Happy Birthday "One Flew Over the Cuckoo's Nest": A Momentous Tale in the Quest for an Effective and Ethical Approach to Psychosurgery.

The anniversary of the publication of 'One Flew Over the Cuckoo's Nest' by Ken Kesey offers an opportunity for reflection on the use of neurosurgery in psychiatry. We used a narrative, historical and dialectical method to deliver an account of the controversial subject. A balanced representation of the negative and positive aspects, acknowledging some of the questionable ethical practices while describing well-reasoned applications is provided. It includes neurosurgeons, psychiatrists who have embraced these procedures with unwarranted enthusiasm and those who have opposed. Neurosurgical techniques for the treatment of severe mental disorders have evolved from rudimentary procedures which were used to 'correct' unwanted behaviours associated with a wide range of severe mental disorders to more refined and selective approaches used as a last resort to treat specific mental health conditions. In the absence of specific aetiological models to guide ablative surgical targets, non-ablative, stimulatory techniques have more recently been developed to allow reversibility when surgical treatment fails to obtain a sizeable improvement in quality of life. The subject is concretely illustrated by two eloquent clinical images: one on a series of brain computed tomography scans carried out on a Canadian population of subjects, who underwent leukotomy decades ago, and the other more contemporary on an implantation surgery to epidural stimulation. Alongside technical advances in psychosurgery, a regulatory framework has gradually developed to ensure vigilance in the appropriateness of patients' selection. Nevertheless, harmonisation of protocols around the world is necessary to ensure consistency in obtaining and maintaining the highest possible ethical standards for the benefit of patients. If the neurosciences promise today, in their new, better framed, and reversible applications, to provide answers to unmet therapeutic needs, we still must remain attentive to drifts linked the introduction of intrusive technologies for purposes of domination or behaviour modification that would impede our individual freedom.

Subjective cognitive complaints in first episode psychosis: A focused follow-up on sex effect and alcohol usage.

A network of early psychosis-specific intervention programs at the University of Montreal in Montreal, Quebec, Canada, conducted a longitudinal naturalistic five-year study at two Urban Early Intervention Services (EIS). In this study, 198 patients were recruited based on inclusion/exclusion criteria and agreed to participate. Our objectives were to assess the subjective cognition complaints of schizophrenic patients assessed by Subjective Scale to Investigate Cognition in Schizophrenia (SSTICS) in their first-episode psychosis (FEP) in relation to their general characteristics. We also wanted to assess whether there are sex-based differences in the subjective cognitive complaints, as well as differences in cognitive complaints among patients who use alcohol in comparison to those who are abstainers. Additionally, we wanted to monitor the changes in the subjective complaints progress for a period of five years follow-up. Our findings showed that although women expressed more cognitive complaints than men [mean (SD) SSTICS, 28.2 (13.7) for women and 24.7 (13.2) for men], this difference was not statistically significant (r = -0.190, 95 % CI, -0. 435 to 0. 097). We also found that abstainers complained more about their cognition than alcohol consumers [mean (SD) SSTICS, 27.9 (13.4) for abstainers and 23.7 (12.9) for consumers], a difference which was statistically significant (r = -0.166, 95 % CI, -0. 307 to -0.014). Our findings showed a drop in the average score of SSTICS through study follow-up time among FEP patients. In conclusion, we suggest that if we want to set up a good cognitive remediation program, it is useful to start with the patients' demands. This demand can follow the patients' complaints. Further investigations are needed in order to propose different approaches between alcohol users and abstinent patients concerning responding to their cognitive complaints.

Catatonia with schizophrenia: From ECT to rTMS.

BACKGROUND: Electroconvulsive therapy is indicated in cases of catatonic schizophrenia following a failure of the challenge test with lorazepam or Zolpidem®. Some patients need maintenance treatment with ECT. Repetitive Transcranial Magnetic Stimulation (rTMS) and anodal Transcranial direct-current stimulation (tDCS) might be effective against catatonia. OBJECTIVE: Consider an alternative to ECT for a refractory patient. REVIEW: Twenty-one articles were identified mainly based on case reports series were found using search on Medline, Google Scholar, PsychInfo, CAIRNS. Key words were:"catatonia", and "rTMS", and more generally with"ECT","tDCS","Zolpidem®". At the end there were only six case reports with rTMS and three with tDCS. We discussed the alternative to ECT and follow up rTMS strategies illustrated by these case reports. FINDINGS: Patients mean age was 35; numbers of previous ECT vary from zero to 556; the most common motor threshold (MT) is 80%, with two patients with 110%, the most common treatment placement is L DLPFC. In one of them, ECT was the only acute-state or maintenance treatment effective in this patient, who underwent 556 ECT sessions over 20 years. High-frequency rTMS was considered as a possible alternative, given the potential adverse effects of chronic maintenance ECT in a patient with comorbid epilepsy. rTMS treatment was 3-4×/week and over time extended to once every two weeks. A persistent objective improvement in catatonia was observed on the Bush-Francis Catatonia Rating Scale. CONCLUSION: rTMS is helpful for acute and maintenance treatment for catatonic schizophrenia who both failed multiple pharmacologic interventions and had safety concerns with continuing maintenance ECT. Clinicians should consider rTMS as a potential treatment option for refractory catatonia.

[Subjective cognition in schizophrenia]. / L'insight neurocognitif dans la schizophrénie.

OBJECTIVES: Given the extent, magnitude and functional significance of the neurocognitive deficits of schizophrenia, growing attention has been paid recently to patients' self-awareness of their own deficits. Thus far, the literature has shown either that patients fail to recognize their cognitive deficits or that the association between subjective and objective cognition is weak in schizophrenia. The reasons for this lack of consistency remain unexplained but may have to do, among others, with the influence of potential confounding clinical variables and the choice of the scale used to measure self-awareness of cognitive deficits. In the current study, we sought to examine the relationships between subjective and objective cognitive performance in schizophrenia, while controlling for the influence of sociodemographic and psychiatric variables. METHODS: Eighty-two patients with a schizophrenia-spectrum disorder (DSM-IV criteria) were recruited. Patients' subjective cognitive complaints were evaluated with the Subjective Scale to Investigate Cognition in Schizophrenia (SSTICS), the most frequently used scale to measure self-awareness of cognitive deficits in schizophrenia. Neurocognition was evaluated with working memory, planning and visual learning tasks taken from Cambridge Neuropsychological Tests Automated Battery. The Stroop Color-Word test was also administered. Psychiatric symptoms were evaluated with the Positive and Negative Syndrome Scale and the Calgary Depression Scale for Schizophrenia. The relationships between subjective and objective cognition were evaluated with multivariate hierarchic linear regression analyses, taking into consideration potential confounders such as sociodemographic and psychiatric variables. Finally, a factor analysis of the SSTICS was performed. RESULTS: For the SSTICS total score, the regression analysis produced a model including two predictors, namely visual learning and Stoop interference performance, explaining a moderate portion of the variance. Visual learning performance was the most consistent predictor of most SSTICS subscores (e.g. episodic memory, attention, executive functioning, language and praxis). Modest associations were found between the PANSS cognitive factor and objective cognition (e.g. Stroop interference, visual learning, and working memory). Finally, the factor analysis revealed a 6-factor solution that echoes the classification of the items of the SSTICS based on the neuropsychological literature. CONCLUSIONS: Using a scale having good internal validity, as shown by the factor analysis, the current study highlighted modest associations between subjective and objective cognitive performance, which suggests that schizophrenia patients are only partially aware of their own cognitive deficits. The results also showed a lack of correspondence between the impaired cognitive domain and the domain of cognitive awareness. It should be noted that clinicians were not better than patients at evaluating their cognitive deficits. Future research will need to determine if the observations reported here are schizophrenia-specific or not.

The long-term clinical benefit and effectiveness of switching to once-daily quetiapine extended release in patients with schizophrenia.

OBJECTIVE: To evaluate the long-term clinical benefit and effectiveness of switching to once-daily quetiapine extended release (XR) from an oral antipsychotic in patients with schizophrenia. Reasons for switching included insufficient efficacy, tolerability, and/or non-acceptability. The primary endpoint was the percentage of patients achieving an improvement in Clinical Global Impression - Clinical Benefit (CGI-CB) scale scores. RESEARCH DESIGN AND METHODS: A 24-week, international, multicentre, open-label, prospective study ( www.clinicaltrials.gov : NCT00640601). After a 7-14 day enrolment period (depending whether prior antipsychotic mono- or combination therapy), all patients received quetiapine XR 300 mg once daily (day 1), 600 mg/day (day 2), 600-800 mg/day (day 3) and 400-800 mg/day thereafter, with down-titration and discontinuation of prior antipsychotic by day 4. RESULTS: A total of 62% of patients completed the study and 56.9% (LOCF, ITT) achieved a significant improvement in CGI-CB (95% CI [0.51, 0.63]; p = 0.02). Switches due to insufficient efficacy showed a significant improvement (60%, 95% CI [0.51, 0.68]; p = 0.02), compared to 54.4% ([0.44, 0.64]; p = 0.38) and 52.4% ([0.36, 0.68]; p = 0.76) of switches due to insufficient tolerability and non-acceptability respectively (both p = ns). Patients previously on olanzapine and quetiapine IR showed a significant improvement in CGI-CB (62.6% [p = 0.02] and 61.2% [p = 0.04], respectively). Somnolence (18.0%) and dizziness (14.6%) were the main adverse events. Anticholinergic use decreased from 7.1 to 2.7%. Overall mean weight gain was 0.4 kg; 12.9% of patients experienced a weight gain of ≥7% and 15% experienced a clinically relevant shift in triglycerides from baseline. CONCLUSIONS: A majority of patients switched from other antipsychotics to quetiapine XR experienced clinical benefit. This was supported by all other efficacy outcomes regardless of the reason for switching. Safety data confirmed quetiapine XR was safe and well tolerated. The open-label design and lack of a placebo group represent limitations.

Neuronal correlates of appetite regulation in patients with schizophrenia: is there a basis for future appetite dysfunction?

BACKGROUND: Given the undesired metabolic side effects of atypical antipsychotic medication it is important to understand the neuronal basis related to processing of appetite regulation in patients affected by schizophrenia. METHODS: Here we used functional magnetic resonance imaging (fMRI) to assess brain activity in response to food cues and neutral stimuli in twenty patients with schizophrenia and eleven healthy individuals. In addition to clinical and dietary habits assessments, we collected, in patients, measurements of fasting glucose, ghrelin, leptin, insulin, prolactin and lipids blood concentration and we correlated the cerebral activity with clinical and metabolic measures. RESULTS: Both groups engaged a common neuronal network while processing food cues, which included the left insula, primary sensorimotor areas, and inferior temporal and parietal cortices. Cerebral responses to appetitive stimuli in thalamus, parahippocampus and middle frontal gyri were specific only to schizophrenic patients, with parahippocampal activity related to hunger state and increasing linearly over time. Antipsychotic medication dosage correlated positively with a cognitive measure reflecting food cravings, whereas the severity of the disease correlated negatively with a cognitive measure indicating dietary restraint in eating habits. These cognitive variables correlated, in turn, with parahippocampal and thalamic neuronal activities, respectively. CONCLUSIONS: We identified a specific neural substrate underlying cognitive processing of appetitive stimuli in schizophrenia, which may contribute to appetite dysfunction via perturbations in processing of homeostatic signals in relation to external stimuli. Our results also suggest that both antipsychotic medication and the disease severity per se could amplify these effects, via different mechanisms and neuronal networks.

Neural changes associated with appetite information processing in schizophrenic patients after 16 weeks of olanzapine treatment.

There is evidence that some atypical antipsychotics, including olanzapine, can produce unwanted metabolic side effects, weight gain and diabetes. However, neuronal correlates of change related to food information processing have not been investigated with these medications. We studied the effect of a pharmacological manipulation with an antipsychotic known to cause weight gain on metabolites, cognitive tasks and neural correlates related to food regulation. We used functional magnetic resonance imaging in conjunction with a task requiring visual processing of appetitive stimuli in schizophrenic patients and healthy controls before and after 16 weeks of antipsychotic medication with olanzapine. In patients, the psychological and neuronal changes associated following the treatment correlated with appetite control measures and metabolite levels in fasting blood samples. After 16 weeks of olanzapine treatment, the patients gained weight, increased their waist circumference, had fewer positive schizophrenia symptoms, a reduced ghrelin plasma concentration and an increased concentration of triglycerides, insulin and leptin. In premotor area, somatosensory cortices as well as bilaterally in the fusiform gyri, the olanzapine treatment increased the neural activity related to appetitive information in schizophrenic patients to similar levels relative to healthy individuals. However, a higher increase in sensitivity to appetitive stimuli after the treatment was observed in insular cortices, amygdala and cerebellum in schizophrenic patients as compared with healthy controls. Furthermore, these changes in neuronal activity correlated with changes in some metabolites and cognitive measurements related to appetite regulation.

Correlations between sadness-induced cerebral activations and schizophrenia symptoms: an fMRI study of sex differences.

BACKGROUND: The functional neuroimaging studies of emotion processing in schizophrenia have revealed variable results attributed partly to differential symptomatology and sex of tested patients. The aim of the present study was to investigate the relationship between cerebral activations during exposure to emotional material and schizophrenia symptoms in men versus women. METHOD: Fifteen men and 10 women with schizophrenia, equivalent in terms of age, medication and experienced symptomatology, underwent functional MRI during viewing sad and neutral film excerpts. Data were analyzed using Statistical Parametric Mapping Software (SPM2). RESULTS: Across all the patients there was a significant inverse relationship between negative symptoms and activations in the right prefrontal cortex during processing of sad versus neutral stimuli. In men, activations during sad versus neutral stimuli in the prefrontal, temporal and anterior cingulate cortex, as well as the caudate and cerebellum, were positively correlated with negative symptoms. In women, there were inverse correlations between positive symptoms and activations in the hippocampus, parietal and occipital cortex during the same condition. CONCLUSION: Present results confirmed association of prefrontal hypofunction with negative symptoms in schizophrenia. More interestingly, the results revealed a diametrically different pattern of symptom-correlated brain activity in men and women with schizophrenia, suggesting that the processing of sadness is mediated via neurophysiological mechanism related to negative symptoms in men and the mechanism related to positive symptoms in women.

[Cognitive remediation and cognitive assistive technologies in schizophrenia]. / Remédiation cognitive et assistants cognitifs numériques dans la schizophrénie.

BACKGROUND: Cognitive impairments are a core feature in schizophrenia. They impact several cognitive abilities but most importantly attention, memory and executive functions, consequently leading to great difficulties in everyday life. Most schizophrenia patients need assurance and require assistance and help from care workers, family members and friends. Family members taking care of a patient have additional daily work burden, and suffer psychological anguish and anxiety. Therefore, improving cognitive functions in schizophrenia patients is essential for the well-being of patients and their relatives. Reducing these deficits may decrease the economic burden to the health care system through lower numbers of hospital admissions and shorter hospitalisation periods, for example. Cognitive rehabilitation was developed to address the limited benefits of conventional treatments on cognitive deficits through the use of assistive technology as a means of enhancing memory and executive skills in schizophrenia patients. OBJECTIVE: To provide clinicians with comprehensive knowledge on cognitive trainings, programs of remediation, and cognitive assistive technologies. METHOD: Literature review. A search in the electronic databases (PubMed, EMBASE, Index Medicus) for recent articles in the last 10 years related to cognitive remediation published in any language using the words: cognitive and remediation or rehabilitation and schizophrenia, and a search for chapters in psychiatry and rehabilitation textbooks. RESULTS: We found 392 articles and 112 review paper mainly in English. First, we identified cognitive remediation programs that were beneficial to schizophrenia patients. Programs available in French (IPT, RECOS, and RehaCom) and others (CET, NET, CRT, NEAR, APT and CAT) were identified. In addition, since memory and executive function impairments could be present in people without schizophrenia, we reviewed inventories of cognitive assistive technologies proven to enhance cognitive skills in other populations. Finally, we present a review of recent studies testing innovative devices developed to assist schizophrenia patients. DISCUSSION: First, we found several cognitive programs proven to be effective with schizophrenia patients, but only three were validated in French. It could be useful to adapt other programs for French-speaking populations. Unfortunately, we found that very few of the existing cognitive assistive technologies are proposed to be used with schizophrenia patients. In fact, most of the available cognitive orthoses were tested primarily in people with neurological injuries (for example, various memory impairments caused by traumas), and in elderly illnesses (like Alzheimer disease). Devices for patients with mental deficits (e.g., mental retardation) were developed later, and only very recently explored for use in schizophrenia. As a result of an international collaboration between France and Canada, currently a tool called MOBUS is being tested. This technology aims at improving the autonomy of schizophrenia patients, by helping them plan and remember their daily activities. Furthermore, it encourages patient-caregiver communication, and permits monitoring patients' subjective reports of their symptoms. The use of cognitive assistive technologies is not meant to isolate patients by replacing the human element of relatives and caregivers by a machine. On the contrary, they offer a sense of security and they improve interpersonal relationships by permitting enhanced autonomy and greater self-confidence. Finally, a literature review of cognitive remediation in schizophrenia emphasizes the importance of a structured application of the technique in order for it to succeed. First, it is crucial to detect the impairments that will be targeted in each patient presenting a specific pattern of impairments. For this purpose, validated and customised neuropsychological tests are required. Then, cognitive remediation programs must be customised to each patient's needs in order to motivate the patient to participate. Finally, long-term effects must be assessed in order to verify whether reinforcement is needed. Following these steps, most of the studies show an improvement in the well-being of patients with schizophrenia. These recommendations are also suitable for the cognitive remediation programs, as for treatments with cognitive assistive devices. An important hurdle facing the advance of cognitive assistive technology programs is that different research groups work individually without a coordinated effort to improve and validate the existing programs. CONCLUSION: Schizophrenia treatments must take into account not only patients' symptoms, but also the associated cognitive deficits which constitute an important factor in their social problems. It has been shown that several cognitive remediation programs are efficient in schizophrenia. New technologies complement the benefits of such programs, and support pharmacological treatments and psychotherapies.

The complex relationships between executive functions and positive symptoms in schizophrenia.

BACKGROUND: Relationships between performance on various tests of executive functions and positive symptoms, especially delusions and hallucinations, have not been found consistently. This may be related to method of rating symptoms, to possible interactions between them, as well as to the low specificity of the cognitive test measures used. In this study, we have investigated the relationships between different aspects of positive symptomatology and several executive subprocesses. METHOD: Stable schizophrenia patients (n=96) were assessed for disorganization, delusion and hallucination symptoms rated from the Scale for Assessment of Positive Symptoms and the Scale for Assessment of Negative Symptoms. Interference sensitivity, inhibition and flexibility were assessed using the Wickens paradigm. The relationships between symptom dimensions as well as with cognitive and other potentially confounding variables were assessed using Pearson correlations and (simple and partial) stepwise regressions. RESULTS: Generally consistent with the cognitive constructs used to account for positive symptoms, the results indicated relationships between delusions, disorganization and inhibition, and between hallucinations and interference sensitivity. However, these relationships appeared more complex than expected, with some being dependent on interactions between symptoms. CONCLUSIONS: These results suggest: (i) that the global measures usually employed may not be appropriate for demonstrating specific relationships between symptoms and executive functions and (ii) that it is necessary to take into account the interactions between positive symptoms as well as with other factors to reveal these relationships.

Violent persons with schizophrenia and comorbid disorders: a functional magnetic resonance imaging study.

The main goal of this functional Magnetic Resonance Imaging (fMRI) study was to verify the hypothesis that seriously violent persons with Sz and the co-morbid diagnoses of an Antisocial Personality Disorder (APD) and a Substance Use Disorder (Sz+APD+SUD) would present a different pattern of prefrontal functioning than seriously violent persons with Sz only. In support with the main hypothesis, frontal basal cortices were significantly less activated in persons with Sz+APD+SUD during the execution of a go/no-go task than in persons with Sz only and non-violent persons without a mental illness. In contrast, significantly higher activations in frontal motor, premotor and anterior cingulate regions were observed in the Sz+APD+SUD group than in the Sz-only group.

[Cognition, schizophrenia and the effect of antipsychotics]. / Cognition, schizophrénie et effet des antipsychotiques: le point de vue d'un laboratoire de recherche clinique.

BACKGROUND: In this review, we conclude that cognitive impairments are as important as positive and negative symptoms in the clinical assessment and management of patients with schizophrenia. This is not a comprehensive review, considering that the new Measurement And Treatment Research to Improve Cognition in Schizophrenia (MATRICS) model will soon provide valuable data. It is however a product of the collective efforts of a French Canadian clinical research team that proposes a synthesis of data of pragmatic interest to clinicians. Medication with improved safety and cognition profile, gene-rally lead to better outcomes by facilitating compliance with drug regimens and rehabilitation programs. In addition, measures of attention and executive function (EF) appear to improve with novel antipsychotics when compared to traditional neuroleptics. Nevertheless, evaluating cognitive performance is not a routine procedure outside the domain of research. For example, procedural learning (PL) -- an important measure of cognitive function -- refers to cognitive and motor learning processes in which execution strategies cannot be explicitly described (ie learning by doing). These actions or procedures are then progressively learned through trial and error until automation of optimal performance is established. Procedural learning is rarely assessed in clinical practice. Inconsistent findings regarding the effects of neuroleptic drugs on PL have been reported. LITERATURE FINDINGS: Trials using acute administration of chlorpromazine in normal subjects induced PL deficits, suggesting the direct effect of neuroleptics, presumably via a D(2) dopamine blockade in the striatum. In a recent study by our group, schizophrenia patients, divided into three groups according to their pharmacological treatment (haloperidol, clozapine and risperidone) were compared to normal controls on two PL tasks; a visuomotor learning task (mirror drawing) and a problem solving learning task (Tower of Toronto). No deficits were detected in patients receiving clozapine, while haloperidol was associated with deleterious effects in both tasks. Risperidone, however, produced different effects depending on the task performed. Another 6-month double-blind Canadian study confirmed the beneficial effect of olanzapine on PL compared to haloperidol and risperidone. The differential effects of drugs on the striatal D(2) receptors, -irrespective of their classification as conventional or atypical neuroleptics and the specific process implicated in each of these PL tasks may explain these results. Tracer studies using radioactive benzamides (IBZM) specific to striatal D receptors determined a relationship between striatal D(2) receptor occupancy and PL performance such as the mirror drawing task. Using this method, data obtained in Montreal on schizophrenia patients receiving olanzapine and haloperidol have shown that the coefficient of determination in a visuomotor PL task varied inversely with D2 receptor saturation. DISCUSSION: This review probes the effect of impaired cognitive functions on schizophrenia patients' quality of life. Cognitive deficits found in schizophrenia affect planning, along with the aptitude to initiate and -regulate a goal-directed behaviour. These impairments have been repeatedly, yet inconclusively, attributed to frontal lobe dysfunction. Morphological findings obtained from neuroimaging studies remain inconsistent, some noting no differences between patients and controls while others observing reduced prefrontal volumes in schizophrenia patients. Conversely, functional neuroimaging (fMRI) demonstrated reduced frontal blood flow relative to global cerebral perfusion in schizophrenia patients. Overall, neuroimaging literature provides reliable evidence of frontal impairments in schizophrenia, although the average magnitude of difference between patients and controls is insufficient to defend a frontal lobe dysfunction hypo-thesis, as far as brain volume, resting cerebral metabolism or blood flow are concerned. The only measurement clearly distinguishing between patients and controls is fMRI of the frontal lobe while performing an experimentally controlled task. Here, schizophrenia patients fail to activate their frontal cortex when required. Sensitive to frontal lobe dysfunction are Neuropsychological tests of executive function. STUDY DESIGN: A study conducted in Montreal assessed the relation between EF impairments and difficulties in planning daily activities in schizophrenia patients scoring more than 3 on at least 4 items of the PANSS negative subscale. Performances on EF, memory and script generation were measured and compared to controls. Script production task required that subjects recite 10-20 actions that would normally be carried out for during daily life activity (going to a restaurant, buying groceries, etc.). Patients' performances were significantly lower with higher perserveration and sequencing impairments. Routine activities such as the ability to cook a meal were similarly investigated. Patients were videotaped in a kitchen while preparing a specific meal. RESULTS: Optimal sequence of micro- and macro-steps necessary to prepare the meal in a minimal time were measured. Sequencing errors, repetitions and omissions were significantly higher compared to controls. In addition, temporal organization was positively correlated with negative symptoms and low EF performance on neuro-psychological tasks. Thus concluding that EF impairment interferes with basic routine activities in schizophrenia patients, notably those with negative symptoms. Last but not least, we assessed the progress of patients' subjective complaints with regards to their cognitive functions using tests such as the SSTICS, specifically developed to address subjective cognitive complaints and insight. CONCLUSION: This review concludes that from now on cognitive deficit should be recognized as a major element in social and professional integration of schizophrenia patients, and should become a standardized assessment approach in clinical practice.

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.

[Effects of listening to previously hallucinated words by schizophrenia patients in remission: a functional magnetic resonance imaging study of six cases]. / Effet de l'écoute de mots déjà hallucinés chez des sujets schizophrènes en rémission: étude de six cas par la résonance magnétique nucléaire fonctionnelle.

BACKGROUND: Despite immense importance of auditory verbal hallucinations (AVHs) in the phenomenology of schizophrenia, the neurocognitive and neurophysiological bases of AVHs remain obscure. On the neurocognitive level, it has been proposed that AVHs arise from the disordered monitoring manifested by patients' inability to recognize their inner speech as being their own. On the neurophysiological level, the AVHs have been attributed to the aberrant activity in the primary auditory cortex (Heschl's gyrus). Although interesting, these models cannot account for the very specific and restricted content of AVHs in individual patients. The specific content of AVHs persists across different psychotic episodes even after extended periods of remission. Furthermore, the AVHs are usually triggered by emotionally charged and stressful situations. DESIGN: We hypothesized that even during absence of AVHs, when patients are in remission, the verbal content remains present in the latent, pre-clinical form. In order to elucidate potential cerebral substrates of the dormant AVHs content, we employed functional magnetic resonance imaging (fMRI) in 6 schizophrenia patients in total remission of AVHs for at least 12 months, during listening to the words hallucinated by them in the past. Specifically, we created the list of previously hallucinated words for each patient and matched the words in terms of length, structure, emotional valence, semantic category and frequency of usage with the non-hallucinated words. Moreover, each patient was paired demographically with the control participant who was presented with the same words. We predicted that exposure to the hallucinated versus non-hallucinated words would result in increased activation in cerebral areas associated with cognitive and emotional content of previously experienced AVHs in patients, whereas the same comparison will not produce any significant changes in blood oxygen level-dependent (BOLD) signal in control participants. In addition, based on existing neuroimaging data obtained during experience of AVHs, we hypothesized that previously hallucinated words may elicit greater activation in the primary auditory cortex than the non-hallucinated words in patients. Each pair of participants was analyzed separately. RESULTS: The most consistent finding in patients, absent in all control participants, was significant activation in the orbitofrontal and medial prefrontal cortex (PFC) during listening to previously hallucinated versus non-hallucinated words. The orbitofrontal and medial PFC are both part of corticolimbic system and play an important role in cognitive control of emotion processing. DISCUSSION: Thus, present results imply that previously hallucinated words, even in remission, are associated with inappropriate emotional response on neurophysiological level in schizophrenia patients. The relative hyperactivation of orbitofrontal and medial PFC in patients may stem from and/or may contribute to anomalous neural plasticity and disordered connectivity in the corticolimbic circuitry. This in turn could lead to attribution of excessive emotional salience to normally neutral stimuli and over time via process of sensitization could result in hallucinations. Potential normalization of this dysfunction could reduce patients' susceptibility to experience AVHs in stressful situations. In addition to observed hyperactivations in the PFC, some schizophrenia patients exhibited anomalous BOLD signal in other regions of the corticolimbic system such as anterior cingulate gyrus and parahippocampal gyrus. These additional anomalies could be related to greater affective sensitivity to the hallucinated versus non-hallucinated words in some patients. CONCLUSION: Finally, in contrast to our initial hypothesis we did not observe any significant differences between processing of the hallucinated versus non-hallucinated words in the primary auditory cortex. In retrospect, this result is not surprising because patients did not experience internally generated AVHs while in the scanner, but instead were exposed exclusively to externally generated stimuli.

Changes in distributed neural circuitry function in patients with first-episode schizophrenia.

BACKGROUND: A number of functional brain abnormalities have been reported in schizophrenia, but it remains to be determined which of them represent trait and state markers of the illness. AIMS: To delineate regional brain dysfunctions that remain stable and those that fluctuate during the course of schizophrenia. METHOD: A cohort of patients with first-episode schizophrenia and a matched group of control participants underwent functional magnetic resonance imaging on two occasions 6-8 weeks apart during performance of a working memory task. The patients' disease was in partial remission at the second scan. RESULTS: Relative to control participants, the function of the left dorsolateral prefrontal cortex, left thalamus and right cerebellum remained disturbed in the people with schizophrenia, whereas the dysfunction of the right dorsolateral prefrontal cortex, right thalamus, left cerebellum and cingulate gyrus normalised, with significant reduction in symptoms. CONCLUSIONS: These results suggest that dysfunction of the left fronto-thalamo-cerebellar circuitry is a relatively stable characteristic of schizophrenia, whereas disturbance of the right circuitry and cingulate gyrusis predominantly a state-related phenomenon.

Negative socio-emotional resonance in schizophrenia: a functional magnetic resonance imaging hypothesis.

The aim of the present study is to use neuroscience theories about brain function (mirror-neurons MN) to draw inferences about the mechanisms supporting emotional resonance in two different groups of schizophrenia patients (with flat affect FA+ n = 13 and without flat affect FA- n = 11). We hypothesize that FA+ will not activate key brain areas involved in emotional processing. Conversely, FA- will have a functional mirror system for emotional resonance confirmed by activation of the prefrontal cortex and behavioral results. To test this hypothesis, we compared the two groups using blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) displaying a passive visual task (44 negative IAPS pictures and 44 neutral pictures). A random-effects analysis, for schizophrenia patients FA-, revealed significant loci of activation in the left mesial prefrontal (MPFC), right orbitofrontal (OFC) and left anterior cingulate cortices (ACC). Correlational analyses carried out between self-report ratings of negative feelings and BOLD signal changes revealed the existence of positive correlation in the LACC, LMPFC and ROFC. Conversely, FA+ did not show significant activation in the prefrontal cortex. We propose that negative emotional resonance induced by passively viewing negative pictures may be a form of "mirroring" that grounds negative feelings via an experiential mechanism. Hence, it could be argued that FA- were able to 'feel' emotions through this resonance behavior. Conversely, we suggest that the dysfunction seen in the FA+ group is a failure or distortion in the development of the MN system. This could be due to genetic or other endogenous causes, which affected prefrontal cortex MN involved in emotional resonance.

Comparison between olanzapine and haloperidol on procedural learning and the relationship with striatal D2 receptor occupancy in schizophrenia.

The striatum is known to play a primary role in procedural learning. In this study, the authors simultaneously assessed the effects of two antipsychotic drugs on procedural learning and on striatal dopamine (D2) receptor occupancy. Twenty-seven patients receiving either olanzapine or haloperidol as antipsychotic medication were assessed with the Computed Visual Tracking Task (CVTT) and Single Photon Emission Computed Tomography (SPECT) following the administration of Iodine 123-IBZM (123I-IBZM), a radioligand with a high affinity and specificity for the D2 receptors. The results showed poorer procedural learning in the haloperidol-treated patients than in normal control subjects, while no difference could be found between olanzapine-treated patients and normal control subjects. In the haloperidol but not the olanzapine group, significant correlations were found between procedural learning deficits and striatal D2 receptor occupancy. However, there was no significant difference in D2 receptor occupancy between olanzapine- and haloperidol-treated patients, and this may be related to the high doses of olanzapine and low doses of haloperidol administered. The authors concluded that: 1) striatal D2 receptor blockade may alter procedural learning in humans; and 2) olanzapine may have a protective effect on procedural learning, even at doses that produce striatal D2 receptor occupancy as high as that found with haloperidol. This protective effect of olanzapine may be related to its atypical pharmacological properties.