., 1993) reported no consistent significant differences between diverse groups with autism (comprising adults and children aged 2.8–33 years, IQ 40–145, and some with major medical co‐morbidity) as compared with an intellectually normal healthy control group. In contrast, we explored PPI in a population of intellectually able, healthy, adult men with Asperger’s and found significant impairment of PPI in the 120 ms/16 db condition. Again, we may find differences where others do not due to differences in our study populations.
The occurrence of sensorimotor gating abnormalities in a number of disorders, as noted above, could simply mean that PPI is a task sensitive to fronto‐striatal damage, but differences may not be specific to Asperger’s syndrome. However, sensorimotor gating deficits in autism may reflect similar difficulties with cognitive gating, rendering the individual unable to inhibit or ‘gate’ the repetitive thoughts, speech and actions characteristic of the disorder. The subsequent information ‘overload’ may lead to higher cognitive difficulties, such as executive function and ‘theory of mind’ (ToM) abnormalities, reported by others in autism. ToM and executive function accounts of autism together explain quite well the socio‐communicative and flexibility problems in this disorder. However, neither account can explain why people with autism are so good at certain tasks. Autism presents a strikingly uneven cognitive profile, with typical peaks on Wechsler block design and digit span. One theoretical account of autism attempts to explain these skills in terms of a bias towards featural versus configural processing. This cognitive style of ‘weak central coherence’ is demonstrated through success of individuals with autism on tasks favouring detail focus, and relative inability on tasks requiring processing of information in context for global form or meaning. Impaired sensorimotor gating permits stimuli indiscriminate access to response output systems without regard for the context of presentation. This is reflected in reduced PPI: the startle response to a given stimulus is not modulated by preceding stimuli. Conceivably, the stimulus which elicits inappropriate startle has been subject to a form of featural processing. We therefore suggest that abnormal gating may contribute to the physiological basis of weak central coherence in autistic spectrum disorders.
White matter deficits and excesses in Asperger’s syndrome
We found widespread white matter anomalies in the brain of people with Asperger’s syndrome; indeed white matter projections to and from abnormal grey matter structures might be expected to be deviant. However, while white matter excesses were distributed bilaterally, deficits appeared to be more prominent in the left hemisphere. This hemisphere normally develops later than the right and, perhaps as a consequence of evolving speech pathways, fronto‐temporal pathways reach maturation later than those linking lower order regions. Thus neuro‐developmental delay in autism may particularly impact on the left hemisphere and consequently explain some of the developmental language anomalies found in the disorder. For example, we found significant fronto‐temporal white matter deficits in people with Asperger’s syndrome, including the left superior temporal lobe speech area [Brodmann area (BA 22)].
Courchesne et al. (2001) recently investigated developmental changes in grey and white matter volume in autistic boys. They noted that expanded white matter volumes in 2–3 year old children with autism were not found in adolescents with autism. In conjunction with the present findings, this suggests that the autistic brain matures differently, and has a complex and anomalous trajectory affecting both brain development and aging. Courchesne’s group of autistic children had IQs ranging from 36 to 122, while the control group had IQs in the normal range, so it is unclear to what extent the presence of learning disability impacted on their results. Clearly the question of structural brain changes throughout the lifespan of autistic individuals deserves further investigation in well‐matched groups.
Conclusions
We found that, compared with controls, people with Asperger’s syndrome have age‐related differences in brain anatomy, structural abnormalities in fronto‐striatal systems and the cerebellum, and impaired sensorimotor gating. We suggest that Asperger’s syndrome probably arises from a generalized abnormality in brain development (causing widespread white matter abnormalities). This neurodevelopmental abnormality may, in turn, be modulated by environmental factors such as social isolation. Some regions are more affected than others, and our findings support the hypothesis that a proportion of autistic symptomatology may be explained by frontostriatal disorder. Further studies are required to examine changes in brain anatomy and function across the lifespan, and to explore their relationship to the behavioural phenotype in people with Asperger’s syndrome.
