Ruth A. Carper

Unusual brain growth patterns in early life in patients with autistic disorder An MRI study

Objective: To quantify developmental abnormalities in cerebral and cerebellar volume in autism. Methods: The authors studied 60 autistic and 52 normal boys (age, 2 to 16 years) using MRI. Thirty autistic boys were diagnosed and scanned when 5 years or older. The other 30 were scanned when 2 through 4 years of age and then diagnosed with autism at least 2.5 years later, at an age when the diagnosis of autism is more reliable. Results: Neonatal head circumferences from clinical records were available for 14 of 15 autistic 2- to 5-year-olds and, on average, were normal (35.1 ± 1.3 cm versus clinical norms: 34.6 ± 1.6 cm), indicative of normal overall brain volume at birth; one measure was above the 95th percentile. By ages 2 to 4 years, 90% of autistic boys had a brain volume larger than normal average, and 37% met criteria for developmental macrencephaly. Autistic 2- to 3-year-olds had more cerebral (18%) and cerebellar (39%) white matter, and more cerebral cortical gray matter (12%) than normal, whereas older autistic children and adolescents did not have such enlarged gray and white matter volumes. In the cerebellum, autistic boys had less gray matter, smaller ratio of gray to white matter, and smaller vermis lobules VI–VII than normal controls. Conclusions: Abnormal regulation of brain growth in autism results in early overgrowth followed by abnormally slowed growth. Hyperplasia was present in cerebral gray matter and cerebral and cerebellar white matter in early life in patients with autism.

Autism and Abnormal Development of Brain Connectivity

It has been said that people with autism suffer from a lack of “central coherence,” the cognitive ability to bind together a jumble of separate features into a single, coherent object or concept ([Frith, 1989][1]). Ironically, the same can be said of the field of autism research, which all too

Cerebral Lobes in Autism: Early Hyperplasia and Abnormal Age Effects

Metabolic, functional, behavioral, and histologic studies suggest that the structure of the cerebrum may be abnormal in autism. In a previous cross-sectional study we found abnormal enlargement of cerebral cortex and cerebral white matter volumes in autistic 2- and 3-year-olds and abnormally slow rates of volume change across later ages. In the present study, we assessed whether these volume abnormalities are limited to particular cerebral regions or are pervasive throughout the cerebrum. We used magnetic resonance imaging (MRI) to quantify volumes of cerebral lobes (frontal, temporal, parietal, and occipital regions), using classic sulcal boundaries to define regions. We examined 38 boys with autism and 39 normal control boys between the ages of 2 and 11 years. Several regions showed signs of gray matter and white matter hyperplasia in 2- and 3-year-old patients (as much as 20% enlargement), but there appeared to be an anterior to posterior gradient in the degree of hyperplasia. The frontal lobe showed the greatest enlargement while the occipital lobe was not significantly different from normal. Gray and white matter differences were not found in the older children. By examining the relationships between regional volumes and subject age, we found that frontal, temporal, and parietal white matter volumes, as well as frontal and temporal gray matter volumes, changed at significantly slower rates in autism patients than in controls across the 2- to 11-year-age range. For example, frontal lobe white matter volume increased by about 45% from 2-4 years of age to 9-11.5 years, but by only 13% in autistic patients. Mechanisms that might account for early hyperplasia are discussed as they might relate to the regional differences in degree of abnormality. For instance, possible influences of neurotrophic factors, or of abnormal afferent activity from other affected brain regions are considered.

Longitudinal magnetic resonance imaging study of cortical development through early childhood in autism

Cross-sectional magnetic resonance imaging (MRI) studies have long hypothesized that the brain in children with autism undergoes an abnormal growth trajectory that includes a period of early overgrowth; however, this has never been confirmed by a longitudinal study. We performed the first longitudinal study of brain growth in toddlers at the time symptoms of autism are becoming clinically apparent using structural MRI scans at multiple time points beginning at 1.5 years up to 5 years of age. We collected 193 scans on 41 toddlers who received a confirmed diagnosis of autistic disorder at ∼48 months of age and 44 typically developing controls. By 2.5 years of age, both cerebral gray and white matter were significantly enlarged in toddlers with autistic disorder, with the most severe enlargement occurring in frontal, temporal, and cingulate cortices. In the longitudinal analyses, which we accounted for age and gender effect, we found that all regions (cerebral gray, cerebral white, frontal gray, temporal gray, cingulate gray, and parietal gray) except occipital gray developed at an abnormal growth rate in toddlers with autistic disorder that was mainly characterized by a quadratic age effect. Females with autistic disorder displayed a more pronounced abnormal growth profile in more brain regions than males with the disorder. Given that overgrowth clearly begins before 2 years of age, future longitudinal studies would benefit from inclusion of even younger populations as well as further characterization of genetic and other biomarkers to determine the underlying neuropathological processes causing the onset of autistic symptoms.

Localized enlargement of the frontal cortex in early autism

BACKGROUND Evidence from behavioral, imaging, and postmortem studies indicates that the frontal lobe, as well as other brain regions such as the cerebellum and limbic system, develops abnormally in children with autism. It is not yet clear to what extent the frontal lobe is affected; that is, whether all regions of frontal cortex show the same signs of structural maldevelopment. METHODS In the present study, we measured cortical volume in four subregions of the frontal cortex in 2-year-old to 9-year-old boys with autism and normal control boys. RESULTS The dorsolateral region showed a reduced age effect in patients when compared with control subjects, with a predicted 10% increase in volume from 2 years of age to 9 years of age compared with a predicted 48% increase for control subjects. In a separate analysis, dorsolateral and medial frontal regions were significantly enlarged in patients aged 2 to 5 years compared with control subjects of the same age, but the precentral gyrus and orbital cortex were not. CONCLUSIONS These data indicate regional variation in the degree of frontocortical overgrowth with a possible bias toward later developing or association areas. Possible mechanisms for these regional differences are discussed.

Neuroanatomic contributions to slowed orienting of attention in children with autism

Previous research has demonstrated that adult autistic patients are abnormally slow to orient attention, with degree of slowed orienting associated with severity of cerebellar hypoplasia. This research was extended to children who, at ages two through six, met diagnostic criteria for autism and underwent magnetic resonance imaging (MRI). An average of 3 years later, when old enough to participate in behavioral experiments, the children returned to the laboratory and completed a spatial attention paradigm. Degree of slowed attentional orienting to visual cues was significantly correlated with degree of cerebellar hypoplasia, but not with size of other neuroanatomic regions. Additionally, there was a trend for orienting speed to differ between diagnostic outcome subgroups; children with confirmed diagnoses of autism at time of behavioral testing had larger orienting deficits than those who no longer met diagnostic criteria for autism. This research is among the first to establish a specific brain-behavior link in autistic children.

Outcome Classification of Preschool Children With Autism Spectrum Disorders Using MRI Brain Measures

OBJECTIVE To test the hypothesis that a combination of magnetic resonance imaging (MRI) brain measures obtained during early childhood distinguish children with autism spectrum disorders (ASD) from typically developing children and is associated with functional outcome. METHOD Quantitative MRI technology was used to measure gray and white matter volumes (cerebrum and cerebellum), total brain volume, and the area of the cerebellar vermis in 52 boys with a provisional diagnosis of autism (aged 1.9-5.2 years) and 15 typically developing young children (aged 1.7-5.2 years). Diagnostic confirmation and cognitive outcome data were obtained after the children reached 5 years of age. RESULTS A discriminant function analysis of the MRI brain measures correctly classified 95.8% of the ASD cases and 92.3% of the control cases. This set of variables also correctly classified 85% of the ASD cases as lower functioning and 68% of the ASD cases as higher functioning. CONCLUSIONS These results indicate that variability in cerebellar and cerebral size is correlated with diagnostic and functional outcome in very young children with ASD.

Localizing Haloperidol Effects on Sensorimotor Gating in a Predictive Model of Antipsychotic Potency

The degree to which a startle response to a loud noise is inhibited by a weak prestimulus is an operational measure of sensorimotor gating. Prepulse inhibition (PPI) can be measured across species and is reduced in schizophrenia patients and dopamine (DA)-activated rats. The ability of DA antagonists to restore PPI in apomorphine (APO)-treated rats correlates highly with their clinical antipsychotic potency. We compared the ability of systemic- vs. intracerebrally (i.c.)-administered haloperidol (HAL) to restore PPI in APO-treated rats. Consistent with previous studies, systemic administration of HAL completely restored PPI in rats treated with APO (0.5 mg/kg s.c.), with an ED50 of approximately 0.02 mg/kg. In an otherwise identical paradigm, HAL failed to fully restore PPI after infusion into either the nucleus accumbens (NACcore or NACshell), NACcore + caudate nucleus (CN), ventral subiculum (VS), medial prefrontal cortex (MPFC), or ventral tegmentum (VTA). A subtotal, but statistically significant restoration of PPI was achieved after HAL infusion into all regions, except the NACshell. Statistically significant effects of i.c. HAL tended to be observed at doses that were only approximately 5-10-fold lower than those at which significant effects were observed after systemic administration. The results suggest that systemically administered HAL may restore PPI in APO-treated rats through its action distributed throughout multiple levels of PPI-regulatory circuitry.

Monozygotic twins with Asperger syndrome: differences in behaviour reflect variations in brain structure and function

A pair of monozygotic twins discordant for symptoms of Asperger syndrome was evaluated at the age of 13.45 years using psychometric, morphometric, behavioural, and functional imaging methods. The lower-functioning twin had a smaller brain overall, a smaller right cerebellum, and a disproportionately large left frontal lobe, and manifested almost no differential activation between distractors of high and low-congruence with target visual stimuli. The higher-functioning twin manifested a typically autistic pattern of anterior deactivation and posterior hyperactivation in response to incongruent distractors, overlaid with a typically normal pattern of activation of superior frontal cortex. The morphometric results are consistent with known correlations between brain structure and behaviour in autism, and the physiological results suggest correspondences between structure and function.

Neuroanatomical and neurophysiological clues to the nature of autism

Of all the developmental brain disorders, autism is perhaps the most fascinating, the most mysterious, and the most telling fascinating, because of its impact on absolutely every aspect of a child’s perception of and interaction with the surrounding world; mysterious, because of the complexity of the many interacting brain systems it perturbs; telling, because it strikes at the social, cognitive, and linguistic abilities that seem, at least on the surface, so essential to one’s very humanity. During the past few decades, the riddle of autism has begun to yield to advances in the study of autistic behaviour and the biological foundations which affect it. The examination of brain anatomy, physiology, histology and function in people with autism continues to supply new information on the nature and aetiology of this complex syndrome. This chapter will focus primarily on the neuroanatomical and neurophysiological abnormalities found in autistic subjects, particularly those seen in magnetic resonance imaging (MRI) and event-related potential (ERP) studies.