RESUMEN

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.

Asunto(s)

RESUMEN

In a sporadic case of autism and language deficit due to auditory processing defects, molecular genetic studies revealed that a chromosomal deletion occurred in the 13q12-->q13 region. No chromosome abnormalities were detected in the parents. We determined that the deletion occurred on the paternally derived chromosome 13. There are two previous reports of chromosome 13 abnormalities in patients with autism. The deletion in the subject described in this paper maps between the two chromosome 13 linkage peaks described by Bradford et al. (2001) in studies of subjects with autism and language deficits. The 9-Mb region deleted in the patient described here contains at least four genes that are expressed in brain and that play a role in brain development. They are NBEA, MAB21L1, DCAMKL1 and MADH9. These genes therefore represent candidate genes for autism and specific language deficits.

Asunto(s)

RESUMEN

OBJECTIVE: To examine the efficacy of intravenous porcine secretin for the treatment of autistic disorder. METHOD: Randomized, double-blind, placebo-controlled, crossover design. Fifty-six subjects with autistic disorder received either a secretin or placebo infusion at baseline and the other substance at week 4. Subjects were given the Autism Diagnostic Observation Schedule (ADOS) and other pertinent developmental measures at baseline and at weeks 4 and 8 to assess drug effects. RESULTS: For the primary efficacy analysis, change of ADOS social-communication total score from week 0 to week 4, no statistically significant difference was obtained between placebo (-0.8 +/- 2.9) and secretin groups (-0.6 +/- 1.4; t54 = 0.346, p < .73). The other measures showed no treatment effect for secretin compared with placebo. CONCLUSION: There was no evidence for efficacy of secretin in this randomized, placebo-controlled, double-blind trial.

Asunto(s)

RESUMEN

We have identified a one megabase deletion in the 15q22-15q23 region in a patient with autism, developmental delay, and mild dysmorphism. Genes that map within the deletion region and genes that are interrupted or rearranged at the deletion breakpoints are candidate genes for autism. Fluroescence in situ hybridization studies in this patient revealed that part or all of the PML gene is absent from one chromosome 15 and a BAC clone containing the D15S124 gene locus hybridizes to only one chromosome 15. BAC clones containing the PTPN9, and SLP-1[hUNC24] genes showed markedly reduced hybridization in the 15q22-q23 region on one chromosome 15 in the patient. These BACs also hybridize to the 15q11-q13 region in close proximity to SNRPN and HERC2, and in this region there is equal intensity of signal on the normal and on the deleted chromosome. There are previous reports of deletions and duplications of the 15q11-q13 region in patients with autism. Our patient represents the first report of a 15q22-q23 deletion. Hybridization of the PTPN9 and Slp-1 Bac clones to the 15q11-q13 and the 15q22-q23 regions of chromosome 15 may be due to the presence of PTPN9 or SLP-1 gene sequences or to the presence of other gene sequences or to non-coding homologous DNA sequences. The PTPN9 gene encodes a non-receptor protein tyrosine phosphatase. The Slp-1 [hUNC24] gene is expressed mainly in the brain. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:765-770, 2000.

Asunto(s)

RESUMEN

The heritable nature of reading disability has been well documented (DeFries & Alarcón, 1996), and possible abnormalities of brain structures have been associated with the disorder (Filipek, 1995). However, the etiology of individual differences in morphological brain measures has not been examined extensively. The purpose of this study was to apply behavioral genetic methods to assess the etiology of individual differences in neuroanatomical structures. Measures of reading performance, cognitive ability, and magnetic resonance imaging scans were obtained from 25 monozygotic (MZ) and 23 same-sex dizygotic (DZ) twin pairs with reading disability, and 9 MZ and 9 DZ control twin pairs participating in the Colorado Learning Disabilities Research Center. Results obtained from multiple regression analyses (DeFries & Fulker, 1985, 1988) of these twin data indicated that individual differences in the size of most cortical and subcortical structures were largely due to heritable influences. Moreover, estimates of heritability did not change appreciably after controlling for IQ and total brain size.

Asunto(s)

RESUMEN

Autism is a common disorder of childhood, affecting 1 in 500 children. Yet, it often remains unrecognized and undiagnosed until or after late preschool age because appropriate tools for routine developmental screening and screening specifically for autism have not been available. Early identification of children with autism and intensive, early intervention during the toddler and preschool years improves outcome for most young children with autism. This practice parameter reviews the available empirical evidence and gives specific recommendations for the identification of children with autism. This approach requires a dual process: 1) routine developmental surveillance and screening specifically for autism to be performed on all children to first identify those at risk for any type of atypical development, and to identify those specifically at risk for autism; and 2) to diagnose and evaluate autism, to differentiate autism from other developmental disorders.

Asunto(s)

RESUMEN

Although it is well known that there is considerable variation among individuals in the size of the human brain, the etiology of less extreme individual differences in brain size is largely unknown. We present here data from the first large twin sample (N=132 individuals) in which the size of brain structures has been measured. As part of an ongoing project examining the brain correlates of reading disability (RD), whole brain morphometric analyses of structural magnetic response image (MRI) scans were performed on a sample of adolescent twins. Specifically, there were 25 monozygotic (MZ) and 23 dizygotic (DZ) pairs in which at least one member of each pair had RD and 9 MZ and 9 DZ pairs in which neither member had RD. We first factor-analyzed volume data for 13 individual brain structures, comprising all of the neocortex and most of the subcortex. This analysis yielded two factors ("cortical" and "subcortical") that accounted for 64% of the variance. We next tested whether genetic and environmental influences on brain size variations varied for these two factors or by hemisphere. We computed intraclass correlations within MZ and DZ pairs in each sample for the cortical and subcortical factor scores, for left and right neocortex, and for the total cerebral volume. All five MZ correlations were substantial (r's=.78 to.98) and significant in both samples, as well as being larger than the corresponding DZ correlations, (r's=0.32 to 0.65) in both samples. The MZ-DZ difference was significant for 3 variables in the RD sample and for one variable in the smaller control sample. These results indicate significant genetic influences on these variables. The magnitude of genetic influence did not vary markedly either for the 2 factors or the 2 hemispheres. There was also a positive correlation between brain size and full-scale IQ, consistent with the results of earlier studies. The total cerebral volume was moderately correlated (r=.42, p<.01, two-tailed) with full-scale IQ in the RD sample; there was a similar trend in the smaller control sample (r=.31, p<.07, two-tailed). Corrections of similar magnitude were found between the subcortical factor and full-scale IQ, whereas the results for the cortical factor (r=.16 and.13) were smaller and not significant. In sum, these results provide evidence for the heritability of individual differences in brain size which do not vary markedly by hemisphere or for neocortex relative to subcortex. Since there are also correlations between brain size and full-scale IQ in this sample, it is possible that genetic influences on brain size partly contribute to individual differences in IQ.

Asunto(s)

RESUMEN

OBJECTIVE: To test for brain structure differences in reading disability (RD) by means of MRI-based morphometry. BACKGROUND: Consensus is lacking on the brain structural correlates of RD. The current study reports on a wider set of structures in the largest sample yet studied, controlling for age, gender, IQ, and attention deficit hyperactivity disorder (ADHD). METHODS: A case-control study was performed that was comprised of 75 individuals with RD (mean age, 17.43+/-4.29 years) and 22 control subjects without RD (mean age, 18.69+/-3.75 years), each a single member of a twin pair. The two groups were similar in age, gender, and handedness, but differed in full-scale IQ (FSIQ), with the RD group having a lower mean FSIQ (101.8+/-9.9 versus 118.3+/-10.3). Using three group-by-structure analyses of covariance, groups were compared in terms of volume (in cubic centimeters) of major neocortical subdivisions, subcortical structures, and midsagittal areas (in square millimeters) of three subdivisions of the corpus callosum. RESULTS: Controlling for age, gender, and IQ, the authors found a significant group-by-structure interaction for the major neocortical subdivisions (p = 0.002), reflecting a different developmental pattern in the RD group, with the insula and anterior superior neocortex being smaller and the retrocallosal cortex being larger in the RD group. In contrast, they found no group main or interaction effects for the subcortical or callosal structures. The pattern of results was essentially the same in subjects without ADHD. CONCLUSIONS: Most brain structures do not differ in size in RD, but cortical development is altered subtly. This study replicates in a larger sample previous findings of insular differences in RD and demonstrates further that those differences are not attributable to comorbid ADHD.

Asunto(s)

RESUMEN

The developmental disorders of childhood autistic, developmental language, reading (dyslexia), and attention deficit-hyperactivity disorders-manifest with deficits in the traditional behavioral domains of cognition, language, visual-spatial function, attention, and socialization. However, none of these disorders has been associated with characteristic discrete focal lesions or recognized encephaloclastic processes. Developmental cognitive neuroscientists must therefore begin with the spectrum of sometimes divergent behaviors occurring within these disorders and work backward in an attempt to identify the responsible anomalous neural systems. Since the advent of "brain imaging" two decades ago, much effort has focused on identifying brain-behavior correlates in these disorders. The results of these neuropathologic, structural, and functional neuroimaging studies are presented and the reasons for the often divergent findings are discussed. As we approach the end of the Decade of the Brain, current neuroimaging techniques give us the technology for the first time to apply a fundamental cognitive approach to brain-behavior relationships in the developmental disorders, to eliminate the conglomeration of "apples and camels" phenomenon. Researchers are working together to create comparable protocols and to adhere to methods that can be replicated across sites. The future prospects for a greater understanding of the developmental disorders are now much brighter with neuroimaging technology.

Asunto(s)

RESUMEN

The Child Neurology Society and American Academy of Neurology recently proposed to formulate Practice Parameters for the Diagnosis and Evaluation of Autism for their memberships. This endeavor was expanded to include representatives from nine professional organizations and four parent organizations, with liaisons from the National Institutes of Health. This document was written by this multidisciplinary Consensus Panel after systematic analysis of over 2,500 relevant scientific articles in the literature. The Panel concluded that appropriate diagnosis of autism requires a dual-level approach: (a) routine developmental surveillance, and (b) diagnosis and evaluation of autism. Specific detailed recommendations for each level have been established in this document, which are intended to improve the rate of early suspicion and diagnosis of, and therefore early intervention for, autism.

Asunto(s)

RESUMEN

OBJECTIVE: To test by MRI-based morphometry the a priori hypotheses that developmental anomalies exist in attention-deficit hyperactivity disorder (ADHD) in left caudate and right prefrontal/frontal/ and/or posterior parietal hemispheric regions, in accord with neurochemical, neuronal circuitry and attentional network hypotheses, and prior imaging studies. DESIGN: Case-control study. SETTING: Academic medical center. PARTICIPANTS: Fifteen male subjects with ADHD without comorbid diagnoses (aged 12.4 +/- 3.4 years) and 15 male normal controls (aged 14.4 +/- 3.4), group-matched for age, IQ, and handedness. MAIN OUTCOME MEASURES: Global and hemispheric regional volumes (in cm3) of cerebral hemispheres, cortex, white matter, ventricles, caudate, lenticulate, central gray nuclei, insula, amygdala, and hippocampus. RESULTS: Despite similar hemispheric volumes, ADHD subjects had smaller volumes of (1) left total caudate and caudate head (p < 0.04), with reversed asymmetry (p < 0.03); (2) right anterior-superior (frontal) region en bloc (p < 0.03) and white matter (p < 0.01); (3) bilateral anterior-inferior region en bloc (p < 0.04); and (4) bilateral retrocallosal (parietal-occipital) region white matter (p < 0.03). Possible structural correlates of ADHD response to stimulants were noted in an exploratory analysis, with the smallest and symmetric caudate, and smallest left anterior-superior cortex volumes found in the responders, but reversed caudate asymmetry and the smallest retrocallosal white matter volumes noted in the nonresponders. CONCLUSIONS: This study is the first to report localized hemispheric structural anomalies in ADHD, which are concordant with theoretical models of abnormal frontal-striatal and parietal function, and with possible differing morphologic substrates of response to stimulant medication.

Asunto(s)

Asunto(s)

RESUMEN

Volumetric magnetic resonance image (MRI)-based morphometry was performed on the brains of 30 normal children (15 males and 15 males) with a mean age of 9 years (range 7-11 years). This age range lies in a late but critical phase of brain growth where not volumetric increment will be small but when the details of brain circuity are being fine-tuned to support the operations of the adult brain. The brain at this age is 95% the volume of the adult brain. The brain of the female child is 93% the volume of the male child. For more than 95% of brain structures, the volumetric differences in male and female child brain are uniformly scaled to the volume difference of the total brain in the two sexes. Exceptions to this pattern of uniform scaling are the caudate, hippocampus and pallidum, which are disproportionately larger in female than male child brain, and the amygdala, which is disproportionately smaller in the female child brain. The patterns of uniform scaling are generally sustained during the final volumetric increment in overall brain size between age 7-11 and adulthood. There are exceptions to this uniform scaling of child to adult brain, and certain of these exceptions are sexually dimorphic. Thus, with respect to major brain regions, the cerebellum in the female but not the male child is already at adult volume while the brainstem in both sexes must enlarge more than the brain as a whole. The collective subcortical gray matter structures of the forebrain of the female child are already at their adult volumes. The volumes of these same structures in the male child, by contrast, are greater than their adult volumes and, by implication, must regress in volume before adulthood. The volume of the central white matter, on the other hand, is disproportionately smaller in female than male child brain with respect to the adult volumes of cerebral central white matter. By implication, relative volumetric increase of cerebral central white matter by adulthood must be greater in the female than male brain. The juxtaposed progressive and regressive patterns of growth of brain structures implied by these observations in the human brain have a soundly established precedent in the developing rhesus brain. There is emerging evidence that sexually dimorphic abnormal regulation of these terminal patterns of brain development are associated with gravely disabling human disorders of obscure etiology.

Asunto(s)

RESUMEN

BACKGROUND: A previous pilot study of only posterior brain regions found lower white-matter volume in patients with obsessive-compulsive disorder than in normal control subjects. We used new cohorts of patients and matched normal control subjects to study whole-brain volume differences between these groups with magnetic resonance imaging-based morphometry. METHODS: Ten female patients with obsessive-compulsive disorder and 10 female control subjects, matched for handedness, age, weight, education, and verbal IQ, underwent magnetic resonance imaging with a 3-dimensional volumetric protocol. Scans were blindly normalized and segmented by means of well-characterized semiautomated intensity contour mapping and differential intensity contour algorithms. Brain structures investigated included the cerebral hemispheres, cerebral cortex, diencephalon, caudate, putamen, globus pallidus, hippocampus amygdala, third and fourth ventricles, corpus callosum, operculum, cerebellum, and brain stem. Anterior to posterior neocortical regions, including precallosum, anterior pericallosum, posterior pericallosum, and retrocallosum, with adjacent white matter were also measured. Volumes found different between groups were correlated with Yale-Brown Obsessive Compulsive Scale score and Rey-Osterieth Complex Figure Test measures. RESULTS: Confirming results of our earlier pilot study and expanding the findings to the whole brain, patients with obsessive-compulsive disorder had significantly less total white matter but, in addition, significantly greater total cortex and opercular volumes. Severity of obsessive-compulsive disorder and nonverbal immediate memory correlated with opercular volume. CONCLUSIONS: Replication of volumetric white-matter differences suggests a widely distributed structural brain abnormality in obsessive-compulsive disorder. Whereas determining the etiogenesis may require research at a microscopic level, understanding its functional significance can be further explored via functional neuroimaging and neuropsychological studies.

Asunto(s)

Asunto(s)

RESUMEN

Two recent magnetic resonance imaging studies, including a retrospective analysis of apparently 'contradictory' data from other investigators, appear to confirm earlier reports of vermal hypoplasia in autism. However, a review of the methodology used in these two studies suggests that definitive conclusions concerning cerebellar vermal pathology in autism are still premature.

Asunto(s)

Asunto(s)

Asunto(s)

RESUMEN

OBJECTIVE: The following study seeks to document possible differences in corpus callosal area and shape between children with attention-deficit hyperactivity disorder (ADHD) and controls. METHODS: Fifteen carefully diagnosed right-handed male subjects with ADHD with overactivity symptomatology were compared to 15 right-handed male control subjects. The corpus callosum was divided into seven areas on the midsagittal slice of a magnetic resonance image with shape analysis also conducted. RESULTS: An exploratory shape analysis showed no significant differences in shape between the groups. No group differences were found in the area, length, or anterior regions of the corpus callosum. The ADHD subjects were found to have significantly smaller posterior corpus callosum regions than the control group, with the splenium accounting for most of the variance between the groups. CONCLUSIONS: The splenial area of the corpus callosum is smaller in children with ADHD than in a sample of normally developing children. These smaller areas may relate to commonly seen sustained attention deficits which in turn negatively impact on the development of more advanced levels of attention such as self-regulation. Further study of the regions surrounding the splenial area is suggested to determine whether they are correlated in size to the smaller corpus callosum.

Asunto(s)

RESUMEN

Morphometric analysis was performed on three-dimensional MRI scans of 10 male and 10 female young adults with four principal objectives: (1) to characterize in vivo volumes of whole brain and substructures, (2) to explore volumetric symmetry in bilateral structures, (3) to consider the extent to which volumetric measures are dimorphic in the male and female brain, and (4) to provide a normal volumetric database for the young adult brain. Total brain volumes ranged between 1173 and 1626 cm3. All bilateral structures were symmetric or nearly symmetric in volume, with the exception of a slightly larger right neocortex and amygdala, and larger left lateral ventricle. Male brains were larger in volume than female brains, a difference that reached significance for cerebellar but not for cerebral hemisphere volume. In females, there was less cerebral white matter while caudate volume was larger than in the male brains. The proportions of caudate and hippocampus relative to total cerebral volumes were larger in females than in males. These four measures accurately predicted gender in 85% of the subjects by discriminant analysis. No gender differences were noted in the structural symmetry analysis. These results represent the first step in establishing a comprehensive database of morphometric parameters, with unexpected findings relative to brain symmetry and sexual dimorphism.

Asunto(s)