Faculty Bibliography

In vitro and in vivo parameters of flumazenil (FMZ) binding were measured in spiking and nonspiking neocortex identified by intraoperative electrocorticography in epileptic patients who underwent cortical resection for seizure control. In vitro measures of receptor affinity (K(D)), number (Bmax) and laminar distribution for [3H]-FMZ binding in the epileptic focus (n = 38) were compared to nonspiking cortex from a subgroup of the patients (n = 12) and to tissue obtained from trauma patients (n = 5). The in vitro binding parameters were compared to in vivo [11C]-FMZ binding measured with positron emission tomography (PET) (n = 19). The Bmax was higher in the 38 spiking tissues as compared to the 12 nonspiking tissues (P = .012). Paired comparison of spiking versus nonspiking binding in the 12 patients from whom nonspiking tissue was available showed increases in both K(D) (P = .037) and Bmax (P = .0047) in spiking cortex. A positive correlation was found between K(D) and Bmax values for 38 patients (r = 0.55, P < .0001), the magnitude of the K(D) increase being twice that of the Bmax increase. In addition, there was a significant correlation between the asymmetry indices of the in vivo FMZ binding on PET and in vitro K(D) of spiking cortex (n = 19, r = 0.52, P = .02). The laminar distribution of [3H]-FMZ showed increased FMZ binding in cortical layers V-VI in spiking cortex compared to nonspiking and control cortex. The increased receptor number in spiking cortical layers V-VI may be a compensatory mechanism to decreased GABAergic input. The increased Bmax in spiking cortex was accompanied by a larger decrease in the affinity of FMZ for the receptor suggesting that decreased FMZ binding in the epileptic focus measured with PET is due to a decrease in the affinity of the tracer for the receptor.

Positron emission tomography (PET) is an accurate and relatively noninvasive way of studying brain activity using systemically administered tracers labeled with positron emitting isotopes. In pediatric neurology, it has great scope not only to elucidate the complexities of the developing brain but also to understand disease processes and characterize biological risk factors. Its greatest clinical utility lies in the field of epilepsy where it is used (in patients with intractable partial epilepsy) to localize epileptogenic foci for surgical resection. In addition, functional brain mapping using PET is increasingly being used to reliably and accurately identify speech and sensory-motor areas to minimize postoperative morbidity. PET is also useful in evaluating neurodegenerative disorders and cognitive abnormalities when magnetic resonance imaging scans are unrevealing. The technology continues to progress rapidly through improvements in imaging and radiopharmacology with potential applications in neurooncology, cerebral vascular disease, and metabolic diseases.

1. There is evidence for pronounced brain plasticity during postnatal maturation. The authors hypothesized that left-hemisphere lesion would be associated with greater than normal language participation of the right hemisphere and that atypical asymmetry of perisylvian language activations would be enhanced after lesion occurring in early childhood as compared to lesion occurring later in life. 2. Eleven patients with left-hemisphere lesion (aged 8-33 yrs.) and 9 normal adult comparison subjects were studied, using [15O]-water positron emission tomography. One patient group (N = 6) had early lesion onset (< or = 6 years of age), a second group (N = 5) had lesion onset later in life (> or = 10 years of age). Regional cerebral blood flow (rCBF) changes during listening to sentences (minus rest) and sentence generation (minus repetition) were compared between groups in predefined regions of interest. 3. Variance of regional activations within early and late lesion onset groups was considerable and qualitative inspection revealed only few robust group differences. However, when 4 patient pairs were approximately matched for chronological age, lesion site and VIQ, significantly reduced leftward asymmetry of activations in early lesion patients was found in the prefrontal, inferior frontal, and inferior parietal regions for expressive language, with concordant and marginally significant trends in the inferior frontal and superior temporal regions for receptive language. 4. The results suggest enhanced postlesional plasticity in childhood, while also reflecting strong individual variability probably due to clinical and demographic factors beside lesion onset.

1. The authors present here a 5-parameter developmental function designed to describe quantitatively the time-course of changes in glucose metabolism with age. This function consists of a plateau phase which is described by the rate of increase with age and the height of the plateau, followed by a decline phase characterized by the rate of decrease to adult levels. These two phases are separated by a distinct point in time, at which the transition between the two phases occurs. 2. The model is designed to fit published data showing that glucose metabolic rate in frontal cortex at birth is about 60% of adult values (mean adult value is 24 mumol/100 g/min) and increases to slightly less than triple adult value by age 3. The metabolic rate remains at this level until the age of approximately 8 years when it starts the decline to adult values. 3. A procedure is presented which allows the approximate computation of the 98% confidence contours in data space for the developmental function. The computation is based on the joint probability function obtained from the model covariance matrix. 4. The newly designed 5-parameter developmental function is well suited to describe maturational changes of glucose metabolism. Due to its excellent model identifiability and the interpretability of individual parameters, this function is better suited for description of maturational changes than the gamma-function. Furthermore, this function may provide a useful framework for interpretation of other data sets during development.

PURPOSE/OBJECTIVE:Coexistence of hippocampal sclerosis and a potentially epileptogenic cortical lesion is referred to as dual pathology and can be responsible for poor surgical outcome in patients with medically intractable partial epilepsy. [11C]Flumazenil (FMZ) positron emission tomography (PET) is a sensitive method for visualizing epileptogenic foci. In this study of 12 patients with dual pathology, we addressed the sensitivity of FMZ PET to detect hippocampal abnormalities and compared magnetic resonance imaging (MRI) with visual as well as quantitative FMZ PET findings. METHODS:All patients underwent volumetric MRI, prolonged video-EEG monitoring, and glucose metabolism PET before the FMZ PET. MRI-coregistered partial volume-corrected PET images were used to measure FMZ-binding asymmetries by using asymmetry indices (AIs) in the whole hippocampus and in three (anterior, middle, and posterior) hippocampal subregions. Cortical sites of decreased FMZ binding also were evaluated by using AIs for regions with MRI-verified cortical lesions as well as for non-lesional areas with visually detected asymmetry. RESULTS:Abnormally decreased FMZ binding could be detected by quantitative analysis in the atrophic hippocampus of all 12 patients, including three patients with discordant or inconclusive EEG findings. Decreased FMZ binding was restricted to only one subregion of the hippocampus in three patients. Areas of decreased cortical FMZ binding were obvious visually in all patients. Decreased FMZ binding was detected visually in nonlesional cortical areas in four patients. The AIs for these nonlesional regions with visual asymmetry were significantly lower than those for regions showing MRI lesions (paired t test, p = 0.0075). CONCLUSIONS:Visual as well as quantitative analyses of FMZ-binding asymmetry are sensitive methods to detect decreased benzodiazepine-receptor binding in the hippocampus and neocortex of patients with dual pathology. MRI-defined hippocampal atrophy is always associated with decreased FMZ binding, although the latter may be localized to only one sub-region within the hippocampus. FMZ PET abnormalities can occur in areas with normal appearance on MRI, but FMZ-binding asymmetry of these regions is lower when compared with that of lesional areas. FMZ PET can be especially helpful when MRI and EEG findings of patients with intractable epilepsy are discordant.

Functional neuroimaging studies have shown enhanced right-hemisphere language activations in adults with left-hemisphere damage. We hypothesized that this effect would be stronger in patients with lesion occurring early in development. Using [15O]-water PET, we studied eight normal adults and 23 patients with unilateral left lesion during rest, listening to sentences, and sentence repetition. Thirteen patients had lesions with early onset (< 5 years) and ten had lesions with late onset (> 20 years). For listening to sentences, frontotemporal blood flow increases were significantly stronger in the left than in the right hemisphere in normal adults. This normal asymmetry was reduced in patients with late lesion and reversed in those with early lesion. For sentence repetition, analogous group differences were significant for the basal ganglia, but failed to reach significance for the (pre)motor and insular regions. We conclude that left lesion leads to alterations in the asymmetry of language activations (in and beyond the perisylvian areas). In addition, rightward shifts of language activation tend to be stronger as a consequence of early (as compared to late) lesion. Finally, postlesional reorganization appears to reflect a coexistence of 'additive' and 'subtractive' effects, i.e., activation in some regions that are not normally involved in language processing and lack of activation in other (undamaged) regions that are normally activated by language tasks.