Faculty Bibliography

OBJECTIVE:To measure brain serotonin synthesis with PET using the tracer alpha-[11C]methyl-L-tryptophan in migraine patients. BACKGROUND:Although the cause of migraine remains poorly understood, there is considerable evidence to support a role of the neurotransmitter serotonin in the pathophysiology of migraine. METHODS:We studied 11 women (aged 33+/-7.7 years) with a diagnosis of migraine according to International Headache Society criteria and 8 healthy women (aged 29+/-9.2 years). Five patients were studied before and after chronic treatment with propranolol or nadolol. RESULTS:Serotonin synthesis capacity (K-complex) values in migraine patients were higher than those measured in controls throughout the brain (p = 0.016); mean K-complex for whole brain was 0.0077 + 0.0020 mL/g/min in patients with migraine and 0.0054+/-0.0003 mL/g/min in controls. The regional pattern did not differ between the two groups. However, the K-complex for whole brain in the subgroup of migraine patients with aura (n = 3) did not differ from that of the control group (p = 0.32). In the five patients studied twice (before and after treatment), we found a trend of increased whole-brain K-complex after drug treatment (p = 0.06). CONCLUSIONS:Our findings indicating increased brain serotonin synthesis capacity in migraine patients are consistent with previous reports of systemic alteration of serotonin metabolism in patients without aura. Our results also suggest that the mechanism of action of beta-adrenergic antagonists for migraine prophylaxis may involve regulation of serotonin synthesis.

OBJECTIVES/OBJECTIVE:To analyze interictal patterns of thalamic nuclei glucose metabolism and benzodiazepine receptor binding in patients with medically intractable temporal lobe epilepsy (TLE) using high-resolution 2-deoxy-2-[18F]fluoro-D-glucose (FDG) and [11C]flumazenil (FMZ) PET. BACKGROUND:Structural and glucose metabolic abnormalities of the thalamus are considered important in the pathophysiology of TLE. The differential involvement of various thalamic nuclei in humans is not known. METHODS:Twelve patients with TLE underwent volumetric MRI, FDG and FMZ PET, and prolonged video-EEG monitoring. Normalized values and asymmetries of glucose metabolism and FMZ binding were obtained in three thalamic regions (dorsomedial nucleus [DMN], pulvinar, and lateral thalamus [LAT]) defined on MRI and copied to coregistered, partial-volume-corrected FDG and FMZ PET images. Hippocampal and amygdaloid FMZ binding asymmetries and thalamic volumes also were measured. RESULTS:The DMN showed significantly lower glucose metabolism and FMZ binding on the side of the epileptic focus. The LAT showed bilateral hypermetabolism and increased FMZ binding. There was a significant correlation between the FMZ binding asymmetries of the DMN and amygdala. The PET abnormalities were associated with a significant volume loss of the thalamus ipsilateral to the seizure focus. CONCLUSIONS:Decreased [11C]flumazenil (FMZ) binding and glucose metabolism of the dorsomedial nucleus (DMN) are common and have strong lateralization value for the seizure focus in human temporal lobe epilepsy. Decreased benzodiazepine receptor binding can be due to neuronal loss, as suggested by volume loss, but also may indicate impaired gamma-aminobutyric acid (GABA)ergic transmission in the DMN, which has strong reciprocal connections with other parts of the limbic system. Increased glucose metabolism and FMZ binding in the lateral thalamus could represent an upregulation of GABA-mediated inhibitory circuits.

UNLABELLED:[11C]flumazenil (FMZ) imaged with PET allows the computation of parametric images of both tracer influx (K1) and volume of distribution (VD). The VD images, which allow visualization of a quantitative measure of benzodiazepine receptor binding, are reported to have high sensitivity and specificity for the delineation of epileptic foci. However, the clinical feasibility of this method is compromised by the necessity of arterial blood sampling. We therefore compared the performance of parametric VD images against simple FMZ activity images for the detection of neocortical epileptic foci. METHODS:FMZ PET data from 7 children with extratemporal lobe epilepsy (mean age [+/- SD] 9.8+/-4.4 y) and 6 healthy adult volunteers (mean age [+/- SD] 40+/-8 y) were analyzed using a semiautomated analysis algorithm. FMZ activity images and parametric VD images were analyzed for asymmetry with cutoff thresholds of 8%, 10% and 12%. RESULTS:The time frame between 10 and 20 min after injection represented overall the best agreement between FMZ activity and VD images independent of the threshold. The normal asymmetry in VD images was determined as 6.4%+/-1.4% and was significantly higher in the FMZ activity images (7.6%+/-1.4%, P = 0.001). Increasing the cutoff threshold resulted in a significant decrease in the area defined as abnormal in both the VD and the FMZ activity images. Abnormalities defined in FMZ activity images identified additional brain regions as abnormal at the 8% threshold, but there was good agreement with VD images at the 10% asymmetry threshold. In those regions where abnormalities in VD and FMZ activity images were not matched, the asymmetry indices obtained from K1 images were significantly higher than those derived from the VD images (P = 0.01). CONCLUSION/CONCLUSIONS:Differences between VD and activity images above the 8% threshold are mainly due to K1. Abnormalities defined in FMZ activity images using a threshold of 10% agree well with those obtained from parametric VD images, indicating that activity images obtained from the time frame of 10-20 min are essentially equivalent to VD images with regard to detection of regions of abnormality for seizure focus localization.

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.

PURPOSE/OBJECTIVE:Intermittent photic stimulation (IPS) is an activation procedure used during electroencephalogram (EEG) recording to elicit paroxysmal discharges in individuals with photosensitivity. Specific responses on EEG recording may be provoked by IPS at different frequencies of flickering in normal individuals and in patients with photosensitive epilepsy. METHODS:Changes in regional cerebral blood flow (rCBF) were studied during IPS in two groups of subjects by using [15O]-water positron emission tomography (PET): a control group consisting of eight healthy adults with photic driving response during IPS on EEG recording (mean age, 25 +/- 10.5 years) without history of neurologic or psychiatric abnormalities and a patient group consisting of four adults (mean age, 33 +/- 7.5 years) with history of photosensitive epilepsy. [15O]-water PET scanning with concomitant EEG monitoring was performed during baseline and IPS at 4-, 14-, and 30-Hz frequencies. RESULTS:The control group showed photic driving response at 14-Hz IPS frequency. The patient group showed photoparoxysmal response at 14 and 30 Hz, but not at 4 Hz. Changes in rCBF were determined by means of statistical parametric mapping. Increases in rCBF in occipital cortex (Brodmann's areas 17, 18, and 19) were observed in both groups. In addition, during photic driving responses, the control group showed rCBF increases in the insula and in the thalamus, on the right side. The patient group showed a significant rCBF increase in the hypothalamic region inferior to the left caudate nucleus during photoparoxysmal response. This activation was not found in the control group. Increased rCBF also was observed in the patient group in the head of the left caudate nucleus, in the left hippocampus, and in left insula during IPS without photoparoxysmal response. No activations in these regions were observed during photoparoxysmal response. CONCLUSIONS:These data may indicate involvement of the hypothalamus in photosensitive epilepsy and may suggest a modulatory function of the caudate nucleus, which might be associated with an inhibition of epileptic discharges during IPS in patients with photosensitive epilepsy.