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Objective: Studies of depressed adults have shown abnormalities in cerebral energy metabolism, as noted by low brain levels of nucleoside triphosphate (NTP), which primarily represents adenosine triphosphate (ATP). This study was undertaken to determine whether proton magnetic resonance spectroscopy (1H MRS) measures of the low-field purine resonance, which arises primarily from adenosine phosphates, can be used to assess abnormalities in cerebral purine metabolism in depressed adults., Method: Data from 1H MRS and phosphorus-31 (31P) MRS were acquired for depressed and nondepressed comparison subjects. Intensities of the purine resonance, by 1H MRS (7.5-8.5 ppm), and of NTP, by 31P MRS, were determined., Results: Purine resonance intensities did not differ on average between depressed patients and comparison subjects. However, purine levels were approximately 30% lower in female depressed subjects who subsequently responded to fluoxetine treatment than in those who did not respond. Beta-NTP was lower by 21% in responders than in nonresponders and was correlated with purine levels for the depressed subjects., Conclusions: Brain purine levels are low in female depressed patients who respond to treatment with fluoxetine, suggesting that response to treatment might be predicted by using 1H MRS. These observations also suggest that agents that increase brain adenosine levels may have antidepressant efficacy.

Objective: This study tested whether a relationship exists between concentration and response following discontinuation of selective serotonin reuptake inhibitors., Method: Eight patients with remitted major depression who were taking 20 mg/day of either fluoxetine or paroxetine underwent placebo substitution for 3 days. Serum drug and brain fluorine levels were obtained before and after placebo substitution., Results: With placebo substitution, a mean of 88% (SD=13%) of brain fluorine signal from fluoxetine (plus fluorinated metabolites) remained, compared with a mean of 38% (SD=17%) of the brain fluorine signal from paroxetine (plus fluorinated metabolites). Among patients taking paroxetine, adverse events during placebo substitution correlated highly with steady-state brain drug levels., Conclusions: The correlation of clinical effects with brain drug levels in the paroxetine group suggests that relationships between drug response and brain drug concentrations merit further investigation.

Objective: Studies have identified two types of antidepressant response: true drug response and placebo pattern response. This study examined the relationship between true drug response and choline-creatine ratios in the basal ganglia of depressed patients treated with fluoxetine., Method: The authors evaluated drug-free outpatients with major depression before (N = 41) and after (N = 15) 8 weeks of fluoxetine treatment, 20 mg/day, by using proton magnetic resonance spectroscopy., Results: There was a significant difference in the degree of change from baseline to week 8 in choline-creatine ratios between the true drug response group (N = 8) and the placebo pattern response/nonresponse group (N = 7); the true drug response patients had a 20% increase in choline-creatine ratios, and the placebo pattern response/nonresponse patients had a 12% decrease in choline-creatine ratios., Conclusions: These data suggest that true drug response to fluoxetine treatment in depression may be associated with an increase in choline-creatine ratios in the basal ganglia.

Objective: The authors evaluated the effect of sex on data derived from activation studies using blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging (MRI)., Method: Gradient echo-echo planar imaging was used to measure BOLD signal response in the primary visual cortex in response to binocular photic stimulation in 16 healthy, young subjects (eight women and eight men)., Results: BOLD signal response was 38% lower in women than in men, and much of the difference was lateralized to the right hemisphere., Conclusions: Lower BOLD signal response in women may reflect a sex difference in the brain's response to a primary visual stimulation or in the physiology underlying BOLD functional MRI signal changes.

Objective: Functional magnetic resonance imaging (MRI) was used to test whether brain activation was detectable in regions previously associated with cocaine cue-induced craving., Method: Blood oxygenation level dependent (BOLD) functional activation was measured during presentation of audiovisual stimuli containing alternating intervals of drug-related and neutral scenes to six male subjects with a history of crack cocaine use and six male comparison subjects., Results: Significant activation was detected in the anterior cingulate and left dorsolateral prefrontal cortex in the cocaine-using group. In addition, a correlation between self-reported levels of craving and activation in these regions was found., Conclusions: These results suggest that functional MRI may be a useful tool to study the neurobiological basis of cue-induced craving.

Objective: Higher than normal cellular levels of the phospholipid catabolic intermediate glycerophosphocholine have been found in postmortem brain tissue of persons with Alzheimer's disease. Proton magnetic resonance spectroscopy (1H-MRS) can detect a choline resonance that is largely due to glycerophosphocholine. The authors tested the hypothesis that treatment with xanomeline, an M1 selective muscarinic cholinergic agonist, would be associated with a decrease in the 1H-MRS choline resonance., Method: Patients with mild to moderate Alzheimer's disease received placebo or xanomeline for 6 months. 1H-MRS spectra were collected at baseline and after treatment discontinuation for 12 patients, two taking placebo and 10 taking xanomeline at a dose of 25 mg t.i.d. (N = 4), 50 mg t.i.d. (N = 3), or 75 mg t.i.d. (N = 3)., Results: For the combined group of patients taking xanomeline, there was a significant decrease in the choline/creatine ratio from baseline to endpoint., Conclusions: Treatment of Alzheimer's disease with a cholinergic agonist is associated with a decrease in the MRS choline resonance. Xanomeline may reduce breakdown of cholinergic neuron membranes by reducing the cellular requirement for free choline for acetylcholine synthesis.

Objective: The purpose of this study was to evaluate whether the concentration of beta-nucleoside triphosphate is lower in the basal ganglia of depressed subjects., Method: In vivo 31P magnetic resonance spectra were acquired from a 45-cm3 region surrounding the basal ganglia of 35 unmedicated depressed subjects and 18 comparison subjects., Results: beta-Nucleoside triphosphate, which arises primarily from beta-ATP, was 16% lower in the depressed subjects than in the comparison subjects., Conclusions: The low level of beta-nucleoside triphosphate is consistent with an abnormality of high-energy phosphate metabolism in the basal ganglia of subjects with major depression.

Objective: The purpose of this study was to investigate the potential effectiveness of dynamic susceptibility contrast magnetic resonance imaging (MRI) to discriminate elderly patients with Alzheimer's disease from normal matched comparison subjects., Method: Images of regional cerebral blood volume (CBV) were generated from echo-planar MRI with the dynamic susceptibility contrast method in 13 Alzheimer's disease patients and 13 comparison subjects group-matched on age and gender., Results: Temporoparietal cerebral blood volume, expressed as a percentage of the cerebellum value, was reduced 17% bilaterally in the patients with Alzheimer's disease. Blood volume in sensorimotor regions was reduced only 8.5% in the patients. Discriminant function analysis based on left and right temporoparietal measures correctly classified 88.5% of the subjects as patients or comparison subjects. Temporoparietal CBV was reduced even in mildly affected Alzheimer's disease patients (Mini-Mental State scores > 24)., Conclusions: Dynamic susceptibility contrast MRI of regional CBV is promising as a nonradioactive, potentially lower-cost alternative to other functional neuroimaging methods for evaluating Alzheimer's disease.

Objective: This study was undertaken to test the feasibility of using functional magnetic resonance imaging (MRI) to examine changes in cortical activation in response to verbal tasks in two brain regions., Method: Twelve schizophrenic patients and 11 comparison subjects underwent functional MRI of the frontal and temporal lobes. Stimulus sequences were divided into five 30-second segments by using a task-activation paradigm that alternated between resting and stimulated states. Functional images were collected every 30 seconds by using a gradient echo pulse sequence., Results: Schizophrenic subjects demonstrated significantly less left frontal activation and greater left temporal activation than comparison subjects during a word fluency task., Conclusions: These preliminary data suggest that functional MRI has the sensitivity to detect differences in activation between comparison subjects and schizophrenic patients during higher cortical functions. These findings are in agreement with PET studies that reported reduced left frontal activation during challenge paradigms for the schizophrenic patients.

Objective: The authors tested the hypothesis that the regional distribution of cerebral vasculature is anomalous in schizophrenia., Method: Dynamic susceptibility contrast magnetic resonance imaging was used to evaluate cerebral blood volume in the right and left occipital cortex, basal ganglia, and cerebellum of 10 subjects with schizophrenia and 10 healthy comparison subjects., Results: Cerebral blood volume was greater in the schizophrenic subjects in every region studied., Conclusions: The findings suggest an abnormality of the configuration of cerebral blood vessels in schizophrenia.

Objective: The authors measured the ratio of N-acetyl aspartate (a putative neuronal marker) to creatine-phosphocreatine in patients with first-episode psychosis by using proton magnetic resonance spectroscopy (MRS)., Method: Temporal lobe 1H MRS was performed bilaterally on 13 patients with first-episode psychosis and 15 comparison subjects. The N-acetyl aspartate/creatine-phosphocreatine and choline/creatine-phosphocreatine ratios were determined., Results: The N-acetyl aspartate/creatine-phosphocreatine ratio of the psychotic patients was significantly lower than that of the comparison subjects., Conclusions: These preliminary data suggest that abnormalities in temporal lobe N-acetyl aspartate concentration are present early in psychotic illness.

Functional echo planar magnetic resonance imaging (MRI) probably will be of importance in assessing brain abnormalities in psychiatric disorders. The authors used functional MRI to measure the relative magnitude of the change in image signal intensity, reflecting changes in regional neuronal activity caused by photic stimulation, in eight patients with schizophrenia and nine normal comparison subjects. The mean signal intensity change in the primary visual cortex was significantly greater in patients with schizophrenia (mean = 4.6%, SD = 1.5%) than in normal comparison subjects (mean = 3.1%, SD = 1.3%). These results may reflect a variety of factors, including diffuse structural brain changes as well as primary or iatrogenic impairment of mitochondrial function or energy metabolism.

In vivo 19fluorine nuclear magnetic resonance spectroscopy was used to measure the brain concentration of fluoxetine and norfluoxetine in five patients with obsessive-compulsive disorder and three with major depression. The mean brain:plasma ratio of the parent drug plus the metabolite was significantly elevated to 2.6 (SD = 1.0) (95% confidence interval = 1.9-3.3). This accumulation may have implications for understanding both the therapeutic and the toxic effects of fluoxetine.