Faculty Bibliography

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.

Although several studies exist which have examined static functional neuroimaging following traumatic brain injury (TBI), controlled cognitive activation studies of episodic memory in this population have not been published. The present investigation studied verbal recall using [O-15]-water positron emission tomography (PET) in 5 individuals who sustained severe TBI (M GCS=6.8; M years post-injury=3.18), and 4 non-injured control participants. Statistical image analysis demonstrated changes in frontoparietal regional cerebral blood flow (rCBF) in both groups, but there were interesting differences between groups and across conditions. Frontal lobe rCBF changes in TBI patients were reduced during free recall but enhanced during recognition, when compared to controls. Changes in cerebellar rCBF were observed in the control group during free recall, but not in the TBI sample. In both groups, bifrontal rCBF increases were noted on recognition tasks. The present findings provide evidence of alterations in specific substrates involved in verbal recall following brain injury.

BACKGROUND:In classical lissencephaly, the cerebral cortex is four-layered, containing neurons that have failed to complete their migration between 12 and 16 weeks of gestation. METHODS:The authors studied the functional activity of lissencephalic cortex using 2-deoxy-2[(18)F]fluoro-D-glucose PET (FDG PET) in eight patients (six girls and two boys, mean age 7.5 years) with isolated lissencephaly sequence. RESULTS:The PET scans revealed a remarkably similar and bilaterally symmetric pattern of glucose metabolism in all eight patients. The cerebral cortex of lissencephaly showed two layers that could be differentiated based on metabolic activity. The inner layer, which probably corresponds to the inner cellular layer of lissencephalic cortex, showed 8 to 63% higher glucose utilization rate than the outer layer, which probably represents a composite of the molecular, outer cellular, and cell-sparse layers. Patients with a higher metabolic ratio between the cortical layers (inner/outer) showed greater delay in communication (p = 0.007) and socialization (p = 0.03). CONCLUSIONS:These findings are consistent with [(14)C]-2-deoxyglucose autoradiography studies in fetal sheep that have shown that before the development of significant numbers of axons, dendrites, and synapses, glucose metabolism appears to be highest in regions with the highest density of cell bodies, compared to the more mature state when glucose metabolism is highest in areas of greatest dendritic arborization. FDG PET studies of classical lissencephaly provide a different perspective in the analysis of brain gyral anomalies than those with traditional neuroanatomic imaging techniques.

Our results and those of others demonstrate that the development of new PET probes with increasing sensitivity and specificity for epileptogenic brain regions is feasible. Further development of novel tracers guided by knowledge of the biochemical characteristics of epileptogenic cortex from basic studies is the logical next step in the application of neuroimaging to localize epileptogenic cortex. Furthermore, computational advances allowing coregistration of biochemical images with high-resolution MRI anatomic images, as well as electrophysiologic data sets, not only has practical value in guiding surgical resection of epileptogenic neocortex, but this approach contributes to further understanding of the biochemical mechanisms involved in the pathophysiology of neocortical epilepsy.

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.

OBJECTIVE:To analyze the clinical utility of [11C]flumazenil (FMZ) PET to detect perilesional and remote cortical areas of abnormal benzodiazepine receptor binding in relation to MRI, 2-deoxy-2-[18F]fluoro-d-glucose (FDG) PET, and electrocorticographic (ECoG) findings as well as clinical characteristics of the epilepsy in epileptic patients with brain lesion. BACKGROUND:The success of resective surgery in patients with medically intractable epilepsy and brain lesion depends not only on removal of the lesion itself but also on the reliable presurgical delineation of the epileptic cortex that commonly extends beyond it. PET could provide a noninvasive identification of such epileptogenic areas. METHODS:Seventeen patients underwent high resolution MRI, FDG and FMZ PET, and presurgical EEG evaluation, including chronic intracranial ECoG monitoring or intraoperative ECoG. Regional cortical FDG/FMZ PET abnormalities were defined on partial volume-corrected PET images using an objective method based on a semiautomated definition of areas with abnormal asymmetry. Structural lesions were defined on coregistered MRI. The marked PET abnormalities visualized on three-dimensional cortical surface were compared with each other, to the extent of MRI-defined lesion, as well as to ECoG findings. RESULTS:The mean surface extent of FMZ PET abnormalities was significantly larger than the corresponding structural lesions, but it was significantly smaller than areas of glucose hypometabolism. The size of perilesional FDG PET abnormalities showed a correlation with the lifetime number of seizures (r = 0.93, p = 0.001). The extent of perilesional FMZ PET abnormalities was independent of the seizure number and showed an excellent correspondence with spiking cortex, the resection of which resulted in seizure-free outcome in all but one operated patient. Remote FMZ PET abnormalities (n = 6) were associated with early age at seizure onset (p = 0.048) and appeared in ipsilateral synaptically connected regions from the lesion area. CONCLUSIONS:Three-dimensional surface-rendered FMZ PET is able to delineate perilesional epileptic cortex, and it may be especially useful to localize such areas in patients with extensive perilesional glucose hypometabolism associated with a large number of seizures. Remote FMZ PET abnormalities in patients with early onset and long duration of epilepsy might represent secondary epileptogenesis, but this requires further study.

OBJECTIVE:Using interictal alpha-[11C]methyl-l-tryptophan ([11C]AMT) PET scan, the authors have undertaken a quantitative analysis of all tubers visible on MRI or 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) PET, to determine the relationship between [11C]AMT uptake and epileptic activity on EEG. BACKGROUND:Tuberous sclerosis complex (TSC) is an autosomal dominant disorder, often associated with cortical tubers and intractable epilepsy. The authors have shown previously that [11C]AMT PET scans show high tracer uptake in some epileptogenic tubers and low uptake in the remaining tubers. METHODS:Eighteen children, age 7 months to 16 years, were studied. Patients underwent video-EEG monitoring, PET scans of [11C]AMT and [18F]FDG, and T2-weighted or fluid-attenuated inversion recovery (FLAIR) MRI. [11C]AMT uptake values were measured in 258 cortical tubers delineated with coregistered MRI or [18F]FDG scans. Uptake ratios were calculated between the [11C]AMT uptake in tubers and those for normal cortex (tuber/normal cortex). Using the region of epileptiform activity, the authors performed receiver operator characteristics (ROC) analysis and determined the optimal uptake ratio for detecting presumed epileptogenic tubers. RESULTS:Tuber uptake ratios ranged from 0.6 to 2.0. Tuber uptake ratios in the epileptic lobes were higher than those in the nonepileptic lobes (p < 0.0001). All 15 patients with focal seizure activity showed one or more lesions with uptake ratio above 0.98 in the epileptic lobe. ROC analysis showed that a tuber uptake ratio of 0.98 resulted in a specificity of 0.91. CONCLUSIONS:Cortical tubers with [11C]AMT uptake greater than or equal to normal cortex are significantly related to epileptiform activity in that lobe. Together, interictal [11C]AMT PET and FLAIR MRI improve the detection of potentially epileptogenic tubers in patients with TSC being evaluated for epilepsy surgery.

The purpose of this study was to examine the relation between glucose metabolism and glutamate concentration in the human brain, in both the normal and diseased state. Regional values of glucose metabolism measured with 2-deoxy-2[F-18]fluoro-D-glucose positron emission tomography (FDG PET) studies and single-voxel proton magnetic resonance spectroscopy (1H MRS) measurements of the glutamate/ glutamine/gamma-aminobutyric acid (Glx) tissue concentration were determined in multiple brain regions in 11 patients (5 girls and 6 boys, mean age 7.5 years) with medically intractable partial epilepsy. FDG PET and 1H MRS studies were performed in the interictal state in seven patients and in the ictal/periictal state in four patients. Regions of interest were identified in epileptic cortex (determined by intracranial and/or scalp electroencephalography) and in contralateral normal brain regions. Lower glucose metabolism and lower Glx concentrations were found in the epileptic focus than in the contralateral normal cortex in all seven patients examined in the interictal state, whereas higher glucose metabolism and higher Glx concentrations were observed in the epileptic focus in the four patients who had ictal/periictal studies. Significant correlations were found between the values of cerebral glucose utilization and Glx concentration in epileptic brain region, in nonepileptic brain regions, and in epileptic and nonepileptic regions combined. These results demonstrate a significant relation between glucose metabolism and glutamate/glutamine concentration in normal and epileptic cerebral cortex. This relation is maintained in both the interictal and ictal states.

Positron emission tomography (PET) of glucose metabolism is often applied for the localization of epileptogenic brain regions, but hypometabolic areas are often larger than or can miss epileptogenic cortex in nonlesional neocortical epilepsy. The present study is a three-dimensional brain surface analysis designed to demonstrate the functional relation between glucose PET abnormalities and epileptogenic cortical regions. Twelve young patients (mean age, 10.8 years) with intractable epilepsy of neocortical origin underwent chronic intracranial electroencephalographic monitoring. The exact location of the subdural electrodes was determined on high-resolution three-dimensional reconstructed magnetic resonance imaging scan volumes. The electrodes were classified according to their locations over cortical areas, which were defined as hypometabolic, normometabolic, or at the border between hypometabolic and normal cortex (metabolic "border zones") based on interictal glucose PET. Electrodes with seizure onset were located over metabolic border zones significantly more frequently than over hypometabolic or normometabolic regions. Seizure spread electrodes also more frequently overlay metabolic border zones than hypometabolic regions. These findings suggest that cortical areas with hypometabolism should be interpreted as regions mostly not involved in seizure activity, although epileptic activity commonly occurs in the surrounding cortex. This feature of hypometabolic cortex is remarkably similar to that of structural brain lesions surrounded by epileptogenic cortex. Cortical areas bordering hypometabolic regions can be highly epileptogenic and should be carefully assessed in presurgical evaluations.