Alan J. Lincoln

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.

Impairment in shifting attention in autistic and cerebellar patients

MRI and autopsy evidence of early maldevelopment of cerebellar vermis and hemispheres in autism raise the question of how cerebellar maldevelopment contributes to the cognitive and social deficits characteristic of autism. Compared with normal controls, autistic patients and patients with acquired cerebellar lesions were similarly impaired in a task requiring rapid and accurate shifts of attention between auditory and visual stimuli. Neurophysiologic and behavioral evidence rules out motor dysfunction as the cause of this deficit. These findings are consistent with the proposal that in autism cerebellar maldevelopment may contribute to an inability to execute rapid attention shifts, which in turn undermines social and cognitive development, and also with the proposal that the human cerebellum is involved in the coordination of rapid attention shifts in a fashion analogous to its role in the coordination of movement.

Evidence of linkage between the serotonin transporter and autistic disorder

The serotonin transporter gene (HTT) is a primary candidate in autistic disorder based on efficacy of potent serotonin transporter inhibitors in reducing rituals and routines. We initiated a candidate gene study of HTT in trios consisting of probands with autistic disorder and both parents. Preliminary transmission/disequilibrium test (TDT) analysis with 86 families revealed no evidence for linkage or linkage disequilibrium between autistic disorder and a polymorphism in the second intron of HTT. However, preferential transmission of a short variant of the HTT promoter was found in the same 86 trios (TDT χ2 = 4.69, 1 d.f., P = 0.030). In further analyses, we considered haplotypes of the HTT promoter variant and second intron locus as alleles in a multiallelic TDT. Results confirmed the significance of the effect of this region (TDT χ2 = 11.85, 4 d.f., P = 0.018). This provides preliminary evidence of linkage and association between HTT and autistic disorder.

II. Hypersociability in Williams Syndrome

Studies of abnormal populations provide a rare opportunity for examining relationships between cognition, genotype and brain neurobiology, permitting comparisons across these different levels of analysis. In our studies, we investigate individuals with a rare, genetically based disorder called Williams syndrome (WMS) to draw links among these levels. A critical component of such a cross-domain undertaking is the clear delineation of the phenotype of the disorder in question. Of special interest in this paper is a relatively unexplored unusual social phenotype in WMS that includes an overfriendly and engaging personality. Four studies measuring distinct aspects of hypersocial behavior in WMS are presented, each probing specific aspects in WMS infants, toddlers, school age children, and adults. The abnormal profile of excessively social behavior represents an important component of the phenotype that may distinguish WMS from other developmental disorders. Furthermore, the studies show that the profile is observed across a wide range of ages, and emerges consistently across multiple experimental paradigms. These studies of hypersocial behavior in WMS promise to provide the ground-work for crossdisciplinary analyses of gene-brain-behavior relationships.

Linkage-Disequilibrium Mapping of Autistic Disorder, with 15q11-13 Markers

Autistic disorder is a complex genetic disease. Because of previous reports of individuals with autistic disorder with duplications of the Prader-Willi/Angelman syndrome critical region, we screened several markers across the 15q11-13 region, for linkage disequilibrium. One hundred forty families, consisting predominantly of a child with autistic disorder and both parents, were studied. Genotyping was performed by use of multiplex PCR and capillary electrophoresis. Two children were identified who had interstitial chromosome 15 duplications and were excluded from further linkage-disequilibrium analysis. Use of the multiallelic transmission-disequilibrium test (MTDT), for nine loci on 15q11-13, revealed linkage disequilibrium between autistic disorder and a marker in the gamma-aminobutyric acidA receptor subunit gene, GABRB3 155CA-2 (MTDT 28.63, 10 df, P=.0014). No evidence was found for parent-of-origin effects on allelic transmission. The convergence of GABRB3 as a positional and functional candidate along with the linkage-disequilibrium data suggests the need for further investigation of the role of GABRB3 or adjacent genes in autistic disorder.

Sensorimotor gating deficits in adults with autism.

BACKGROUND Prepulse inhibition (PPI) is an operational measure of sensorimotor gating and is impaired in a family of neuropsychiatric disorders characterized by abnormalities of inhibitory function. Adults with autistic disorder (AD) exhibit clinical features of inhibitory deficits, such as restrictive and repetitive behaviors, that may be explained by deficits in sensorimotor gating. METHODS Acoustic startle reactivity, habituation, and PPI (30-, 60-, 120-msec interstimulus intervals) were assessed in 14 adult men diagnosed with AD and 16 typically developing normal comparison (NC) participants. All participants were administered measures of intelligence and frontal-executive functioning. RESULTS Adults with AD exhibited significantly less PPI in the 60-msec condition than NC participants, which was correlated with increased ratings of restricted and repetitive behaviors. The groups did not differ on measures of startle amplitude or overall habituation. There was, however, a significant group-by-block habituation effect. Furthermore, PPI was not related to intelligence but was moderately associated with performance on a measure of frontal-executive functioning. CONCLUSIONS Adults with AD have sensorimotor gating deficits similar to other neurodevelopmental disorders, implicating a failure of normal inhibitory regulation of sensory, motor, and attentional mechanisms. Thus, PPI deficits may be indirectly linked to one of the hallmark features of AD.

Event-related brain potential correlates of the processing of novel visual and auditory information in autism

Event-related brain potentials (ERPs) elicited by visual and auditory stimuli were recorded from nonretarded individuals with autism (ages 13–25 years) and age-matched normal controls. In “no-task” conditions, subjects simply looked at or listened to these stimuli; only one difference was found between subject groups. Several ERP differences between groups were found in “task” conditions; subjects pressed a button at the occurrence of target stimuli intermixed with unexpected, novel stimuli and also with expected, nonnovel stimuli. Visual ERP abnormalities in the autistic group differed from auditory abnormalities. Results suggest that (1) nonretarded autistic individuals may have a limited capacity to process novel information — they are neither hypersensitive to novel information nor misperceive it as non-novel and insignificant; (2) classification of simple visual information may be less impaired than auditory; and (3) with one exception, visual and auditory ERP abnormalities do not seem to reflect maturational delay.

Cross‐sectional area of the posterior hippocampus in autistic patients with cerebellar and corpus callosum abnormalitiGs

Article abstract—Using MRI methods previously shown to optimize visualization of cytoarchitectonic details in the body of the hippocampal formation caudal to the pes hippocampi, we imaged and quantified the hippocampus proper including the subiculum and the dentate gyrus in 33 autistic patients between the ages of 6 and 42 years and in 23 age-matched normal healthy volunteers. Measures of these structures in autistic patients and normal healthy volunteers differed nonsignificantly, by less than 1.4%, regardless of whether or not the autistic patients were retarded or had a history of seizure episodes. By contrast, measures of vermian lobules VI and VII and the posterior portion of the corpus callosum in these same autistic and normal volunteers differed significantly, by more than 9.9%. The lack of a significant difference in the cross-sectional size of the posterior hippocampal formation between autistic and normal 6–to 42–year-olds is discrepant with predictions based on some, but not all, autopsy studies. This suggests that there is a need for additional quantitative autopsy study of the hippocampal formation and quantitative MRI study of rostral hippocampal regions that we did not explore in the present report. Also, quantitative autopsy and MRI studies have yet to examine hippocampal development in autistic patients younger than 6 years of age; whether early stages of growth are normal or not is unknown.

Pathophysiologic findings in nonretarded autism and receptive developmental language disorder.

In nonretarded autistic, receptive developmental language disordered, and normal subject groups, we recorded in auditory and visual target detection tasks two neurophysiological components of the event-related brain potential, Nc and P3b. Existent research shows that, in normals, Nc and P3b appear early in development, are associated with attention and memory processes, and are endogenous which means that they are triggered by internal, consciously initiated attentional and cognitive mechanisms and that they can be triggered even by theomission of sensory stimulation so long as it has meaning or importance for the subject. In this report, Nc and P3b were recorded in response to auditory and visual stimulation and to the omission of auditory and visual stimulation. Consistent with the hypothesis that nonretarded autism involves abnormal attentional and cognitive responses to important information, P3b was found to be smaller than normal and Nc was small and often absent in the nonretarded autistic group even under the condition when no auditory language or sensory processing was required. Receptive developmental language disorder has been linked with difficulties in processing sequences of auditory stimuli, and in this study P3b was found to be somewhat enlarged in this group even under the conditions when P3b was elicited by stimuli separated by 1 sec and also when P3b was elicited by the omission of stimulation.

Psychological Adjustment and Treatment of Children and Families With Parents Deployed in Military Combat

The effects of the military deployment of parent-soldiers on children and families need to be understood in the context of military culture as well as from developmental risk for maladjustment. Although research addressing such effects is limited in both scope and certainty, we can identify several key factors that relate to psychological risk, adjustment, and outcome. Most children are resilient to the effects of deployment of at least one of their parents, but children with preexisting psychological conditions, such as anxiety and depression, may be particularly vulnerable, as well as children with specific risk factors, such as child abuse, family violence, or parental substance abuse. A series of case vignettes illustrate the psychological adjustment and treatment implications for children with parents deployed in support of military combat operations.