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Noradrenergic dysfunction and abnormality in monoamine oxidase (MAO) enzyme activity have been reported previously in Lesch-Nyhan (LN) disease. This study examines peripheral indices of adrenergic, noradrenergic, and MAO function in children and young adults with LN disease (n = 11), and healthy subjects (n = 9). Blood samples, collected in identical conditions prior to a positron emission tomography (PET) study, were assayed for concentrations of epinephrine (EPI), norepinephrine (NE), and 3-methoxy-4-hydroxyphenylglycol (DHPG) (which results from the degradation of NE by monoamine oxidase type A [MAO-A]). The LN subjects had significantly higher EPI levels by 245% (p < .00) and lower DHPG levels by 42% (p < .00) compared to the control group. No group differences were noted in NE plasma levels. Cognitive function (IQ tested by Stanford Binet Intelligence Scale) was associated with EPI in the LN group (r = 0.77, p = .009), but not in the control group. The abnormally high EPI plasma concentrations may indicate another biochemical dysfunction secondary to the absence of the HPRT enzyme in LN patients. Such a biochemical deficit is likely to originate from the adrenal medulla, which is the primary site of EPI synthesis. The adrenal medulla may be directly affected by the absence of hypoxanthine guanine phosphoribosyl transferase (HPRT) enzyme, or may receive inappropriately high descending activation input from the brain. The abnormally low DHPG levels, in the context of normal NE levels, indicates low MAO activity, either as a primary deficit, or as secondary adaptive changes to spare NE levels that would otherwise be too low for adequate noradrenergic function.

The regional cerebral glucose metabolic rates of clozapine-treated and fluphenazine-treated women with schizophrenia and normal controls were obtained by positron emission tomography (PET) using [18F]-2-fluoro-2-deoxy-D-glucose (FDG) as the tracer. The regional metabolic patterns were compared to each other and to the changes previously observed in men. In women, as in men, both clozapine- and fluphenazine-treatment were associated with lower metabolism in the superior prefrontal cortex and higher metabolism in the medial temporal lobe. In both men and women, clozapine treatment led to a greater lowering of inferior prefrontal cortex activity than fluphenazine, which was statistically significant in the larger male cohort. Fluphenazine led to higher metabolic rates in the lateral temporal lobe than clozapine did, but the differences between the two neuroleptics were not statistically significant in either group. The greatest differences in the female as compared to the male responses to fluphenazine and clozapine were in the cingulate and striatum. As compared to controls, the cingulate metabolic rates of women were reduced by 9.1% and 11.4% on clozapine and fluphenazine, respectively; whereas, men have a statistically nonsignificant reduction of 0.1% with clozapine and a 3.2% increase with fluphenazine. In men, fluphenazine was associated with a much greater elevation in basal ganglia metabolic rates than was clozapine, 23.5% as compared to 3.75%; whereas, in women, basal ganglia metabolic rates are nearly equally increased by fluphenazine (21.6%) and clozapine (15.1%).

The regional cerebral metabolic rates of 19 male medication-withdrawn schizophrenic patients were determined by positron emission tomography (PET) while performing an auditory discrimination task (CPT). Regardless of the accuracy of their CPT performance, the schizophrenic patients had lower metabolic rates in their prefrontal cortex and higher rates in their posterior putamen compared to 41 healthy males. Abnormally low right anterior midprefrontal cortex metabolic rates predicted better clinical response while high basal ganglia rates and low mid-cingulate rates predicted poor treatment response to neuroleptics. The findings imply that the sustained attention pathway and its distributed network of brain structures are likely to play an important role in the expression of psychotic symptoms and the mediation of their response to antipsychotics.

This study reports the effects of intravenous dextroamphetamine on cerebral glucose metabolism assayed by positron emission tomography (PET) and [fluorine-18]fluorodeoxyglucose (FDG) in 13 healthy adults during the performance of a continuous visual attention task. Two FDG PET scans were performed within a single experimental session. The first scan was preceded by the injection of placebo and the second scan by the injection of 0.15 mg/kg dextroamphetamine. Global and normalized regional glucose metabolic rates (rCMRglc) were examined as a function of pharmacological challenge and subjective experience. Subcortical, limbic, frontal, and cerebellar rCMRglc significantly increased after dextroamphetamine, whereas rCMRglc of the temporal cortex significantly decreased. Physiological and self-report measures of subjective states showed the expected alterations. These rCMRglc changes reflect both the direct pharmacological effect of dextroamphetamine on monoaminergic neurotransmitter systems as well as enhancement of the activation of the neural network mediating the performance of the continuous attention task.

Two consecutive positron emission scans were done in one session using a double injection method of [18F]2-fluoro-2-deoxyglucose administration to examine the effects of the antimuscarinic drug scopolamine on cerebral glucose metabolism in ten older adults. Scopolamine causes temporary memory impairment, and its effects have been used to model aspects of the cognitive impairment that occur in Alzheimer's disease (AD). Cortical metabolic rates of patients with AD have been reported to be depressed, especially in parietal, temporal, and frontal association areas. After scopolamine administration to the elderly volunteers, absolute and normalized glucose metabolic rates were depressed in prefrontal and occipital regions and increased in parietal-occipital cortical regions and a left middle temporal region. These changes in the older volunteers are generally not consistent with changes seen in AD. We conclude that deficits in muscarinic system function may contribute to some but not all of the hypometabolic changes seen in AD patients.

This study used positron-emission tomography to examine cerebral metabolic rates of glucose (CMRG) in 17 patients with DSM III-R diagnoses of personality disorder. Within the group of 17 personality disorder patients, there was a significant inverse correlation between a life history of aggressive impulse difficulties and regional CMRG in the frontal cortex of the transaxial plane approximately 40 mm above the canthomeatal line (CML) (r = -.56, p = 0.17). Diagnostic groups included antisocial (n = 6), borderline (n = 6), dependent (n = 2), and narcissistic (n = 3). Regional CMRG in the six antisocial patients and in the six borderline patients was compared to a control group of 43 subjects using an analysis of covariance with age and sex as covariates. In the borderline personality disorder group, there was a significant decrease in frontal cortex metabolism in the transaxial plane approximately 81 mm above the CML and a significant increase in the transaxial plane approximately 53 mm above the CML (F[1,45] = 8.65, p = .005; and F[1,45] = 7.68, p = .008, respectively.

Recent work in our laboratory has demonstrated both global and regional reductions in cerebral glucose metabolism in adult subjects with attention-deficit hyperactivity disorder (ADHD). The purpose of the present study was to examine the effects of an acute dose of stimulant medication on cerebral metabolism in adults with ADHD using positron emission tomography with fluorodeoxyglucose-18 as the tracer. Each subject underwent scanning twice, once off-drug and again after receiving a single oral dose of either dextroamphetamine (0.25 mg/kg) or methylphenidate (0.35 mg/kg). Subjects completed behavioral self-report measures before and after the scan and performed an auditory continuous performance task during the tracer uptake period. Neither drug changed global metabolism. Both drugs increased systolic blood pressure, and dextroamphetamine improved performance on the auditory attention task. Each stimulant produced a differential pattern of increases and decreases in regional metabolism throughout the regions of interest that were sampled. Rather than increasing glucose utilization in specific brain regions with lowered metabolic rates in adults with ADHD, stimulants may act by altering glucose use throughout the brain.

Positron emission tomography scans of nine patients diagnosed with summer seasonal affective disorder (SSAD) were compared with scans of 45 normal control subjects to investigate differences in brain glucose metabolism. All subjects performed an auditory discrimination task beginning several minutes before injection of F-18-deoxyglucose and continuing for 30 minutes after injection. Regional glucose metabolic rates were extracted from 60 rectangular regions of interest measured in five planes selected as atlas matches from 28 total slices. Statistically significant differences between patients with SSAD and normal control subjects were found in cerebral glucose metabolic rate and also in normalized regional glucose metabolic rates in the orbital frontal cortex and in the left inferior parietal lobule.

Regional glucose metabolic rates were measured in patients with panic disorder during the performance of auditory discrimination. Those regions examined by Reiman and colleagues in their blood flow study of panic disorder [Nature 310:683 (1984)] were examined with a higher resolution positron emission tomography (PET) scanner and with the tracer [F-18]-2-fluoro-2-deoxyglucose (FDG). In contrast to the blood flow findings of Reiman et al., we did not find global gray metabolic differences between patients with panic disorder and normal controls. Consistent with the findings of Reiman et al. [Nature; Am J Psychiatry 143:469 (1986)], we found hippocampal region asymmetry. We also found metabolic decreases in the left inferior parietal lobule and in the anterior cingulate (trend), as well as an increase in the metabolic rate of the medial orbital frontal cortex (trend) of panic disorder patients. It is unclear whether the continuous performance task (CPT) enhanced or diminished findings that would have been noted in a study performed without task.

Regional glucose metabolic rates were measured in affectively disordered patients during the performance of auditory discrimination. Those regions previously observed as abnormal in schizophrenia were examined to see if similar alterations might be associated with affective disorder. The abnormalities observed in the mid-prefrontal cortex, an area that appears to be an important biologic determinant of the sustained attention required of subjects in this task, are similar to those previously observed in schizophrenia. Moreover, the abnormalities do not appear to relate directly to symptomatology or the subject's performance. The authors discuss the possibility that this abnormality may reflect dysfunction in the integrating component of the attention network critical for the maintenance of goal-directed behavior and thus represent a psychosis vulnerability factor in some patients.

Brain metabolism was measured with positron emission tomography and [18F] 2-fluoro-2-deoxyglucose in normal subjects and in patients with obsessive compulsive disorder (OCD) while they performed a continuous auditory discrimination task designed to evaluate the functional localization of sustained attention. Data on 8 nondepressed patients with OCD were compared with 30 normal volunteers. We observed significantly higher normalized regional metabolism both in the right orbital frontal cortex (p = 0.002, two-tailed t test) and in the left anterior orbital frontal cortex (p = 0.017, one-tailed t test) and in patients with OCD as compared to normal controls. We observed no normalized glucose metabolic differences in basal ganglia structures in patients with OCD as compared to our normal controls. There were no statistical differences in global glucose metabolic values between the OCD and the control group. Our findings are consistent with the findings of Baxter et al. (Arch Gen Psychiatry 44:211-218, 1987). Regions in the parietal cortex also appear to show differences in this preliminary study.