Brain asymmetries in autism and developmental language disorder: a nested whole-brain analysis.

We report a whole-brain MRI morphometric survey of asymmetry in children with high-functioning autism and with developmental language disorder (DLD). Subjects included 46 boys of normal intelligence aged 5.7-11.3 years (16 autistic, 15 DLD, 15 controls). Imaging analysis included grey-white segmentation and cortical parcellation. Asymmetry was assessed at a series of nested levels. We found that asymmetries were masked with larger units of analysis but progressively more apparent with smaller units, and that within the cerebral cortex the differences were greatest in higher-order association cortex. The larger units of analysis, including the cerebral hemispheres, the major grey and white matter structures and the cortical lobes, showed no asymmetries in autism or DLD and few asymmetries in controls. However, at the level of cortical parcellation units, autism and DLD showed more asymmetry than controls. They had a greater aggregate volume of significantly asymmetrical cortical parcellation units (leftward plus rightward), as well as a substantially larger aggregate volume of right-asymmetrical cortex in DLD and autism than in controls; this rightward bias was more pronounced in autism than in DLD. DLD, but not autism, showed a small but significant loss of leftward asymmetry compared with controls. Right : left ratios were reversed, autism and DLD having twice as much right- as left-asymmetrical cortex, while the reverse was found in the control sample. Asymmetry differences between groups were most significant in the higher-order association areas. Autism and DLD were much more similar to each other in patterns of asymmetry throughout the cerebral cortex than either was to controls; this similarity suggests systematic and related alterations rather than random neural systems alterations. We review these findings in relation to previously reported volumetric features in these two samples of brains, including increased total brain and white matter volumes and lack of increase in the size of the corpus callosum. Larger brain volume has previously been associated with increased lateralization. The sizeable right-asymmetry increase reported here may be a consequence of early abnormal brain growth trajectories in these disorders, while higher-order association areas may be most vulnerable to connectivity abnormalities associated with white matter increases.

Dissociations of cerebral cortex, subcortical and cerebral white matter volumes in autistic boys.

High-functioning autistic and normal school-age boys were compared using a whole-brain morphometric profile that includes both total brain volume and volumes of all major brain regions. We performed MRI-based morphometric analysis on the brains of 17 autistic and 15 control subjects, all male with normal intelligence, aged 7-11 years. Clinical neuroradiologists judged the brains of all subjects to be clinically normal. The entire brain was segmented into cerebrum, cerebellum, brainstem and ventricles. The cerebrum was subdivided into cerebral cortex, cerebral white matter, hippocampus-amygdala, caudate nucleus, globus pallidus plus putamen, and diencephalon (thalamus plus ventral diencephalon). Volumes were derived for each region and compared between groups both before and after adjustment for variation in total brain volume. Factor analysis was then used to group brain regions based on their intercorrelations. Volumes were significantly different between groups overall; and diencephalon, cerebral white matter, cerebellum and globus pallidus-putamen were significantly larger in the autistic group. Brain volumes were not significantly different overall after adjustment for total brain size, but this analysis approached significance and effect sizes and univariate comparisons remained notable for three regions, although not all in the same direction: cerebral white matter showed a trend towards being disproportionately larger in autistic boys, while cerebral cortex and hippocampus-amygdala showed trends toward being disproportionately smaller. Factor analysis of all brain region volumes yielded three factors, with central white matter grouping alone, and with cerebral cortex and hippocampus-amygdala grouping separately from other grey matter regions. This morphometric profile of the autistic brain suggests that there is an overall increase in brain volumes compared with controls. Additionally, results suggest that there may be differential effects driving white matter to be larger and cerebral cortex and hippocampus-amygdala to be relatively smaller in the autistic than in the typically developing brain. The cause of this apparent dissociation of cerebral cortical regions from subcortical regions and of cortical white from grey matter is unknown, and merits further investigation.

Skewing of the brain midline in schizophrenia.

Our laboratory has observed marked craniofacial dysmorphology along the frontonasal-maxillary juncture in schizophrenic probands and their relatives. Embryologic fate-mapping studies relate this craniofacial juncture to the diencephalic-mesencephalic border, and on the basis of this correspondence we have predicted brain midline maldevelopment arising at this border in schizophrenia. Analysis of magnetic resonance images has borne out this prediction, with midline deviation scores in schizophrenia exceeding control values. High deviation scores were also observed among the siblings of these schizophrenic patients. Further, brain and face dysmorphology scores cohered within subjects, supporting this embryologically derived model.

Auditory discrimination reversal learning and assessment of behavioral teratogenesis in rats.

Qualitative auditory discrimination procedures were used to evaluate discrimination acquisition and reversal learning in rats. Twelve adult rats prenatally exposed to ethanol (ETOH) and 12 unexposed isocaloric controls (CON) were given training with a positively reinforced successive discrimination procedure. Most ETOH subjects were impaired relative to CON subjects on accuracy during early training sessions and the number of sessions required to meet an 80% accuracy criterion. Some ETOH subjects were also impaired on the rate of learning over a series of repeated discrimination reversals. Individual differences in reversal learning rates varied more widely with ETOH subjects than with CON subjects. Our results indicate that the auditory discrimination procedures may find application in assessments of behavioral teratogenesis.

Genetic latent structure analysis of dysmorphology in attention deficit disorder.

Dysmorphology--in the form of minor physical anomalies--has been frequently reported in children with attention deficit disorder (ADD). The authors report an overrepresentation of minor physical anomalies in both ADD probands and their first-degree relatives. Further, ADD probands who are not dysmorphic have non-ADD relatives who are dysmorphic; this familial pattern suggests that a single underlying factor may influence transmission of both traits. A genetic latent structure model was fit to these data to describe the factor's mode of transmission. In this analysis, an autosomal dominant model emerged. Successfully fitting this model is not equivalent to testing the validity of the model itself. Meaningful tests of the model will require larger samples than available at present, and would benefit from diagnostic refinement of the ADD and dysmorphic phenotypes.

Asymmetries in nostrils and the surrounding tissues of the soft nose--a morphometric study.

Seven measurements and two qualities of the soft nose and nasal bridge were recorded in 156 healthy young adult North American Caucasians. Nostril-type asymmetries and alar base dislocations (31 and 38 of 156, respectively) were associated with other minor nasal disfigurements more often than symmetrical nares or alar base levels. A true alar base dislocation between alae of the same shape was distinguished from pseudodislocation caused by differing alar configurations (two-thirds of cases) or configuration differences along with dislocation (one-third of cases). Columellar deviations, columellar length asymmetry, and alar base dislocations were more frequently to the left, whereas nasal bridge deviations and septal dislocations were more often to the right. On the left side the extent of columellar deviation (5.9 degrees) and degree of alar base dislocation (1.5 mm) were significantly greater than on the right (4.0 degrees, p less than 0.05, and 1.0 mm, p less than 0.01, respectively). Quantitative analysis of the relationship of the minor nasal disfigurements offers valuable data for both surgeons and clinical geneticists.

Objective assessment of standard nostril types--a morphometric study.

Nostril type was assigned according to the inclination of the medial longitudinal axis of the nostrils, generally following the Topinard system in a group of randomly selected, healthy young North Americans. The group was composed of 156 Caucasians, 55 Asians, and 32 blacks. The 33 noses with asymmetrical nares were excluded from the remainder of the study. Five other measurements of the soft nose were taken (protrusion of the nasal tip, width of the nose, width of the columella, and length of the right and left columellar rims). Three indices showing the relationships of these measurements were also calculated. The most common nares were Type II in Caucasians (52.8%), Type III in Asians (52.8%), and Type VI in blacks (50.0%). Specific columellar and alar base configurations were associated with many nostril types. These data about nostril types and the soft nose provide important guidelines for reconstructive and cosmetic surgery.

Testosterone-responsive mouse kidney glycosphingolipids: developmental and inbred strain effects.

Mouse kidney and urinary glycosphingolipids from developing C57BL/6J and adults of several other inbred strains were analyzed by high performance liquid chromatographic techniques. Glycosphingolipids from male and female C57BL/6J kidneys were similar until the fifth week of age. Galactosylceramide containing nonhydroxy fatty acids and galabiglycosylceramide containing nonhydroxy fatty acids first appeared in male kidneys, followed by an increase in galabiglycosylceramide containing hydroxy fatty acids. Galabiglycosylceramide was observed in male urine from the earliest collection period (26 days of age). At 5 weeks, globotriglycosylceramides were present in male urine, and by 6 weeks, they became the major glycolipid species. Analysis of the glycosphingolipids from adult male and female DBA/2J, CBA/J, C3H/HeJ, and AKR/J kidneys revealed that galactosylceramides and galabiglycosylceramides which contain nonhydroxy fatty acids were absent in all females and present in all males. The globotriglycosylceramides were elevated in male kidneys of all strains. Galabiglycosylceramides and globotriglycosylceramides were present in male urine of all strains. Each strain exhibited a characteristic pattern of urinary glycosphingolipids which varied not only in the different levels of di- and triglycosylceramides but also in the ratio of components that are distinguished by their fatty acid and long chain base composition. These data provide evidence that in several inbred strains of mice, testosterone induces the production of specific di- and triglycosylceramides, which are components of lysosomal organelles that are normally excreted in the urine.

Antagonism of tertiary butanol by ACTH4-10, naloxone and dexamethasone.

Male C57 mice were pretreated with naloxone (4 mg/kg), ACTH4-10 (30 micrograms/kg), or saline 15 minutes prior to an injection of tertiary butanol (1.5 g/kg). Both naloxone and ACTH4-10 lengthened induction time (time to lose righting reflex) and shortened the duration of sleep time. Dexamethasone (.6 mg/kg) pretreatment of mice injected with ethanol (3.75 g/kg) or tertiary butanol (1.5 g/kg) lengthened induction time, but did not alter sleep time. The data do not support a primary role for acetaldehyde or TIQ involvement in the acute depressant effects of alcohol, but do suggest that some of the observed effects may in part be mediated through an endogenous opioid system.