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Auditory verbal hallucinations (AVH) in patients with schizophrenia are associated with abnormal hyperactivity in the left temporo-parietal junction (TPJ) and abnormal connectivity between frontal and temporal areas. Recent findings suggest that fronto-temporal transcranial Direct Current stimulation (tDCS) with the cathode placed over the left TPJ and the anode over the left prefrontal cortex can alleviate treatment-resistant AVH in patients with schizophrenia. However, brain correlates of the AVH reduction are unclear. Here, we investigated the effect of tDCS on the resting-state functional connectivity (rs-FC) of the left TPJ. Twenty-three patients with schizophrenia and treatment-resistant AVH were randomly allocated to receive 10 sessions of active (2 mA, 20 min) or sham tDCS (2 sessions/d for 5 d). We compared the rs-FC of the left TPJ between patients before and after they received active or sham tDCS. Relative to sham tDCS, active tDCS significantly reduced AVH as well as the negative symptoms. Active tDCS also reduced rs-FC of the left TPJ with the left anterior insula and the right inferior frontal gyrus and increased rs-FC of the left TPJ with the left angular gyrus, the left dorsolateral prefrontal cortex and the precuneus. The reduction of AVH severity was correlated with the reduction of the rs-FC between the left TPJ and the left anterior insula. These findings suggest that the reduction of AVH induced by tDCS is associated with a modulation of the rs-FC within an AVH-related brain network, including brain areas involved in inner speech production and monitoring., (© The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Background: Obsessive-compulsive disorder (OCD) is a severe mental illness. OCD symptoms are often resistant to available treatments. Abnormalities within the orbitofronto-striato-pallido-thalamic circuitry, especially orbitofrontal cortex (OFC) hyperactivity and cerebellar hypoactivity have been observed in patients. Non-invasive brain stimulation studies have indicated that transcranial direct current stimulation (tDCS) may be a useful alternative to alleviate treatment-resistant symptoms in various neuropsychiatric conditions., Methods: In an open-label pilot study, 8 patients with treatment-resistant OCD received 10 sessions (twice a day) of 2mA tDCS applied with the cathode over the left OFC and the anode over the right cerebellum. OCD (Y-BOCS and OCD-VAS) as well as depressive (MADRS) symptoms were measured 4 times: one time before tDCS and 3 times after (immediately after, 1 and 3months after the 10th tDCS session)., Results: We reported a significant 26.4% (±15.8) decrease of Y-BOCS score (p=0.002). The beneficial effect lasted during the 3month follow-up. No effect of tDCS was observed on depressive symptoms. At end point, 5 out of 8 patients had a decrease of ≥25%; and 3 out of 8 patients had a decrease of ≥35% in Y-BOCS score. tDCS was well tolerated., Conclusion: tDCS with the cathode placed over the left OFC combined with the anode placed over the right cerebellum is a suitable and safe approach to decrease OCD symptoms in patients with treatment-resistant OCD. Large scale randomized controlled studies are needed to confirm this promising result., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Obsessive-compulsive disorder (OCD) is a disabling and frequent neuropsychiatric disorder. Forty percent to 60% of patients with OCD fail to respond to available treatments. Neuroimaging studies have highlighted an association between the severity of obsessive and compulsive symptoms and an increased activity of the left orbitofrontal cortex (OFC) in patients with OCD. Transcranial direct current stimulation (tDCS) is a powerful and easy-to-use tool to modulate brain activity. Cathodal tDCS (c-tDCS) is assumed to decrease cortical excitability in the targeted brain region. We hypothesized that c-tDCS applied over the left OFC alleviates symptoms in patients with treatment-resistant OCD. We report here the case of a patient who received 10 sessions (2 mA, 20 minutes) of c-tDCS. The tDCS sessions were delivered twice a day with a 2-hour interval, with the cathode (35 cm²) placed over the left OFC and the anode (100 cm²) placed over the contralateral occipital region. No adverse event was reported. One month after the completion of the tDCS sessions, we observed a 26% reduction in severity of obsessive and compulsive symptoms measured using the Yale-Brown Obsessive Compulsive Scale scores. These findings are consistent with a previous study reporting a similar reduction in obsessive and compulsive symptoms after a low-frequency repetitive transcranial magnetic stimulation was given to the left OFC. Our results indicate that c-tDCS applied over the left OFC may be a suitable and safe treatment in patients with treatment-resistant OCD.

Cognitive dysfunction is one of the hallmark deficits of schizophrenia. A wide range of studies illustrate how it is strongly interconnected to clinical presentation and daily life functioning [see Ref. (1, 2)]. Hence, cognition is an important treatment target in schizophrenia. To address the challenge of cognitive enhancement in schizophrenia, a large number of cognitive remediation programs have been developed and evaluated over the past several decades. First, an overview of these programs is presented highlighting their specificity to cognitive deficit in schizophrenia using an integrated method. In this case, cognitive training focuses on enhancing several elementary cognitive functions considered as a prerequisite to social skills or vocational training modules. These programs are based on the neurodevelopmental hypothesis of schizophrenia. However, moderate improvement for patients who benefit from these therapies has been observed as described in Wykes et al. review (3). Next, neuropsychological models of schizophrenia are then presented. They highlight the critical role of the internally generated intentions in appropriate willful actions. The cognitive control mechanism deals with this ability. Interestingly, available cognitive remediation programs have not been influenced by these models. Hence, we propose another alternative to set up a specific cognitive remediation program for schizophrenia patients by targeting the cognitive control mechanism. We describe the PrACTice program that is in the process of being validated.

Objective: "Michael's game" (MG) is a card game targeting the ability to generate alternative hypotheses to explain a given experience. The main objective was to evaluate the effect of MG on delusional conviction as measured by the primary study outcome: the change in scores on the conviction subscale of the Peters delusions inventory (PDI-21). Other variables of interest were the change in scores on the distress and preoccupation subscales of the PDI-21, the brief psychiatric rating scale, the Beck cognitive insight scale, and belief flexibility assessed with the Maudsley assessment of delusions schedule (MADS)., Methods: We performed a parallel, assessor-blinded, randomized controlled superiority trial comparing treatment as usual plus participation in MG with treatment as usual plus being on a waiting list (TAU) in a sample of adult outpatients with psychotic disorders and persistent positive psychotic symptoms at inclusion., Results: The 172 participants were randomized, with 86 included in each study arm. Assessments were performed at inclusion (T1: baseline), at 3 months (T2: post-treatment), and at 6 months after the second assessment (T3: follow-up). At T2, a positive treatment effect was observed on the primary outcome, the PDI-21 conviction subscale (p = 0.005). At T3, a sustained effect was observed for the conviction subscale (p = 0.002). Further effects were also observed at T3 on the PDI-21 distress (p = 0.002) and preoccupation subscales (p = 0.001), as well as on one of the MADS measures of belief flexibility ("anything against the belief") (p = 0.001)., Conclusion: The study demonstrated some significant beneficial effect of MG.

Reduced N-acetyl-aspartate (NAA) levels have been reported in the prefrontal cortex (PFC) in patients with schizophrenia using proton magnetic resonance spectroscopy. However, it is unclear whether this NAA reduction predates the illness onset and is reported in subjects at-risk for developing schizophrenia (HRS). The aim of this study was to assess NAA levels in the PFC in HRS. We hypothesized that HRS display lower NAA levels than healthy controls in the PFC. Studies assessing levels of NAA/Creatine (NAA/Cr) in the PFC in HRS were extracted from literature. Meta-analysis tools were used to compute effect sizes of nine selected studies meeting our inclusion criteria (clinical and/or genetic HRS, groups of HRS, and healthy controls matched for age and gender, spectral acquisition in the PFC). We reported that HRS exhibited a significant lower NAA/Cr level (2.15 ± 0.29; n = 208) than healthy controls (2.21 ± 0.32; n = 234) in the PFC with a medium pooled effect size [Hedges's g = -0.42; 95% confidence interval: (-0.61; -0.23); p < 0.0001] corresponding to an average 5.7% of NAA/Cr decrease. Secondary analysis revealed that this reduction was observed in young HRS (<40 years old) who have not reached the peak age of risk for schizophrenia (-11%, g = -0.82, p < 0.00001) but not in old HRS (>40 years old) who have already passed the peak age (g = 0.11, p = 0.56), when they are compared with their matched healthy controls. Our findings suggest that the NAA/Cr reduction in the PFC reported in patients with schizophrenia is observable only in HRS who have not passed the peak age of risk for schizophrenia. NAA/Cr level in the PFC could therefore be considered as a biological vulnerability marker of schizophrenia.

Background: STOP/MAP6 null (KO) mice recapitulate behavioral abnormalities related to positive and negative symptoms and cognitive deficits of schizophrenia. Here, we investigated whether decreased expression of STOP/MAP6 proteins in heterozygous mice (only one allele expressed) would result in abnormal behavior related to those displayed by STOP null mice., Methods: Using a comprehensive test battery, we investigated the behavioral phenotype of STOP heterozygous (Het) mice compared with STOP KO and wild type (WT) mice on animals raised either in standard conditions (controls) or submitted to maternal deprivation., Results: Control Het mice displayed prominent deficits in social interaction and learning, resembling KO mice. In contrast, they exhibited short-lasting locomotor hyperreactivity to acute mild stress and no impaired locomotor response to amphetamine, much like WT mice. Additionally, perinatal stress deteriorated Het mouse phenotype by exacerbating alterations related to positive symptoms such as their locomotor reactivity to acute mild stress and psychostimulant challenge., Conclusion: Results show that the dosage of susceptibility genes modulates their putative phenotypic contribution and that STOP expression has a high penetrance on cognitive abilities. Hence, STOP Het mice might be useful to investigate cognitive defects related to those observed in mental diseases and ultimately might be a valuable experimental model to evaluate preventive treatments.

It has been suggested that the left pre-supplementary motor area (pre-SMA) could be implicated in facial emotion expression and recognition, especially for laughter/happiness. To test this hypothesis, in a single-blind, randomized crossover study, we investigated the impact of transcranial magnetic stimulation (TMS) on performances of 18 healthy participants during a facial emotion recognition task. Using a neuronavigation system based on T1-weighted magnetic resonance imaging of each participant, TMS (5 pulses, 10 Hz) was delivered over the pre-SMA or the vertex (control condition) in an event-related fashion after the presentation of happy, fear, and angry faces. Compared with performances during vertex stimulation, we observed that TMS applied over the left pre-SMA specifically disrupted facial happiness recognition (FHR). No difference was observed between the 2 conditions neither for fear and anger recognition nor for reaction times (RT). Thus, interfering with pre-SMA activity with event-related TMS after stimulus presentation produced a selective impairment in the recognition of happy faces. These findings provide new insights into the functional implication of the pre-SMA in FHR, which may rely on the mirror properties of pre-SMA neurons.

To investigate the impact of various antipsychotic drugs on the 5-HT1A serotoninergic system, we performed a [F]4-(2-methoxyphenyl)-1-[2-(N-2-pirydynyl)-p-luorobenzamido]-ethyl-piperazine PET study in 19 schizophrenic patients treated with either aripiprazole, which has a partial agonist activity at 5-HT1A receptors, or second-generation antipsychotics (SGA) (olanzapine or risperidone), which do not demonstrate such property. We used a simplified reference tissue model to generate parametric images of [F]MPPF-binding potential (BPND). A significant reduction of [F]MPPF BPND was found in treated schizophrenic patients compared to age- and sex-matched healthy subjects. These modifications were mainly localized in the frontal and orbitofrontal cortex and may reflect either the pathophysiology of schizophrenia or medication effects. The schizophrenic patients treated with aripiprazole showed a reduction of global [F]MPPF BPND compared with healthy subjects and schizophrenic patients with SGA treatment. In addition, compared with matched controls, the reduction of regional [F]MPPF BPND was more marked in the schizophrenic patients treated with aripiprazole compared with those receiving SGA treatment, possibly reflecting the partial agonist of aripiprazole activity at 5-HT1A receptors.

This is the first [¹⁸F]MPPF PET study in positron emission tomography study in depressed patients, both before and after treatment with a selective serotonin reuptake inhibitor (SSRI). Dynamic changes in [¹⁸F]MPPF binding potential were observed primarily in the medial orbital regions from baseline to 30 days of treatment, suggesting SSRI-mediated serotoninergic adaptative mechanisms., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Patients suffering from various neurological and psychiatric disorders show different levels of facial emotion recognition (FER) impairment, sometimes from the early phases of the disease. Investigating the relative severity of deficits in FER across different clinical and high-risk populations has potential implications for the diagnosis and treatment of these diseases, and could also allow us to understand the neurobiological mechanisms of emotion perception itself. To investigate the role of the dopaminergic system and of the frontotemporal network in FER, we reanalyzed and compared data from four of our previous studies investigating FER performance in patients with frontotemporal dysfunctions and/or dopaminergic system abnormalities at different stages. The performance of patients was compared to the performance obtained by a specific group of matched healthy controls using Cohen's d effect size. We thus compared emotion and gender recognition in patients with frontotemporal dementia (FTD), amnestic mild cognitive impairment (aMCI), Alzheimer's disease (AD) at the mild dementia stage, major depressive disorder, Parkinson's disease treated by l-DOPA (PD-ON) or not (PD-OFF), remitted schizophrenia (SCZ-rem), first-episode schizophrenia treated by antipsychotic medication (SCZ-ON), and drug-naïve first-episode schizophrenia (SCZ-OFF), as well as in unaffected siblings of patients with schizophrenia (SIB). The analyses revealed a pattern of differential impairment of emotion (but not gender) recognition across pathological conditions. On the one hand, dopaminergic medication seems not to modify the moderate deficits observed in SCZ and PD groups (ON vs. OFF), suggesting that the deficit is independent from the dopaminergic system. On the other hand, the observed increase in effect size of the deficit among the aMCI, AD, and FTD groups (and also among the SIB and SCZ-rem groups) suggests that the deficit is dependent on neurodegeneration of the frontotemporal neural networks. Our transnosographic approach combining clinical and high-risk populations with the impact of medication provides new information on the trajectory of impaired emotion perception in neuropsychiatric conditions, and on the role of the dopaminergic system and the frontotemporal network in emotion perception.

Objectives: Repetitive transcranial magnetic stimulation (rTMS) seems to be effective as an antidepressant, however, some confusion remains about the best parameters to apply and the efficacy of its association with pharmacological antidepressant treatments., Method: In a single blind randomized study 14 patients with unipolar resistant depression to one antidepressant treatment were enrolled to receive, in combination with venlafaxine (150 mg), either 20 sessions of 10 Hz rTMS (2000 pulses per session) applied over the left dorsolateral prefrontal cortex (DLPFC) or 20 sessions of 1 Hz rTMS (120 stimulations per sessions) applied over the right DLPFC., Results: A similar antidepressant effect was observed in both groups with a comparable antidepressant delay of action (2 weeks) and a comparable number of responders (MADRS < 15) after 4 weeks of daily rTMS sessions (66 vs 50%)., Conclusion: Low- and high- frequency rTMS seems to be effective as an add-on treatment to venlafaxine as monotherapy in pharmacological refractory major depression (stage 1). Due to its short duration (one session of 1 Hz rTMS lasts 4 min vs 16 for 10 Hz rTMS) and its safety, low frequency rTMS may be a useful alternative treatment for patients with refractory depression.

The line bisection task is used as a bedside test of spatial neglect patients who typically bisect lines to the right of true centre. To disambiguate the contribution of perceptual from motor biases in bisection, previous research has used the landmark task in which participants determine whether a transection mark is left or right of centre. One recent study using stimuli that reliably leads to leftward perceptual biases in healthy individuals, found that ocular judgements of centre were biased to the right of centre, whereas manual bisections were biased leftwards. Here we used behavioural measures and functional MRI in healthy individuals to investigate ocular and perceptual judgements of centre. Ocular judgements were made by having participants fixate the centre of a horizontal bar that was dark at one end and light at the other (i.e., a 'greyscale' stimulus), whereas perceptual responses were made by having participants indicate whether a transection mark on the greyscales stimuli was to the left or right of centre. Behavioural data indicated a leftward bias in the first, second and longest fixations for bisection. Moreover, greyscale orientation (i.e., dark extremity to the right or to the left), and stimulus position modulated fixations. In contrast, for the landmark task, initial fixations were attracted towards the transection mark, whereas subsequent fixations were closer to veridical centre. Imaging data showed a large bilateral network, including superior parietal and lingual cortex, that was active for bisection. The landmark task activated a predominantly right hemisphere network including superior and inferior parietal cortices. Taken together these results indicate that very different strategies and underlying neural networks are invoked by the bisection and landmark tasks., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Schizophrenia patients demonstrate behavioural and cerebral lateralised anomalies, prompting some authors to suggest they exhibit a mild form of right unilateral neglect. To better describe and understand lateralised visuospatial anomalies in schizophrenia, three experiments were run using tasks often utilised to study visuospatial processing in healthy individuals and in neglect patients: the Behavioural Inattention Test (BIT), the manual line bisection task with and without a local cueing paradigm, the landmark task (or line bisection judgement), and the number bisection task. Although the schizophrenia patients did not exhibit the full-blown neglect syndrome, they did demonstrate marked spatial biases that differentiated them from controls on all but two tasks. More specifically, schizophrenia patients showed neither a simple perceptual deficit nor an asymmetry, but demonstrated (1) lateralised anomalies on a simple manual line bisection task; (2) unilateral attentional deficits for line bisection within a local cueing paradigm; and (3) a lateralised deficit in the visuospatial representations of numbers. Altogether, these results suggest a right hemineglect-like deficit in schizophrenia in attentional, representational, and motor-intentional processes. Yet it does not appear to be as strong a phenomenon. Indeed, it could be considered as an accentuation of the normal asymmetry in visuospatial processing.

Unlabelled: Cognitive remediation therapy (CRT) is a non biological treatment that aims to correct cognitive deficits through repeated exercises. Its efficacy in patients with schizophrenia is well recognized, but little is known about its effect on cerebral activity. Our aim was to explore the impact of CRT on cerebral activation using functional magnetic resonance imaging (fMRI) in patients with schizophrenia. Seventeen patients and 15 healthy volunteers were recruited. Patients were divided into two groups: one group received CRT with Rehacom® software (n=8), while a control group of patients (non-CRT group) received no additional treatment (n=9). The three groups underwent two fMRI sessions with an interval of 3months: they had to perform a verbal and a spatial n-back task at the same performance level. Patients were additionally clinically and cognitively assessed before and after the study. After CRT, the CRT group exhibited brain over-activations in the left inferior/middle frontal gyrus, cingulate gyrus and inferior parietal lobule for the spatial task. Similar but nonsignificant over-activations were observed in the same brain regions for the verbal task. Moreover, CRT patients significantly improved their behavioural performance in attention and reasoning capacities. We conclude that CRT leads to measurable physiological adaptation associated with improved cognitive ability. Trial name: Cognitive Remediation Theraphy and Schizophrenia. http://clinicaltrials.gov/ct2/show/NCT01078129., Registration Number: NCT01078129., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Objective: There is considerable interest in cognitive remediation for schizophrenia. Our study aimed to evaluate, in a large sample of patients with schizophrenia, the interest of a computer-assisted cognitive remediation program on cognitive performances of patients as well as in clinical and functional outcome., Method: Seventy-seven patients with remitted schizophrenia were randomly assigned to 14 2-hours individual sessions of computer-assisted cognitive remediation (n=39) or a control condition (n=38). Remediation was performed using RehaCom ® software. Four procedures were chosen to train four cognitive functions involved in different stages of the information processing: attention/concentration, working memory, logic, and executive functions. Primary outcomes were remediation exercise metrics, neuropsychological composites (episodic memory, working memory, attention, executive functioning, and processing speed), clinical and community functioning measures., Results: Cognitive performances concerning Attention/vigilance, verbal working memory and verbal learning memory and reasoning/problem solving improved significantly in the remediation condition when no difference was reported in the control condition between the 2 assessments. However, there were no significant benefits of cognitive remediation on non-verbal working memory and learning and speed of processing or functional outcome measures., Conclusions: Cognitive remediation for people with schizophrenia was effective in improving performance, but the benefits of training did not generalize to functional outcome measures. Long term follow-up studies are needed to confirm the maintenance of such improvements., (Copyright © 2010 Elsevier B.V. All rights reserved.)

We aimed to identify and compare cerebral activations in schizophrenia patients and controls during a working memory (WM) task at the same performance level for both a verbal and a spatial task. Whereas the performances of the patients (n=22) and controls (n=15) were similar, cerebral activations were significantly increased in the patients, particularly in the thalamus/basal ganglia for the two tasks and in regions of the prefrontal cortex and the cerebellum for the spatial task only. Our results suggest that stronger activations of deep brain structures in patients may be the result from a compensating mechanism for WM difficulties., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Introduction: schizophrenia (SCH) is a heterogeneous syndrome characterized by positive and negative symptoms. Despite appropriate medication, about 1/4 of patients suffer for refractory positive and/or negative symptoms, which are associated with functional handicap, increase of duration and of the number of hospitalizations. Numerous studies have suggested that the pathophysiology of auditory hallucinations (AH) is related to a hyper activity of the left temporoparietal cortex (TPC). On the other hand, negative symptoms are associated with a prefrontal hypoactivity and the efficiency of pharmacological treatments is frequently partial. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation tool with excellent tolerability and safety. Given its hypothesized mechanisms of action and the clinical beneficial effects obtained in several types of pathology (Aleman et al. 2007), the efficacy of rTMS has been investigated for drug-resistant SCH symptoms., Objective: our objective is to expose the knowledge concerning the rTMS use in the treatment of these symptoms and to purpose a critical analysis of these data., Method: a systematic review of the literature has been conducted using NIH Pubmed. The following search terms were used: TMS - rTMS - Schizophrenia - negative symptoms - hallucinations., Results: concerning the treatment of AH, 16 publications and 4 meta analyses were selected. For the negative symptoms, we retained 16 studies and 3 meta analyses. The most extensively investigated application for rTMS in SCH is the use of low-frequency stimulation to the left TPC with the aim to improve AH symptomatology. When compared to sham, this type of acute course of rTMS has been proven to induce a substantial and significant reduction in AH. But this effect does not seem long-lasting and maintenance protocols must be developed. Concerning negative symptoms, the results are less solid but we find some works which demonstrate an improvement of these symptoms while various stimulation parameters were used. Recently, new parameters of stimulation in particular the theta burst stimulation have permitted us to obtain larger effects with longer duration. The interest of these new parameters will be discussed here., Conclusion: overall, rTMS studies have demonstrated some promise in the treatment of SCH. However, more research is required to enhance rTMS efficacy and increase its beneficial effect duration and to test new therapeutic strategies in this topic.

A genetic alteration in sensitivity to stress, mediated by mesolimbic hyperdopaminergia, is thought to play a role in the onset, exacerbation and relapse of schizophrenia. Dopamine sensitivity to stress was tested in individuals at higher than average genetic risk for schizophrenia (siblings of patients). Using a PET paradigm of [(11)C]raclopride in a bolus plus constant infusion tracer injection, the central DA response to acute metabolic stress (bolus of 2-Deoxy-d-Glucose, 40mg/kg) in unaffected siblings of patients with schizophrenia (n=8) and healthy controls (n=10) was measured by BP(ND) of [(11)C]raclopride before and after the 2DG challenge. After metabolic stress, controls but not siblings displayed a significant decrease in BP(ND) of [(11)C]raclopride in the striatum; no such differences were apparent in the ventral striatum. Siblings but not controls displayed significant asymmetry (L>R) in the stress-induced DA release, especially in ventral striatum, which correlated strongly with psychometric measures of psychosis liability. The results suggest that asymmetry in the mesolimbic DA response to stress is associated with genetic risk for schizophrenia, possibly reflecting the functional consequences of structural disconnectivity underlying psychotic symptoms., (Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.)

Rat with excitotoxic neonatal ventral hippocampal lesions (NVHL rats) is considered as a heuristic neurodevelopmental model for studying schizophrenia. Extensive study of this model is limited by the lack of clear validity criteria of such lesions and because ascertaining of the lesions is realized postmortem with histological examination after completing experiments. Here, in a first experiment, by assessing the locomotor response to amphetamine in adult NVHL rats, we further specify that the lesions must be bilateral and confined to the ventral hippocampus to obtain the validated behavioral phenotype. We then show a longitudinal magnetic resonance imaging (MRI) protocol suitable for the detection of brain structural changes in NVHL rats. The T(2)-weighted images acquired in adult NVHL rats reveal the same structural changes as those appraised with histological protocol. Moreover, we demonstrate that the lesion status in adulthood can be accurately predicted from the T(2)-weighted images acquired in the juvenile period. As technical advantages, our MRI protocol makes possible to select animals according to lesion criteria as soon as in the juvenile period before long-lasting experiments and gives access in vivo to a quantitative parameter indicative of the lesion extent. Finally, we show that the lesion size increases only slightly between juvenile and adult periods. These latter results are discussed in the context of the specific postpubertal emergence of the behavioral deficits in NVHL rats.

The objectives were to determine the neurological soft signs (NSS) scores in unaffected siblings of patients with schizophrenia compared with healthy controls and to examine their relationships with schizotypal dimensions. Participants comprised 31 unaffected siblings of patients with schizophrenia and 60 healthy controls matched according to age, gender and school level who were assessed by the Schizotypal Personality Questionnaire (SPQ) and the Krebs et al. NSS Scale. Higher NSS total scores and sub-scores were found in the unaffected siblings compared with the controls. The SPQ total score was significantly higher in unaffected siblings compared with control subjects. The NSS total score was positively correlated with the SPQ total score and the SPQ disorganization sub-score in unaffected siblings of patients with schizophrenia. Additionally, in unaffected siblings, motor coordination and integration abnormalities were positively correlated with the SPQ total score and the cognitive-perceptual sub-score. Motor integration abnormalities were also correlated with the SPQ disorganization sub-score. These results reveal that NSS, especially motor signs, are associated with some schizotypal dimensions in siblings of patients with schizophrenia, suggesting the value of using both assessments to study high risk populations.

This work describes a label-free microarray analysis technique capable of detecting biomolecule target interactions with probes being anchored with a new linker-diluent system on indium-tin-oxide. The method is based on the differential work function characteristics of the substrate measured by a scanning Kelvin nanoprobe in terms of contact potential difference signals.

Objective. The phenotypic complexity, together with the multifarious nature of the so-called "schizophrenic psychoses", limits our ability to form a simple and logical biologically based hypothesis for the disease group. Biological markers are defined as biochemical, physiological or anatomical traits that are specific to particular conditions. An important aim of biomarker discovery is the detection of disease correlates that can be used as diagnostic tools. Method. A selective review of the WFSBP Task Force on Biological Markers in schizophrenia is provided from the central nervous system to phenotypes, functional brain systems, chromosomal loci with potential genetic markers to the peripheral systems. Results. A number of biological measures have been proposed to be correlated with schizophrenia. At present, not a single biological trait in schizophrenia is available which achieves sufficient specificity, selectivity and is based on causal pathology and predictive validity to be recommended as diagnostic marker. Conclusions. With the emergence of new technologies and rigorous phenotypic subclassification the identification of genetic bases and assessment of dynamic disease related alterations will hopefully come to a new stage in the complex field of psychiatric research.

Overt schizophrenia is preceded by a prodromal phase during which juvenile patients display attenuated schizophrenia-related symptoms. Here, we have looked for evidence of a prodromal phase in juvenile STOP null mice, which, during adulthood, imitate features of schizophrenia. We have principally examined locomotor activity, which is abnormal in adult STOP null mice, and its apparent relationship with perturbed glutamatergic and dopaminergic transmission. When compared to corresponding wild-type mice, juvenile STOP null mice did not exhibit the basal hyperlocomotion or locomotor hypersensitivity to mild stress observed in adult mice. Juvenile STOP null mice also lacked disturbed locomotor sensitivity to MK-801, which was evident in adult mice. In contrast, juvenile STOP null mice exhibited a similar hypersensitivity to amphetamine as that found in adult mice. Thus, STOP null mice exhibited both a progression of locomotor activity defects over time and subtle alterations in the prepubertal period. We suggest that the pattern of locomotor disturbances observed in this study is related to altered dopaminergic reactivity in juvenile mice without major disturbance in glutamatergic transmission, whereas both neurotransmitter systems are impaired in adult mice.

In a double-blind-crossover-study, 10 patients with schizophrenia, 10 of their unaffected siblings and 9 healthy controls randomly received metabolic stressor and placebo. A significant HVA plasma elevation in response to stress was found in siblings whose response was intermediate to that of patients and controls. Only siblings additionally displayed an exaggerated 5HIAA response.

Summer birth has been associated with the deficit Schizophrenia syndrome, while DSM-IV schizophrenia is associated with winter birth. We confirm these monthly differences in a Tunisian sample of patients with schizophrenia, with a summer birth peak (n=34 deficit patients) and an expected winter birth peak (n=46 non-deficit patients).

Background: Epidemiological studies of schizophrenia suggest that this disorder has a substantial genetic component. Cognitive and social abilities, as well as the volumes of brain regions involved in emotion processing, have been found to be distributed along a continuum when comparing patients, siblings and controls, with siblings showing intermediate scores., Aims: To establish whether facial expression recognition is impaired in unaffected siblings of patients., Method: Emotion and gender recognition were evaluated in a three-group pre-post study design in drug-naive patients with first-episode schizophrenia (n=40) and their unaffected siblings (n=30) compared with controls (n=26)., Results: Patients and their healthy siblings showed impaired emotion recognition but normal gender recognition compared with controls. Patients'performance did not improve despite effective clinical stabilisation., Conclusions: Impaired performance in healthy siblings and time stability in patients provides evidence of impairment of facial emotion recognition as an actual phenotype of schizophrenia.

Previous studies have suggested a right hemineglect in schizophrenia, however few assessed possible visual-perceptual implication in this lateralized anomaly. A manual line bisection without (i.e., lines presented on their own) or with a local cueing paradigm (i.e., a number placed at one or both ends of the line) and the Motor-free Visual Perceptual Test-Vertical format (MVPT-V) were used to assess the visual-perceptual abilities of healthy controls, schizophrenia and depressed patients. Whereas healthy controls and depressed patients showed a non-significant leftward bias in manual line bisection, schizophrenia patients bisected significantly to the left of the true centre of the line. Interestingly, the pattern of performances in response to the local cueing paradigm was similar in depressed and schizophrenia patients such that both groups demonstrated a significant change in their bisection performance only in response to a cue placed at the right extremity of the line (control performance was modified by cues at either end of the line). Finally, in the MVPT-V, schizophrenia patients were impaired relative to the other two groups, especially in the spatial working memory and visual closure categories. These results suggest that: 1/a deficit towards the right hemifield, consistent with a mild form of right hemineglect, can be observed in schizophrenia; 2/lateralized anomalies could also be observed in depression using an appropriate tool such as manual line bisection; 3/performances in the MVPT-V suggested that a simple visual-perceptual deficit could not explain the lateralized anomaly observed in the manual line bisection, as it is the case in the hemineglect syndrome.

The new water-soluble ligand dmPTA(OSO(2)CF(3))(2) (1) (dmPTA = N,N'-dimethyl-1,3,5-triaza-7-phosphaadamantane) has been synthesized by reaction of PTA with MeOSO(2)CF(3) in acetone (PTA = 1,3,5-triaza-7-phosphatricycle[3.3.1.1(3,7)]decane). The reaction of 1 with KOH gave rise to the new water-soluble ligand dmoPTA (3) (dmoPTA = 3,7-dimethyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane) by elimination of the -CH(2)- group located between both NCH(3) units. Compound dmPTA(BF(4))(2) (2) and complex [RuClCp(HdmoPTA)(PPh(3))](OSO(2)CF(3)) (4) have also been synthesized, while compounds HdmoPTA(BF(4)) (3a) and [RuClCp(dmPTA)(PPh(3))](OSO(2)CF(3)) (5) were characterized but not isolated. The new ligands and the complex have been fully characterized by NMR, IR, elemental analysis, and X-ray crystal structure determination (ligand 1 and complex 4). The synthetic processes for 3 and 4 were studied.

Introduction: Numerous authors have reported the existence of lateralised abnormalities towards the right side in patients with schizophrenia., Methods: In the present study, a manual line bisection task was used to assess the existence of a visuospatial bias in patients with schizophrenia as compared to healthy subjects and left unilateral neglect patients. In addition, we used a local cueing paradigm (consisting of a number placed on the right, on the left, or at both ends of the line)., Results: Healthy subjects showed a leftwards trend in the "no cue" condition (known as pseudoneglect) and neglect patients showed a right bias in all cue conditions. In contrast, patients with schizophrenia placed their manual estimation of the centre further to the left than healthy subjects in all cue conditions, reflecting neglect of the right side of the line. Moreover, like healthy subjects and neglect patients, patients with schizophrenia were affected by the local cueing., Conclusion: Hence, patients with schizophrenia show a bias in their spatial representation, which does not interfere with local context processing.

Aims: Abnormal emotion processing in schizophrenia affects social and functional outcome. Spatiotemporal brain mechanisms underlying this deficit are unclear., Materials and Methods: Event-related potential (ERP) responses to emotional and neutral face processing during an implicit (gender detection) and an explicit (expression detection) task were compared between a group of healthy volunteers (n=10) and a group of patients with schizophrenia (n=10)., Results: Whereas patients had normal primary visual cortex responses, the early modulation of occipital, temporal, and frontal responses by emotional expression observed in controls was absent in patients. The occipito-temporal N170 amplitude was reduced in patients relative to controls during expression detection, but not during gender detection. Frontal activity within 180-250ms was reduced in patients compared to controls. As opposed to controls, no significant difference was seen in patients at the right temporal electrode (T6) between amplitudes of long-latency ERPs elicited by distinct emotions during the expression detection task., Conclusion: In patients with schizophrenia, abnormal early extraction of expression-related information in the occipito-temporal cortex (before 170ms) impairs structural encoding of facial expressions (N170) and may disrupt motivation- and task-dependent context processing (180-250ms time window) of expression-related facial features. Moreover, top-down neuromodulation from frontal and limbic structures to visual occipito-temporal cortex may not be sufficient to optimize the extraction of expression-specific face features.

Introduction: In 1985, Barker et al. showed that it was possible to stimulate both nerves and brain using external magnetic stimulation without significant pain. During the past 10 years, therapeutic effects of repeated Transcranial Magnetic Stimulation (rTMS) have been widely studied in psychiatry and its efficacy has been demonstrated in the treatment of major depressive disorders, particularly as an alternative to electroconvulsivotherapy (ECT). Facing the large range of studies, we found necessary to propose an up-to-date review in French of the methodological and therapeutic variations among them., Method: Based on an exhaustive consultation of Medline data and the Avery-George-Holtzheimer Database of rTMS Depression-Studies, supplemented by a manual research, only works evaluating the therapeutic efficacy of rTMS on depressive symptoms were retained, excluding all studies exclusively investigating the stimulation parameters or the tolerance as well as case reports., Results: Out the 66 available reports we retained 30 studies. After a description of the main results of these 30 studies, several elements of the 66 will be discussed. Open studies demonstrated that short courses rTMS (5 to 10 sessions) produced a decrease in the mean Hamilton Depression Ratting Scale (HDRS) scores, although significant remission of depression in individuals was rare. Most authors had used high frequency rTMS applied to the left Dorso Lateral Prefrontal Cortex (left DLPFC). However, low frequency rTMS applied to the right DLPFC was also followed by significant reduction of HDRS scores. Parallel arm, double blind versus placebo studies are designed to clarify the therapeutic efficacy of rTMS therapy but conclude in contradicting results. Literature data globally confirms a greater efficacy of rTMS compared to placebo (37% responders in the active group vs 20% in the sham). This efficacy could in fact be even greater because the sham procedure is disputable in most studies. Indeed, positioning rTMS coil at 45 or 90 from the scalp may not represent an accurate sham procedure and the use of real sham coil is to be recommended. Only one study has suggested that associating rTMS and ECT could decrease the number of general anesthesia required. Therapeutic efficacy has been shown by either inhibiting the right DLPFC or by stimulating the left DLPFC, although some patients exhibit paradoxical responses. High frequency rTMS (>5 Hz) increases cortical excitability and metabolism, while low-frequency rTMS stimulation ( 1 Hz) has the opposite effect. Other parameters are: relevant: intensity (from 80 to 110% of motor threshold), total number of stimulations (from 120 to 2 000) and total number of rTMS sessions (from 5 to 20). As suggested in most recent studies, higher-intensity pulses, higher number of stimulation or longer treatment courses may be more effective. Greater responsiveness to rTMS may be predicted by several patients' factors, including the absence of psychosis, younger age and previous response to rTMS therapy., Discussion: Conclusions on these factors and others, such as the importance of anatomically accurate coil placement and the distance from the coil to the brain, await further investigation. Despite heterogeneity of these reports according to methodology and treatment parameters, the antidepressive properties of rTMS now appear obvious, opening interesting prospects, in particular in the treatment of pharmacoresistant major depressive patients and, we hope, administered as adjuvant therapy in non-resistant depression., Conclusion: Thus, many questions remain unanswered concerning the optimal stimulation parameters, privileged indications and maintenance sessions. This justifies the development of structured evaluation trials on larger samples.

Several visuo-motor tasks can be used to demonstrate biases towards left hemispace in schizophrenic patients, suggesting a minor right hemineglect. Recent studies in neglect patients used a new number bisection task to highlight a lateralized defect in their visuo-spatial representation of numbers. To test a possible lateralized representational deficit in schizophrenia, we used the number bisection task in 11 schizophrenic patients compared to 11 healthy controls. Participants were required to orally indicate the central number of an interval orally presented. Whereas healthy subjects showed no significant bias, schizophrenic patients presented a significant leftward bias. Therefore, these results suggest an impairment in higher order representations of the number space in patients with schizophrenia, an impairment that is qualitatively similar to the deficit described in neglect patients.

Biological markers for depression are of great interest to aid in elucidating the causes of major depression. We assess currently available biological markers to query their validity for aiding in the diagnosis of major depression. We specifically focus on neurotrophic factors, serotonergic markers, biochemical markers, immunological markers, neuroimaging, neurophysiological findings, and neuropsychological markers. We delineate the most robust biological markers of major depression. These include decreased platelet imipramine binding, decreased 5-HT1A receptor expression, increase of soluble interleukin-2 receptor and interleukin-6 in serum, decreased brain-derived neurotrophic factor in serum, hypocholesterolemia, low blood folate levels, and impaired suppression of the dexamethasone suppression test. To date, however, none of these markers are sufficiently specific to contribute to the diagnosis of major depression. Thus, with regard to new diagnostic manuals such as DSM-V and ICD-11 which are currently assessing whether biological markers may be included in diagnostic criteria, no biological markers for major depression are currently available for inclusion in the diagnostic criteria.

Patients with schizophrenia, particularly those with positive symptoms show impaired verbal source monitoring. Specific cognitive deficits have been observed during both active and remission phases of the illness as well as in groups of unaffected first degree relatives of patients with schizophrenia. This type of schizophrenia vulnerability marker may precede the onset of frank psychotic symptoms and contribute to their developments. The aim of this study was first to determine if unaffected siblings were impaired in discriminate internal vs. external generated events when compared to their remitted schizophrenics relatives and healthy subjects. Performances of healthy subjects were then compared with results from previous studies with acute hallucinating patients, acute non-hallucinating patients and patients with resistant auditory verbal hallucinations. Compared with healthy subjects, unaffected siblings are impaired (effect size, ES=0.7), remitted or acute non-hallucinating patients are more impaired than siblings (ES=1.4); patients with verbal auditory hallucinations (acute or resistant) are even more impaired than non-hallucinating patients (ES=2.1). Our results suggest that a source monitoring deficit could be considered as an intermediate vulnerability marker of schizophrenia.

Some auditory event-related potential (ERP) abnormalities characterize both patients with schizophrenia and subjects with schizotypal personality disorder. It was therefore hypothesized that subjects from the community with schizotypal traits might also present ERP abnormalities. In this study, we compared auditory ERP latencies and amplitudes in 13 subjects with high (H-SPQ) and 12 subjects with low (L-SPQ) scores on the Schizotypal Personality Questionnaire (SPQ), selected from 198 Tunisian students. Auditory ERPs were recorded at Fz, Cz, and Pz, with a standard oddball paradigm. Smaller P300 amplitudes and delayed P300 latencies were found in H-SPQ compared with L-SPQ participants. Confirming previous reports, our results suggest that reduced P300 amplitudes and delayed P300 latencies may be considered as vulnerability markers of the schizophrenia spectrum in nonclinical subjects from the community.

In two source memory tests, hallucinating patients with schizophrenia (N=30), compared to non-hallucinating (N=31), are impaired in recognizing internal self-generated items and misattribute them to an external event. They are not impaired in recognizing events from two internal sources. Results support a selective source-monitoring deficit in the occurrence of auditory hallucinations.

Introduction: Despite recent developments, the impact of pharmacotherapy on social autonomy and interpersonal problem solving skills in patients with schizophrenia remains limited, with consequences in terms of socio-professional functioning. Indeed, independently of the positive, negative and/or disorganization symptoms, functional deficits in patients with schizophrenia rely mainly on various cognitive impairments., Objectives: To determine the impact of a new Cognitive Remediation Strategy on interpersonal problem solving skills, social autonomy and symptoms in patients with schizophrenia., Methods: Thirty patients with schizophrenia were enrolled in a program consisting of 14 training sessions of 4 cognitive functions (attention/concentration, topological memory, logical reasoning, executive functions) using the REHACOM software. Measurements of attention (Continuous Performance Test, CPT), memory (Rivermead Behavioural Memory Test, RBMT) and executive functions (Wisconsin Card Sorting Test, WCST) as well as interpersonal problem solving skills (Assessment of Interpersonal Problem-Solving Skills, AIPSS) and social autonomy (Social Autonomy Scale, EAS) and finally schizophrenia symptoms (Positive And Negative Syndrom Scale, PANSS) were undertaken at the beginning and the end of the 14 remediation meetings., Results: Cognitive functions, interpersonal problems solving skills, social autonomy and symptoms were significantly improved by the Cognitive Remediation Strategy., Conclusion: Our results confirm the therapeutic impact of a Cognitive Remediation Strategy among 30 schizophrenic patients stabilised on clinical, therapeutic and functional levels. The question of the long-term maintenance of such improvements still requires further investigation.

The new water-soluble ruthenium(II) chiral complexes [RuCpX(L)(L')](n+) (X = Cl, I. L = PPh3; L' = PTA, mPTA; L = L' = PTA, mPTA) (PTA = 1,3,5-triaza-7-phosphaadamantane; mPTA = N-methyl-1,3,5-triaza-7-phosphaadamantane) have been synthesized and characterized by NMR and IR spectroscopy and elemental analysis. The salt mPTA(OSO2CF3) was also prepared and fully characterized by spectroscopic techniques. X-ray crystal structures of [RuClCp(PPh3)(PTA)] (2), [RuCpI(PPh3)(PTA)] (3), and [RuCpI(mPTA)(PPh3)](OSO2CF3) (9) have been determined. The binding properties toward DNA of the new hydrosoluble complexes have been studied using the mobility shift assay. The ruthenium chloride complexes interact with DNA depending on the hydrosoluble phosphine bonded to the metal, while the corresponding compounds with iodide, [RuCpI(PTA)2] (1), [RuCpI(PPh3)(PTA)] (3), [RuCpI(mPTA)2](OSO2CF3)2 (6), and [RuCpI(mPTA)(PPh3)](OSO2CF3) (9), do not bind to DNA.

Objective: This study's first objective was to confirm that patients with schizophrenia and their nonmentally ill siblings share the same impaired executive function when compared to healthy control subjects. The second objective was to study the relation between Wisconsin card sorting task (WCST) performance and the persistence and severity of clinical symptoms, as well as different clinical dimensions., Method: Ninety subjects were involved in this study, divided in 3 groups of 30 each: one group of patients with schizophrenia, one group of their siblings, and a control group. Symptom severity was assessed with the Positive and Negative Syndrome Scale (PANSS), and social functioning was measured by the Global functioning scale (GFS). The WCST was administered to all 3 groups., Results: Patients with schizophrenia and their siblings had a significantly lower WCST performance than control subjects. Statistical analysis showed that the patient group had a significantly greater impaired WCST performance than the 2 other groups. Siblings also had a significantly lower performance than the control subjects. Furthermore, no significant relation was found between WCST performance and other variables, including age, gender, education, illness duration, treatment, and different PANSS and GFS scores., Conclusion: Patients with schizophrenia and their nonmentally ill siblings share the same impaired executive function. These findings suggest that WCST performance can be considered a schizophrenia vulnerability marker in siblings of patients with schizophrenia.

Impairments of olfactory processing in patients with schizophrenia (SZ) have been reported in various olfactory tasks such as detection, discrimination, recognition memory, identification, and naming. The purpose of our study was to determine whether impairments in odor familiarity and hedonicity judgments observed in SZ patients during a previous behavioral study are associated with modifications of the activation patterns in olfactory areas. Twelve SZ patients, and 12 healthy comparison (HC) subjects, were tested using the H2(15)O-PET technique and 48 different odorants delivered during 8 scans. In addition to an odorless baseline condition, they had either to detect odor, or to judge odor familiarity or hedonicity, giving their responses by pressing a button. Regional cerebral blood flows during olfactory conditions were compared with those for baseline condition. Between-group analyses were then performed, and completed by regions of interest analyses. Both groups had equivalent ability for the detection of suprathreshold odorants, but patients found odors less familiar, and pleasant odors less pleasant than HC subjects. These behavioral results were related to functional abnormalities in temporo-limbic and orbital olfactory regions lateralized in the left hemisphere: the posterior part of the piriform cortex and orbital regions for familiarity judgments, the insular gyrus for hedonicity judgments, and the left inferior frontal gyrus and anterior piriform cortex/putamen region for the three olfactory tasks. They mainly resulted from a lack of activation during task conditions in the SZ patients. These data could explain olfactory disturbances and other clinical features of schizophrenia such as anhedonia.