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Despite the impressive literature describing atypical neural activation in visuoperceptual face processing regions in autism, almost nothing is known about whether these perturbations extend to more affective regions in the circuitry and whether they bear any relationship to symptom severity or atypical behavior. Using fMRI, we compared face-, object-, and house-related activation in adolescent males with high-functioning autism (HFA) and typically developing (TD) matched controls. HFA adolescents exhibited hypo-activation throughout the core visuoperceptual regions, particularly in the right hemisphere, as well as in some of the affective/motivational face-processing regions, including the posterior cingulate cortex and right anterior temporal lobe. Conclusions about the relative hyper- or hypo-activation of the amygdala depended on the nature of the contrast that was used to define the activation. Individual differences in symptom severity predicted the magnitude of face activation, particularly in the right fusiform gyrus. Also, among the HFA adolescents, face recognition performance predicted the magnitude of face activation in the right anterior temporal lobe, a region that supports face individuation in TD adults. Our findings reveal a systematic relation between the magnitude of neural dysfunction, severity of autism symptoms, and variation in face recognition behavior in adolescents with autism. In so doing, we uncover brain-behavior relations that underlie one of the most prominent social deficits in autism and help resolve discrepancies in the literature.

Background: Procedural learning is an implicit process in which a behavioral response is refined through repeated performance. Neural systems supporting this cognitive process include specific frontostriatal systems responsible for the preparation and timing of planned motor responses. Evaluating performance on procedural learning tasks can provide unique information about neurodevelopmental disorders in which frontostriatal disturbances have been reported, such as autism., Methods: Fifty-two individuals with autism and 54 age-, IQ-, and gender-matched healthy individuals performed an oculomotor serial reaction time task and a sensorimotor control task., Results: Whereas the rate of procedural learning and the precision of planned motor responses were unimpaired in autism, a lateralized alteration in the ability to time predictive responses was observed. Rightward saccadic responses were speeded in individuals with autism relative to healthy control subjects., Conclusions: Speeded rightward predictive saccades suggest atypical functioning of left hemisphere striatal chronometric systems in autism.

The corpus callosum (CC) is the major commissure connecting the cerebral hemispheres and there is evidence of its continuing development into young adulthood [Ann. Neurol. 34 (1993) 71]. Yet, little is known about changes in the size and tissue characteristics of its sub-regions. The sub-regions of the CC (genu, body, isthmus and splenium) are topographically organized to carry interhemispheric fibres representing heteromodal and unimodal cortical brain regions. Studies of the development of each of these sub-regions can therefore provide insights into the time course of brain development. We assessed age-related changes in the size and the signal intensities (SI) of the subregions of the corpus callosum in the Magnetic Resonance Imaging (MRI) scans of a cross-sectional sample of 109 healthy young individuals aged 7-32 years. Age was significantly positively correlated with the size of the callosal sub-regions (with the exception of the isthmus). On the other hand, there was an age-related decrease in SI across all the CC sub-regions. The rates of CC regional size increases appeared to be most pronounced in childhood. By contrast, SI decreases occurred during childhood and adolescence but reached an asymptote during young adulthood. Finally, the observed size and SI changes were similar across CC sub-regions. The observed increases in CC size in conjunction with the decreases in signal intensity reflect continued maturation of the structure from childhood through young adulthood. An increase in axonal size may underlie growth in the size of the CC during childhood. The continued decrease in the CC signal intensity during adolescence may in addition be related to ongoing maturation of the axonal cytoskeleton. CC maturational changes appeared synchronous across sub-regions suggesting parallel maturation of diverse brain regions during childhood and adolescence.

Objective: To determine whether the sizes and volumes of the posterior fossa structures are abnormal in non-mentally retarded autistic adolescents and adults., Method: Volume measurements of the cerebellum, vermis, and brainstem were obtained from coronal magnetic resonance imaging scans in 16 autistic subjects and 19 group-matched healthy controls. For the purpose of comparison with previous studies, area measurements of the midbrain, pons, medulla, total cerebellar vermis, and its three subregions were also obtained from a larger sample of 22 autistic males (mean age: 22.4 years; range: 12.2-51.8 years) and 22 individually matched controls (mean age 22.4 years; range: 12.9-52.2 years)., Results: The total volume of the cerebellum and the cerebellar hemispheres were significantly larger in the autistic subjects with and without correcting for total brain volume. Volumes of the vermis and the brainstem and all area measurements did not differ significantly between groups., Conclusions: There is an increase in the volume of the cerebellum in people with autism consistent with the increase in regional and total brain size reported in this developmental disorder. This finding is also concordant with evidence of cerebellar abnormalities from neuropathological and neuropsychological studies that point to the role of this structure, as part of a complex neural system, in the pathophysiology of autism.

In this pilot study, brain high energy phosphate and membrane phospholipid metabolism were investigated in the dorsal prefrontal cortex of 11 high-functioning autistic adolescent and young adult men (the age range is 12-36 years) and 11 age-, gender-, IQ, race- and socioeconomic status-matched normal controls using in vivo 31P nuclear magnetic resonance spectroscopy (MRS). The autistic group had decreased levels of phosphocreatine and esterified ends (alpha ATP + alpha ADP + dinucleotides + diphosphosugars) compared to the controls. When the metabolite levels were compared within each subject group with neuropsychologic and language test scores, a common pattern of correlations was observed across measures in the autistic group, but not in the control group. As test performance declined in the autistic subjects, levels of the most labile high energy phosphate compound and of membrane building blocks decreased, and levels of membrane breakdown products increased. No significant correlations were present with age in either group or with IQ in the control group, suggesting that these findings were not the consequence of age or IQ effects. This pilot study provides tentative evidence of alterations in brain energy and phospholipid metabolism in autism that correlate with the neuropsychologic and language deficits. The findings are consistent with a hypermetabolic energy state and undersynthesis of brain membranes and may relate to the neurophysiologic and neuropathologic abnormalities in autism.

The brainstem-cerebellar circuitry has been implicated in the pathophysiology of autism for several decades. Recent magnetic resonance imaging (MRI) studies of the posterior fossa have reported various abnormalities, the most noteworthy of which has been selective hypoplasia of the neocerebellar vermis. However, these initial MRI studies are limited by problems in both subject and control selection. The present study was undertaken to further investigate these MRI findings and the role of the cerebellum in autism, taking into consideration these methodologic issues. Eighteen high-functioning autistic subjects were recruited and matched with 18 normal controls on the basis of age, gender, IQ, race and socioeconomic status (SES). The midsagittal areas of the cerebellar vermis, vermal lobes, and the fourth ventricle were measured on 3 mm contiguous magnetic resonance images. Mean areas and standard deviations were comparable for all regions of interest and no statistically significant between-group differences were found. These negative findings argue against theories of autism based on gross structural abnormalities of the cerebellum. Previous reports of posterior fossa abnormalities may be related to technical and methodological factors, based on comparison of extant literature and recently available normative data.

Human erythrocytes and lymphocytes were isolated from venous blood and subjected to one of two protocols. In one protocol the suspended cells were labeled with fluorophore (fluorescamine or 12(9)AS). This procedure was followed sequentially by cellular lysis, cellular fractionation, and fluorescence and absorption readings. In the other protocol the suspended cells were lysed, and then the cellular homogenate labeled with fluorophore followed by cellular fractionation and spectroscopy readings. The lymphocytes were fractionated into plasma membrane, cytosol, and nuclear-mitochondrial fractions and the erythrocytes into plasma membrane and cytosol fractions. The results demonstrate that under the given labeling conditions, both fluorescamine and 12(9)AS are highly localized to the plasma membrane of intact human erythrocytes and lymphocytes. Furthermore, by P-31 NMR analysis, fluorophore labeling did not alter cellular high energy phosphate metabolism or cellular permeability to Mn2+. Therefore, these fluorophores are potentially powerful probes of human erythrocyte and lymphocyte plasma membrane dynamics in inherited and acquired disease states.

Recent reports link the fragile X chromosome abnormality to autism, with the association ranging from 0 to 53%, but the diagnostic criteria for autism were unclear in some of the studies. The need for fragile X chromosome studies in larger populations of autistic children and adults was recognized. In this study, chromosome analyses were performed on 85 carefully diagnosed autistic males, yielding a 2.4% incidence of the fragile X abnormality. It is concluded that the incidence of the fragile X chromosome abnormality in autistic individuals is likely the same as that in the mentally retarded male population and therefore does not increase the risk for autism above that of mental retardation itself.

Erythrocytes from normal adults with no personal or family history of bipolar affective disorder were analyzed by fluorescence spectroscopy to determine what effect, if any, acute in vitro incubation with lithium had on erythrocyte membrane dynamics. The effects on erythrocyte membrane molecular dynamics of varying concentrations of Li2CO3 (0.25-2.0 meq/liter), varying incubation temperatures (25-40 degrees C), and varying incubation times (5-185 min) were investigated. Following incubation with Li2CO3, the erythrocytes were labeled with either 4-phenylspiro-[furan-2(3H),--1'phthalan]--3,3'-dione (fluorescamine), which binds to membrane surface primary amines, or 12(9)anthroyl stearate [12(9)AS], which inserts deep in the membrane hydrocarbon core. The membrane molecular dynamics were then determined by fluorescence anisotropy measurements. These studies demonstrate that clinically relevant concentrations of Li+ incubated with intact normal human erythrocytes significantly alters molecular dynamics on the erythrocyte membrane surface, with less striking changes in the hydrocarbon core. A possible interpretation of these findings is that hydrated Li+ alters the electrostatic interaction of membrane surface molecules, as well as the surrounding solvent (water) structure, with a resultant increase in the molecular motion of these molecules. Alterations in membrane receptor motion could potentially alter receptor functional activity. If similar motional alterations were to occur in the interior of a membrane channel, such as an ionophore, the functional activity of the channel could also be potentially altered. These findings provide additional insight into possible biological actions of Li+, as well as potential molecular alterations in bipolar affective disorder erythrocytes.

Lymphocyte plasma membrane dynamics were studied by energy-transfer polarization in twenty-three neurologically normal individuals at-risk for Huntington's disease (HD). The results were compared to 10 normal controls and 10 known HD patients. The normal and HD subjects segregated into two distinct groups. The at-risk group had findings distributed along a continuum with values similar to known HD patients or to normal controls. These findings suggest that further studies of membrane dynamics will contribute to understanding the molecular defect in HD and to the development of a potential molecular marker.