Pauline A. Filipek

The Screening and Diagnosis of Autistic Spectrum Disorders

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.

Practice parameter: Screening and diagnosis of autism Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Child Neurology Society

Article abstract 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.

Volumetric MRI analysis comparing subjects having attention-deficit hyperactivity disorder with normal controls

Article abstract-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. NEUROLOGY 1997;48: 589-601

Localization of white matter volume increase in autism and developmental language disorder

Increased brain volume in autism appears to be driven mainly by an unexplained white matter enlargement, and we have reported a similar phenomenon in developmental language disorder (DLD). Localization of this enlargement would strongly guide research into its cause, tissue basis, and functional implications. We utilized a white matter parcellation technique that divides cerebral white matter into an outer zone containing the radiate compartment and an inner zone containing sagittal and bridging system compartments. In both high‐functioning autism and DLD, enlargement localized to the radiate white matter (all lobes in autism, all but parietal in DLD), whereas inner zone white matter compartments showed no volume differences from controls. Furthermore, in both autism and DLD, later or longer‐myelinating regions showed greater volume increases over controls. Neither group showed cerebral cortex, corpus callosum, or internal capsule volume differences from control. Radiate white matter myelinates later than deep white matter; this pattern of enlargement thus is consistent with striking postnatal head circumference percentile increases reported in autism. These findings suggest an ongoing postnatal process in both autism and DLD that is probably intrinsic to white matter, that primarily affects intrahemispheric and corticocortical connections, and that places these two disorders on the same spectrum.

Anatomic segmentation and volumetric calculations in nuclear magnetic resonance imaging

A comprehensive methodology for image segmentation is presented. Tools for differential and intensity contouring, and outline optimization are discussed, as well as the methods for automating such procedures. After segmentation, regional volumes and image intensity distributions can be determined. The methodology is applied to nuclear magnetic resonance images of the brain. Examples of the results of volumetric calculations for the cerebral cortex, white matter, cerebellum, ventricular system, and caudate nucleus are presented. An image intensity distribution is demonstrated for the cerebral cortex.

Attention-deficit hyperactivity disorder: magnetic resonance imaging morphometric analysis of the corpus callosum.

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.

Using MRI to Examine Brain-Behavior Relationships in Males With Attention Deficit Disorder With Hyperactivity

OBJECTIVE The relationship between neuropsychological measures of inhibition and sustained attention and structural brain differences in the regions of the caudate and the frontal region was examined in males with attention deficit disorder with hyperactivity (ADD/H). METHOD Ten males with ADD/H (aged 8-17) and 11 male controls (aged 9-18) participated in a neuropsychological evaluation and had a magnetic resonance imaging scan. RESULTS As had been reported previously by these authors, the children with ADD/H were found to have reversed asymmetry of the head of the caudate, smaller volume of the left caudate head, and smaller volume of the white matter of the right frontal lobe. Children with ADD/H were found to score more poorly on measures of inhibition and sustained attention but not on measures of IQ, achievement, or motor speed. Comparison of neuropsychological measures and brain structure measures indicated a significant relationship between reversed caudate asymmetry and measures of inhibition and externalizing behavior; i.e., children with reversed caudate asymmetry performed more poorly on measures of inhibition regardless of group membership. Poorer performance on sustained attention tasks was related to smaller volume of the right-hemispheric white matter. CONCLUSIONS There is emerging evidence that compromised brain morphology of selected regions is related to behavioral measures of inhibition and attention.

A Twin MRI Study of Size Variations in the Human Brain

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 (rs=.78 to .98) and significant in both samples, as well as being larger than the corresponding DZ correlations, (rs=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.

Long-term neuropsychological outcomes of very low birth weight: associations with early risks for periventricular brain insults.

Few follow-up studies of children with very low birth weight (VLBW, <1,500 g) have examined neuropsychological sequelae at later ages or neonatal risks as predictors of these outcomes. The present study assessed cognitive skills at mean age 16 years in 48 participants with <750 g birth weight, 47 with 750-1,499 g birth weight, and 52 term-born controls. Our major objectives were to delineate the long-term cognitive consequences of VLBW, and to determine if risks for periventricular brain insults accounted for variations in outcomes. Analysis revealed poorer outcomes for the <750 g group than for term-born controls on nearly all measures, with specific impairments in visual-motor skills, spatial memory, and executive function. Predictors of outcome for participants with VLBW included lower birth weight, lower weight for gestational age, and a longer period of oxygen requirement for chronic lung disease. The longer-term consequences of VLBW are consistent with expectations based on early brain pathology and suggest limitations to functional plasticity.

Mitochondrial Dysfunction in Autistic Patients with 15q Inverted Duplication

Two autistic children with a chromosome 15q11‐q13 inverted duplication are presented. Both had uneventful perinatal courses, normal electroencephalogram and magnetic resonance imaging scans, moderate motor delay, lethargy, severe hypotonia, and modest lactic acidosis. Both had muscle mitochondrial enzyme assays that showed a pronounced mitochondrial hyperproliferation and a partial respiratory chain block most parsimoniously placed at the level of complex III, suggesting candidate gene loci for autism within the critical region may affect pathways influencing mitochondrial function. Ann Neurol 2003;53:801–804