Sharp curvature of frontal lobe white matter pathways in children with autism spectrum disorders: tract-based morphometry analysis.

BACKGROUND AND PURPOSE: Because we had previously observed geometric changes of frontal lobe association pathways in children with ASD, in the present study we analyzed the curvature of these white matter pathways by using an objective TBM analysis. MATERIALS AND METHODS: Diffusion tensor imaging was performed in 32 children with ASD and 14 children with typical development. Curvature, FA, AD, and RD of bilateral AF, UF, and gCC were investigated by using the TBM group analysis assessed by P(FDR) for multiple comparisons. RESULTS: Significantly higher curvatures were found in children with ASD, especially at the parietotemporal junction for AF (left, P(FDR) < .001; right, P(FDR) < .01), at the frontotemporal junction for UF (left, P(FDR) < .005; right, P(FDR) < .03), and at the midline of the gCC (P(FDR) < .0001). RD was significantly higher in children with ASD at the same bending regions of AF (left, P(FDR) < .03, right, P(FDR) < .02), UF (left, P(FDR) < .04), and gCC (P(FDR) < .01). CONCLUSIONS: Higher curvature and curvature-dependent RD changes in children with ASD may be the result of higher attenuation of thinner axons in these frontal lobe tracts.

Aberrant diffusion and geometric properties in the left arcuate fasciculus of developmentally delayed children: a diffusion tensor imaging study.

BACKGROUND AND PURPOSE: One of the neurologic substrates of poor language in children with DD is the abnormal development of perisylvian language networks. We sought to determine whether this manifests as aberrant regional changes in diffusivity or geometry of the left AF. MATERIALS AND METHODS: We performed DTI studies in 16 young (age, 55.4 ± 18.95 months) patients with DD and 11 age- and sex-matched TD children (age, 60.09 ± 21.27 months). All children were right-handed. To detect the malformation of left AF structure in native or standard space, we proposed new methodology consisting of 2 complementary approaches, principal fiber orientation quantification in color-coded anisotropic maps and tract-based morphometry analysis. RESULTS: Patients with DD did not show the typical pattern of age-related maturity of the AP and ML pathways passing through the left AF (R(2) of the AP pathway: DD versus TD = 0.002 versus 0.4542; R(2) of the ML pathway: DD versus TD = 0.002 versus 0.4154). In addition, the patients with DD showed significantly reduced FA in the temporal portion of the AF (mean FA of DD versus TD = 0.37 ± 0.11 versus 0.48 ± 0.06, P < .001), and the AF showed higher curvatures in the parietotemporal junction, resulting in sharper bends to the Wernicke area (mean curvature of DD versus TD = 0.12 ± 0.03 versus 0.06 ± 0.02, P < .001). CONCLUSIONS: The proposed methods successfully revealed regional abnormalities in the axonal integrity of the left AF in the patients with DD. These abnormalities support the notion that the perisylvian language network is malformed in children with DD.

Diffusion tensor imaging study of the cortical origin and course of the corticospinal tract in healthy children.

BACKGROUND AND PURPOSE: Several studies have questioned the traditional belief that the corticospinal tract (CST) arises exclusively from the precentral gyrus and passes through the anterior half of the posterior limb of the internal capsule (PLIC) in humans; however, no direct evidence existed from structural imaging, and developmental aspects of CST origin have not been clarified. We used diffusion tensor imaging (DTI) tractography to test the hypotheses that CST can originate from both pre- and postcentral gyri and is located posteriorly in the PLIC, and we also determined how age, sex, or handedness affected these locations. MATERIALS AND METHODS: Forty-two healthy children (2.6-17.5 years of age; 20 girls) underwent DTI. Subsequently, tractography was performed on the basis of fiber assignment by continuous tracking (FACT) algorithm and brute force approach, with a fractional anisotropy (FA) threshold of <0.2 and an angle threshold of >50 degrees . The CST was isolated by using a knowledge-based region-of-interest approach, and its cortical origin and location on the PLIC was determined. RESULTS: DTI revealed that the CST originated from both pre- and postcentral gyri in 71.4% of hemispheres, from the precentral gyrus only in 19%, and from the postcentral gyrus only in 7.1%. The overall distribution was similar in both hemispheres. However, children with CST originating from both pre- and postcentral gyri were older (mean, 11.1 years of age) than those with precentral origin (mean, 5.8 years of age) or postcentral origin (mean, 7.8 years of age) only (P = .00003). The center of the CST was localized at 65% of the length (from its anterior margin) of the PLIC, and the CST occupied 26.5% of its anteroposterior length. There was a significant positive correlation between age and FA of the CST (r = 0.49; P = .002). The volume of the precentral portion of the left CST was significantly higher than that of its postcentral portion (P = .01) and that of the right CST (P = .0002). The pattern of cortical origin of CST, its location at the level of PLIC, and its volume and FA were unaffected by sex or handedness. CONCLUSIONS: The CST most frequently originates from both pre- and postcentral gyri, especially in older children, and is typically centered approximately two thirds of the distance from the anterior margin of the PLIC and occupies about a quarter of its anteroposterior length. In young children, the CST can often be seen originating exclusively from the precentral gyrus by DTI.

Characteristics of abnormal diffusivity in normal-appearing white matter investigated with diffusion tensor MR imaging in tuberous sclerosis complex.

BACKGROUND AND PURPOSE: Although patients with tuberous sclerosis complex (TSC) manifest various structural abnormalities, we hypothesized that white matter (WM) structures that appear normal on conventional MR imaging may be accompanied by microstructural changes, such as gliosis and myelinization defects. Our objective was to determine in vivo whether there was evidence for WM microstructural changes by using diffusion tensor imaging (DTI). MATERIALS AND METHODS: We used DTI to evaluate diffusivity and anisotropy in normal-appearing WM (NAWM) of 6 children with TSC and 12 age-matched control subjects. The anterior and posterior limbs of the internal capsule, the external capsule, and the genu and splenium of the corpus callosum were assessed. We hypothesized that previously reported DTI abnormalities of NAWM in patients with TSC may not be equal in all diffusion directions as measured by the major, middle, and minor eigenvalues. RESULTS: When combining NAWM regions in patients with TSC, we observed a significant increase in mean diffusivity (P = .003) and a decrease in anisotropy (P = .03) compared with those of controls. However, the increase in diffusivity was more pronounced in directions orthogonal to the axons measured by the minor and middle eigenvalues (P = .005) than by the major eigenvalue (P = .02). CONCLUSION: Our findings revealed a decrease in anisotropy and an increase in longitudinal and radial diffusivities in NAWM beyond the location of TSC lesions seen on conventional MR imaging. The axonal microstructural changes suggested by our study may be related to changes in myelin packing due to giant cells accompanied by gliosis and myelination defects known to occur in TSC WM.

Increased visual cortex glucose metabolism contralateral to angioma in children with Sturge-Weber syndrome.

Functional reorganization after focal brain injury can lead to altered cerebral metabolism of glucose. Sturge-Weber syndrome (SWS) with unilateral involvement is a clinical model for evaluating the effects of early focal brain injury on brain metabolism and function. In this study, 2-deoxy-2[(18)F]fluoro-D-glucose (FDG) positron emission tomography (PET) was used to measure glucose metabolism in cortex and basal ganglia, both ipsilateral and contralateral to the angioma, in 17 children (eight males, nine females; age range 1y 8mo-10y 4mo; mean 5y 7mo [SD 2y 11mo]) with unilateral SWS and epilepsy. The PET findings were compared with those of a control group of 11 age-matched children (four males, seven females; age range 3y-10y 8mo; mean 6y [SD 2y 10mo]) with partial epilepsy but normal magnetic resonance imaging and PET scans. In the SWS group, visual and parietal cortex showed decreased glucose metabolism on the side of the angioma (p=0.001) but increased metabolism on the contralateral side (p=0.002). In particular, glucose metabolism was very high in contralateral visual cortex of childrenwith SWS, showing severe occipital hypometabolism on the side of the angioma. Eight children with visual field defect showed increased metabolism in the contralateral visual cortex (p=0.012). These findings indicate that early, severe unilateral cortical damage in SWS may induce increased glucose metabolism in the contralateral visual cortex, probably reflecting reorganization.

Multimodality imaging of cortical and white matter abnormalities in Sturge-Weber syndrome.

BACKGROUND AND PURPOSE: Impaired cortical venous outflow and abnormal deep venous collaterals are common in Sturge-Weber syndrome (SWS), but their relation to brain metabolism and function is poorly understood. In this study, advanced MR imaging techniques, such as susceptibility-weighted imaging (SWI) and diffusion tensor imaging (DTI), were applied in conjunction with positron-emission tomography (PET), to assess cortical and white matter structural abnormalities and their relation to cortical glucose metabolism and cognitive functions in children with unilateral SWS. MATERIALS AND METHODS: Thirteen children (age, 1.5-10.3 years) with unilateral SWS underwent MR imaging with SWI and DTI, glucose metabolism PET, and comprehensive neuropsychologic assessment prospectively. The MR imaging and PET images were coregistered and cortical regions showing decreased glucose metabolism were compared with locations of SWI signal intensity abnormalities, changes in white matter water diffusion, and cognitive functions. RESULTS: SWI detected both cortical abnormalities (n=8) and deep transmedullary veins (n=9), including those in young children with no cortical SWI signal intensity changes. These veins were often located under cortex adjacent to hypometabolic regions. DTI showed abnormal water diffusion both under hypometabolic cortex and in adjacent white matter with collateral veins. Cognitive dysfunction was associated with abnormal water diffusion in the posterior white matter. CONCLUSIONS: Transmedullary venous collaterals can be detected early by SWI and persist in white matter adjacent to damaged cortex in children with SWS. Microstructural white matter damage extends beyond cortical abnormalities and may contribute to cognitive impairment. SWI and DTI can be incorporated into clinical MR imaging acquisitions to objectively assess microstructural abnormalities at different stages of SWS.

Evolution of cortical metabolic abnormalities and their clinical correlates in Sturge-Weber syndrome.

BACKGROUND: The natural course of Sturge-Weber syndrome (SWS) is poorly understood, although neurological symptoms are often progressive. AIMS: To track longitudinal changes in brain glucose metabolism measured with positron emission tomography (PET) and their relation to clinical changes during the early course of SWS. METHODS: Fourteen children (age 3 months to 3.9 years at enrollment) with SWS and unilateral leptomeningeal angioma underwent two consecutive glucose metabolism PET scans with a mean follow-up time of 1.2 years. Longitudinal changes of the extent of cortical glucose hypometabolism on the angioma side were measured and correlated with age, clinical seizure frequency and hemiparesis. RESULTS: An increase in the size of the hypometabolic cortex was seen in 6 children, coinciding with an age-related increase in cortical glucose metabolism measured in unaffected contralateral cortex. These 6 patients were younger both at the initial (mean age 0.75 vs. 2.8 years; p<0.001) and the second scan (mean age 1.8 vs. 4.2 years; p=0.001) than those with no change in the extent of hypometabolic cortex (n=6). The area of cortical hypometabolism decreased in the two remaining children, and this was associated with resolution of an initial hemiparesis in one of them. Seizure frequency between the two scans was higher in children who showed progressive enlargement of cortical hypometabolism, as compared to those with no progression (p=0.008). CONCLUSIONS: In SWS, detrimental metabolic changes occur before 3 years of age coinciding with a sharp increase of developmentally regulated cerebral metabolic demand. Progressive hypometabolism is associated with high seizure frequency in these children. However, metabolic abnormalities may remain limited or even partially recover later in some children with well-controlled seizures. Metabolic recovery accompanied by neurological improvement suggests a window for therapeutic intervention in children with unilateral SWS.

Alpha-methyl-L-tryptophan PET detects epileptogenic cortex in children with intractable epilepsy.

BACKGROUND: In children with tuberous sclerosis, the PET tracer alpha[11C]methyl-L-tryptophan (AMT) has been shown to be selectively taken up by epileptogenic tubers, thus allowing differentiation from nonepileptogenic tubers in the interictal state. OBJECTIVE: To determine whether cortical areas showing increased AMT uptake in children without tuberous sclerosis complex with intractable neocortical epilepsy indicate the epileptogenic zone, and to assess the relative contributions of AMT and 2-deoxy-2[18F]fluoro-D-glucose (FDG) PET abnormalities to the localization of epileptogenic cortical regions. METHODS: Areas of increased AMT and decreased FDG uptake were marked objectively as regions with abnormal asymmetry using an in-house written software in 27 children who underwent comprehensive evaluation for resective epilepsy surgery. The marked PET abnormalities were compared to the locations of scalp and subdural EEG epileptiform abnormalities, as well as histology and surgical outcome. RESULTS: Focal cortical increases of AMT uptake were found in 15 patients. The lobar sensitivity (39.0%) of AMT PET for seizure onset was lower, but its specificity (100%) was higher (p < 0.0001) than that of hypometabolism on FDG PET (sensitivity 73.2%, specificity 62.7%). AMT PET abnormalities were smaller than corresponding FDG PET hypometabolic regions (p = 0.002), and increased AMT uptake occurred in two patients with nonlocalizing FDG PET. Histologically verified cortical developmental malformations were associated with increased AMT uptake (p = 0.044). Subdural electrodes adjacent to the area of increased AMT uptake were most often involved in seizure onset. CONCLUSIONS: Focal increase of cortical AMT uptake in children is less sensitive but more specific for the lobe of seizure onset than corresponding FDG PET hypometabolism, and it is often associated with epileptogenic cortical developmental malformations. AMT PET can assist placement of subdural electrodes even when MRI and FDG PET fail to provide adequate localizing information. Cortical areas adjacent to increased AMT uptake should be carefully addressed by intracranial EEG because these regions often show a high degree of epileptogenicity.

Prolonged vigabatrin treatment modifies developmental changes of GABA(A)-receptor binding in young children with epilepsy.

PURPOSE: To determine whether prolonged treatment with vigabatrin (VGB), an antiepileptic drug (AED) that acts by elevating brain gamma-aminobutyric acid (GABA) levels, interferes with age-related changes of in vivo GABA(A)-receptor binding in children with epilepsy. METHODS: Using [11C]flumazenil (FMZ)-positron emission tomography (PET) imaging, 15 children (aged 1-8 years) with medically intractable epilepsy were studied. Seven of these children were treated with VGB (1,000-2,500 mg/day) for > or =3 months before the FMZ-PET study. The remaining eight patients were medicated with other drugs that are known not to act directly on the GABAergic system. Absolute quantification of PET data was performed by using the volume of distribution (VD) of FMZ in brain tissue representing FMZ ligand binding. RESULTS: After controlling for age, hemispheric FMZ VD values were significantly lower in children treated with VGB as compared with the non-VGB group (p = 0.012). Regional FMZ VD values of the VGB-treated patients were significantly lower in all cortical regions and the cerebellum, whereas the difference was not significant in the thalamus and basal ganglia. No significant drug effect or drug-by-region interaction could be determined when the patients were separated according to treatment with carbamazepine (p = 0.97) or valproate (p = 0.55). CONCLUSIONS: VGB induces a decrease in GABA(A)-receptor binding in the cortex and cerebellum of the developing epileptic brain. A similar effect of other drugs and substances of abuse targeting the GABAergic system may be hypothesized. Because of the important role of the GABAergic system in developmental plasticity, the reversibility and functional consequences of this age-specific drug effect should be further studied.

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.

Neuroradiological assessment of brain structure and function and its implication in the pathogenesis of West syndrome.

Neuroimaging studies with magnetic resonance imaging (MRI) and positron emission tomography (PET) scanning have contributed significantly to our understanding of West syndrome. Cortical dysplastic lesions are the most common abnormalities seen with MRI in infants with spasms, but other structural lesions are also detected occasionally. An underlying cortical dysplasia may not be apparent until myelination has advanced in the brain and poor gray-white matter differentiation becomes observable. Many cortical dysplastic lesions can only be detected using PET scanning of glucose metabolism or gamma-aminobutyric acid(A) (GABA(A)) receptor binding. The MRI and PET findings, together with neurophysiological observations, strongly suggest that infantile spasms are initiated as cortical epileptic discharges that, during a 'critical' developmental period, may undergo secondary generalization in an age-dependent mechanism to emerge as spasms. The onset of spasms often coincides with the functional maturation of cerebral cortex. Based on data from glucose metabolism PET scanning as well as electrophysiological and neurochemical findings on infants with spasms, we have postulated that the offending lesion is a focal or diffuse cortical abnormality which, at a critical stage of maturation, causes abnormal functional interactions with brainstem raphe nuclei which project widely throughout the brain. Raphe-cortical projections could mediate the hypsarrhythmic changes seen on EEG. The prominent serotonergic raphe-striatal pathway and descending spinal pathways may be responsible for secondary generalization of the cortical discharges to result in the relatively symmetric spasms. It is likely that additional factors (e.g. genetic) play a role in the manifestation of the age-specific electroclinical features of West syndrome. Recently developed PET tracers can be used to detect epileptogenic brain regions and also to investigate developmental abnormalities of serotonergic (using the tracer alpha[(11)C]methyl-L-tryptophan) and GABAergic (using [(11)C]flumazenil) neurotransmitter systems. These systems are implicated in epileptogenesis, and their involvement in the pathophysiology of West syndrome can be further addressed by future functional neuroimaging studies.

Surgical treatment of West syndrome.

The discovery of focal or multifocal cortical lesions using magnetic resonance imaging (MRI) and positron emission tomography (PET) scanning in the majority of infants with West syndrome has led to a surgical approach in the treatment of some patients with intractable infantile spasms. The locations of these lesions should be concordant with localization of focal ictal and/or interictal electroencephalographic (EEG) abnormalities prior to proceeding with cortical resection. When a single lesion is present on the MRI or PET, and there is good correlation with EEG localization, surgical treatment is generally quite favorable in terms of both seizure control and cognitive development. Interictal glucose metabolism PET scans in children with intractable cryptogenic infantile spasms show unifocal cortical hypometabolism in about 20% of cases. In the majority, however, multifocal asymmetric hypometabolism is suggestive of multifocal underlying lesions, possibly multifocal cortical dysplasia. When the pattern of glucose hypometabolism is symmetric, a lesional etiology is less likely, thus neurometabolic or neurogenetic disorders should be considered. Therefore, the pattern of glucose hypometabolism on PET in infants with intractable cryptogenic spasms is a useful guide to decide whether a medical or surgical approach should be undertaken. In order to achieve the best cognitive outcome with surgery, it is important to resect the entire 'nociferous' area rather than just the seizure focus. Our research with new PET imaging probes has attempted to provide a comprehensive evaluation of the epileptogenic zone including the 'nociferous' cortex. We have used [(11)C]flumazenil (FMZ), which labels gamma aminobutyric acid(A) (GABA(A)) receptors, and have found this to be particularly useful in showing: (i) decreased receptor binding with medial temporal involvement thus indicating resection of medial temporal structures, (ii) the peri-lesional epileptogenic zone surrounding MRI lesions, (iii) the seizure onset zone in MRI-negative cases, and (iv) potential secondary epileptic foci. Another recently developed PET probe, alpha[(11)C]methyl-L-tryptophan (AMT) which is a precursor for the serotonin and the kynurenine metabolism pathways, is capable of differentiating between epileptogenic and non-epileptogenic tubers in patients with tuberous sclerosis complex and intractable epilepsy (including infantile spasms). Subsequently, we have applied AMT PET in patients with multifocal cortical dysplasia to determine the predominant seizure focus, and the results have been promising with regard to seizure control but not cognitive development. Thus, the introduction of newer more specific PET probes for epilepsy has led to improved and more accurate localization of seizure foci that should ultimately improve outcome of epilepsy surgery in West syndrome.

Autism in tuberous sclerosis complex is related to both cortical and subcortical dysfunction.

OBJECTIVE: To examine the relationship between autism and epilepsy in relation to structural and functional brain abnormalities in children with tuberous sclerosis complex (TSC). METHODS: Children with TSC and intractable epilepsy underwent MRI as well as PET scans with 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) and alpha-[(11)C]methyl-L-tryptophan (AMT). Based on the results of Autism Diagnostic Interview-Revised, Gilliam Autism Rating Scale, and overall adaptive behavioral composite (OABC) from Vineland Adaptive Behavior Scale, subjects were divided into three groups: autistic (OABC < 70; n = 9), mentally-retarded nonautistic (OABC < 70; n = 9), and relatively normal intelligence (OABC > or = 70; n = 8). RESULTS: PET studies showed that the autistic group had decreased glucose metabolism in the lateral temporal gyri bilaterally, increased glucose metabolism in the deep cerebellar nuclei bilaterally, and increased AMT uptake in the caudate nuclei bilaterally, compared to the mentally-retarded nonautistic group. In addition, a history of infantile spasms and glucose hypometabolism in the lateral temporal gyri were both significantly associated with communication disturbance. Glucose hypermetabolism in the deep cerebellar nuclei and increased AMT uptake in the caudate nuclei were both related to stereotypical behaviors and impaired social interaction, as well as communication disturbance. CONCLUSIONS: These results suggest that generalized epilepsy in early life and functional deficits in the temporal neocortices may be associated with communication delays, and that functional imbalance in subcortical circuits may be associated with stereotypical behaviors and impaired social interaction in children with TSC.

Bilateral medial prefrontal and temporal neocortical hypometabolism in children with epilepsy and aggression.

PURPOSE: To identify brain regions with abnormal function in children with intractable partial epilepsy and aggressive behavior by using 2-deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography (PET). METHODS: Six children (mean age, 9.9 years) with intractable partial epilepsy and aggressive behavior underwent detailed psychodevelopmental assessment and FDG-PET scanning. The objective technique of statistical parametric mapping (SPM) was applied to define focal abnormalities of glucose metabolism, and compared those with those of a group of normal adult subjects (n = 17) as well as age-matched children with epilepsy with similar seizure characteristics but without aggression (n = 7). The findings were analyzed further by using a region-of-interest (ROI) approach. RESULTS: The aggressive children all showed developmental delay, and four of them also manifested autistic symptoms. SPM analysis demonstrated extensive glucose hypometabolism in the aggressive group bilaterally in the temporal and prefrontal cortex compared with that in normal adult controls. A focal area of medial prefrontal glucose hypometabolism was defined in the aggressive children as compared with the nonaggressive pediatric group with SPM, whereas ROI comparison of these groups confirmed prefrontal hypometabolism and also showed glucose hypometabolism of the temporal neocortex in the aggressive children. Severity of aggression correlated inversely with glucose metabolism of the left temporal as well as bilateral medial prefrontal cortex. CONCLUSIONS: Bilateral prefrontal and temporal neocortical brain glucose hypometabolism in children with epilepsy and aggressive behavior may indicate a widespread dysfunction of cortical regions, which normally exert an inhibitory effect on subcortical aggressive impulses. PET studies may be used to elucidate the neurobiologic basis of aggressive behavior in children.

Sturge-Weber syndrome: correlation between clinical course and FDG PET findings.

OBJECTIVE: To determine whether the extent and degree of glucose hypometabolism defined by PET correlate with seizure characteristics, cognitive function, and interictal EEG abnormalities in children with unilateral cerebral involvement of Sturge-Weber syndrome (SWS). METHODS: 2-Deoxy-2[18F]fluoro-D-glucose (FDG) PET was performed in 13 children (age range 0.7 to 15.1 years; five boys, eight girls) with unilateral SWS. Based on asymmetries between homologous cortical areas in FDG PET images, cortical areas of mildly (10% to 20% decrease), and severely (>20% decrease) asymmetric cortical metabolism were defined. These areas were normalized to the size of the ipsilateral hemisphere and correlated with clinical seizure characteristics, full-scale IQ, and interictal EEG abnormalities. RESULTS: Both seizure frequency (p = 0.027) and lifetime number of seizures (p = 0.017) showed a positive correlation with the area (expressed as the percentage of cortical area of ipsilateral hemisphere) of mildly asymmetric cortical metabolism. Patients with higher IQ had a shorter duration of epilepsy (p = 0.044) and a larger area of severely asymmetric cortical metabolism (p = 0.044). Patients with bilateral interictal EEG abnormalities had larger lifetime number of seizures (p = 0.042), lower IQ (p = 0.024), and smaller area of severely asymmetric cortical metabolism (p = 0.019) than those with only ipsilateral EEG abnormalities. CONCLUSIONS: Association of severely asymmetric cortical metabolism with relatively preserved cognitive function in SWS suggests that functional reorganization occurs more readily when cortex is severely rather than mildly damaged. Therefore, the area of mildly asymmetric cortical metabolism may exert a nociferous effect on the remaining of the brain. Thus, the extent and degree of glucose asymmetry detected by PET are sensitive markers of seizure severity and cognitive decline in SWS.

A study of novel polymorphisms in the upstream region of vasoactive intestinal peptide receptor type 2 gene in autism.

We investigated the vasoactive intestinal peptide receptor type 2 (VIPR2) gene as a candidate gene for autism. We searched for mutations in the VIPR2 gene in autistic individuals, and 10 novel polymorphisms were identified. Three polymorphisms in the upstream region were studied in detail, and there was no significant difference in the frequencies between the autistic group (n = 14) and unrelated controls (n = 52). The distribution of the genotypes in two of the three polymorphisms differed somewhat between autistic subjects with gastrointestinal problems and those without. Moreover, there was a trend showing a correlation between the genotypes for the third polymorphism and the severity of stereotypical behavior as ranked by the Gilliam Autism Rating Scale. These preliminary results suggest that VIPR2 may have a role in gastrointestinal symptoms and stereotypical behaviors in autism, although a larger collection of samples suitable for transmission disequilibrium tests is necessary to validate the results.

Relationship of flumazenil and glucose PET abnormalities to neocortical epilepsy surgery outcome.

BACKGROUND: Cortical areas showing abnormal glucose metabolism and [(11)C]flumazenil (FMZ) binding are commonly seen on PET scans of patients with intractable partial epilepsy, but it is unclear whether these must be totally resected to achieve seizure control. OBJECTIVE: To analyze whether the extent of cortex showing 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) or FMZ PET abnormalities correlates with the outcome of resective epilepsy surgery. METHODS: Cortical FDG and FMZ PET abnormalities in 15 young patients (mean age, 12.2 +/- 7.0 years) with intractable partial epilepsy of neocortical origin were marked as regions with abnormal asymmetry using an objective semiautomated software package. These marked regions were then projected and measured on the brain surface reconstructed from the coregistered high-resolution MRI. Following cortical resection, the size of nonresected cortex with preoperative PET abnormalities was also measured (calculated separately for marked areas in the lobe of seizure onset as defined by long-term video EEG monitoring, and in remote cortical areas). Extent of preoperative PET abnormalities and postoperative nonresected cortex abnormalities on PET were correlated with outcome scores. RESULTS: Large preoperative FMZ PET abnormalities were associated with poor outcome (r = 0.57; p = 0.025). Larger areas of nonresected cortex with preoperative FMZ PET abnormalities in the lobe of seizure onset were also associated with worse outcome in the whole group (r = 0.66; p = 0.007) as well as in patients with extratemporal resection (r = 0.73; p = 0.007), and in those with no lesion on MRI (r = 0.60; p = 0.049). Patients with seizure-free outcome had significantly smaller nonresected cortex with preoperative FMZ PET abnormalities than those who continued to have seizures (p = 0.022). No significant correlations between nonresected FDG PET abnormalities and surgical outcome were found. CONCLUSIONS: Extensive cortical abnormalities on FMZ PET predict poor outcome in neocortical epilepsy surgery. Resection of FMZ abnormalities in the lobe of seizure onset is associated with excellent outcome even in the absence of a structural lesion. In contrast, although FDG PET abnormalities regionalized the epileptogenic area, their size was not related to the extent of epileptogenic tissue to be removed.

Postnatal maturation of human GABAA receptors measured with positron emission tomography.

During brain development in nonhuman primates, there are large changes in GABAA receptor binding and subunit expression. An understanding of human GABAA receptor ontogeny is highly relevant in elucidating the pathophysiology of neurodevelopmental disorders in which GABAergic mechanisms play a role as well as in understanding differences that occur during development in the pharmacology of drugs acting on this system. We have measured age-related changes in the brain distribution of the GABAA receptor complex in vivo using positron emission tomography (PET) in epileptic children under evaluation for surgical treatment. PET imaging was performed using the tracer [11C]flumazenil (FMZ), a ligand that binds to alpha subunits of the GABAA receptor. FMZ binding was quantified using a two-compartment model yielding values for the volume of distribution (VD) of the tracer in tissue. All brain regions studied showed the highest value for FMZ VD at the youngest age measured (2 years), and the values then decreased exponentially with age. Medial temporal lobe structures, primary visual cortex, and thalamus showed larger differences between values for age 2 years and adults (approximately 50% decrease) than did basal ganglia, cerebellum, and other cortical regions (25-40% decreases). Furthermore, subcortical regions reached adult values earlier (14-17.5 years) than did cortical regions (18-22 years). The ontogeny data of FMZ VD from children may contribute to understanding regional differences in synaptic plasticity as well as improve rational therapeutic use of drugs acting at the GABAA receptor in the pediatric population.