Thomas E. Nordahl

Cerebral glucose metabolism in adults with hyperactivity of childhood onset

Abstract Background and Methods. The cause of childhood hyperactivity (attention deficit–hyperactivity disorder) is unknown. We investigated the hypothesis that cerebral glucose metabolism might differ between normal adults (controls) and adults with histories of hyperactivity in childhood who continued to have symptoms. Each patient was also the biologic parent of a hyperactive child. None of the adults had ever been treated with stimulant medication. To measure cerebral glucose metabolism, we administered 148 to 185 MBq (4 to 5 mCi) of [18F]fluoro-2-deoxy-D-glucose intravenously to 50 normal adults and 25 hyperactive adults while they performed an auditory-attention task. Images were obtained for 30 minutes with a Scanditronix positron-emission tomograph with a resolution of 5 to 6 mm. Whole-brain and regional rates of glucose metabolism were measured with computer assistance by two trained research assistants, working independently, who were blinded to the subjects status (control or hyperactive). Res...

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.

Dysfunction in a prefrontal substrate of sustained attention in schizophrenia

Regional brain metabolism was measured in normal subjects and patients with schizophrenia while they performed an auditory discrimination task designed to emphasize sustained attention. A direct relationship was found in the normal subjects between metabolic rate in the middle prefrontal cortex and accuracy of performance. The metabolic rate in the middle prefrontal cortex of patients with schizophrenia, even those who performed as well as normals, was found to be significantly lower than normal and unrelated to performance. The findings point to a role of the mid-prefrontal region in sustained attention and to dysfunction of this region in schizophrenia.

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 typeractivity 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 flurodeoxyglucose-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.

Metabolic brain pattern of sustained auditory discrimination

SummaryPositron emission tomography of [18F]-2-fluorodeoxyglucose was used to assess the functional brain activity of normal subjects while performing auditory discrimination (CPT), while receiving an identical set of tones as in CPT, but with the instructions that they were background noise, or while at rest. The present study: (1) confirms earlier findings of an association between the functional activity of the right midprefrontal cortex and the performance of auditory discrimination, (2) localizes this increase in right prefrontal cortex activity to the middle prefrontal gyrus; and (3) provides a framework of specific testable hypotheses for the evaluation of the importance of certain limbic and paralimbic areas in the biological determination of sustained attention to be addressed in future studies. The framework accounts for the now confirmed finding that the middle cingulate has lower metabolic activity in CPT than at rest, and new findings of alterations in temporal lobe processing of tones in response to attention.

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.

Metabolic and cognitive changes in hereditary ataxia

Fourteen subjects (affected, n = 7; at risk, n = 7) from one well-known kindred with adult onset autosomal dominant olivopontocerebellar atrophy (OPCA), were studied with [18F]-2-deoxy-D-glucose (FDG) positron emission tomography (PET), magnetic resonance imaging (MRI), cognitive testing and scored neurological examination, and compared with normal controls. The neurological examination, MRI and cognitive tests showed no significant differences between at risk and normal control subjects. Mild cognitive deficits were seen in affected subjects; the degree of cognitive change appeared to relate to the severity of the illness. MRI demonstrated cerebellar and brainstem atrophy in all affected subjects. PET studies showed higher global metabolic rates (mean [SD]) in at risk subjects (10.5 [1.5] mg per min per 100 g) as compared to affected (9.0 [0.8] mg per min per 100 g) and normal control subjects (9.1 [1.5] mg per min per 100 g). Normalized (region/global average) regional metabolic rates were reduced in cerebellar hemispheres and vermis, and in frontal and prefrontal areas of affected subjects in comparison to at risk and normal control subjects. These findings indicate that functional changes in some forms of autosomal dominant hereditary cerebellar ataxia may extend beyond the cerebellum and brainstem to involve other parts of the neuraxis.

The metabolic brain pattern of young subjects given scopolamine

The effect of an intravenous dose of 0.5 mg of scopolamine on the functional brain activity of normal subjects performing auditory discrimination (CPT) was determined in two independent positron emission tomography studies with [18F] 2-fluoro-deoxyglucose. In the first preliminary study, the most significant effect found was a reduction in the functional activity of the thalamus. In the second “hypothesis-testing” study, an equally prominent effect on thalamic functional activity was seen. Because the second study was performed on a high-resolution scanner with improved methodology, we re-examined scopolamines effects on those brain regions established as determinants of CPT. Of the regions affected, the reduction in cingulate and the increase in basal ganglia metabolic rates were the most notable. We concluded that scopolamines effects on the functions of thalamic, cingulate and basal ganglia are the likely causes of scopolamines well-described attention-altering properties. Alterations in these same brain structures could be responsible for scopolamines effects on other cognitive functions, e.g., memory. Alternatively, scopolamines effects on other brain structures such as the hippocampus and frontal cortex could underlie scopolamines effects on these other cognitive functions. Studies of scopolamines regional metabolic effects in subjects performing these other cognitive tasks at more than a single dose and at more than one post-drug time are needed to discriminate between these two possibilities.

Brain Regional α-[11C]Methyl-L-Tryptophan Trapping in Medication-Free Patients With Obsessive-Compulsive Disorder

CONTEXTnThe hypothesis of a serotonin (5-hydroxytryptamine [5-HT]) dysfunction in obsessive-compulsive disorder (OCD) stems largely from the clinical efficacy of 5-HT reuptake inhibitors. Serotonergic abnormalities in the unmedicated symptomatic state, however, remain to be fully characterized.nnnOBJECTIVEnTo investigate brain regional 5-HT synthesis, as indexed by positron emission tomography and the α-[(11)C]methyl-L-tryptophan trapping constant (K*), in treatment-free adults meeting criteria for OCD.nnnDESIGNnBetween-group comparison.nnnSETTINGnDepartment of Psychiatry and Montreal Neurological Institute, McGill University, and Department of Psychology, McGill University Health Centre, Quebec, Canada.nnnPARTICIPANTSnTwenty-one medication-free patients with OCD (15 men with a mean [SD] age of 33.2 [9.3] years and 6 women with a mean [SD] age of 35.8 [7.1] years) and 21 healthy controls matched for age and sex (15 men with a mean [SD] age of 32.9 [10.1] years and 6 women with a mean [SD] age of 36.5.5 [8.6] years). Main Outcome Measure The α-[(11)C]methyl-L-tryptophan brain trapping constant K*, which was analyzed with Statistical Parametric Mapping (SPM8) and with proportional normalization (extent threshold of 100 voxels with a peak threshold of P ≤ .005).nnnRESULTSnCompared with healthy controls, the patients with OCD exhibited significantly greater α-[(11)C]methyl-L-tryptophan trapping in the right hippocampus and left temporal gyrus (Brodmann area 20). In the larger subsample of all men, these same differences were also evident, as well as higher K* values in the caudate nucleus. Individual differences in symptom severity correlated positively with K* values sampled from the caudate and temporal lobe of the patients with OCD, respectively. There were no regions where the patients exhibited abnormally low K* values. Volumetric analyses found no morphometric alterations that would account for the group differences.nnnCONCLUSIONnThe results support previous reports of greater striatal and temporal lobe activity in patients with OCD than in healthy controls and suggest that these disturbances include a serotonergic component. Previously reported glucose metabolic disturbances in OCD involving the orbitofrontal and cingulate cortices, in comparison, might reflect postsynaptic changes in the serotonergic system.

Longitudinal neuropsychological findings from Stony Brook first episode study

comprehensive neuropsychological test battery during the midluteal phase (one time), and blood levels of estrogen and progesterone were collected weekly over the four week period. Average estrogen levels were positively and strongly associated with cognitive performance across all domains, including verbal and nonverbal abilities. Perceptual-motor speed (Symbol Digit Modalities Test), verbal memory (WMS Associate Learning. CVLT), and visual memory (WMS Visual Reproduction, Benton VRT) showed the strongest relationships (0.77 ~r.~0.8l; p<O.OOOOl). Average estrogen levels were also inversely correlated with the BPRS negative symptom scale (rho=-0.44, p<O.05), but not with pos itive symptoms. It appears that estrogen is more strongly related to cognitive abilities than to symptomatology. These data may have implications for hormone replacement therapy in schizophrenic patients. Supported by Napa State Hospital, California Department of Mental Health, NARSAD, and MH30854.