[Value of brain imaging in assessment of cognitive symptoms. Cognitive and emotional impact of antipsychotic drug treatment]].
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Adolescent↗
Biomedical subjects
J L Martinot
Publications and source records attributed to J L Martinot.
Modulation of language areas with functional MR image-guided magnetic stimulation.
Repetitive transcranial magnetic stimulation (rTMS) can interfere with linguistic performance when delivered over language areas. At low frequency (1 Hz), rTMS is assumed to decrease cortical excitability; however, the degree of TMS effect on cortical language areas may depend on the localization of the stimulation coil with respect to the inter-individual anatomo-functional variations. Hence, we aimed at investigating individual brain areas involved in semantic and phonological auditory processes. We hypothesized that active rTMS targeted over Wernicke's area might modify the performance during a language-fragment-detection task. Sentences in native or foreign languages were presented to 12 right-handed male healthy volunteers during functional magnetic resonance imaging (fMRI). 3D-functional maps localized the posterior temporal activation (Wernicke) in each subject and MRI anatomical cortical landmarks were used to define Broca's pars opercularis (F3Op). A frameless stereotaxy system was used to guide the TMS coil position over Wernicke's and F3Op areas in each subject. Active and placebo randomized rTMS sessions were applied at 1 Hz, 110% of motor threshold, during the same language-fragment-detection task. Accuracy and response time (RT) were recorded. RT was significantly decreased by active rTMS compared to placebo over Wernicke's area, and was more decreased for native than for foreign languages. No significant RT change was observed for F3Op area. rTMS conditions did not impair participants' accuracy. Thus, low-frequency rTMS over Wernicke's area can speed-up the response to a task tapping on native language perception in healthy volunteers. This individually-guided stimulation study confirms that facilitatory effects are not confined to high-frequency rTMS.
Adult↗
Cerebral gray and white matter reductions and clinical correlates in patients with early onset schizophrenia.
Few magnetic resonance imaging studies of schizophrenia have investigated brain tissue volumes and their relation to clinical symptoms in patients with an early age at illness onset. The twofold purpose of the study was to investigate both gray and white matter volumes in schizophrenic men with an early age at illness onset, and to determine whether clinical features correlated with tissue volume changes, using an automated voxel-by-voxel image analysis procedure. Twenty male patients with DSM-IV diagnoses of schizophrenia, and an early age at onset (m+/-SD=19+/-2) were compared with 20 age-matched health men. Magnetic resonance (1.5-T) scans were obtained with an Inversion-Recovery prepared fast gradient echo sequence enhancing gray and white matter contrast. Statistical Parametric Mapping was used for image segmentation and comparison. Patients had significant gray matter reductions in medial frontal gyri, left insula, left parahippocampus, and left fusiform gyrus; bilateral white matter reductions in frontal lobes, and increased total cerebrospinal fluid volume were also observed. Negative symptom scores were negatively related to white matter volumes in cingulate regions, and in the right internal capsule. These findings emphasize a pattern of left-hemisphere gray matter abnormalities, and suggest that fronto-paralimbic connectivity may be altered in men with early onset schizophrenia.
Adult↗
In vivo extrastriatal and striatal D2 dopamine receptor blockade by amisulpride in schizophrenia.
Amisulpride, a substituted benzamide with high affinity for dopamine D2 and D3 receptors only, has been reported to have therapeutic effects on both negative and positive schizophrenic symptoms, although at distinct dose ranges (50-300 mg/day vs. 400-1,200 mg/day). The purpose of this study was to investigate the binding of amisulpride to extrastriatal (i.e., thalamus and temporal cortex) and striatal D2 dopamine receptors with respect to plasma amisulpride determinations. Ten patients with schizophrenia treated with amisulpride over a wide range of doses (25-1,200 mg/day) were studied. Positron emission tomography images were acquired by using 76Br-FLB-457, a highly specific antagonist of the D2 and D3 dopamine receptors. Binding indexes (BI) in the regions studied were estimated with reference to values from six healthy subjects. A curvilinear relationship was demonstrated between plasma concentration of amisulpride and the BI in extrastriatal regions. The BI also varied as a function of plasma concentration in striatum. Furthermore, the data provide evidence for different binding profiles: low plasma concentrations (28-92 ng/mL) induced marked extrastriatal binding and low striatal binding, whereas higher plasma concentrations (>153 ng/mL) induced marked binding both in extrastriatal and striatal regions. Dose-dependent differential binding profiles of amisulpride to D2 receptors in extrastriatal and striatal regions were demonstrated, and two therapeutic ranges of plasma concentrations for negative and positive schizophrenic symptoms, respectively, are suggested.
Adult↗
Extrastriatal and striatal D(2) dopamine receptor blockade with haloperidol or new antipsychotic drugs in patients with schizophrenia.
BACKGROUND: Both traditional and atypical antipsychotics have been hypothesised to be effective in schizophrenia through limbic and cortical D(2) dopamine receptor blockade. AIMS: To investigate this hypothesis with the D(2)/D(3)-selective positron emission tomography (PET) probe [(76)Br]-FLB457. METHOD: PET scans were performed on 6 controls and 18 patients with schizophrenia treated with haloperidol or with risperidone, clozapine, amisulpride or olanzapine. RESULTS: The D(2) dopamine receptor blockade was high in the temporal cortex with both haloperidol and atypical antipsychotics. The atypicals, however, induced a significantly lower D(2) binding index than haloperidol in the thalamus and in the striatum. CONCLUSIONS: Results suggest that cortical D(2) dopamine receptors are a common target of traditional and atypical antipsychotics for therapeutic action. Higher in vivo binding to the D(2) receptors in the cortex than in the basal ganglia is suggested as an indicator of favourable profile for a putative antipsychotic compound.
Adult↗
Altered hemispheric functional dominance during word generation in negative schizophrenia.
Functional brain imaging studies have reported decreased frontal activations in schizophrenia, but hemispheric dominance for language has rarely been assessed. To investigate regional activation and lateralization during word production, we determined normalized regional cerebral blood flow (rCBF) variations with positron emission tomography (PET) and H2(15)O (water labeled with the isotope oxygen 15) in 14 negative schizophrenia patients and 14 volunteers. Subjects were scanned during two trials of three conditions: rest, vocalized verbal fluency, and spontaneous word production. Images were analyzed using an anatomical volumes of interest method, and the two groups' changes were compared, using rest as a baseline. Differences in the lateralization of changes were detected in homologous frontal and inferior parietal regions. The lateralization effects in patients arose from lower activations in the left frontal regions, abnormal right inferior frontal activations, and weaker right inferior parietal deactivation, during the word production tasks. The right hemisphere changes correlated negatively with the performance in verbal fluency. Thus in negative schizophrenia patients, while the activations were less focused on the left hemisphere regions usually engaged in word generation, rCBF changes in the right hemisphere might reflect a compensatory functional pattern.
Adult↗
A prognostic study of clinical dimensions in adolescent-onset psychoses.
Adolescent-onset psychoses often raise diagnostic difficulties because of the mixture of schizophrenic and affective features. This study examined prospectively which clinical dimensions contribute to difficulty in initial diagnosis and which clinical features have predictive value for outcomes of schizophrenia or affective disorders, and for eventual psychosocial functioning. Thirty-six adolescents consecutively admitted for a psychotic episode were followed up for 1 to 4 years. Symptoms were assessed at admission, at discharge, and once a year. DSM-III-R (APA 1989) diagnoses were assessed at admission and once a year. Comparisons were performed across initial and followup diagnostic groups. Positive symptoms did not differentiate the initial clinical pictures, while negative symptoms, manic symptoms, and disorganization differentiated the manic and depressive episodes in the acute phase. When initial positive symptoms (mainly delusions) were severe, they predicted a final diagnosis in the schizophrenia spectrum. Poor outcome was associated with more anhedonia-associality and lower functioning scores at admission. Results suggest (1) a higher vulnerability to positive symptoms in adolescents who will further develop schizophrenia and (2) the low specificity of affective symptoms at this age.
Acute Disease↗
Working memory control in patients with schizophrenia: a PET study during a random number generation task.
OBJECTIVE: The authors' goal was to investigate brain regions involved in the deficiency of working memory control processes in patients with schizophrenia. METHOD: Regional cerebral blood flow was measured with positron emission tomography in eight men with stabilized schizophrenia and eight healthy men while they were performing a graded random number generation task. Twelve scans were made for each subject. Covariations between randomness of responses and regional activation were analyzed. RESULTS: The pattern of covariation between randomness of responses and activation in the anterior cingulate and superior parietal regions differed between patients and healthy subjects. CONCLUSIONS: These results suggest a cinguloparietal dysfunction underlying the impairment of working memory control processes during a random number generation task in patients with schizophrenia.
Adult↗
The cortical serotonin2 receptors studied with positron-emission tomography and [18F]-setoperone during depressive illness and antidepressant treatment with clomipramine.
BACKGROUND: Changes in serotonin (5-HT)2 receptor densities were reported in depression by postmortem studies and following treatment with tricyclic antidepressants in animal studies. Here, 5-HT2 receptors were studied in vivo in depressed patients. METHODS: Cortical 5-HT2 receptors were investigated prospectively using positron-emission tomography and [18F]-setoperone in 7 depressed patients, before and after at least 3 weeks of clomipramine (CMI), 150 mg daily. They were compared to 7 age-matched controls. RESULTS: There was no significant difference between the untreated patients and the controls, except in the frontal region, where the [18F]-setoperone specific binding was slightly lower in patients. After CMI treatment, depression scores significantly improved and [18F]-setoperone specific binding decreased in cortical regions, suggesting receptor occupancy and/or receptor regulation, by CMI; however, no clinical score correlated with the 5-HT2 receptor measurements either in the untreated or in the treated conditions. CONCLUSIONS: These data substantiate the view that tricyclic antidepressants such as clomipramine significantly interact with cortical 5-HT2 serotoninergic receptors in actual therapeutic situations.
Adult↗
Functional connectivity in depressive, obsessive-compulsive, and schizophrenic disorders: an explorative correlational analysis of regional cerebral metabolism.
In order to investigate the changes in functional relationships between brain regions in three psychiatric disorders, an exploratory statistical analysis of the regional cerebral metabolic rates for glucose (rCMRglu) obtained with positron emission tomography (PET) was performed. Correlations between various rCMRglu were computed in control, depressive, obsessive-compulsive, and schizophrenic groups to determine whether alterations of the correlation pattern were found in the psychiatric groups. The absence of correlation between left and right frontal lobes was common to the three psychiatric groups studied. Depressive patients recovered a better frontal interhemispheric coupling after successful treatment and the alterations in the depressed state also involved the relation between the right temporal cortex and the right thalamus. Obsessive-compulsive patients had not only lateral frontal dysfunction but also alterations in the functional relationships between cortex and thalami. In schizophrenic patients, the modifications of regional cerebral metabolic correlations involved both anterior and posterior cortical regions. Thus, although the relationship between left and right frontal lobes was altered in three psychiatric disorders, the pattern of functional connectivity between frontal regions, posterior cortical and subcortical regions differed depending on the diagnostic group.
Adult↗
No serotonin 5-HT2A receptor density abnormality in the cortex of schizophrenic patients studied with PET.
To investigate putative abnormalities of cortical 5-HT2A receptor density in schizophrenia, we used positron emission tomography and [18F]setoperone, a high-affinity 5-HT2A receptor radioligand, in 14 neuroleptic-free or -naive schizophrenic patients and in 15 normal controls. No significant difference between the groups was observed in the whole or regional cortical binding potential of [18F]setoperone, indicating an absence of major 5-HT2A receptor cortical density abnormalities in schizophrenics.
Adult↗
Frontal dysfunction in neurologically normal chronic alcoholic subjects: metabolic and neuropsychological findings.
BACKGROUND: Neuropsychological and imaging studies suggest that frontal dysfunction may occur in apparently normal chronic alcoholic subjects. METHODS: To investigate this issue further, we performed neuropsychological and fluorodeoxy-glucose-PET studies in 17 chronic alcoholics without patent neurological and psychiatric complications. RESULTS: Metabolic abnormalities were found in the mediofrontal and in the left dorsolateral prefrontal cortex, but not in the orbitofrontal cortex. Neuropsychological testing revealed significantly reduced verbal fluency and impaired performance on the Stroop test. The mediofrontal hypometabolism correlated with the reduction in verbal fluency and the time necessary to perform the interference condition of the Stroop test. The left dorsolateral prefrontal hypometabolism correlated with the number of errors on the Stroop test. CONCLUSION: These data indicate that circumscribed frontal dysfunctions may occur in chronic alcoholic subjects before clinically obvious neurological complications, and may account for some of the alcohol-related neuropsychological and behavioural impairments.
Adult↗
Binding of antipsychotic drugs to cortical 5-HT2A receptors: a PET study of chlorpromazine, clozapine, and amisulpride in schizophrenic patients.
OBJECTIVE: This study examined the binding to cortical serotonin 5-HT2A receptors of conventional doses of the typical neuroleptic chlorpromazine in comparison with clozapine, the prototype atypical antipsychotic, and amisulpride, a specific dopamine D2-D3 blocker. METHOD: Seventeen schizophrenic patients treated with chlorpromazine (75-700 mg/day), four treated with clozapine (200-600 mg/day), and five treated with amisulpride (200-1200 mg/day) were studied. Cortical 5-HT2A binding was estimated by reference to the values for 14 antipsychotic-free schizophrenic subjects with the use of positron emission tomography and [18F]setoperone, a high-affinity radioligand for cortical 5-HT2A receptors. RESULTS: A dose-dependent decrease in the number of available cortical binding sites for [18F] setoperone was demonstrated in the chlorpromazine group; for the highest dose, there was a virtual lack of sites available for binding. A very low percentage of available binding sites was also observed in the clozapine-treated patients at all doses. This suggests a high level of 5-HT2A blockade with both clozapine and high doses of chlorpromazine. No significant binding of amisulpride to 5-HT2A receptors was detected. CONCLUSIONS: A high level of 5-HT2A receptor blockade does not appear specific to clozapine in comparison with high doses of chlorpromazine, suggesting that the distinct clinical profiles of both drugs are unrelated to 5-HT2A blockade itself.
Adolescent↗
Presynaptic dopaminergic function in the striatum of schizophrenic patients.
The dopaminergic hypothesis of schizophrenia postulates increased brain dopaminergic activity. Two previous studies reported increased 18F-DOPA uptake with positron emission tomography in schizophrenic patients (n = 5, n = 7). In the present study, striatal dopaminergic function was assessed in vivo in six untreated schizophrenics and seven control subjects, comparable for age and sex. The 18F-fluoro-L-DOPA (18F-DOPA) uptake rate constant Ki was determined in the caudate and putamen using coregistered positron emission tomography and magnetic resonance imaging. No difference between groups for mean Ki was found. The variability of the 18F-DOPA uptake values was higher in the caudate (p < 0.01) and in the putamen (p < 0.001) in schizophrenic patients than in control subjects, suggesting that schizophrenia is a disorder involving heterogeneous states of the striatal presynaptic dopaminergic function.
Adolescent↗
Frontal 5-HT2A receptors studied in depressive patients during chronic treatment by selective serotonin reuptake inhibitors.
To investigate adaptative changes of 5-HT2A receptors induced by SSRIs, six patients chronically treated for a depressive episode (four with fluoxetine, two with fluvoxamine) were studied with PET and [18F]setoperone. They were compared to eight untreated depressive patients. The mean frontal to cerebellum radioactivity concentration ratio, an index of the [18F]setoperone specific binding to 5-HT2A receptors, was higher in treated than in untreated patients, when age was taken into account. This suggests that chronic treatment by SSRIs could induce an up-regulation of the 5-HT2A receptors, and that 5-HT2A receptor down-regulation is not a common mechanism for the therapeutic effects of all serotoninergic antidepressive drugs.
Adult↗
In vivo characteristics of dopamine D2 receptor occupancy by amisulpride in schizophrenia.
The relationship between the daily oral dose of the benzamide amisulpride and the striatal D2-dopamine receptors occupancy was investigated in 11 schizophrenic patients using positron emission tomography with 76Br-bromolisuride. The patients were studied before and during chronic treatment with amisulpride over a wide range of doses. The test-retest variability of the method was estimated to be 5.8% in a group of four patients receiving placebo. A curvilinear relationship was demonstrated between the amisulpride doses and the D2-receptor occupancy. A range of 70-80% occupancy of the striatal D2 receptors, suggested as an optimal interval for therapeutic action on positive psychotic symptoms, was obtained with doses of amisulpride ranging between 630 and 910 mg per day, while an occupancy of 85%, suggested to be associated with pronounced extrapyramidal side-effects, was reached with 1,100 mg per day.
Adult↗
[Brain imaging in schizophrenic psychoses].
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Antipsychotic Agents↗
Time course of prefrontal lobe dysfunction in severely depressed in-patients: a longitudinal neuropsychological study.
The Stroop Colour-Word Test (SCWT) and the Verbal Fluency Test (VFT), two tests that have been suggested to be particularly sensitive to prefrontal dysfunction, were administered to 23 severely depressed in-patients. Both tests were impaired in patients at inclusion, but only verbal fluency normalized with successful treatment of depression. VFT impairment is consistent with the hypothesis of a left prefrontal cortex dysfunction in depression. Moreover, the persistence of an impaired performance on SCWT in patients at discharge suggests that a selective attention deficit may persist in patients beyond a clear clinical improvement.
Adolescent↗