Joseph Wu

Cortical glucose metabolic rate correlates of abstract reasoning and attention studied with positron emission tomography

Abstract Three groups of young, healthy males underwent positron emission tomography of the head, using 18fluoro-2-deoxyglucose as the uptake tracer. During the uptake, one group (n = 8) did an abstract reasoning test (Ravens Advanced Progressive Matrices [RAPM]); another (n = 13) performed a visual vigilance task (Continuous Performance Test [CPT] task); and the other (n = 9) simply watched flashing visual stimuli (CPT no task). ANOVA revealed that both the RAPM and the CPT groups activated the right hemisphere. A priori and exploratory t-tests indicated some left-hemisphere areas of activation for the RAPM, especially posterior cortex. Performance on the RAPM showed significant negative correlations with cortical metabolic rates. CPT performace showed few significant correlations with cortical metabolic rate. Although this study does not strongly implicate any one brain region in performance of the RAPM or CPT task, the inverse glucose/RAPM performance correlations suggest that some individual differences in cognitive ability may be related to efficiency or density of neutral circuits.

Frontal cortex and basal ganglia metabolic rates assessed by positron emission tomography with [18F]2-deoxyglucose in affective illness.

Twenty affective disorder patients (16 bipolar and 4 unipolar) and 24 normal controls received scans with positron emission tomography (PET) using [18F]2-deoxyglucose (FDG) as a tracer. Subjects received a series of brief electrical stimuli to their right arms during FDG uptake. Patients with bipolar affective illness had significantly lower frontal to occipital glucose metabolic rate ratios (relative hypofrontality) and significantly lower metabolic rates in their basal ganglia in comparison to whole slice metabolism than normal controls. Patients with unipolar illness showed significantly higher frontal to occipital ratios, and also showed relatively decreased metabolism in the basal ganglia. All results in unipolar patients should be considered exploratory due to the small number of patients. Clinical depression ratings correlated negatively with whole slice metabolic rate.

Regional cerebral glucose metabolic rate in human sleep assessed by positron emission tomography

The cerebral metabolic rate of glucose was measured during nighttime sleep in 36 normal volunteers using positron emission tomography and fluorine-18-labeled 2-deoxyglucose (FDG). In comparison to waking controls, subjects given FDG during non-rapid eye movement (NREM) sleep (primarily stages 2 and 3) showed about a 23% reduction in metabolic rate across the entire brain. This decrease was greater for the frontal than temporal or occipital lobes, and greater for basal ganglia and thalamus than cortex. Subjects in rapid eye movement (REM) sleep tended to have higher cortical metabolic rates than waking subjects. The cingulate gyrus was the only cortical structure to show a significant increase in glucose metabolic rate in REM sleep in comparison to waking. The basal ganglia were relatively more active on the right in REM sleep and symmetrical in NREM sleep.

Positron emission tomography studies of basal ganglia and somatosensory cortex neuroleptic drug effects: Differences between normal controls and schizophrenic patients

Glucose metabolic rate in the basal ganglia, thalamus, and somatosensory cortex was examined in eight patients with schizophrenia before and after receiving neuroleptic medication. Basal ganglia metabolic rates were increased with medication: more on the right than on the left and more in putamen than caudate. The cortical anteroposterior ratio, an index of relative hypofrontality, was not affected by neuroleptics. The brain areas that were found to be altered by neuroleptics were selected for comparison between off-medication schizophrenics and controls. Metabolic rates in the basal ganglia tended to be low in patients with schizophrenia in comparison to 24 age- and sex-matched controls.

Rapid and Sustained Antidepressant Response with Sleep Deprivation and Chronotherapy in Bipolar Disorder

BACKGROUNDnThe development of a rapid-acting and sustainable treatment for bipolar disorder (BPD) depression has been a goal for decades. The most widely documented rapid-onset antidepressant therapy is sleep deprivation (SD), which acts within 24-48 hours in 40%-60% of depressed patients. Conventional antidepressants usually require 2-8 weeks to meet response criteria. The delay, which may prolong suffering and increase suicidal risk, underlines the urgency of alternative treatment strategies. This study evaluates the combined efficacy of three established circadian-related treatments (SD, bright light [BL]), sleep phase advance [SPA]) as adjunctive treatment to lithium and antidepressants.nnnMETHODSnForty-nine BPD patients were randomly assigned to a chronotherapeutic augmentation (CAT; SD+ BL+ SPA) or to a medication-only (MED) group. Clinical outcome was assessed using the Hamilton Rating Scale for Depression.nnnRESULTSnSignificant decreases in depression in the CAT versus MED patients were seen within 48 hours of SD and were sustained over a 7-week period.nnnCONCLUSIONSnThis is the first study to demonstrate the benefit of adding three noninvasive circadian-related interventions to SD in medicated patients to accelerate and sustain antidepressant responses and provides a strategy for the safe, fast-acting, and sustainable treatment of BPD.

PET in generalized anxiety disorder.

Positron emission tomography (PET) measurements of cerebral glucose use were made in 18 patients with generalized anxiety disorder (GAD) during a passive viewing task off medication, and an active vigilance viewing task before and after medication or placebo treatment. In the passive viewing task, patients with GAD were compared with 15 normal controls. A significant difference in pattern of absolute brain metabolism was found. Patients showed lower absolute metabolic rates in basal ganglia and white matter. Relative metabolism was increased in the left inferior area 17 in the occipital lobe, right posterior temporal lobe, and the right precentral frontal gyrus. Significant left-right asymmetry of the parahippocampal gyri was not found in patients with GAD. An active vigilance task resulted in activation of relative basal ganglia metabolism in patients. Benzodiazepine therapy resulted in decreases in absolute metabolic rates for cortical surface, limbic system, and basal ganglia and was not associated with normalization of patterns of glucose metabolism. Change in anxiety scores was significantly correlated with change in limbic system and basal ganglia for the placebo group. The normal-anxious difference in the basal ganglia and the change seen in this region after benzodiazepine treatment are suggestive of a role in anxiety for this structure.

D2 dopamine receptor polymorphism and brain regional glucose metabolism

Positron emission tomography (PET) studies have shown decreased glucose metabolism in brain regions of detoxified alcoholics and cocaine abusers. However, it is not clear whether this decrease is due to chronic drug abuse or a pre-existing condition. Molecular genetic studies have found an association of the D2 dopamine receptor (DRD2) A1 allele with alcoholism and drug abuse. Moreover, reduced central dopaminergic function has been suggested in subjects who carry the A1 allele (A1+) compared with those who do not (A1-). In the present study, using 18F-deoxyglucose, regional glucose metabolism was determined in healthy nonalcohol/nondrug-abusing subjects with the A1+ or A1- allele. The mean relative glucose metabolic rate (GMR) was significantly lower in the A1+ than the A1- group in many brain regions, including the putamen, nucleus accumbens, frontal and temporal gyri and medial prefrontal, occipito-temporal and orbital cortices. Decreased relative GMR in the A1+ group was also found in Brocas area, anterior insula, hippocampus, and substantia nigra. A few brain areas, however, showed increased relative GMR in the A1+ group. Since polymorphism of the DRD2 gene is commonly observed in humans, the importance of differentiating A1+ and A1- alleles subjects in PET studies is suggested.

Brain metabolic and clinical effects of rivastigmine in Alzheimer's disease

In-vivo metabolic measures with positron emission tomography using (18)F-fluorodeoxyglucose (FDG-PET) have demonstrated hypometabolism in temporal, frontal, and hippocampal areas during the early stages of Alzheimers disease (AD). Progression of the dementia in AD involves compromised cholinergic functioning. Cholinesterase inhibitors have demonstrated efficacy in improving cognition and behaviour in AD. In this study, we demonstrate the usefulness of FDG-PET in measuring the progression of untreated AD and its modification by treatment with rivastigmine (Exelon, Novartis Pharmaceuticals, East Hanover, New Jersey, USA), a centrally selective cholinesterase inhibitor of the carbamate type. Patients with mild to moderate probable AD (Mini-Mental Status Exam scores of 10-26, inclusive) were enrolled in a double-blind, placebo controlled comparison of three fixed daily doses of rivastigmine (3, 6, or 9 mg/d) or placebo for 26 wk. FDG-PET scans were obtained on 27 patients at baseline and following 26 wk of treatment using the Snodgrass Picture Naming activation task. A total of 71.4% of the patients treated with placebo deteriorated clinically compared to only 25.0% of the patients treated with rivastigmine (chi2 = 4.8; p & 0.03). Rivastigmine-responders (i.e. those who clinically improved or remained clinically stable as measured by the Clinicianaposs Interview-Based Impression of Change-plus) showed a marked increase in brain metabolism (p <0.01) involving, but not limited to, structures comprising the memory-related cortices and the prefrontal system. These metabolic changes were not observed in the placebo-treated patients or the rivastigmine non-responders. Of note is that responders increased hippocampal metabolism by 32.5% (p < 0.03) compared to a non-significant decrease in the non-responders (6.4%) and placebo-treated patients (4.1%). These results are consistent with the literature suggesting that FDG-PET can sensitively measure the progression of AD and its improvement with cholinesterase inhibitors. Rivastigmine prevented the expected deterioration in clinical status and dramatically increased brain metabolic activity in a majority of patients.

Cerebral metabolic activity correlates of subsyndromes in chronic schizophrenia.

Seventy-nine patients with schizophrenia and 47 healthy controls received positron-emission tomography (PET) with 18F-2-deoxyglucose uptake while executing the Continuous Performance Test (CPT). Patients had been off all psychoactive medication for at least four weeks. Patients symptoms were assessed with the Brief Psychiatric Rating Scale and factor scale scores were obtained. These scores were used in cluster analysis to identify patients with predominantly delusional, negative, disorganized, and remitted symptoms. To address the interconnective nature of cerebral functioning, regions of interest were defined on the basis of the results of a factor analysis of metabolic rate in selected brain regions. This procedure identified six cortical and eight subcortical region of interest factors. Metabolic rate factor scale scores were compared between the patients clusters and the healthy controls. The delusional cluster showed a significantly reduced hippocampal activity, while the negative symptoms cluster presented with a prominent hypofrontality and significantly increased left temporal cortex values. Concurrently, both clusters were associated with a decreased activity on the factor anterior cingulum and medial frontal gyrus. The disorganized cluster was characterized by a significant overactivity in the parietal cortex and motor strip and a decreased activity in the corpus callosum. The subsyndromes of chronic schizophrenia are therefore characterized by deviant patterns of cerebral activity rather than deficits in a single location.

Positron emission tomography assessment of effects of benzodiazepines on regional glucose metabolic rate in patients with anxiety disorder.

Patients with generalized anxiety disorder (n = 18) entered a 21-day, double-blind, placebo-controlled random assignment trial of clorazepate. Positron emission tomography with 18F-deoxyglucose was carried out before and after treatment. Decreases in glucose metabolic rate in visual cortex and relative increases in the basal ganglia and thalamus were found. A correlation between regional changes in metabolic rate and regional benzodiazepine receptor binding density from other human autopsy studies was observed; brain regions highest in receptor density showed the greatest decrease in rate.