Faculty Bibliography

Local cerebral serotonin synthesis capacity was measured with alpha-[C-11]methyl-L-tryptophan ([C-11]AMT) in normal adult human brain (n = 10; five males, five females; age range, 18-38 years, mean 28.3 years) by using positron emission tomography (PET). [C-11]AMT is an analog of tryptophan, the precursor for serotonin synthesis, and is converted to alpha-[C-11]methyl-serotonin ([C-11]AM-5HT), which is trapped in serotonergic neurons because [C-11]AM-5HT is not degraded by monoamine oxidase. Kinetic analysis of [C-11] activity in brain after injection of [C-11]AMT confirmed the presence of a compartment with unidirectional uptake that represented approximately 40% of the activity in the brain at 50 min after tracer administration. The undirectional rate constant K, which represents the uptake of [C-11]AMT from the plasma to brain tissue followed by the synthesis and physiologic trapping of [C-11]AM-5HT, was calculated using the Patlak graphic approach on a pixel-by-pixel basis, thus creating parametric images. The rank order of K values for different brain regions corresponded well to the regional concentrations of serotonin in human brain (P < .0001). High serotonin synthesis capacity values were measured in putamen, caudate, thalamus, and hippocampus. Among cortical regions, the highest values were measured in the rectal gyrus of the inferior frontal lobe, followed by transverse temporal gyrus; anterior and posterior cingulate gyrus; middle, superior, and inferior temporal gyri; parietal cortex; occipital cortex, in descending order. Values in women were 10-20% higher (P < .05, MANOVA) throughout the brain than those measured in men. Differences in the serotonin synthesis capacity between men and women measured in this study may reflect gender differences of importance to both normal and pathologic behavior. This study demonstrates the suitability of [C-11]AMT as a tracer for PET scanning of serotonin synthesis capacity in human brain and provides normal adult values for future comparison with patient groups.

The capacity of the developing brain for compensatory reorganization after early hemispherectomy has been previously shown in neurobehavioral studies, above all with regard to language recovery. The present study examines the organization of motor and language areas by means of [(15)O]-water positron emission tomography (PET) in a 6-year-old boy who underwent right functional hemispherectomy at age 3 years. The results suggest that compensatory allocation for movement of the weak hand primarily involves the premotor, inferior frontal, and insular cortices, and the supplementary motor area in the retained hemisphere, as well as the bilateral cerebellum. Receptive language and prosodic functions primarily activated the left perisylvian cortices. However, language and motor activations were also seen in cortical and subcortical remains on the hemispherectomized side suggesting incomplete disconnection by functional hemispherectomy.

Alternating hemiplegia of childhood is a rare disorder characterized by episodic paroxysmal attacks of neurologic dysfunction and has historically been thought to represent a migraine equivalent, an unusual form of epilepsy, or a movement disorder. Medical treatment with a variety of anticonvulsants and migraine agents is largely unsuccessful, and progressive mental deterioration is universally expected. Despite extensive laboratory studies, the pathophysiologic basis of this condition has thus far eluded identification. Recently, an international workshop was held to generate testable hypotheses regarding the pathophysiology of alternating hemiplegia of childhood. This paper summarizes the major proceedings of that workshop, and hopes to stimulate further interest in elucidating the molecular and cellular mechanisms underlying this unusual disorder.

We designed a semiautomated method for the objective detection of abnormal regions of tracer accumulation in the brain. The purpose of the present study was to examine the diagnostic performance of this method by applying it to patients with clinically intractable epilepsy of unilateral origin; they underwent [F-18] deoxyglucose positron emission tomography (PET) prior to surgical resection of epileptic foci. A semiautomated method for assessment of asymmetries in the brain cortex was developed that compares activity concentrations in homotopic cortical areas. When these differences exceeded a predefined threshold, the areas with lower activity were marked and 3-dimensional surface rendered images were created to guide placement of intracranial electrodes (ECoG) followed by surgical resection. The normal amount of asymmetry between small (0.5-0.7 cm2) homotopic cortical regions was determined as 5.9 +/- 4.0% (mean +/- SD). The false-positive fraction was determined for cutoff thresholds of 1 SD (10%), 1.5 SD (12%), and 2 SD (15%) outside the mean and was found to be 89, 44, and 0%, respectively. The obtained sensitivity-specificity pairs for correct localization of epileptogenic lobes based on the ECoG results were best for the 15% threshold (80/94%, accuracy 0.90). This objective PET method allows the accurate determination of cortical asymmetries, and it proved to be highly efficient in guiding epilepsy surgery.

Most language mapping studies have focussed on activations for single-word tasks. We examined activations for verbal auditory and generation tasks using sentence stimuli. [15O]-water PET was performed in 4 female and 5 male normal adults. Listening to sentences (minus rest) activated the superior and middle temporal gyri bilaterally, but mean activation was significantly stronger on the left. The strongest activation for sentence generation (minus repetition) was seen in the left middle and inferior frontal gyri (area 46). This focus appears to be anterior to activations reported for single-word generation, possibly due to greater verbal working memory demands of the sentential task. Additional activation of the left inferior temporal lobe can be attributed to lexicosemantic processing.

Landau-Kleffner syndrome (acquired epileptic aphasia) is characterized by language regression following normal acquisition of language skills, accompanied by epileptiform abnormalities on the electroencephalogram (EEG) with or without clinical seizures. Continuous spikes and waves during slow wave sleep may be seen on the EEG, but are not required to make the diagnosis. Structural neuroimaging with computed tomography (CT) and magnetic resonance imaging (MRI) is typically normal. We have evaluated 17 children (aged 2.4 to 10.6 yr) with Landau-Kleffner syndrome using positron emission tomography (PET) with 2-deoxy-2-[18F]fluoro-D-glucose (FDG) in order to determine whether there are metabolic abnormalities common to this syndrome. Patients were awake for the uptake period of FDG, and the EEG was monitored. On a visual analysis of the PET images, patients showed metabolic abnormalities in the temporal lobes. Two children had focal hypermetabolism in the left temporal cortex, one of whom also showed right temporal cortex hypometabolism. The remaining patients (n = 15) showed bilateral temporal hypometabolism, and comparison of these patients with a neurologically normal age-matched control group (n = 8) demonstrated significantly reduced glucose metabolism bilaterally in middle temporal gyrus (P < .02). In addition, other cortical regions displayed hypometabolism, although these regions were not consistently abnormal in all patients. The finding of temporal lobe abnormalities in all Landau-Kleffner syndrome patients suggests that temporal lobe structures are important in the pathophysiology of this syndrome, whereas the presence of additional cortical abnormalities in many patients indicates that extensive brain functional disturbances are common.

PURPOSE/OBJECTIVE:Presurgical evaluation for intractable frontal lobe epilepsy (FLE) is difficult and invasive, partly because anatomic neuroimaging studies with computed tomography (CT) and magnetic resonance imaging (MRI) typically do not show a discrete lesion. In adult patients with FLE, functional neuroimaging of glucose metabolism with positron emission tomography (PET) is less sensitive in detecting focal metabolic abnormalities than in temporal lobe epilepsy (TLE). Comparable data on children with FLE are not available. METHODS:We used high-resolution PET scanning of glucose metabolism to evaluate 13 children (age 17 months to 17 years; mean age 9.5 years) with intractable FLE being considered for surgical treatment. Only children with normal CT and MRI scans were included. RESULTS:Hypometabolism including the frontal lobe was evident in 12 of the 13 children, was unilateral in 11 of 13, and was restricted to the frontal lobe in 8 of 13. One child showed bilateral frontal cortex hypometabolism and another had an ictal PET scan demonstrating unilateral frontal cortex hypermetabolism surrounded by hypometabolism. Additional hypometabolic areas outside the frontal cortex were observed in 5 children in parietal and/or temporal cortex. Localization of seizure onset on scalp EEG was available in 10 children and corresponded to the location of frontal lobe PET abnormality in 8. However, in 4 of the 10 children, the extent of hypometabolism exceeded the epileptogenic region indicated by ictal EEG. In 2 of the 13 children, the abnormality evident on EEG was more extensive than that evident on PET. In the remaining 3 children for whom only interictal EEG data were available, the PET foci did not correspond in location to the interictal EEG abnormalities. In 11 of the 13 children, the presumed region of seizure onset in the frontal lobe, as based on analysis of seizure semiology, corresponded to the locations of frontal lobe glucose metabolism abnormalities. CONCLUSIONS:Although high-resolution PET appears to be very sensitive in localizing frontal lobe glucose metabolic abnormalities in children with intractable FLE and normal CT/MRI scans, the significance of extrafrontal metabolic disturbances requires further study; these may represent additional epileptogenic areas, effects of diaschisis, seizure propagation sites, or secondary epileptogenic foci.

Using high-resolution positron emission tomography (PET), we have recently described the normal pattern of glucose utilization in 11 anatomical regions of the human cerebellum. In the present study, we evaluated the phenomenon of crossed cerebellar diaschisis in 40 patients (mostly children) with unilateral cerebral injury sustained at various periods of brain development. Diaschisis refers to a functional impairment at a remote site following injury to an anatomically connected area of brain and, presumably due to a loss of afferent input to the remote site. Of the 40 patients, 11 had sustained their cerebral injury prenatally, 7 in the perinatal period (+/- 24 hours of birth), and 22 postnatally (1 day to 15 years). Crossed cerebellar hypometabolism was seen in 22 patients; symmetric cerebellar metabolism was found in 16 subjects. The presence of crossed cerebellar hypometabolism was typically associated (75% of cases) with a postnatal injury, while symmetric cerebellar metabolism was seen only in patients with injury occurring prior to 4 weeks of age (13 of the 16 had prenatal or perinatal insults). A third pattern of cerebellar metabolism, consisting of paradoxical crossed cerebellar hypermetabolism, was seen in two patients; both had sustained their cerebral injury at 4 months of age. These findings suggest the presence of considerable plasticity, which is dependent on age at injury, in the cerebrocerebellar pathway of developing brain.

This study examines whether or not in Sturge-Weber syndrome hypoperfused brain areas that are affected by calcification continue to retain some function and participate in language and motor activations. [15O]-Water positron emission tomography (PET) was used for brain mapping of these functions in two patients with extensive unilateral calcification and hypoperfusion and in one patient with calcification and hypoperfusion restricted to the left posterior region. Task-related regional cerebral blood flow changes suggest that (1) hypoperfused areas may become activated during language and motor performance, and (2) progressive calcification in Sturge-Weber syndrome is associated with functional reorganization in the language and motor domains. Interhemispheric reorganization appears to be more pronounced for language than for motor functions.