Preliminary data on the metabolic brain pattern of patients with winter seasonal affective disorder.

The brain metabolic pattern of patients with winter seasonal affective disorder with and without light treatment was determined by positron emission tomography. Compared with controls, patients with seasonal affective disorder with and without light treatment had globally lower metabolic rates, relatively lower superior medial frontal cortex rates, and somewhat higher basal ganglia rates. Patients receiving light treatment had a relatively higher rate in an occipital region of interest containing the primary visual cortex. Patients without light treatment had relatively higher metabolic rates in right parietal and medial orbitofrontal cortex and lower rates in the left parietal cortex. Patients not receiving light treatment had a hemispheric metabolic asymmetry (left greater than right) for the midprefrontal cortex located 67 mm above the canthomeatal line. The right side of this region, previously found reduced in manic-depressive illness and schizophrenia, was decreased primarily in patients with seasonal affective disorder with fewer atypical depressive symptoms. These "abnormal" prefrontal and parietal cortex regions appeared highly "coupled" in the patients with seasonal affective disorder.

Local cerebral glucose metabolic rates in obsessive-compulsive disorder. Patients treated with clomipramine.

In a recent study, we reported abnormal local cerebral glucose metabolic rates in the orbital frontal cortex of patients with obsessive-compulsive disorder. Eight patients with obsessive-compulsive disorder scanned previously were scanned again during treatment with the tricyclic antidepressant clomipramine hydrochloride. Comparisons of local cerebral glucose metabolic rates for both groups showed a relative decrease in regions of the orbital frontal cortex and the left caudate, and an increase in other areas of the basal ganglia, including the right anterior putamen. When comparing patients who responded well to clomipramine with those who were either poor or partial responders, we found significant decreases only in the left caudate of patients who responded well to the drug. The present study suggests that clomipramine-induced improvement in obsessive-compulsive symptoms is associated with a return of regional brain metabolism to a more normal level in regions of the orbital frontal cortex and the caudate nucleus.

The brain metabolic patterns of clozapine- and fluphenazine-treated patients with schizophrenia during a continuous performance task.

BACKGROUND: The comparison of the effects of 2 classes of neuroleptic drugs on regional brain functional activities may reveal common mechanisms of antipsychotic drug efficacy. METHODS: The regional cerebral glucose metabolic rates of patients with schizophrenia who were and were not receiving neuroleptic drugs and normal control subjects were obtained by positron emission tomography using fludeoxyglucose F 18 as the tracer. RESULTS: Compared with normal controls and patients not receiving medication, fluphenazine hydrochloride- and clozapine-treated patients had lower global gray matter absolute metabolic rates throughout the cortex. When normalized regional glucose metabolic rates were examined, both medications lowered rates in the superior prefrontal cortex and increased rates in the limbic cortex. Fluphenazine, but not clozapine, increased metabolic rates in the subcortical and lateral temporal lobes, whereas clozapine, but not fluphenazine, decreased inferior prefrontal cortex activity. CONCLUSIONS: These changes are consistent with the idea that neuroleptic drugs lead to "compensation" and "adaptation" rather than "normalization" of the functional activities of brain structures in schizophrenia. The overall similarity of their global and regional metabolic effects suggests that both classes of antipsychotic drugs share some common mechanisms of action. One possibility is that of inducing a shift in the balance of cortical to limbic cortex activity. Differential effects in the inferior prefrontal cortex and the basal ganglia might underlie differences in the therapeutic efficacy and side effect profile of clozapine and fluphenazine.

Attentional asymmetry in schizophrenia: controlled and automatic processes.

Two versions of Posner's covert orienting task were administered to 14 drug-free schizophrenic patients and 12 normal controls. In the schizophrenic subjects, automatic orienting to exogenous cues in the right visual field was impaired. However, this lateralizing general deficit was not present when the schizophrenics were able to direct attention effortfully in the second version of the task using endogenous cues. These findings support the hypothesis that there is a deficit in left hemispheric mechanisms mediating visual spatial attention in schizophrenia. However, when schizophrenics are given the opportunity to use an attentional strategy they are able to partially overcome this lateralized processing deficit.

Regional cerebral metabolic asymmetries replicated in an independent group of patients with panic disorders.

BACKGROUND: Abnormal left/right (L/R) hemispheric ratios of regional cerebral glucose metabolic rates (rCMRglc) (hippocampus and inferior prefrontal cortex) have been noted in unmedicated panic disorder patients. METHODS: An independent group of panic disorder patients placed on imipramine was studied with positron-emission tomography, testing for evidence of normalization versus persistence of the abnormal rCMRglc ratios. Differences in orbital frontal rCMRglc values between the imipramine-treated and the previously reported unmedicated panic disorder patients were tested examining for evidence that the differences would resemble those noted in obsessive-compulsive disorder (OCD) patients treated with clomipramine. RESULTS: We found the same abnormally low L/R hippocampal and posterior inferior prefrontal rCMRglc ratios in the imipramine-treated panic disorder patients. In addition, we found posterior orbital frontal rCMRglc decreases in the imipramine-treated panic disorder patients compared with the unmedicated panic disorder patients. CONCLUSIONS: These abnormal asymmetries found in unmedicated panic disorder patients and now in imipramine-treated panic disorder patients may reflect a trait abnormality. The orbital frontal rCMRglc differences between the imipramine-treated and unmedicated patients are similar to changes noted in OCD patients treated with clomipramine and may reflect direct or indirect effects of imipramine treatment in panic disorder patients.

Association of estrogen levels with neuropsychological performance in women with schizophrenia.

OBJECTIVE: This study sought to determine the relationship of estrogen levels with psychiatric symptoms and neuropsychological function in female patients with schizophrenia. METHOD: Psychiatric symptoms were assessed and average estrogen and progesterone levels from four consecutive weekly blood samples were measured in 22 female inpatients with schizophrenia who were also administered a neuropsychological battery. RESULTS: There were strong positive correlations between average estrogen level and cognitive function, especially measures of global cognitive function, verbal and spatial declarative memory, and perceptual-motor speed. Correlations of hormone levels with psychiatric symptoms were nonsignificant. CONCLUSIONS: Higher estrogen levels in female patients with schizophrenia are associated with better cognitive ability. These results may have implications for potential treatment of cognitive dysfunction with adjunctive estrogen in female patients with schizophrenia.

The brain metabolic patterns of clozapine- and fluphenazine-treated female patients with schizophrenia: evidence of a sex effect.

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%).

Abnormalities in the distributed network of sustained attention predict neuroleptic treatment response in schizophrenia.

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.

Cerebral glucose metabolic rates in obsessive compulsive disorder.

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.

Effects of acute stimulant medication on cerebral metabolism in adults with hyperactivity.

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.

Cerebral glucose metabolism in patients with summer seasonal affective disorder.

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.

Cerebral glucose metabolic differences in patients with panic disorder.

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.

Evidence for common alterations in cerebral glucose metabolism in major affective disorders and schizophrenia.

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.

Anterior cingulate metabolism correlates with stroop errors in paranoid schizophrenia patients.

UNLABELLED: Using [O-15]-H(2)O PET Carter et al. (1997) reported that medicated patients with schizophrenia performing computerized single trial Stroop (1935) showed a reduction in the anterior cingulate activation response to the more attention demanding, incongruent Stroop condition. In that study, both patients and controls also showed a direct correlation between anterior cingulate activation and errors committed during incongruent trials of the task. In this study we follow up with an examination of paranoid schizophrenia outpatients and controls with very high resolution positron emission tomography (PET) and the longer half-life tracer [F-18]-fluorinated deoxyglucose (FDG) (Valk et al. 1990). All subjects (10 controls and 9 paranoid schizophrenia patients) were studied with FDG-PET while performing a computerized trial-by-trial version of the Stroop task during the uptake phase of the tracer (Carter et al. 1992). RESULTS: As in previous studies using the single trial Stroop, patients were able to perform the task but made more color-naming errors during incongruent trials than controls. The patients in the present study showed a trend towards increased metabolic activity in the right anterior cingulate cortex. In the patient group, but not in controls, the anterior cingulate glucose metabolic rate correlated positively with the total incongruent trial errors. CONCLUSION: These results are consistent with the hypothesis that the anterior cingulate plays a performance-monitoring role during human cognition. This study does not rule out a reduction in error sensitivity in this region of the brain in schizophrenia, as other studies have suggested, however the data show that in unmedicated patients with the paranoid subtype this function is preserved to some extent.

Temporal lobe metabolic differences in medication-free outpatients with schizophrenia via the PET-600.

Regional cerebral glucose metabolic rates (rCMRglc) were compared in 18 unmedicated outpatients with schizophrenia and 11 normal controls using high resolution positron emission tomography (PET) and the tracer [F-18]-2-fluoro-2D-deoxyglucose (FDG). From previous work we expected to see abnormal hippocampal rCMRglc in the patients, but no striatal abnormalities. Trial-by-trial Stroop cognitive task, which has been shown to activate the anterior cingulate, was performed within a day of the PET study. As our patients performed abnormally on the Stroop we tested for a correlation between the anterior cingulate rCMRglc and Stroop performance. We found no whole slice cortical average glucose metabolic abnormalities. As, predicted we found abnormally decreased left hippocampal rCMRglc in the patients. No striatal or cingulate rCMRglc abnormalities were noted in patients, but they demonstrated a highly positive correlation between anterior and cingulate rCMRglc and Stroop facilitation. Patients with higher Stroop interference had more prominent hippocampal metabolic decreases. These localized temporal lobe abnormalities could account for some of the patient's positive symptoms and are consistent with recent findings in the literature.

The cortical topography of temporal lobe hypometabolism in early Alzheimer's disease.

Alzheimer's disease (AD) is characterized by a pathological process with specific predilection for association neocortex and the mesial temporal lobes. Recently developed high-resolution positron emission tomographs (PET) are able to quantitate regional cerebral metabolic rates for glucose (rCMRglc) in these brain regions and map the distribution of the metabolic consequences of Alzheimer pathology. In order to evaluate the relative involvement of mesial and neocortical temporal lobe brain regions in AD, we studied 22 AD patients, 11 of whom were mildly demented and 11 of whom were moderately demented in comparison to 8 age-matched control subjects. We used a PET instrument with 2.6 mm in-plane resolution and quantitated rCMRglc in anterior, middle, and posterior temporal neocortex, visual association cortex, primary visual cortex, and mesial temporal cortex. Although the moderately demented AD patients showed significantly lower metabolic rates than controls in visual association cortex and all temporal lobe regions except right anterior temporal neocortex, the mildly demented patients were different from the controls in only middle temporal neocortex. Considerable variability was found in the relative involvement of mesial temporal lobes and temporal neocortex in the AD patients, however, as shown by greater variance of a ratio of mesial temporal lobe rCMRglc to temporal neocortical rCMRglc (MES/NEO ratio) in the AD patients than the controls. A series of stepwise multiple regressions showed that this ratio was related to patient cognitive symptomatology, with more severely memory-impaired patients showing lower MES/NEO ratios, while patients with visuospatial disturbances showed higher MES/NEO ratios. In addition, the only biological variable that was related to this ratio was patient age, with older patients showing lower MES/NEO ratios. These results indicate that mesial temporal lobe structures are not invariably the earliest nor the most severely metabolically involved brain regions in AD and that the relative involvement of the mesial and neocortical temporal lobe is related to the patient's cognitive symptoms and age.

From syndrome to illness: delineating the pathophysiology of schizophrenia with PET.

The Section on Clinical Brain Imaging of the Laboratory of Cerebral Metabolism has been engaged in studying regional brain metabolism by positron emission tomography (PET) to establish the pathophysiology of schizophrenia. Recent studies have revealed that the fluorodeoxyglucose (FDG) PET methodology can be applied successfully to determine the anatomical substrata of directed attention. In normal controls, the metabolic rate in the middle prefrontal cortex, measured during the ongoing performance of auditory discrimination, is associated with their accuracy of performance. In unmedicated patients with schizophrenia, even those who performed as well as normals, the metabolic rate in the mid-prefrontal cortex was found to be significantly lower than normal. Further, this decreased metabolic rate was unrelated to performance. In medicated patients with schizophrenia, at least part of the metabolic deficit remains, but this deficit appears to be performance-related. These findings suggest several conclusions. The mid-prefrontal cortex and its dopamine neurotransmitter pathway input are important biological determinants of sustained attention. Two types of prefrontal metabolic deficits may contribute to dysfunctional goal-directed behavior and, more speculatively, vulnerability to psychosis in some patients with schizophrenia. One deficit is sensitive to neuroleptics, and thus presumably to a change in the balance of regional brain dopamine input. A second deficit is unaffected by neurolpetic treatment.

Attentional asymmetry in schizophrenia: the role of illness subtype and symptomatology.

1. Patients with undifferentiated and paranoid schizophrenia, and normal controls were compared using 2 versions of the covert orienting of attention procedure which evaluate exogenous (automatic) and endogenous (controlled) cuing mechanisms. 2. For both tasks, attentional performance varied with illness subtype, but in different ways. 3. On measures of automatic orienting undifferentiated patients showed evidence consistent with a mild right visual field deficit, while paranoid showed a reduction of inhibition-of-return, a mechanism which biases against returning to previously attended locations. 4. On measures of controlled orienting only the undifferentiated group showed the asymmetry of costs which has been the emphasis of most previous studies. The pattern of cost asymmetry was similar to that previously associated with prominent negative symptoms. Additionally, the magnitude of cost asymmetry correlated positively with negative symptoms in the overall patient group. 5. These findings show that systematically considering cue type and symptomatology are critical in interpreting varying patterns of performance by different groups of patients with schizophrenia on the covert orienting procedure. The implications of these findings for understanding the psychopathology of attention in schizophrenia and its neurobiological substrates are discussed.

The effects of antipsychotic medication on sequential inhibitory processes.

The authors used a Stroop negative priming paradigm to examine the effects of antipsychotic medication on selective attentional processes. The performance of 14 patients with schizophrenia who were withdrawn from neuroleptic medication was compared with that of 10 medicated patients and 16 matched controls. Results demonstrated an increase in negative priming to normal levels with neuroleptic therapy. In contrast, within-trial interference and facilitation effects appeared to be less sensitive to medication therapy. The sustainment of inhibitory processes over time may differentiate the inhibitory mechanisms of the medication-withdrawn patients from both the medicated patients and the matched controls. The study of sequential inhibitory processes and their response to neuroleptic treatment could be important methods for understanding the temporal parameters associated with inhibition in schizophrenia.

The effect of neuroleptics on dysfunction in a prefrontal substrate of sustained attention in schizophrenia.

Regional brain metabolism was measured in patients with schizophrenia during the performance of auditory discrimination to evaluate the effect of neuroleptic medication on the middle prefrontal cortex, an area that appears to be an important biological determinant of the sustained attention required of subjects in this task. While unmedicated patients with schizophrenia have lower than "normal" metabolic rates in this cortical area that are unrelated to performance, patients receiving neuroleptics appear to have this metabolic deficit attenuated with higher metabolism in this area associated with greater accuracy of performance. This change occurs in the context of differential neuroleptic effects on the cortical regions of the frontal cortex, increased metabolism in the basal ganglia, thalamus and temporal lobes, and no apparent effect in the parietal and occipital cortices. The findings suggest that only part of the abnormality in the prefrontal cortex determination of sustained attention in schizophrenia is sensitive to neuroleptic treatment.