Diane C. Chugani

Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children.

Serotonin content, serotonin uptake sites, and serotonin receptor binding measured in animal studies are all higher in the developing brain, compared with adult values, and decline before puberty. Furthermore, a disruption of synaptic connectivity in sensory cortical regions can result from experimental increase or decrease of brain serotonin before puberty. The purpose of the present study was to determine whether brain serotonin synthesis capacity is higher in children than in adults and whether there are differences in serotonin synthesis capacity between autistic and nonautistic children. Serotonin synthesis capacity was measured in autistic and nonautistic children at different ages, using α[11C]methyl‐L‐tryptophan and positron emission tomography. Global brain values for serotonin synthesis capacity (K complex) were obtained for autistic children (n = 30), their nonautistic siblings (n = 8), and epileptic children without autism (n = 16). K‐complex values were plotted according to age and fitted to linear and five‐parameter functions, to determine developmental changes and differences in serotonin synthesis between groups. For nonautistic children, serotonin synthesis capacity was more than 200% of adult values until the age of 5 years and then declined toward adult values. Serotonin synthesis capacity values declined at an earlier age in girls than in boys. In autistic children, serotonin synthesis capacity increased gradually between the ages of 2 years and 15 years to values 1.5 times adult normal values and showed no sex difference. Significant differences were detected between the autistic and epileptic groups and between the autistic and sibling groups for the change with age in the serotonin synthesis capacity. These data suggest that humans undergo a period of high brain serotonin synthesis capacity during childhood, and that this developmental process is disrupted in autistic children. Ann Neurol 1999;45:287–295

Local Brain Functional Activity Following Early Deprivation: A Study of Postinstitutionalized Romanian Orphans

Early global deprivation of institutionalized children may result in persistent specific cognitive and behavioral deficits. In order to examine brain dysfunction underlying these deficits, we have applied positron emission tomography using 2-deoxy-2-[(18)F]fluoro-D-glucose in 10 children (6 males, 4 females, mean age 8.8 years) adopted from Romanian orphanages. Using statistical parametric mapping (SPM), the pattern of brain glucose metabolism in the orphans was compared to the patterns obtained from two control groups: (i) a group of 17 normal adults (9 males, 8 females, mean age 27.6 years) and (ii) a group of 7 children (5 males and 2 females, mean age 10.7 years) with medically refractory focal epilepsy, but normal glucose metabolism pattern in the contralateral hemisphere. Consistent with previous studies of children adopted from Romanian orphanages, neuropsychological assessment of Romanian orphans in the present study showed mild neurocognitive impairment, impulsivity, and attention and social deficits. Comparing the normalized glucose metabolic rates to those of normal adults, the Romanian orphans showed significantly decreased metabolism bilaterally in the orbital frontal gyrus, the infralimbic prefrontal cortex, the medial temporal structures (amygdala and head of hippocampus), the lateral temporal cortex, and the brain stem. These findings were confirmed using a region-of-interest approach. SPM analysis showed significantly decreased glucose metabolism in the same brain regions comparing the orphans to the nonepileptic hemisphere of the childhood epilepsy controls. Dysfunction of these brain regions may result from the stress of early global deprivation and may be involved in the long-term cognitive and behavioral deficits displayed by some Romanian orphans.

Abnormal brain connectivity in children after early severe socioemotional deprivation: A diffusion tensor imaging study

OBJECTIVES. We previously reported that children who were subjected to early socioemotional deprivation in Romanian orphanages showed glucose hypometabolism in limbic and paralimbic structures, including the orbital frontal gyrus, infralimbic prefrontal cortex, hippocampus/amygdala, lateral temporal cortex, and the brainstem. The present study used diffusion tensor imaging tractography to examine the integrity of white matter tracts that connect these brain regions. METHODS. Fractional anisotropy and apparent diffusion coefficient for uncinate fasciculus, stria terminalis, fornix, and cingulum were measured in 7 right-handed children (5 girls and 2 boys; mean age: 9.7 ± 2.6 years) with a history of early severe socioemotional deprivation in Eastern European orphanages and compared with similar measurements in 7 right-handed normal children (4 girls and 3 boys; mean age: 10.7 ± 2.8 years). RESULTS. Neuropsychological assessment of the orphans verified the relatively mild specific cognitive impairment and impulsivity consistent with previous studies of children who were adopted from Romanian orphanages. Fractional anisotropy values in the left uncinate fasciculus were decreased significantly in the early deprivation group compared with control subjects. Apparent diffusion coefficient values for the early deprivation group tended to be greater than that in control subjects in all of the tracts measured, without reaching statistical significance. CONCLUSION. Our study demonstrates in children who experienced socioemotional deprivation a structural change in the left uncinate fasciculus that partly may underlie the cognitive, socioemotional, and behavioral difficulties that commonly are observed in these children.

Diffusion Tensor Imaging of Frontal Lobe in Autism Spectrum Disorder

To investigate frontal lobe white matter in children with autism spectrum disorder (ASD), we performed diffusion tensor imaging (DTI) in 50 ASD children (mean age: 57.5 ± 29.2 months, 43 males) and 16 typically developing children (mean age: 82.1 ± 41.4 months, 11 males). The apparent diffusion coefficient (ADC) was significantly higher for whole frontal lobe (P = 0.011), long (P < 0.001) and short range (P = 0.0126) association fibers in ASD group. There was a trend toward statistical significance in the fractional anisotropy (FA) of whole frontal lobe fibers (P = 0.11). FA was significantly lower in ASD group for short range fibers (P = 0.0031) but not for long range fibers (P = not significant [NS]). There was no between-group difference in the number of frontal lobe fibers (short and long) (P = NS). The fiber length distribution was significantly more positively skewed in the normal population than in the ASD group (P < 0.001). The long range association fibers of frontal lobe were significantly longer in ASD group (P = 0.026 for both left and right hemispheres). Abnormal frontal FA and ADC may be due to white matter organization abnormalities in ASD. Lack of evidence for excessive short range connectivity in ASD in this study may need to be re-examined with future advances in DTI technology.

Statistical parametric mapping: assessment of application in children.

SPM is a powerful technique for the comparison of functional imaging data sets among groups of patients. While this technique has been widely applied in studies of adults, it has rarely been applied to studies of children, due in part to the lack of validation of the spatial normalization procedure in children of different ages. In order to determine if spatial normalization of FDG PET images using SPM96 to an adult template can be successfully applied in children, we applied PET-derived transformation parameters to coregistered MRI images. We then compared contours of spatially normalized MRI images obtained from 13 children with epilepsy (ages 2-14 years, mean 7.6 +/- 3.9 years) with those derived from 17 adult controls (mean age 27.6 +/- 4.5 years). Contours of spatially normalized MRI image volumes derived from the pediatric group were more variable than those obtained from adult controls. The average deviation from the mean adult contour was age-dependent and decreased with age (average deviation (mm) = 2.22 (mm) - 0.021 (mm/year) x years, r = 0.70, P < 0.001). Separate SPM analyses were performed for children less than 6 years (N1 = 6) and for children between 6 and 14 years of age (N2 = 7). SPM analyses performed in both pediatric groups showed significant regions of hypometabolism in locations consistent with their epileptic foci. SPM analyses in the younger group also showed significant artifacts. Therefore, the error associated with spatial normalization of pediatric brains to an adult template in children less than 6 years of age precludes the application of statistical parametric mapping in this age group. Although the error in the spatial normalization procedure for children ages 6 to 14 years is higher than in adults, it appears that this error does not result in artifacts in the SPM analysis. Furthermore, in contrast our previous studies showing large age-related changes in the absolute glucose metabolic rate at puberty, the SPM analysis showed children over 6 years of age appear to display the same pattern of glucose utilization as adults. However, small differences in the pattern of glucose utilization which might occur during late childhood and adolescence may not have been detected due to the sample size.

Brain Mapping of Language and Auditory Perception in High-Functioning Autistic Adults: A PET Study

We examined the brain organization for language and auditory functions in five high-functioning autistic and five normal adults, using [15O]-water positron emission tomography (PET). Cerebral blood flow was studied for rest, listening to tones, and listening to, repeating, and generating sentences. The autism group (compared to the control group) showed (a) reversed hemispheric dominance during verbal auditory stimulation; (b) a trend towards reduced activation of auditory cortex during acoustic stimulation; and (c) reduced cerebellar activation during nonverbal auditory perception and possibly expressive language. These results are compatible with findings of cerebellar anomalies and may suggest a tendency towards atypical dominance for language in autism.

Significance of abnormalities in developmental trajectory and asymmetry of cortical serotonin synthesis in autism

The role of serotonin in prenatal and postnatal brain development is well documented in the animal literature. In earlier studies using positron emission tomography (PET) with the tracer alpha[11C]methyl‐l‐tryptophan (AMT), we reported global and focal abnormalities of serotonin synthesis in children with autism. In the present study, we measured brain serotonin synthesis in a large group of autistic children (n = 117) with AMT PET and related these neuroimaging data to handedness and language function. Cortical AMT uptake abnormalities were objectively derived from small homotopic cortical regions using a predefined cutoff asymmetry threshold (>2 S.D. of normal asymmetry). Autistic children demonstrated several patterns of abnormal cortical involvement, including right cortical, left cortical, and absence of abnormal asymmetry. Global brain values for serotonin synthesis capacity (unidirectional uptake rate constant, K‐complex) values were plotted as a function of age. K‐complex values of autistic children with asymmetry or no asymmetry in cortical AMT uptake followed different developmental patterns, compared to that of a control group of non‐autistic children. The autism groups, defined by presence or absence and side of cortical asymmetry, differed on a measure of language as well as handedness. Autistic children with left cortical AMT decreases showed a higher prevalence of severe language impairment, whereas those with right cortical decreases showed a higher prevalence of left and mixed handedness. Global as well as focal abnormally asymmetric development in the serotonergic system could lead to miswiring of the neural circuits specifying hemispheric specialization.

Evidence of altered energy metabolism in autistic children.

1. In this pilot study, the authors investigated the hypotheses there are increased concentrations of lactate in brain and plasma and reduced brain concentrations of N-acetyl-aspartate (NAA) in autistic children. 2. NAA and lactate levels in the frontal lobe, temporal lobe and the cerebellum of 9 autistic children were compared to 5 sibling controls using MRS. Plasma lactate levels were measured in 15 autistic children compared to 15 children with epilepsy. 3. Preliminary results show lower levels of NAA cerebellum in autistic children (p = 0.043). Lactate was detected in the frontal lobe in one autistic boy, but was not detected any of the other autistic subjects or siblings. 4. Plasma lactate levels were higher in the 15 autistic children compared to 15 children with epilepsy (p = 0.0003). 5. Higher plasma lactate in the autistic group is consistent with metabolic changes in some autistic children. The findings of altered brain NAA and lactate in autistic children suggest that MRS may be useful characterizing regional neurochemical and metabolic abnormalities in autistic children.

Functional brain reorganization in children

Developmental brain plasticity in association with focal brain injury is dependent on a number of factors, including age of the individual at the time of injury, size and topography of the brain lesion, maturational state of the brain system injured, integrity of brain areas surrounding and contralateral to the lesion, presence and duration of epilepsy, and medication effects. Recently developed functional neuroimaging tools now make it possible to study non-invasively several aspects of human brain functional reorganization in response to injury. Clinical models which are suitable for the study of developmental brain plasticity include patients who have undergone cortical resections for the alleviation of intractable epilepsy, patients who have sustained unilateral cerebrovascular insults at various periods of development, patients with chronic progressive unilateral brain injury such as in the Sturge-Weber syndrome, and patients with early sensory deprivation such as blind or deaf subjects. Although evidence of functional brain reorganization can be demonstrated in these models, it is emphasized that the neurobiological rules that govern intrahemispheric versus interhemispheric reorganization of function in the brain are, at present, poorly understood.

Alterations in Frontal Lobe Tracts and Corpus Callosum in Young Children with Autism Spectrum Disorder

Major frontal lobe tracts and corpus callosum (CC) were investigated in 32 children with autism spectrum disorder (ASD, mean age: 5 years), 12 nonautistic developmentally impaired children (DI, mean age: 4.6 years), and 16 typically developing children (TD, mean age: 5.5 years) using diffusion tensor imaging tractography and tract-based spatial statistics. Various diffusion and geometric properties were calculated for uncinate fasciculus (UF), inferior fronto-occipital fasciculus (IFO), arcuate fasciculus (AF), cingulum (Cg), CC, and corticospinal tract. Fractional anisotropy was lower in the right UF, right Cg and CC in ASD and DI children; in right AF in ASD children; and in bilateral IFO in DI children, compared with TD children. Apparent diffusion coefficient was increased in right AF in both ASD and DI children. The ASD group showed shorter length of left UF and increased length, volume, and density of right UF; increased length and density of CC; and higher density of left Cg, compared with the TD group. Compared with DI group, ASD group had increased length, volume, and density of right UF; higher volume of left UF; and increased length of right AF and CC. Volume of bilateral UF and right AF and fiber density of left UF were positively associated with autistic features.