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.     

Comprehensive examination of frontal regions in boys and girls with attention-deficit/hyperactivity disorder

The current study examined regional frontal lobe volumes based on functionally relevant subdivisions in contemporaneously recruited samples of boys and girls with and without attention-deficit/hyperactivity disorder (ADHD). Forty-four boys (21 ADHD, 23 control) and 42 girls (21 ADHD, 21 control), ages 8-13 years, participated. Sulcal-gyral landmarks were used to manually delimit functionally relevant regions within the frontal lobe: primary motor cortex, anterior cingulate, deep white matter, premotor regions [supplementary motor complex (SMC), frontal eye field, lateral premotor cortex (LPM)], and prefrontal cortex (PFC) regions [medial PFC, dorsolateral PFC (DLPFC), inferior PFC, lateral orbitofrontal cortex (OFC), and medial OFC]. Compared to sex-matched controls, boys and girls with ADHD showed reduced volumes (gray and white matter) in the left SMC. Conversely, girls (but not boys) with ADHD showed reduced gray matter volume in left LPM; while boys (but not girls) with ADHD showed reduced white matter volume in left medial PFC. Reduced left SMC gray matter volumes predicted increased go/no-go commission rate in children with ADHD. Reduced left LPM gray matter volumes predicted increased go/no-go variability, but only among girls with ADHD. Results highlight different patterns of anomalous frontal lobe development among boys and girls with ADHD beyond that detected by measuring whole lobar volumes.     

Magnetic resonance imaging and head circumference study of brain size in autism: birth through age 2 years

CONTEXT: While the neuroanatomical basis of autism is not yet known, evidence suggests that brain enlargement may be characteristic of this disorder. Inferences about the timing of brain enlargement have recently come from studies of head circumference (HC). OBJECTIVES: To examine brain volume and HC in individuals with autism as compared with control individuals. DESIGN: A cross-sectional study of brain volume was conducted at the first time point in an ongoing longitudinal magnetic resonance imaging study of brain development in autism. Retrospective longitudinal HC measurements were gathered from medical records on a larger sample of individuals with autism and local control individuals. SETTING: Clinical research center. PARTICIPANTS: The magnetic resonance imaging study included 51 children with autism and 25 control children between 18 and 35 months of age (the latter included both developmentally delayed and typically developing children). Retrospective, longitudinal HC data were examined from birth to age 3 years in 113 children with autism and 189 local control children. MAIN OUTCOME MEASURES: Cerebral cortical (including cortical lobes) and cerebellar gray and white matter magnetic resonance imaging brain volumes as well as retrospective HC data from medical records were studied. RESULTS: Significant enlargement was detected in cerebral cortical volumes but not cerebellar volumes in individuals with autism. Enlargement was present in both white and gray matter, and it was generalized throughout the cerebral cortex. Head circumference appears normal at birth, with a significantly increased rate of HC growth appearing to begin around 12 months of age. CONCLUSIONS: Generalized enlargement of gray and white matter cerebral volumes, but not cerebellar volumes, are present at 2 years of age in autism. Indirect evidence suggests that this increased rate of brain growth in autism may have its onset postnatally in the latter part of the first year of life.     

Voxel-based morphometry study on brain structure in children with high-functioning autism

Earlier studies have suggested abnormal brain volumes in autism, but inconsistencies exist. Using voxel-based morphometry, we compared global and regional brain volumes in 17 high-functioning autistic children with 15 matched controls. We identified significant reduction in left white matter volume and white/gray matter ratio in autism. Regional brain volume reductions were detected for right anterior cingulate, left superior parietal lobule white matter volumes, and right parahippocampal gyrus gray matter volume, whereas enlargements in bilateral supramarginal gyrus, right postcentral gyrus, right medial frontal gyrus, and right posterior lobe of cerebellum gray matter in autism. Our findings showed global and regional brain volumes abnormality in high-functioning autism.     

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.     

Cortical gray and white brain tissue volume in adolescents and adults with autism.

BACKGROUND: A number of studies have found brain enlargement in autism, but there is disagreement as to whether this enlargement is limited to early development or continues into adulthood. In this study, cortical gray and white tissue volumes were examined in a sample of adolescents and adults with autism who had demonstrated total brain enlargement in a previous magnetic resonance imaging (MRI) study. METHODS: An automated tissue segmentation program was applied to structural MRI scans to obtain volumes of gray, white, and cerebrospinal fluid (CSF) tissue on a sample of adolescent and adult males ages 13-29 with autism (n = 23) and controls (n = 15). Regional differences for brain lobes and brain hemispheres were also examined. RESULTS: Significant enlargement in gray matter volume was found for the individuals with autism, with a disproportionate increase in left-sided gray matter volume. Lobe volume enlargements were detected for frontal and temporal, but not parietal or occipital lobes, in the subjects with autism. Age and nonverbal IQ effects on tissue volume were also observed. CONCLUSIONS: These findings give evidence for left-lateralized gray tissue enlargement in adolescents and adults with autism, and demonstrate a regional pattern of cortical lobe volumes underlying this effect.     

Sex steroids and brain structure in pubertal boys and girls

Sex steroids exert important organizational effects on brain structure. Early in life, they are involved in brain sexual differentiation. During puberty, sex steroid levels increase considerably. However, to which extent sex steroid production is involved in structural brain development during human puberty remains unknown. The relationship between pubertal rises in testosterone and estradiol levels and brain structure was assessed in 37 boys and 41 girls (10-15 years). Global brain volumes were measured using volumetric-MRI. Regional gray and white matter were quantified with voxel-based morphometry (VBM), a technique which measures relative concentrations ('density') of gray and white matter after individual global differences in size and shape of brains have been removed. Results showed that, corrected for age, global gray matter volume was negatively associated with estradiol levels in girls, and positively with testosterone levels in boys. Regionally, a higher estradiol level in girls was associated with decreases within prefrontal, parietal and middle temporal areas (corrected for age), and with increases in middle frontal-, inferior temporal- and middle occipital gyri. In boys, estradiol and testosterone levels were not related to regional brain structures, nor were testosterone levels in girls. Pubertal sex steroid levels could not explain regional sex differences in regional gray matter density. Boys were significantly younger than girls, which may explain part of the results. In conclusion, in girls, with the progression of puberty, gray matter development is at least in part directly associated with increased levels of estradiol, whereas in boys, who are in a less advanced pubertal stage, such steroid-related development could not (yet) be found. We suggest that in pubertal girls, estradiol may be implicated in neuronal changes in the cerebral cortex during this important period of brain development.     

Testing for association of the monoamine oxidase A promoter polymorphism with brain structure volumes in both autism and the fragile X syndrome

Background

Autism and the fragile X syndrome (FXS) are related to each other genetically and symptomatically. A cardinal biological feature of both disorders is abnormalities of cerebral cortical brain volumes. We have previously shown that the monoamine oxidase A (MAOA) promoter polymorphism is associated with cerebral cortical volumes in children with autism, and we now sought to determine whether the association was also present in children with FXS.

Methods

Participants included 47 2-year-old Caucasian boys with FXS, some of whom also had autism, as well as 34 2-year-old boys with idiopathic autism analyzed in a previous study. The MAOA promoter polymorphism was genotyped and tested for relationships with gray and white matter volumes of the cerebral cortical lobes and cerebro-spinal fluid volume of the lateral ventricles.

Results

MAOA genotype effects in FXS children were the same as those previously observed in idiopathic autism: the low activity MAOA promoter polymorphism allele was associated with increased gray and white matter volumes in all cerebral lobes. The effect was most pronounced in frontal lobe gray matter and all three white matter regions: frontal gray, F = 4.39, P = 0.04; frontal white, F = 5.71, P = 0.02; temporal white, F = 4.73, P = 0.04; parieto-occipital white, F = 5.00, P = 0.03. Analysis of combined FXS and idiopathic autism samples produced P values for these regions <0.01 and effect sizes of approximately 0.10.

Conclusions

The MAOA promoter polymorphism is similarly associated with brain structure volumes in both idiopathic autism and FXS. These data illuminate a number of important aspects of autism and FXS heritability: a genetic effect on a core biological trait of illness, the specificity/generalizability of the genetic effect, and the utility of examining individual genetic effects on the background of a single gene disorder such as FXS.     

Brain structural abnormalities in young children with autism spectrum disorder

OBJECTIVE: To explore the specific gross neuroanatomic substrates of this brain developmental disorder, the authors examine brain morphometric features in a large sample of carefully diagnosed 3- to 4-year-old children with autism spectrum disorder (ASD) compared with age-matched control groups of typically developing (TD) children and developmentally delayed (DD) children. METHODS: Volumes of the cerebrum, cerebellum, amygdala, and hippocampus were measured from three-dimensional coronal MR images acquired from 45 children with ASD, 26 TD children, and 14 DD children. The volumes were analyzed with respect to age, sex, volume of the cerebrum, and clinical status. RESULTS: Children with ASD were found to have significantly increased cerebral volumes compared with TD and DD children. Cerebellar volume for the ASD group was increased in comparison with the TD group, but this increase was proportional to overall increases in cerebral volume. The DD group had smaller cerebellar volumes compared with both of the other groups. Measurements of amygdalae and hippocampi in this group of young children with ASD revealed enlargement bilaterally that was proportional to overall increases in total cerebral volume. There were similar findings of cerebral enlargement for both girls and boys with ASD. For subregion analyses, structural abnormalities were observed primarily in boys, although this may reflect low statistical power issues because of the small sample (seven girls with ASD) studied. Among the ASD group, structural findings were independent of nonverbal IQ. In a subgroup of children with ASD with strictly defined autism, amygdalar enlargement was in excess of increased cerebral volume. CONCLUSIONS: These structural findings suggest abnormal brain developmental processes early in the clinical course of autism. Research currently is underway to better elucidate mechanisms underlying these structural abnormalities and their longitudinal progression.     

Evidence for cortical dysfunction in autism: a proton magnetic resonance spectroscopic imaging study.

BACKGROUND: Although brain imaging studies have reported neurobiological abnormalities in autism, the nature and distribution of the underlying neurochemical irregularities are unknown. The purpose of this study was to examine cerebral gray and white matter cellular neurochemistry in autism with proton magnetic resonance spectroscopic imaging (MRSI). METHODS: Proton MRSI examinations were conducted in 26 males with autism (age 9.8 +/- 3.2 years) and 29 male comparison subjects (age 11.1 +/- 2.4 years). Estimates of cerebral gray and white matter concentrations of N-acetylaspartate (NAA), creatine + phosphocreatine, choline-containing compounds, myo-inositol, and glutamate + glutamine (Glx) were made by linear regression analysis of multi-slice MRSI data and compared between groups. Regional estimates of metabolite concentration were also made with multivariate linear regression, allowing for comparisons of frontal, temporal, and occipital gray matter, cerebral white matter, and the cerebellum. RESULTS: Patients with autism exhibited significantly lower levels of gray matter NAA and Glx than control subjects. Deficits were widespread, affecting most cerebral lobes and the cerebellum. No significant differences were detected in cerebral white matter or cerebellar metabolite levels. CONCLUSIONS: These results suggest widespread reductions in gray matter neuronal integrity and dysfunction of cortical and cerebellar glutamatergic neurons in patients with autism.     

Brain development in children with new onset epilepsy: A prospective controlled cohort investigation

Purpose: To characterize prospective neurodevelopmental changes in brain structure in children with new and recent‐onset epilepsy compared to healthy controls. Methods: Thirty‐four healthy controls (mean age 12.9 years) and 38 children with new/recent‐onset idiopathic epilepsy (mean age 12.9 years) underwent 1.5 T magnetic resonance imaging (MRI) at baseline and 2 years later. Prospective changes in total cerebral and lobar gray and white matter volumes were compared within and between groups. Results: Prospective changes in gray matter volume were comparable for the epilepsy and control groups, with significant (p < 0.0001) reduction in total cerebral gray matter, due primarily to significant (p < 0.001) reductions in frontal and parietal gray matter. Prospective white matter volume changes differed between groups. Controls exhibited a significant (p = 0.0012) increase in total cerebral white matter volume due to significant (p < 0.001) volume increases in the frontal, parietal, and temporal lobes. In contrast, the epilepsy group exhibited nonsignificant white matter volume change in the total cerebrum (p = 0.51) as well as across all lobes (all p’s > 0.06). The group by white matter volume change interactions were significant for total cerebrum (p = 0.04) and frontal lobe (p = 0.04). Discussion: Children with new and recent‐onset epilepsy exhibit an altered pattern of brain development characterized by delayed age‐appropriate increase in white matter volume. These findings may affect cognitive development through reduced brain connectivity and may also be related to the impairments in executive function commonly reported in this population.     

Neuroanatomic variation in monozygotic twin pairs discordant for the narrow phenotype for autism

OBJECTIVE: The broader autism phenotype includes relatives of individuals with autism who display social and language deficits that are qualitatively similar to those of autism but less severe. In previous studies of monozygotic twins discordant for autism, more than 75% of the twins without autism displayed the broader phenotype. Differences in neuroanatomy between discordant monozygotic twins might be associated with the narrow and broader behavioral phenotypes. The authors examined the relationship of twin pair differences in clinical phenotype to differences in neuroanatomic phenotype. METHOD: The subjects were 16 monozygotic twin pairs between the ages of 5 and 14 years and 16 matched singleton comparison subjects. Seven twin pairs were clinically concordant and nine twin pairs were clinically discordant for strictly defined autism. After magnetic resonance imaging, a semiautomated procedure was applied to images in which the brain tissue was subdivided into neurofunctional regions and segmented into gray, white, and ventricular compartments. RESULTS: Both the concordant and discordant twin pairs exhibited concordance in cerebral gray and white matter volumes. However, only the clinically concordant pairs exhibited concordance in cerebellar gray and white matter volumes. Within the discordant twin pairs, both the twins with autism and their co-twins exhibited frontal, temporal, and occipital white matter volumes that were lower than those of the comparison subjects. CONCLUSIONS: These findings support the role and the limits of genetic liability in autism. Continuing to clarify the neuroanatomic pathways in autistic spectrum disorders could illuminate the etiology of autism and, ultimately, contribute to treatments.     

Altered white matter integrity and development in children with autism: a combined voxel-based morphometry and diffusion imaging study

Background

A combined protocol of voxel-based morphometry (VBM) and diffusion-weighted imaging (DWI) was applied to investigate the neurodevelopment of gray and white matter in autism.

Methods

Twenty children with autism (mean age = 7 ± 2.75 years old; age range: 4-14; 2 girls) and 22 matched normally developing children (mean age = 7.68 ± 2.03 years old; age range: 4-11; 2 girls) underwent magnetic resonance imaging (MRI). VBM was employed by applying the Template-o-Matic toolbox (TOM), a new approach which constructs the age-matched customized template for tissue segmentation. Also, the apparent diffusion coefficients (ADC) of water molecules were obtained from the analysis of DWI. Regions of interests (ROIs), standardized at 5 pixels, were placed in cortical lobes and corpus callosum on the non-diffusion weighted echo-planar images (b = 0) and were then automatically transferred to the corresponding maps to obtain the ADC values.

Results

Compared to normal children, individuals with autism had significantly: (1) increased white matter volumes in the right inferior frontal gyrus, the right fusiform gyrus, the left precentral and supplementary motor area and the left hippocampus, (2) increased gray matter volumes in the inferior temporal gyri bilaterally, the right inferior parietal cortex, the right superior occipital lobe and the left superior parietal lobule, and (3) decreased gray matter volumes in the right inferior frontal gyrus and the left supplementary motor area. Abnormally increased ADC values in the bilateral frontal cortex and in the left side of the genu of the corpus callosum were also reported in autism. Finally, age correlated negatively with lobar and callosal ADC measurements in individuals with autism, but not in children with normal development.

Conclusions

These findings suggest cerebral dysconnectivity in the early phases of autism coupled with an altered white matter maturation trajectory during childhood potentially taking place in the frontal and parietal lobes, which may represent a neurodevelopmental marker of the disorder, possibly accounting for the cognitive and social deficits.     

Development of cortical and subcortical brain structures in childhood and adolescence: a structural MRI study

The purpose of the present study was to describe in greater anatomical detail the changes in brain structure that occur during maturation between childhood and adolescence. High-resolution MRI, tissue classification, and anatomical segmentation of cortical and subcortical regions were used in a sample of 35 normally developing children and adolescents between 7 and 16 years of age (mean age 11 years; 20 males, 15 females). Each cortical and subcortical measure was examined for age and sex effects on raw volumes and on the measures as proportions of total supratentorial cranial volume. Results indicate age-related increases in total supratentorial cranial volume and raw and proportional increases in total cerebral white matter. Gray-matter volume reductions were only observed once variance in total brain size was proportionally controlled. The change in total cerebral white-matter proportion was significantly greater than the change in total cerebral gray-matter proportion over this age range, suggesting that the relative gray-matter reduction is probably due to significant increases in white matter. Total raw cerebral CSF volume increases were also observed. Within the cerebrum, regional patterns varied depending on the tissue (or CSF) assessed. Only frontal and parietal cortices showed changes in gray matter, white matter, and CSF measures. Once the approximately 7% larger brain volume in males was controlled, only mesial temporal cortex, caudate, thalamus, and basomesial diencephalic structures showed sex effects with the females having greater relative volumes in these regions than the males. Overall, these results are consistent with earlier reports and describe in greater detail the regional pattern of age-related differences in gray and white matter in normally developing children and adolescents.     

Volume changes in gray matter in patients with schizophrenia

OBJECTIVE: Schizophrenia is generally characterized by a progressive decline in functioning. Although structural brain abnormalities, particularly decrements in gray matter volume, are considered important to the pathology of schizophrenia, it is not resolved whether the brain abnormalities become more prominent over time. METHOD: Magnetic resonance brain images from 159 patients with schizophrenia and 158 healthy comparison subjects between 16 and 70 years of age were compared. Using linear regression analysis, the authors analyzed the relationship between the volumes of the total brain, gray and white matter, cerebellum, and lateral and third ventricles with patient age. RESULTS: Total brain (-2.2%), cerebral gray matter (-3.3%), prefrontal gray matter (-4.4%), and prefrontal white matter (-3.5%) volumes were smaller, and lateral (27%) and third (30%) ventricle and peripheral CSF (11%) volumes were larger in schizophrenia patients. A significant group-by-age interaction for gray matter volume was found, as shown by a steeper regression slope between age and gray matter volume in patients (-3.43 ml/year) than in healthy comparison subjects (-2.74 ml/year). CONCLUSIONS: The smaller brains of the patients with schizophrenia can be explained by decreases in gray matter volume. Moreover, the finding that the smaller gray matter volume was more pronounced in older patients with schizophrenia may suggest progressive loss of cerebral gray matter in schizophrenia patients.     

Cerebral volumetric analysis over time in children with malformations of cortical development: a quantitative investigation

Malformations of cortical development are common neurological disorders characterized by disruptions in the normal development of cerebral gray and white matter during fetal life. We performed a quantitative, partly longitudinal investigation of cerebral volumes in a cohort of children with cortical malformations to investigate how their anatomical abnormalities change over time. Cortical malformation subjects showed volumetric curves that were comparable with those reported for healthy individuals, and reached peak cerebral volume, gray matter volume, and white matter volume at ages similar to those reported for healthy children. Volumes of heterotopic gray matter, however, demonstrated increases that were out of proportion to changes in cortical volume or caudate nucleus volume, suggesting that misplaced gray matter can have a unique pattern of maturation. Our findings demonstrate that overall brain growth in children with cortical malformations appears to mirror that of the healthy population, although malformed regions can show distinct growth patterns.     

Cerebral cortical gray matter overgrowth and functional variation of the serotonin transporter gene in autism

CONTEXT: Autism is a heritable neurodevelopmental disorder characterized biologically by enlargement of the head and brain and abnormalities of serotonin neurotransmission. OBJECTIVE: To evaluate whether 5-HTTLPR, a functional promoter polymorphism of the serotonin transporter gene SLC6A4, influences cerebral cortical structure volumes in young male children with autism. DESIGN: Association study of a genetic variant with quantitative traits. SETTING: Autism research centers at the University of North Carolina (UNC), Chapel Hill, and the University of Washington (UW), Seattle. PARTICIPANTS: Forty-four male children, 2 to 4 years old, with autism participating in longitudinal brain magnetic resonance imaging studies. MAIN OUTCOME MEASURES: Cerebral cortical and cerebellar gray and white matter volumes. RESULTS: We found that 5-HTTLPR genotype influenced gray matter volumes of the cerebral cortex (F(2,23) = 7.29, P = .004) and of 3 lobe-based subregions in the UNC sample of 29 children (frontal lobe gray matter: F(2,23) = 6.36, P = .01). The 5-HTTLPR short allele appeared to be additively associated with increasing gray matter volumes, an observation affirmed by tests of linear genotype effects (cortical gray matter: F(1,24) = 14.11, P = .001; frontal lobe gray matter: F(1,24) = 13.20, P = .001). Genotype did not influence cerebellar volumes. Confirmation was pursued by means of the UW sample of 15 children. While effects were not significant in the UW sample alone, the patterns of adjusted means resembled those found in the UNC sample. Positive Cochran-Mantel-Haenszel test results supported the concordance of relationships across the 2 sites, and analyses of covariance of the combined sample that included a site covariate showed significant linear genotype effects on structure volumes (cortical gray matter: F(1,38) = 5.73, P = .02; frontal lobe gray matter: F(1,38) = 11.73, P = .002). Effect sizes of 5-HTTLPR genotype on total cortical and frontal lobe gray matter volumes were 10% and 16%, respectively. CONCLUSION: The SLC6A4 promoter polymorphism 5-HTTLPR influences cerebral cortical gray matter volumes in young male children with autism.     

White matter volume as a major predictor of cognitive function in Sturge-Weber syndrome

OBJECTIVE: To assess the role of gray and white matter volume loss vs seizures in cognitive impairment of children with Sturge-Weber syndrome with unilateral involvement. DESIGN: Patients were enrolled in this prospective cohort during a period of 3 years. SETTING: Pediatric neurology clinic with national referral through the Sturge-Weber Foundation. PARTICIPANTS: Twenty-one children (age range, 1 year 6 months to 10 years 4 months) with unilateral Sturge-Weber syndrome. MAIN OUTCOME MEASURES: Cortical gray matter and hemispheric white matter volumes were measured on segmented volumetric magnetic resonance imaging and correlated with the age of the participants. Global intellectual function (IQ) was correlated with magnetic resonance imaging and seizure variables in both univariate and multivariate analyses. RESULTS: Both gray and white matter volumes showed an age-related linear increase. Tissue volumes on the side of the angioma showed a positive correlation with IQ after controlling for age in univariate regression analyses (white matter, r = 0.71, P < .001; gray matter, r = 0.48, P = .03), while seizure variables did not correlate with IQ (P > .1). A multivariate regression showed that hemispheric white matter volume ipsilateral to the angioma was an independent predictor of IQ (R = 61, P = .006), which also showed a negative correlation with age (R = - 0.52, P = .022) but no correlation with gray matter volumes. CONCLUSIONS: Early hemispheric white matter loss may play a major role in cognitive impairment in children with Sturge-Weber syndrome. Future therapeutic approaches should aim at preserving white matter integrity in addition to seizure control to improve cognitive outcome.     

Investigation of neuroanatomical differences between autism and Asperger syndrome

BACKGROUND: Autism and Asperger syndrome (ASP) are neurobiological conditions with overlapping behavioral symptoms and of unknown etiologies. Results from previous autism neuroimaging studies have been difficult to replicate, possibly owing to site differences in subject samples, scanning procedures, and image-processing methods. We sought (1) to determine whether low-functioning autism (LFA; IQ<70), high-functioning autism (HFA; IQ>or=70), and ASP constitute distinct biological entities as evidenced by neuroanatomical measures, and (2) to assess for intersite differences. METHODS: Case-control study examining coronally oriented 124-section spoiled gradient echo images acquired on 3 magnetic resonance imaging (MRI) systems, and processed by BrainImage 5.X. Participants were recruited and underwent scanning at 2 academic medicine departments. Participants included 4 age-matched groups of volunteer boys aged 7.8 to 17.9 years (13 patients with LFA, 18 with HFA, 21 with ASP, and 21 control subjects), and 3 volunteer adults for neuroimaging reliability. Main outcome measures included volumetric measures of total, white, and gray matter for cerebral and cerebellar tissues. RESULTS: Intersite differences were seen for subject age, IQ, and cerebellum measures. Cerebral gray matter volume was enlarged in both HFA and LFA compared with controls (P =.009 and P =.04, respectively). Cerebral gray matter volume in ASP was intermediate between that of HFA and controls, but nonsignificant. Exploratory analyses revealed a negative correlation between cerebral gray matter volume and performance IQ within HFA but not ASP. A positive correlation between cerebral white matter volume and performance IQ was observed within ASP but not HFA. CONCLUSIONS: Lack of replication between previous autism MRI studies could be due to intersite differences in MRI systems and subjects' age and IQ. Cerebral gray tissue findings suggest that ASP is on the mild end of the autism spectrum. However, exploratory assessments of brain-IQ relationships reveal differences between HFA and ASP, indicating that these conditions may be neurodevelopmentally different when patterns of multiple measures are examined. Further investigations of brain-behavior relationships are indicated to confirm these findings.     

Smaller prefrontal and premotor volumes in boys with attention-deficit/hyperactivity disorder.

BACKGROUND: Anatomic magnetic resonance imaging (MRI) studies of attention-deficit/hyperactivity disorder (ADHD) have been limited by use of callosal rather than sulcal/gyral landmarks in defining cerebral lobes and functionally relevant sublobar regions (e.g., prefrontal cortex). We present an investigation of cerebral volumes in ADHD using a Talairach-based approach that uses cortical landmarks to define functionally relevant regions. METHODS: Volumes were compared between groups of 12 boys with ADHD and 12 age- and gender-matched control subjects, using a series of multiple analyses of variance. RESULTS: Boys with ADHD had (on average) 8.3% smaller total cerebral volumes. Significant reductions in lobar volumes were seen only for the frontal lobes. Within the frontal lobes, a reduction was seen in both gray and white matter volumes, with some evidence suggesting lateralization of these findings: reduction in frontal white matter volume was specific to the left hemisphere; there was a bilateral reduction in frontal gray matter volume but more so in the right hemisphere. Subparcellation of the frontal lobe revealed smaller prefrontal, premotor, and deep white matter volumes. CONCLUSIONS: Findings suggest that ADHD is associated with decreased frontal lobe gray and white matter volumes. More than one subdivision of the frontal lobes appears to be reduced in volume, suggesting that the clinical picture of ADHD encompasses dysfunctions attributable to anomalous development of both premotor and prefrontal cortices.