Differential brain glucose metabolic patterns in antipsychotic-naïve first-episode schizophrenia with and without auditory verbal hallucinations.

BACKGROUND: Auditory verbal hallucinations (AVHs) are a core symptom of schizophrenia. Previous reports on neural activity patterns associated with AVHs are inconsistent, arguably owing to the lack of an adequate control group (i.e., patients with similar characteristics but without AVHs) and neglect of the potential confounding effects of medication. METHODS: The current study was conducted in a homogeneous group of patients with schizophrenia to assess whether the presence or absence of AVHs was associated with differential regional cerebral glucose metabolic patterns. We investigated differences between patients with commenting AVHs and patients without AVHs among a group of dextral antipsychotic-naive inpatients with acute first-episode schizophrenia examined with [(18)F]fluoro-deoxyglucose positron emission tomography (FDG-PET) at rest. Univariate and multivariate approaches were used to establish between-group differences. RESULTS: We included 9 patients with AVHs and 7 patients without AVHs in this study. Patients experiencing AVHs during FDG uptake had significantly higher metabolic rates in the left superior and middle temporal cortices, bilateral superior medial frontal cortex and left caudate nucleus (cluster level p < 0.005, family wise error-corrected, and bootstrap ratio > 3.3, respectively). Additionally, the multivariate method identified hippocampal-parahippocampal, cerebellar and parietal relative hypoactivity during AVHs in both hemispheres (bootstrap ratio < -3.3). LIMITATIONS: The FDG-PET imaging technique does not provide information regarding the temporal course of neural activity. The limited sample size may have increased the risk of false-negative findings. CONCLUSION: Our results indicate that AVHs in patients with schizophrenia may be mediated by an alteration of neural pathways responsible for normal language function. Our findings also point to the potential role of the dominant caudate nucleus and the parahippocampal gyri in the pathophysiology of AVHs. We discuss the relevance of phenomenology-based grouping in the study of AVHs.

Fluordeoxyglucose-PET study in first-episode schizophrenic patients during the hallucinatory state, after remission and during linguistic-auditory activation.

OBJECTIVES: We tested the hypothesis that endogenous auditory verbal hallucinations (AVH) involve activation of auditory/linguistic association cortices that are usually activated by externally presented speech. METHODS: Nine neuroleptic-naive patients with first-episode schizophrenia (Diagnostic and Statistical Manual for Mental Disorders-IV criteria) with prominent AVH underwent three PET scans using F-fluordeoxyglucose (FDG): (i) shortly after presentation, while experiencing prominent and frequent AVH; (ii) after medication-induced remission (R), using a stable dose of risperidone; (iii) also in remission, during bilateral linguistic auditory activation (LAA) induced by spoken text mimicking the content of the hallucinations experienced while the first PET was performed, using headphones. PET scans were acquired using an Advanced-Nxi Scanner (GE Healthcare). Intrasubject realignment, spatial normalization and statistical analysis of PET images were carried out using statistical parametric mapping. Differences between AVH and R and between LAA and R were statistically evaluated using a voxel-wise paired t-test. A voxel level threshold of P<0.01 was used to determine which regions underwent the most significant changes in F-FDG uptake. RESULTS: During AVH, patients demonstrated a significant activation of the supplementary motor area, anterior cingulum, medial superior frontal area and cerebelum. Activation was also observed in the left superior frontal area, right superior temporal pole and right orbitofrontal region. During LAA, greater FDG uptake was observed in the right and left superior and middle temporal cortices, left hippocampus and parahippocampal regions. CONCLUSION: Our findings show a different pattern of regional cerebral glucose metabolism between AVH and physiological auditory activation. This feature does not support the hypothesis that AVH in acute schizophrenic patients reflects an abnormal activation of auditory-linguistic pathways. However, it does suggest that cortical regions implicated in the generation of inner speech could be involved.

Decreased striatal dopamine transporter binding assessed with [123I] FP-CIT in first-episode schizophrenic patients with and without short-term antipsychotic-induced parkinsonism.

RATIONALE: Drug-induced parkinsonism (DIP) is one of the main causes of treatment drop-out in schizophrenic patients causing a high incidence of relapse that leads patients to a bad clinical prognosis. The dopaminergic nigrostriatal pathway is involved in the movement control, so the study of the dopamine transporter (DAT) could be of great value to determine its implication in the appearance of DIP. OBJECTIVE: The goal of the study is to determine the striatal DAT binding assessed with [(123)I] FP-CIT SPECT in first-episode neuroleptic-naive schizophrenic in-patients with DIP after short-term antipsychotic treatment. METHOD: The [(123)I] FP-CIT binding ratios of ten schizophrenic in-patients who developed DIP during the first 4-week period of risperidone treatment (6+/-2 mg/day) were compared with ten schizophrenic in-patients treated with the same doses of risperidone and who do not developed DIP and with ten age-matched healthy subjects. Quantitative analyses of SPECTs were performed using regions of interest located in caudate, putamen and occipital cortex. Parkinsonism was assessed by the Simpson-Angus Scale and the psychopathological status by the Clinical General Impression and Positive and Negative Syndrome Scales. RESULTS: Whole striatal [(123)I] FP-CIT binding ratios were significantly lower in patients with and without DIP than in healthy subjects (p<0.001). This was also observed in whole putamen (p<0.001) and caudate nucleus (p<0.001). Females showed higher whole striatal [(123)I] FP-CIT binding ratios than males (p<0.05). No differences in psychopathological scales were observed between patients with and without DIP. CONCLUSION: Our first-episode schizophrenic patients with and without DIP after short-term risperidone treatment have a decreased striatal DAT binding assessed with [(123)I] FP-CIT. This alteration could be related to the schizophrenic disease or may be secondary to the antipsychotic treatment.

Striatal dopamine D2 receptor density in neuroleptic-naive and in neuroleptic-free schizophrenic patients: an 123I-IBZM-SPECT study.

Most post-mortem autoradiographic studies have described striatal dopamine D(2) receptor up-regulation due to chronic neuroleptic exposure. The aim of our study was to compare in-vivo striatal D(2) receptor density in neuroleptic-naive and neuroleptic-free schizophrenic patients. We included 28 young (mean age: 28+/-8 years) acute psychotic patients meeting DSM-IV criteria for schizophrenia or schizophreniform disorder. Enrolled patients were either first-episode neuroleptic-naive (n=12) or neuroleptic-free (n=16) after a minimum washout period of 7 days. All neuroleptic-free subjects had previously received neuroleptic treatment for a median period of 3.5 years. Both groups were evaluated using standard clinical scales. In-vivo striatal D(2) receptor binding was assessed by basal ganglia/frontal cortex ratios using (123)I-IBZM SPECT. No statistically significant differences were found in age or clinical assessment between neuroleptic-naive and neuroleptic-free schizophrenic patients. No differences were found in the basal ganglia/frontal cortex ratios of neuroleptic-naive (1.78+/-0.11) and neuroleptic-free (1.81+/-0.15) patients. No striatal uptake laterality was observed in either group. No correlation was demonstrated between BG/FC ratios and duration of illness, period of neuroleptic exposure or time of drug washout. We conclude that our neuroleptic-naive and neuroleptic-free schizophrenic patients did not show differences in striatal D(2) receptor binding, suggesting that IBZM-SPECT fails to detect D(2) receptor up-regulation induced by chronic exposure to neuroleptic drugs.

Lack of sex differences in striatal dopamine D2 receptor binding in drug-naive schizophrenic patients: an IBZM-SPECT study.

Differences in antipsychotic treatment response, clinical course and outcome of schizophrenia could be related to gender-related cerebral differences in anatomy and function. The aim of the study was to assess sex differences in the striatal dopamine D2 receptor binding in 15 drug-naive schizophrenic patients (seven males, eight females) using (123)I-IBZM single photon emission computed tomography. Basal ganglia/frontal cortex (BG/FC) uptake ratios were obtained. No significant differences were found in global, left and right BG/FC ratios or laterality indices between males and females. No correlation was found between BG/FC ratios and age, duration of illness or scores on symptom rating scales. Our data indicate a lack of sex differences in striatal D2 receptor binding in drug-naive schizophrenic patients and do not support previous reports of left lateralized striatal asymmetry in male schizophrenic patients.

Brain metabolism during hallucination-like auditory stimulation in schizophrenia.

Auditory verbal hallucinations (AVH) in schizophrenia are typically characterized by rich emotional content. Despite the prominent role of emotion in regulating normal perception, the neural interface between emotion-processing regions such as the amygdala and auditory regions involved in perception remains relatively unexplored in AVH. Here, we studied brain metabolism using FDG-PET in 9 remitted patients with schizophrenia that previously reported severe AVH during an acute psychotic episode and 8 matched healthy controls. Participants were scanned twice: (1) at rest and (2) during the perception of aversive auditory stimuli mimicking the content of AVH. Compared to controls, remitted patients showed an exaggerated response to the AVH-like stimuli in limbic and paralimbic regions, including the left amygdala. Furthermore, patients displayed abnormally strong connections between the amygdala and auditory regions of the cortex and thalamus, along with abnormally weak connections between the amygdala and medial prefrontal cortex. These results suggest that abnormal modulation of the auditory cortex by limbic-thalamic structures might be involved in the pathophysiology of AVH and may potentially account for the emotional features that characterize hallucinatory percepts in schizophrenia.