Effect of fluoxetine on regional cerebral metabolism in autistic spectrum disorders: a pilot study.

The regional metabolic effects of fluoxetine were examined in patients with autism spectrum disorders. Six adult patients with DSM-IV and Autism Diagnostic Interview (ADI) diagnoses of autism (n = 5) and Asperger's syndrome (n = 1), entered a 16-wk placebo-controlled cross-over trial of fluoxetine. The patients received (18)F-deoxyglucose positron emission tomography with co-registered magnetic resonance imaging at baseline and at the end of the period of fluoxetine administration. After treatment, the patients showed significant improvement on the scores of the Yale--Brown Obsessive--Compulsive Scale -- Obsessions subscale and the Hamilton Anxiety Scale; Clinical Global Impressions -- Autism scores showed 3 of the patients much improved and 3 unchanged. Relative metabolic rates were significantly higher in the right frontal lobe following fluoxetine, especially in the anterior cingulate gyrus and the orbitofrontal cortex. Patients with higher metabolic rates in the medial frontal region and anterior cingulate when unmedicated were more likely to respond favourably to fluoxetine. These results are consistent with those in depression indicating that higher cingulate gyrus metabolic rates at baseline predict SRI response.

Patterns of cortical activity and memory performance in Alzheimer's disease.

BACKGROUND: Declarative memory changes are the hallmark of Alzheimer's disease, although their functional neuroanatomy is not restricted to a single structure. Factor analysis provides statistical methods for evaluating patterns of cerebral changes in regional glucose uptake. METHODS: Thirty-three Alzheimer's patients and 33 age- and gender-matched control subjects were studied with magnetic resonance imaging and positron emission tomography with [(18)F] deoxyglucose. During the tracer-uptake period, subjects performed a serial verbal learning task. Cortical activity was measured in 32 regions of interest, four in each lobe on both hemispheres. RESULTS: Factor analysis with varimax rotation identified seven factors explaining 80% of the variance ("parietal cortex," "occipital cortex," "right temporo-prefrontal areas," "frontal cortex," "motor strip," "left temporal cortex," and "posterior temporal cortex"). Relative to control subjects, Alzheimer's patients showed significantly reduced values on the factors occipital cortex, right temporo-prefrontal areas, frontal cortex, and left temporal cortex. The factor temporo-prefrontal areas showed large differences between patients with good and poor performance, but little difference when control subjects were similarly divided. CONCLUSIONS: Findings suggest that Alzheimer's disease is characterized by altered patterns of cortical activity, rather than deficits in a single location, and emphasize the importance of right temporo-prefrontal circuitry for understanding memory deficits.

Feeling unreal: a PET study of depersonalization disorder.

OBJECTIVE: The goal of this study was to assess brain glucose metabolism and its relationship to dissociation measures and clinical symptoms in DSM-IV depersonalization disorder. METHOD: Positron emission tomography scans coregistered with magnetic resonance images of eight subjects with depersonalization disorder were compared to those of 24 healthy comparison subjects. The two groups did not differ in age, sex, education, performance on a baseline neuropsychological battery, or performance on a verbal learning task administered during [(18)F]fluorodeoxyglucose uptake. A cortical analysis by individual Brodmann's areas was performed. RESULTS: Compared to the healthy subjects, subjects with depersonalization disorder showed significantly lower metabolic activity in right Brodmann's areas 22 and 21 of the superior and middle temporal gyri and had significantly higher metabolism in parietal Brodmann's areas 7B and 39 and left occipital Brodmann's area 19. Dissociation and depersonalization scores among the subjects with depersonalization disorder were significantly positively correlated with metabolic activity in area 7B. CONCLUSIONS: Depersonalization appears to be associated with functional abnormalities along sequential hierarchical areas, secondary and cross-modal, of the sensory cortex (visual, auditory, and somatosensory), as well as areas responsible for an integrated body schema. These findings are in good agreement with the phenomenological conceptualization of depersonalization as a dissociation of perceptions as well as with the subjective symptoms of depersonalization disorder.

Shape and size of the corpus callosum in schizophrenia and schizotypal personality disorder.

The size and shape of the corpus callosum were assessed on sagittal section magnetic resonance images in 27 patients with schizophrenia, 13 patients with schizotypal personality disorder (SPD), and 30 healthy volunteers. High-resolution 1.2mm axial SPGR images were acquired and resectioned so that the sagittal plane passed through the anterior and posterior commissures and was parallel to the interhemispheric fissure. The corpus callosum and the whole brain were traced on midsagittal section slices of each brain, and the callosum was divided into 30 anteroposterior sectors. Pixel-by-pixel chi-square and thin-plate spline analyses were used to assess between-group shape differences. Size of the corpus callosum was smaller anteriorly in the genu of the corpus callosum and posteriorly in the splenium in schizophrenic patients than in normal controls. The genu of the corpus callosum was larger in SPD patients than in schizophrenic patients or normal controls. The posterior corpus callosum was largest in normal controls, smaller in SPD patients, and smallest in schizophrenic patients. Shape analysis was consistent with these size comparisons, and suggested a downward bowing of the corpus callosum in schizophrenic and SPD patients. SPD patients also had a region of the callosum just posterior to the genu that was narrower than in the other two groups. The decreases in corpus callosal size in schizophrenia varied directly with length of illness, perhaps indicative of a progressive process. The patient-control differences in callosal size and shape are consistent with a hypothesis of decreased connectivity between the left and the right hemispheres in schizophrenia and SPD.

Three-dimensional analysis with MRI and PET of the size, shape, and function of the thalamus in the schizophrenia spectrum.

OBJECTIVE: In an exploration of the schizophrenia spectrum, the authors compared thalamic size, shape, and metabolic activity in unmedicated patients with schizophrenia and schizotypal personality disorder to findings in age- and sex-matched healthy control subjects. METHOD: Coregistered magnetic resonance imaging (MRI) and positron emission tomography scans were obtained in 27 schizophrenic patients, 13 patients with schizotypal personality disorder, and 32 control subjects who performed a serial verbal learning test during tracer uptake. After thalamus edges were outlined on 1.2-mm MRI scans, a radial warping program yielded significance probability mapping in three dimensions. RESULTS: Significance probability mapping (with resampling) identified an area in the region of the mediodorsal nucleus bilaterally with significantly lower relative metabolism in the schizophrenia group than in either the control or schizotypal personality disorder groups, which did not differ from each other. The three groups did not differ significantly in total thalamic volume in square millimeters or thalamic volume relative to brain volume. Shape analyses revealed that schizophrenic patients had significantly fewer pixels in the left anterior region, whereas patients with schizotypal personality disorder had significantly fewer pixels in the region of the right mediodorsal nucleus than did control subjects. CONCLUSIONS: Schizophrenic patients showed significant metabolism and shape differences from control subjects in selective subregions of the thalamus, whereas patients with schizotypal personality disorder showed only a difference in shape. Because the mediodorsal and anterior nuclei have different connections with limbic and prefrontal structures, the anterior thalamic shrinkage and mediodorsal metabolic and shape changes might relate to the different clinical pictures in schizotypal personality disorder and schizophrenia.

Visualizing fronto-striatal circuitry and neuroleptic effects in schizophrenia.

Disturbances in fronto-striatal circuitry have been postulated to be important in schizophrenia. Positron emission tomography typically shows decreased metabolic rates in these areas relative to other brain areas in schizophrenia. After treatment with typical neuroleptics, striatal metabolic rates are increased, but other brain areas tend not to show significant changes. Atypical neuroleptics less markedly affect striatal metabolic rates, but show wider cortical effects. In order to examine fronto-striatal circuitry, a technique for visualizing the correlations between metabolic rates in all brain areas was applied in 33 controls and 27 unmedicated schizophrenic patients. Correlation images revealed strong fronto-striatal connections in controls, but weak fronto-striatal links in schizophrenic patients. Changes in striatal circuits, also reflected in recent anatomical studies, may be important for understanding antipsychotic effects.

d,l-fenfluramine response in impulsive personality disorder assessed with [18F]fluorodeoxyglucose positron emission tomography.

Reduced serotonergic activity has been associated with impulsive aggression in personality disordered patients in metabolite and pharmacologic challenge studies. This study used positron emission tomography to explore whether reduced serotonergic function occurs in critical brain regions such as orbital frontal and cingulate cortex that, may play a role in modulating aggression. Six impulsive-aggressive patients and five healthy volunteers were evaluated for changes in regional glucose metabolism after administration of the serotonergic releasing agent d,l-fenfluramine (60 mg, p.o.) or placebo. Volunteers demonstrated increases in orbital frontal and adjacent ventral medial frontal cortex, cingulate, and inferior parietal cortex, whereas impulsive-aggressive patients showed no significant increases in glucose metabolism after fenfluramine in any region. Compared with volunteers, patients showed significantly blunted metabolic responses in orbital frontal, adjacent ventral medial and cingulate cortex, but not in inferior parietal lobe. These results are consistent with reduced serotonergic modulation of orbital frontal, ventral medial frontal, and cingulate cortex in patients with impulsive-aggressive personality disorders.

Ventricular enlargement in poor-outcome schizophrenia.

BACKGROUND: A subset of patients with schizophrenia, defined on the basis of longitudinal deficits in self-care, may show a classic ("Kraepelinian") degenerative course. An independent validator of the phenomenologically defined Kraepelinian subtype might be provided by a structural indicator of possible brain degeneration: ventricular size as measured by computed tomography (CT). METHODS: To examine whether Kraepelinian patients would show a differential increase in ventricular size over time, two CT scans were conducted at intervals separated by > 4 years, an average of 5 years. Fifty-three male patients with DSM-III-R diagnoses of chronic schizophrenia were subdivided into Kraepelinian (n = 22; mean age = 42 +/- 6 years) and non-Kraepelinian (n = 31; mean age = 38 +/- 12.2 years) subgroups. Kraepelinian patients were defined on the basis of longitudinal criteria: > 5 years of complete dependence on others for life necessities and care, lack of employment, and sustained symptomatology. Thirteen normal elderly volunteers (mean age = 60 +/- 17.8) were also scanned at 4-year intervals. CT measurements were made by raters without knowledge of subgroup membership. A semiautomated computer program was used to trace the anterior horn, lateral ventricles, and temporal horns for each slice level on which they were clearly seen. RESULTS: The ventricles showed a bilateral increase in size over the 4-year interval in the Kraepelinian subgroup, more marked in the left hemisphere than the right. By contrast, neither the non-Kraepelinian subgroup nor the normal volunteers showed significant CT changes from scan 1 to scan 2. CONCLUSIONS: Thus, the longitudinal dysfunctions in self-care that characterize the Kraepelinian patients were associated with an independent indicator of brain abnormality.

Dorsal striatal size, shape, and metabolic rate in never-medicated and previously medicated schizophrenics performing a verbal learning task.

BACKGROUND: Magnetic resonance imaging and positron emission tomography were used to study the size and metabolic rate of the caudate and the putamen in 18 patients with schizophrenia (n=16) or schizo-affective disorder (n=2) and 24 age- and sex-matched control subjects. METHODS: The patients were either never medicated (n=7) or drug free (n=11) for a median of 3 weeks. During uptake of fludeoxyglucose F 18, all patients performed a serial verbal learning test. Positron emission tomographic and magnetic resonance imaging scans were coregistered, and the caudate and the putamen were traced on the magnetic resonance image. RESULTS: The striatum had a significantly lower relative metabolic rate in schizophrenics than in controls. Never-medicated patients had lower metabolic rates in the right putamen (ventral part of the dorsal striatum) than previously medicated patients. The caudate was significantly smaller in never-medicated patients than in controls and largest in previously medicated patients. Patients with higher relative metabolic rates in the putamen scored higher on the Abnormal Involuntary Movements Scale. CONCLUSIONS: The findings are consistent with reports of striatal enlargement in previously medicated patients and size increases after neuroleptic treatment. Never-medicated patients, in contrast, had ventral striatal structures that were smaller and less active than those observed in controls and previously medicated patients.

Age-related shift in brain region activity during successful memory performance.

Coregistered positron emission tomography (PET)/magnetic resonance imaging (MRI) was used to characterize brain function in 70 volunteers, aged 20-87 years, during a verbal memory task. Frontal activity showed an age-related decline that remained significant after statistical control for sulcal atrophy. Analyses of young and old subgroups matched for memory scores revealed that young good performers activated frontal regions, whereas old good performers relied on occipital regions. Although activating different cortical regions, good performers of all ages used the same cognitive strategy semantic clustering. Age-related functional change may reflect dynamic re-allocation in a network of brain areas, not merely anatomically fixed neuronal loss or diminished capacity to perform.

A method of basal forebrain anatomical standardization for functional image analysis.

Functional as well as structural assessment of the basal forebrain has mostly focused on the dorsal caudate and putamen in axial slices where they are easily outlined or their centers located with stereotaxic methods. The more ventral extent of the basal forebrain, where the irregular form and indistinct boundaries of the nucleus accumbens and substantia innominata are difficult to trace and where the brain's ventral surface may contribute partial volume artifacts to measurement, has been less studied. We present a method based on coronal sections, landmarks placed on clearly visible anchor points, and the computational technique of thin-plate spline warping which allows the alignment of groups of individuals to common coordinates for pixel-by-pixel statistical mapping. The reliability of the landmarks across independent raters yields a median absolute difference of 1.3-1.6 mm. The validity of the method is confirmed by variance maps which reveal significant decreases in variance over spindle and bounding box alignment.

Anterior cingulate gyrus volume and glucose metabolism in autistic disorder.

OBJECTIVE: This study reports the first paired measurements of glucose metabolism and volume of the anterior cingulate gyrus in autism. METHOD: Magnetic resonance imaging (MRI) and positron emission tomography (PET) scans of seven high-functioning autistic patients and seven sex- and age-matched normal volunteers were coregistered. After the anterior cingulate gyri were outlined on the MRI images, the volumes of the structures were measured and corrected for brain volume. The volumes were then applied to the PET images and metabolic maps were obtained. RESULTS: Right anterior cingulate area 24' was significantly smaller in relative volume, and both area 24 and area 24' were metabolically less active, in the autistic patients than in the normal subjects. CONCLUSIONS: Autism may be characterized by structural and functional alterations in the anterior cingulate gyrus.

Ventricular enlargement associated with linkage marker for schizophrenia-related disorders in one pedigree.

We previously obtained evidence indicating a genetic linkage marker for schizophrenia and related disorders (two-point lod score = 3.72, P = 0.01) on the short arm of chromosome 5(5p14.1-13.1) in one large pedigree. Automated computer algorithms were used to edge the brain and measure the volume of the ventricles, regional sulcal atrophy, and skull size and shape in the original nuclear family members. Of the 11 subjects who underwent computed tomography, six (three schizophrenic, two with schizotypal personality disorder, and one unaffected) carried the marker allele that co-segregated with schizophrenia-related disorders, while five (all unaffected) did not. The family members with the marker allele linked to schizophrenia-related disorders (n = 6) had significantly (P < 0.05) larger ventricle-brain ratios (VBRs) and more fronto-parietal atrophy (controlling for age) than the family members lacking the schizophrenia-related marker allele (n = 5). The three individuals with the largest VBRs all carried the marker, although they received diagnoses of no schizophrenia-related disorder, schizotypal personality disorder, and schizophrenia. Regional cortical values indicative of cerebrospinal fluid content were higher in the frontal and parietal regions of family members carrying the marker. The hypothesis that genetic linkage is associated with structural brain pathology is difficult to test because of all the potential compounding factors. Our findings suggest the possibility that, in this family, relatively enlarged VBR and fronto-parietal atrophy, as determined by computed tomograph, may be associated with a schizophrenia-related gene and present susceptibility to schizophrenia-related disorders. In addition to a replication of these findings in other similarly linked families yet to be identified, further studies using higher resolution structural and functional neuroimaging techniques will be required.