Adham Mancini-Marïe

Brain activity during emotionally negative pictures in schizophrenia with and without flat affect : An fMRI study

The aim of this functional magnetic resonance imaging (fMRI) study was to compare regional brain activity in schizophrenia subjects with (FA+) and without (FA-) flat affect during the viewing of emotionally negative pictures. Thirteen FA+ subjects and 11 FA- subjects were scanned while being presented with a series of emotionally negative and neutral pictures. Experientially, the viewing of the negative pictures induced a negative emotional state whose intensity was significantly greater in the FA- group than in the FA+ group. Neurally, the Negative minus Neutral contrast revealed, in the FA- group, significant loci of activation in the midbrain, pons, anterior cingulate cortex, insula, ventrolateral orbitofrontal cortex, anterior temporal pole, amygdala, medial prefrontal cortex, and extrastriate visual cortex. In the FA+ group, this contrast produced significant loci of activation in the midbrain, pons, anterior temporal pole, and extrastriate visual cortex. When the brain activity measured in the FA+ group was subtracted from that measured in the FA- group, only the lingual gyrus was significantly activated. Perhaps in FA+ subjects an amygdaloid malfunction rendered the amygdala unable to correctly evaluate the emotional meaning of the pictures presented, thus preventing effective connectivity linking the amygdala to the brain regions implicated in the physiological and experiential dimensions of emotion. Alternatively, a disturbance of effective connectivity in the neural networks linking the midbrain and the medial prefrontal system may have been responsible for the quasi absence of emotional reaction in FA+ subjects, and the abnormal functioning of the medial prefrontal cortex and anterior cingulate cortex in the FA+ group.

Quetiapine in patients with comorbid schizophrenia-spectrum and substance use disorders: an open-label trial.

ABSTRACT Background: Preliminary evidence suggests that clozapine relieves the craving for psychoactive substances in schizophrenia patients. Quetiapine shares crucial pharmacological properties with clozapine. Promising results have been described with quetiapine therapy in patients with psychosis and substance use disorder. Methods: Based on Diagnostic and Statistical Manual of Mental Disorders – fourth edition (DSM‐IV) criteria, patients were diagnosed with comorbid schizophrenia-spectrum and substance use disorders. Patients were switched to quetiapine for a 12‐week open-label trial. Craving, quantities used, days of consumption, and severity of substance abuse were assessed every 3 weeks. Alcohol and Drug Use Scales were administered on baseline and end-point. Psychiatric symptoms, depressive symptoms, extrapyramidal symptoms, and cognition were also assessed at baseline, week 6 and week 12. Results: Twenty-four schizophrenia-spectrum patients were included in the last observation carried forward (LOCF) analyses, responding to one or more of the following substance use disorders: cannabis (15 patients), alcohol (10 patients), and other psychoactive substances (nine patients). Overall, severity of substance abuse improved during the study. Less weekly days were spent on drugs of abuse. A decrease in the weekly Canadian dollars spent on psychoactive substances was also observed. Cognition, psychiatric, depressive, and extrapyramidal symptoms also significantly improved ( p < 0.05). Conclusions: In this open-label, uncontrolled trial, significant improvements were noted in substance abuse, psychiatric symptoms, extrapyramidal symptoms, and cognition during quetiapine therapy. The study suffered from three main limitations: (1) the open-label design of the study; (2) the patients’ poor compliance; and (3) the small sample size involved. Controlled studies on the use of quetiapine in dual diagnosis schizophrenia are warranted to confirm that the effects are drug-related.

Increased extrapyramidal symptoms in patients with schizophrenia and a comorbid substance use disorder

Few data have been gathered about the impact of psychoactive substances on extrapyramidal symptoms (EPS) in schizophrenia, and so far, inconsistent results have been reported. We studied 41 outpatients with schizophrenia (based on DSM-IV criteria), who were divided into two groups: with (n = 17) and without (n = 24) a substance use disorder (alcohol, cannabis, and/or cocaine). Both groups were matched for sociodemographic data and psychiatric symptoms (Positive and Negative Syndrome Scale). EPS were evaluated with the Extrapyramidal Symptoms Rating Scale and the Barnes Akathisia Scale, and all patients were stable on either quetiapine or clozapine. Patients receiving anticholinergic drugs were excluded. Analyses of variance were conducted on both groups and showed that schizophrenia patients with a comorbid substance use disorder (especially cocaine) displayed more EPS compared with non-abusing patients.

Disturbed sexual dimorphism of brain activation during mental rotation in schizophrenia.

BACKGROUND Sex differences in visuo-spatial abilities have been well documented in the general population, but there are only a few inconsistent reports in schizophrenia. The purpose of the present study was to examine potential sex differences in performance and pattern of brain activations during mental rotation in schizophrenia patients relative to control participants. METHODS Thirty three schizophrenia patients (17 women and 16 men) were compared to thirty five healthy control participants (17 women and 18 men), while performing a classic mental rotation task (3-D figures). Blood oxygen level dependent (BOLD) echo-planar images were acquired on a 3-Tesla Siemens TRIO system. Random-effect analyses were performed using SPM5 (UK Wellcome Institute). RESULTS Behavioural data revealed a diagnosis-by-sex interaction with healthy men (HM) performing significantly better than schizophrenia men (SZ-M) and no significant difference between healthy women (HW) and schizophrenia women (SZ-W). fMRI results revealed an overall similar pattern of extensive cerebral activations (in the parietal and lateral prefrontal cortex) and deactivations (in the medial prefrontal cortex) in HM and SZ-W during performance of the mental rotation versus control task. In contrast, both HW and SZ-M showed much more restricted activations and no significant deactivations. CONCLUSIONS Sex differences in performance and cerebral activations during mental rotation in schizophrenia patients deviated significantly from what we observed in healthy volunteers. This finding supports and extends existing evidence of a disturbed sexual dimorphism in schizophrenia. Moreover, the results emphasize the importance of including both sexes in neurocognitive and neuroimaging studies of schizophrenia.

Sex/gender differences in the brain and cognition in schizophrenia

The early conceptualizations of schizophrenia have noted some sex/gender differences in epidemiology and clinical expression of the disorder. Over the past few decades, the interest in differences between male and female patients has expanded to encompass brain morphology and neurocognitive function. Despite some variability and methodological shortcomings, a few patterns emerge from the available literature. Most studies of gross neuroanatomy show more enlarged ventricles and smaller frontal lobes in men than in women with schizophrenia; finding reflecting normal sexual dimorphism. In comparison, studies of brain asymmetry and specific corticolimbic structures, suggest a disturbance in normal sexual dimorphism. The neurocognitive findings are somewhat consistent with this picture. Studies of cognitive functions mediated by the lateral frontal network tend to show sex differences in patients which are in the same direction as those observed in the general population, whereas studies of processes mediated by the corticolimbic system more frequently reveal reversal of normal sexual dimorphisms. These trends are faint and future research would need to delineate neurocognitive differences between men and women with various subtypes of schizophrenia (e.g., early versus late onset), while taking into consideration hormonal status and gender of tested participants.

Differential hemodynamic brain activity in schizophrenia patients with blunted affect during quetiapine treatment

Abstract: Blood-oxygenation-level-dependent (BOLD) brain changes underlying response to quetiapine were examined using passive viewing of emotionally negative stimuli. Twelve DSM-IV schizophrenia patients with blunted affect (BA+) were scanned before and after 22 weeks of quetiapine treatment. Whole-brain, voxel-based methods were used to assess the differential hemodynamic response to quetiapine. In addition, a post hoc comparison to an independent group of 11 schizophrenia patients without blunted affect (BA−) was performed to compare them with BA+ (postquetiapine) in response to emotion processing. A 22-week treatment with quetiapine resulted in significant clinical improvement in the 12 study completers (mean ± SD posttreatment PANSS blunted affect score of 5.50 ± 0.76 at baseline to 2.08 ± 1.00 at end point; t = 7.78, df = 11, P < 0.0001). Treatment response was associated with significant BOLD changes: increases in prefrontal cortex activation particularly in the right dorsolateral prefrontal cortex (DLPFC, BA 46) and the right anterior cingulate cortex (ACC, BA 32); and in the left putamen, right anterior temporal pole (ATP), and right amygdala. Conversely, before treatment with quetiapine, the same subjects activated the midbrain bilaterally and the right pons. The post hoc conjunctional analyses demonstrated that BA− subjects activated the left ACC, left insula, left ATP (BA 21), left ATP (BA 38), left amygdala, and right medial prefrontal cortex. Quetiapine seems to affect clinical recovery by modulating the functioning of specific brain regions. Unique BOLD changes in the putamen and DLPFC with quetiapine, in the BA+ postquetiapine, may reflect modality-specific effects. Controlled studies are needed to further assess these preliminary findings.

Neural correlates of emotional recognition memory in schizophrenia: effects of valence and arousal.

Schizophrenia patients are often impaired in their memory for emotional events compared with healthy subjects. Investigations of the neural correlates of emotional memory in schizophrenia patients are scarce in the literature. The present study aimed to compare cerebral activations in schizophrenia patients and healthy controls during memory retrieval of emotional images that varied in both valence and arousal. In a study with functional magnetic resonance imaging, 37 schizophrenia patients were compared with 37 healthy participants while performing a yes/no recognition paradigm with positive, negative (differing in arousal intensity) and neutral images. Schizophrenia patients performed worse than healthy controls in all experimental conditions. They showed less cerebral activation in limbic and prefrontal regions than controls during retrieval of negatively valenced stimuli, but had a similar pattern of brain activation compared with controls during retrieval of positively valenced stimuli (particularly in the high arousal condition) in the cerebellum, temporal lobe and prefrontal cortex. Both groups demonstrated increased brain activations in the high relative to low arousing conditions. Our results suggest atypical brain function during retrieval of negative pictures, but intact functional circuitry of positive affect during episodic memory retrieval in schizophrenia patients. The arousal data revealed that schizophrenia patients closely resemble the control group at both the behavioral and neurofunctional level.

Sex differences in the cerebral function associated with processing of aversive stimuli by schizophrenia patients

Objective: Impaired processing of various emotions is considered one of the fundamental features of schizophrenia. In the recent study intriguing sex differences were observed in the cerebral function associated with the experience of sadness in schizophrenia patients. The aim of the present study was to explore this phenomenon during exposure to aversive stimuli. Method: Fifteen men and 10 women with the DSM-IV diagnosis of schizophrenia underwent functional magnetic resonance imaging (fMRI) while viewing alternating blocks of negative and neutral pictures. Data were analysed using random-effects model within statistical parametric mapping (SPM99) software. Results: Processing of negative stimuli evoked significantly greater activations in men in the thalamus, cerebellum, temporal, occipital and posterior cingulate cortex, while women exhibited greater activations in the left middle frontal gyrus. Conclusions: The sex differences in the cerebral activations in schizophrenia patients deviate from what has been observed in the general population during exposure and experience of negative affect. As such the present study supports and extends the authors’ preliminary observation of the anomalous sexual dimorphism in schizophrenia at the functional neuroanatomical level, suggesting potential masculinization of female subjects and feminization of male subjects with schizophrenia.

The paradox of quetiapine in obsessive-compulsive disorder.

Schizophrenia and obsessive-compulsive disorder (OCD) have historical, clinical, and epidemiological links. The clinical use of atypical neuroleptics (ie, dual serotonin-dopamine antagonists) to treat both conditions sheds a new light on them. We report the first two cases of obsessive-compulsive symptoms (OCS) induced by quetiapine in schizophrenia patients. A case of successful augmentation by quetiapine in refractory OCD is also presented. A review of the literature on OCS induced by atypical neuroleptics follows. This paradoxically induced OCD symptomology in schizophrenia patients administered atypical neuroleptics is discussed from new pathophysiological and clinical perspectives. The discussion emphasizes the prognostic implications of OCS in schizophrenia and available therapies for this comorbidity.

Increased grey matter densities in schizophrenia patients with negative symptoms after treatment with quetiapine : a voxel-based morphometry study

Among new-generation antipsychotics, quetiapine was found to be associated with a partial ‘normalization’ of reduced functional activation in prefrontal and temporal areas and studies conducted by our group found a clinical improvement in negative symptoms in addition to restoration of frontal activation in schizophrenia patients with blunted affect after treatment with quetiapine. Here we investigated the parallelism between improved clinical symptoms and grey mater density (GMD) changes in the frontal region after quetiapine treatment in 15 schizophrenia patients. We hypothesize that improvement in clinical symptoms will be associated with change in GMD in prefrontal regions of interest. By using voxel-based morphometry, paired t-test random-effect analysis showed a significant increase in GMD bilaterally in the inferior frontal cortex/orbitofrontal gyrus and anterior cingulate cortex after 5.5 months of treatment with quetiapine. This GMD increase was associated with a significant improvement in negative symptoms. When GMD was correlated with psychiatric assessment scores, there was a negative correlation between GMD in the anterior cingulate cortex and the Rating Scale for Emotional Blunting score (r=−665, P=0.008) and between the orbitofrontal gyrus and the total Positive and Negative Syndrome Scale negative score (r=−764, P=0.001). Results suggest that increased GMD in some frontal regions are associated with an improvement of negative symptoms. Although not unique to quetiapine, it would be reasonable to attribute the GMD changes in the study to treatment.