Orbitofrontal sulcal patterns in catatonia.

BACKGROUND: Catatonia is a psychomotor syndrome frequently observed in disorders with neurodevelopmental impairments, including psychiatric disorders such as schizophrenia. The orbitofrontal cortex (OFC) has been repeatedly associated with catatonia. It presents with an important interindividual morphological variability, with three distinct H-shaped sulcal patterns, types I, II, and III, based on the continuity of the medial and lateral orbital sulci. Types II and III have been identified as neurodevelopmental risk factors for schizophrenia. The sulcal pattern of the OFC has never been investigated in catatonia despite the role of the OFC in the pathophysiology and the neurodevelopmental component of catatonia. METHODS: In this context, we performed a retrospective analysis of the OFC sulcal pattern in carefully selected homogeneous and matched subgroups of schizophrenia patients with catatonia (N = 58) or without catatonia (N = 65), and healthy controls (N = 82). RESULTS: Logistic regression analyses revealed a group effect on OFC sulcal pattern in the left (χ2 = 18.1; p < .001) and right (χ2 = 28.3; p < .001) hemispheres. Catatonia patients were found to have more type III and less type I in both hemispheres compared to healthy controls and more type III on the left hemisphere compared to schizophrenia patients without catatonia. CONCLUSION: Because the sulcal patterns are indirect markers of early brain development, our findings support a neurodevelopmental origin of catatonia and may shed light on the pathophysiology of this syndrome.

Abnormalities in one-carbon metabolism in young patients with psychosis.

Introduction: Folates, the main actors in one-carbon (C1) metabolism, are involved in synthesising monoamines and maintaining genomic stability. Previous studies support the association between C1 metabolism and schizophrenia. The main purpose of this study was to assess the prevalence of plasma folate, and/or vitamin B12 deficiencies and hyperhomocysteinemia in young patients with psychotic disorders. Methods: We included young inpatients (15-30 years old) with psychosis between 2014 and 2017 from Sainte-Anne Hospital in Paris. Plasma folate, vitamin B12 deficiency and homocysteinemia dosages were done at admission. Clinical data were extracted retrospectively, and patients diagnosed with a first-episode psychosis (FEP), schizophrenia, schizoaffective disorder, or persistent delusional disorder were retained for the analysis. Results: Among the 334 inpatients, 188 (56%) had C1 dosages available (135 males; 53 females). From the 188 patients, 32% had a C1 abnormality. This abnormality reached 38% of FEP patients. The most frequent abnormality was folate deficiency: 21% of all patients and 27% of FEP. Lower levels of folates were found in males compared to females (p = 0.02) and were correlated with more severe disorder, as assessed by Clinical Global Impression - Severity (CGI-S; p = 0.009). Antipsychotic dosage was positively associated with B12 levels (p = 0.013) and negatively with homocysteinemia (p = 0.034). Conclusion: One-carbon metabolism anomalies in young patients with psychotic disorders are highly prevalent, reaching almost half of the patients with FEP. Potential protective effects from females and antipsychotics have emerged. These results spotlight the need for new therapeutic prospects, such as folate supplementation, to achieve personalised medical approaches to the early stages of psychotic disorders.

Real world transcranial magnetic stimulation for major depression: A multisite, naturalistic, retrospective study.

BACKGROUND: In 2008, the U.S. FDA approved rTMS as a treatment against medication-resistant depression. However, real-world rTMS outcomes remain understudied. This study investigates how rTMS for depression is delivered in routine clinical practice in France, and measures its effectiveness as well as its moderators. METHODS: Five centers provided retrospective data on patients who were treated with rTMS for treatment-resistant depression from January 2015 to December 2020. Patients were assessed twice using a hetero-questionnaire, with baseline and immediate post-treatment assessments. We conducted univariate analyses to study which factors were significantly associated with rTMS effectiveness. We then included age, gender, and significant factors in a multivariate model. RESULTS: We collected data from 435 patients with a mean age of 51.27 (14.91): 66 % were female, and 26 % suffered from bipolar depression. Stimulation was delivered using four different stimulation parameters: 1 Hz (7 % of the individuals), 10 Hz (43 %), 20 Hz (12 %), and 50 Hz (intermittent Theta Burst Stimulation, iTBS) (38 %). The mean improvement of depressive symptoms was 33 % (p < 0.001, effect-size: 0.79). Response and remission rates were of 31 % and 22.8 %, respectively. In the multivariate analysis, improvement in depressive symptoms was associated with higher baseline symptoms. CONCLUSION: This is one of the largest studies that investigates, with careful clinician-rated scales by trained psychiatrists, the effect of rTMS in naturalistic settings. Repetitive TMS appears to be effective in routine clinical practice, although its efficacy could be improved by analyzing predictors of response, as well as personalized targeting of specific brain areas.

Peripheral proteomic changes after electroconvulsive seizures in a rodent model of non-response to chronic fluoxetine.

Major depressive disorder (MDD) is the psychiatric disorder with the highest prevalence in the world. Pharmacological antidepressant treatment (AD), such as selective serotonin reuptake inhibitors [SSRI, i.e., fluoxetine (Flx)] is the first line of treatment for MDD. Despite its efficacy, lack of AD response occurs in numerous patients characterizing Difficult-to-treat Depression. ElectroConvulsive Therapy (ECT) is a highly effective treatment inducing rapid improvement in depressive symptoms and high remission rates of ∼50-63% in patients with pharmaco-resistant depression. Nevertheless, the need to develop reliable treatment response predictors to guide personalized AD strategies and supplement clinical observation is becoming a pressing clinical objective. Here, we propose to establish a proteomic peripheral biomarkers signature of ECT response in an anxio/depressive animal model of non-response to AD. Using an emotionality score based on the analysis complementary behavioral tests of anxiety/depression (Elevated Plus Maze, Novelty Suppressed Feeding, Splash Test), we showed that a 4-week corticosterone treatment (35 µg/ml, Cort model) in C57BL/6JRj male mice induced an anxiety/depressive-like behavior. A 28-day chronic fluoxetine treatment (Flx, 18 mg/kg/day) reduced corticosterone-induced increase in emotional behavior. A 50% decrease in emotionality score threshold before and after Flx, was used to separate Flx-responding mice (Flx-R, n = 18), or Flx non-responder mice (Flx-NR, n = 7). Then, Flx-NR mice received seven sessions of electroconvulsive seizure (ECS, equivalent to ECT in humans) and blood was collected before and after ECS treatment. Chronic ECS normalized the elevated emotionality observed in Flx-NR mice. Then, proteins were extracted from peripheral blood mononuclear cells (PBMCs) and isolated for proteomic analysis using a high-resolution MS Orbitrap. Data are available via ProteomeXchange with identifier PXD037392. The proteomic analysis revealed a signature of 33 peripheral proteins associated with response to ECS (7 down and 26 upregulated). These proteins were previously associated with mental disorders and involved in regulating pathways which participate to the depressive disorder etiology.

Elevated Effort Cost Identified by Computational Modeling as a Distinctive Feature Explaining Multiple Behaviors in Patients With Depression.

BACKGROUND: Motivational deficit is a core clinical manifestation of depression and a strong predictor of treatment failure. However, the underlying mechanisms, which cannot be accessed through conventional questionnaire-based scoring, remain largely unknown. According to decision theory, apathy could result either from biased subjective estimates (of action costs or outcomes) or from dysfunctional processes (in making decisions or allocating resources). METHODS: Here, we combined a series of behavioral tasks with computational modeling to elucidate the motivational deficits of 35 patients with unipolar or bipolar depression under various treatments compared with 35 matched healthy control subjects. RESULTS: The most striking feature, which was observed independent of medication across preference tasks (likeability ratings and binary decisions), performance tasks (physical and mental effort exertion), and instrumental learning tasks (updating choices to maximize outcomes), was an elevated sensitivity to effort cost. By contrast, sensitivity to action outcomes (reward and punishment) and task-specific processes were relatively spared. CONCLUSIONS: These results highlight effort cost as a critical dimension that might explain multiple behavioral changes in patients with depression. More generally, they validate a test battery for computational phenotyping of motivational states, which could orientate toward specific medication or rehabilitation therapy, and thereby help pave the way for more personalized medicine in psychiatry.

Preserved Unconscious Processing in Schizophrenia: The Case of Motivation.

BACKGROUND AND HYPOTHESIS: Motivation deficit is a hallmark of schizophrenia that has a strong impact on their daily life. An alteration of reward processing has been repeatedly highlighted in schizophrenia, but to what extent it involves a deficient amplification of reward representation through conscious processing remains unclear. Indeed, patients with schizophrenia exhibit a disruption of conscious processing, whereas unconscious processing appears to be largely preserved. STUDY DESIGN: To further explore the nature of motivational deficit in schizophrenia and the implication of consciousness disruption in this symptom, we used a masking paradigm testing motivation both under conscious and unconscious conditions in patients with schizophrenia (n = 31) and healthy controls (n = 32). Participants were exposed to conscious or subliminal coin pictures representing money at stake and were subsequently asked to perform an effort-task by squeezing a handgrip as hard as possible to win this reward. STUDY RESULTS: We observed a preserved effect of unconscious monetary rewards on force production in both groups, without any significant difference between them. By contrast, in the conscious condition, patients with schizophrenia were less sensitive to rewards than controls. Our results confirm that unconscious incentives have effects on exerted forces in the general population, and demonstrate that patients with schizophrenia exhibit a dissociation between an impaired conscious motivation and a preserved unconscious motivation. CONCLUSIONS: These findings suggest the existence of several steps in motivational processes that can be differentially affected and might have implication for patient care.

Efficacy of Transcranial Direct-Current Stimulation in Catatonia: A Review and Case Series.

Catatonia is a severe neuropsychiatric syndrome, usually treated by benzodiazepines and electroconvulsive therapy. However, therapeutic alternatives are limited, which is particularly critical in situations of treatment resistance or when electroconvulsive therapy is not available. Transcranial direct-current stimulation (tDCS) is a promising non-invasive neuromodulatory technique that has shown efficacy in other psychiatric conditions. We present the largest case series of tDCS use in catatonia, consisting of eight patients in whom tDCS targeting the left dorsolateral prefrontal cortex and temporoparietal junction was employed. We used a General Linear Mixed Model to isolate the effect of tDCS from other confounding factors such as time (spontaneous evolution) or co-prescriptions. The results indicate that tDCS, in addition to symptomatic pharmacotherapies such as lorazepam, seems to effectively reduce catatonic symptoms. These results corroborate a synthesis of five previous case reports of catatonia treated by tDCS in the literature. However, the specific efficacy of tDCS in catatonia remains to be demonstrated in a randomized controlled trial. The development of therapeutic alternatives in catatonia is of paramount importance.

Examining transcranial random noise stimulation as an add-on treatment for persistent symptoms in schizophrenia (STIM'Zo): a study protocol for a multicentre, double-blind, randomized sham-controlled clinical trial.

BACKGROUND: One out of three patients with schizophrenia failed to respond adequately to antipsychotics and continue to experience debilitating symptoms such as auditory hallucinations and negative symptoms. The development of additional therapeutic approaches for these persistent symptoms constitutes a major goal for patients. Here, we develop a randomized-controlled trial testing the efficacy of high-frequency transcranial random noise stimulation (hf-tRNS) for the treatment of resistant/persistent symptoms of schizophrenia in patients with various profiles of symptoms, cognitive deficits and illness duration. We also aim to investigate the biological and cognitive effects of hf-tRNS and to identify the predictors of clinical response. METHODS: In a randomized, double-blind, 2-arm parallel-group, controlled, multicentre study, 144 patients with schizophrenia and persistent symptoms despite the prescription of at least one antipsychotic treatment will be randomly allocated to receive either active (n = 72) or sham (n = 72) hf-tRNS. hf-tRNS (100-500 Hz) will be delivered for 20 min with a current intensity of 2 mA and a 1-mA offset twice a day on 5 consecutive weekdays. The anode will be placed over the left dorsolateral prefrontal cortex and the cathode over the left temporoparietal junction. Patients' symptoms will be assessed prior to hf-tRNS (baseline), after the 10 sessions, and at 1-, 3- and 6-month follow-up. The primary outcome will be the number of responders defined as a reduction of at least 25% from the baseline scores on the Positive and Negative Syndrome Scale (PANSS) after the 10 sessions. Secondary outcomes will include brain activity and connectivity, source monitoring performances, social cognition, other clinical (including auditory hallucinations) and biological variables, and attitude toward treatment. DISCUSSION: The results of this trial will constitute a first step toward establishing the usefulness of hf-tRNS in schizophrenia whatever the stage of the illness and the level of treatment resistance. We hypothesize a long-lasting effect of active hf-tRNS on the severity of schizophrenia symptoms as compared to sham. This trial will also have implications for the use of hf-tRNS as a preventive intervention of relapse in patients with schizophrenia. TRIAL REGISTRATION: ClinicalTrials.gov NCT02744989. Prospectively registered on 20 April 2016.

Towards Deciphering the Fetal Foundation of Normal Cognition and Cognitive Symptoms From Sulcation of the Cortex.

Growing evidence supports that prenatal processes play an important role for cognitive ability in normal and clinical conditions. In this context, several neuroimaging studies searched for features in postnatal life that could serve as a proxy for earlier developmental events. A very interesting candidate is the sulcal, or sulco-gyral, patterns, macroscopic features of the cortex anatomy related to the fold topology-e.g., continuous vs. interrupted/broken fold, present vs. absent fold-or their spatial organization. Indeed, as opposed to quantitative features of the cortical sheet (e.g., thickness, surface area or curvature) taking decades to reach the levels measured in adult, the qualitative sulcal patterns are mainly determined before birth and stable across the lifespan. The sulcal patterns therefore offer a window on the fetal constraints on specific brain areas on cognitive abilities and clinical symptoms that manifest later in life. After a global review of the cerebral cortex sulcation, its mechanisms, its ontogenesis along with methodological issues on how to measure the sulcal patterns, we present a selection of studies illustrating that analysis of the sulcal patterns can provide information on prenatal dispositions to cognition (with a focus on cognitive control and academic abilities) and cognitive symptoms (with a focus on schizophrenia and bipolar disorders). Finally, perspectives of sulcal studies are discussed.

A New Look on an Old Issue: Comprehensive Review of Neurotransmitter Studies in Cerebrospinal Fluid of Patients with Schizophrenia and Antipsychotic Effect on Monoamine's Metabolism.

Neurotransmitters metabolism has a key role in the physiopathology of schizophrenia as demonstrated by studies measuring monoamine metabolites in patient's cerebrospinal fluid (CSF) since the beginning of the antipsychotic use. This comprehensive review aims to understand the anomalies of CSF monoamines in schizophrenia and their correlation with clinical and paraclinical features. We also review the influence of antipsychotic treatment on CSF monoamines and discuss the connection with metabolic and inflammatory processes. Studies comparing CSF homovanillic acid (HVA) levels between patients and controls are miscellaneous, due to the heterogeneity of samples studies. However, low HVA is associated with more positive symptoms and a poorer outcome and negatively correlated with brain ventricle size. Based on humans and animals' studies, antipsychotic treatments increase HVA during the first week of administration and decrease progressively over the time with a fall-off after withdrawal. 5-hydroxyindolacetic acetic acid levels do not seem to be different in the patient's CSF compared to controls. Considering metabolic co-factors of neurotransmitters synthesis, there is evidence supporting an increase of kynurenic acid in the CSF of patients with schizophrenia. Few studies explore folate metabolism in CSF. Literature also emphasizes the relationship between folate metabolism, inflammation and monoamine's metabolism. Those results suggest that the CSF monoamines could be correlated with schizophrenia symptoms and treatment outcome. However, further studies, exploring the role of CSF monoamines as biomarkers of disease severity and response to treatment are needed. They should assess the antipsychotic prescription, inflammatory markers and folate metabolism as potential confounding factors.

Inhibition of the replication of SARS-CoV-2 in human cells by the FDA-approved drug chlorpromazine.

INTRODUCTION: Urgent action is needed to fight the ongoing coronavirus disease 2019 (COVID-19) pandemic by reducing the number of infected cases, contagiousness and severity. Chlorpromazine (CPZ), an antipsychotic from the phenothiazine group, is known to inhibit clathrin-mediated endocytosis and has antiviral activity against severe acute respiratory syndrome coronavirus-1 (SARS-CoV-1) and Middle East respiratory syndrome coronavirus. The aim of this in-vitro study was to test CPZ against SARS-CoV-2 in monkey and human cells. MATERIALS AND METHODS: Monkey VeroE6 cells and human alveolar basal epithelial A549-ACE2 cells were infected with SARS-CoV-2 in the presence of various concentrations of CPZ. Supernatants were harvested at day 2 and analysed by quantitative reverse transcription polymerase chain reaction (RT-qPCR) for the presence of SARS-CoV-2 RNA. Cell viability was assessed in non-infected cells. RESULTS: CPZ was found to have antiviral activity against SARS-CoV-2 in monkey VeroE6 cells, with a half maximal inhibitory concentration (IC50) of 8.2 µM, half maximal cytotoxic concentration (CC50) of 13.5 µM, and selectivity index (SI) of 1.65. In human A549-ACE2 cells, CPZ was also found to have anti-SARS-CoV-2 activity, with IC50 of 11.3 µM, CC50 of 23.1 µM and SI of 2.04. DISCUSSION: Although the measured SI values are low, the IC50 values measured in vitro may translate to CPZ dosages used in routine clinical practice because of the high biodistribution of CPZ in lungs and saliva. Also, the distribution of CPZ in brain could be of interest for treating or preventing neurological and psychiatric forms of COVID-19. CONCLUSIONS: These preclinical findings support clinical investigation of the repurposing of CPZ, a drug with mild side effects, in the treatment of patients with COVID-19.

The Combination of Propofol and Ketamine Does Not Enhance Clinical Responses to Electroconvulsive Therapy in Major Depression-The Results From the KEOpS Study.

OBJECTIVE: We investigated the clinical effects of the combination of ketamine and propofol as anesthetic agents during electroconvulsive therapy (ECT) in patients with uni- or bipolar major depressive episodes. We hypothesized that ketamine may confer short- and long- term advantages in improving depressive symptoms at the early stages of ECT. METHODS: In a randomized placebo-controlled trial, remission rates after 4 and 8 weeks of ECT were compared between patients who were randomly allocated to receive either the combination of ketamine (0.5 mg/kg) + propofol (n= 11) or placebo + propofol (n = 16). Depressive symptoms were assessed weekly using the Montgomery-Åsberg Depression Rating Scale (MADRS); ECT sessions were administered twice per week for a maximum of 8 weeks (16 sessions). RESULTS: After 4 weeks, we observed significantly fewer remitters (MADRS score < 10) in the ketamine + propofol group (0/11; 0%) than in the placebo + propofol group (5/16; 31%; χ2 = 4.22; p = 0.040). No significant difference was observed between the two groups regarding the number of patients who achieved remission weekly throughout the study period (Chi² = 3.588; p = 0.058). The mean duration of seizures was significantly shorter in the ketamine + propofol group than in the placebo + propofol group. CONCLUSIONS: The results from the current study corroborated results from previously published studies and did not support the use of the combination of ketamine + propofol as an anesthetic agent for ECT in patients with major depressive episodes in clinical settings.

Employment, Studies and Feelings: Two to Nine Years After a Personalized Program of Cognitive Remediation in Psychiatric Patients.

Employment rate in psychiatry is around 10 to 30%. Cognitive remediation (CR) associated with psychosocial rehabilitation shows good functional outcomes, with a high level of satisfaction in participants provided by tailored CR. However, few studies looked at the long-term outcome in participants who experienced such a program. This retrospective survey examines the outcome of persons having psychiatric diseases 2 to 9 years after being treated with a personalized CR program. The survey included 12 domains with questions relevant to work, studies, before CR (T1) and at the moment of the survey (T2), questions about housing, relatedness, familiar relationships and daily activities at T2. Finally, a narrative interview was included to express feelings of the participants about CR. Sixty-six participants completed the survey, and were treated with neurocognitive or social cognition programs. Their diagnosis was: schizophrenia (80.3%), neurodevelopment disorder (autism as well as genetic or metabolic disease with psychiatric expression) (15.2%) and bipolar disorder (4.5%). The comparison between T1 and T2 showed significant difference for job employment (P < 0.001), even for competitive jobs (p < 0.007), for performing studies (p = 0.033), for practicing a physical activity (0.033) or reading (0.002). Outcome was also examined in reference to the delay from CR to highlight changes in patient characteristics and service delivery over the years. Hence, the total sample was split in two subgroups: CR delivered in 2009-2013 (n = 37); CR delivered in 2014-2016 (n = 29). While in the former group more participants were working (p = 0.037), in the latter group, which was younger (p = 0.04), more participants were studying (p = 0.02). At T2, a majority of persons experienced no relapse, three years (79.1%) to 8 years (56.8%) after CR, when referring to the anamnesis. Concerning subjective perception of CR, participants expressed feelings concerning positive impact on clarity of thought, on cognitive functions, self-confidence, perceiving CR as an efficient help for work and studies. To conclude, even long years after a personalized CR program, good benefits in terms of employment or studies emerge when compared to the status before CR, with good determinants for recovery in terms of leisure or physical activity practice.

Toi Même, a Mobile Health Platform for Measuring Bipolar Illness Activity: Protocol for a Feasibility Study.

BACKGROUND: The diagnosis and management of bipolar disorder are limited by the absence of available biomarkers. Patients with bipolar disorder frequently present with mood instability even during remission, which is likely associated with the risk of relapse, impaired functioning, and suicidal behavior, indicating that the illness is active. OBJECTIVE: This research protocol aimed to investigate the correlations between clinically rated mood symptoms and mood/behavioral data automatically collected using the Toi Même app in patients with bipolar disorder presenting with different mood episodes. This study also aimed to assess the feasibility of this app for self-monitoring subjective and objective mood/behavior parameters in those patients. METHODS: This open-label, nonrandomized trial will enroll 93 (31 depressive, 31 euthymic, and 31 hypomanic) adults diagnosed with bipolar disorder type I/II (Diagnostic and Statistical Manual of Mental Disorders, 5th edition criteria) and owning an iPhone. Clinical evaluations will be performed by psychiatrists at the baseline and after 2 weeks, 1 month, 2 months, and 3 months during the follow-up. Rather than only accessing the daily mood symptoms, the Toi Même app also integrates ecological momentary assessments through 2 gamified tests to assess cognition speed (QUiCKBRAIN) and affective responses (PLAYiMOTIONS) in real-life contexts, continuously measures daily motor activities (eg, number of steps, distance) using the smartphone's motion sensors, and performs a comprehensive weekly assessment. RESULTS: Recruitment began in April 2018 and the completion of the study is estimated to be in December 2021. As of April 2019, 25 participants were enrolled in the study. The first results are expected to be submitted for publication in 2020. This project has been funded by the Perception and Memory Unit of the Pasteur Institute (Paris) and it has received the final ethical/research approvals in April 2018 (ID-RCB: 2017-A02450-53). CONCLUSIONS: Our results will add to the evidence of exploring other alternatives toward a more integrated approach in the management of bipolar disorder, including digital phenotyping, to develop an ethical and clinically meaningful framework for investigating, diagnosing, and treating individuals at risk of developing bipolar disorder or currently experiencing bipolar disorder. Further prospective studies on the validity of automatically generated smartphone data are needed for better understanding the longitudinal pattern of mood instability in bipolar disorder as well as to establish the reliability, efficacy, and cost-effectiveness of such an app intervention for patients with bipolar disorder. TRIAL REGISTRATION: ClinicalTrials.gov NCT03508427; https://clinicaltrials.gov/ct2/show/NCT03508427. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/18818.

Brain imaging in catatonia: systematic review and directions for future research.

BACKGROUND: Catatonia is a frequent, complex and severe identifiable syndrome of motor dysregulation. However, its pathophysiology is poorly understood. METHODS: We aimed to provide a systematic review of all brain imaging studies (both structural and functional) in catatonia. RESULTS: We identified 137 case reports and 18 group studies representing 186 individual patients with catatonia. Catatonia is often associated with brain imaging abnormalities (in more than 75% of cases). The majority of the case reports show diffuse lesions of white matter, in a wide range of brain regions. Most of the case reports of functional imaging usually show frontal, temporal, or basal ganglia hypoperfusion. These abnormalities appear to be alleviated after successful treatment of clinical symptoms. Structural brain magnetic resonance imaging studies are very scarce in the catatonia literature, mostly showing diffuse cerebral atrophy. Group studies assessing functional brain imaging after catatonic episodes show that emotional dysregulation is related to the GABAergic system, with hypoactivation of orbitofrontal cortex, hyperactivation of median prefrontal cortex, and dysconnectivity between frontal and motor areas. CONCLUSION: In catatonia, brain imaging is abnormal in the majority of cases, and abnormalities more frequently diffuse than localised. Brain imaging studies published so far suffer from serious limitations and for now the different models presented in the literature do not explain most of the cases. There is an important need for further studies including a better clinical characterisation of patients with catatonia, functional imaging with concurrent catatonic symptoms and the use of novel brain imaging techniques.

High diagnostic value of plasma Niemann-Pick type C biomarkers in adults with selected neurological and/or psychiatric disorders.

Late-onset Niemann-Pick type C (NP-C) is a rare, underdiagnosed lysosomal disease with neurological manifestations. A specific treatment, miglustat, can stabilize the disease if given early. Recently, three plasma screening biomarkers (PSBs) were developed [cholestane3ß,5α,6ßtriol (C-triol), 7-ketocholesterol (7-KC), and lysosphingomyelin-509 (LSM-509)], allowing a simpler and quite robust screening of patients suitable for genetic testing. The objective of our study was to evaluate practical utility and feasibility of large-scale PSB screening for NP-C in selected adult patients. Patients were prospectively enrolled if they showed, starting from 12 years of age, at least one of the three initial neuro-psychiatric manifestations described in NP-C: (1) gait disorder (cerebellar and/or dystonic); (2) cognitive decline with frontal lobe syndrome; (3) atypical psychosis. PSBs were measured in plasma of all patients and, if positive (LSM-509 and/or C-triol + 7-KC elevated), sequencing of NPC1 and NPC2 genes was performed. A total of 251 patients [136 males, 115 females; median age 42.1 (range 12.2-85.6) years] were screened. Six patients had positive PSBs. Two were confirmed to have NP-C (0.8% diagnostic yield, both with all three PSBs highly increased, especially LSM-509). False-positive rate was 1.2%, which was identical if only considering LSM-509. By contrast, false-positive rates were 8.1% and 5.7% for 7-KC and C-triol, respectively. We showed that selecting patients with neurologic and/or psychiatric symptoms consistent with NP-C for large-scale PSB screening is a simple and valid strategy to identify new adult NP-C patients, and would probably lead to earlier diagnosis and treatment administration if widely applied.

Deviations in early hippocampus development contribute to visual hallucinations in schizophrenia.

Auditory hallucinations (AHs) are certainly the most emblematic experiences in schizophrenia, but visual hallucinations (VHs) are also commonly observed in this developmental psychiatric disorder. Notably, several studies have suggested a possible relationship between the clinical variability in hallucinations' phenomenology and differences in brain development/maturation. In schizophrenia, impairments of the hippocampus, a medial temporal structure involved in mnesic and neuroplastic processes, have been repeatedly associated with hallucinations, particularly in the visual modality. However, the possible neurodevelopmental origin of hippocampal impairments in VHs has never been directly investigated. A classic marker of early atypical hippocampal development is incomplete hippocampal inversion (IHI). In this study, we compared IHI patterns in healthy volunteers, and two subgroups of carefully selected schizophrenia patients experiencing frequent hallucinations: (a) those with pure AHs and (b) those with audio-visual hallucinations (A+VH). We found that VHs were associated with a specific IHI pattern. Schizophrenia patients with A+VH exhibited flatter left hippocampi than patients with pure AHs or healthy controls. This result first confirms that the greater clinical impairment observed in A+VH patients may relate to an increased neurodevelopmental weight in this subpopulation. More importantly, these findings bring crucial hints to better specify the sensitivity period of A+VH-related IHI during early brain development.

[Mood disorders: When should we use repetitive transcranial magnetic stimulation?] / Troubles de l'humeur : quand recourir à la stimulation magnétique transcrânienne ?

Repeated transcranial magnetic stimulation (rTMS) is still a recent treatment in psychiatry. This article aims at updating the clinicians'knowledge about rTMS in the treatment of mood disorders (uni and bipolar depressive disorders, manic/mixed states, suicidal risk, catatonia). It is intended for clinicians who are required to indicate and/or use rTMS in their current practice. rTMShas the highest level of evidence for the treatment of unipolar depression, provided that effective parameters are used, that is to say, for classical high frequency protocols: 20 to 30 sessions, 1000 pulses/session, 5 to 20Hz, and 110 % of the motor threshold. Low frequency protocol are also efficient and well tolerated. The duration of the efficacy varies with relapses rates around 50 % at one year. Pharmacological treatment generally remains associated. With regard to manic states, and mixed states the results are preliminary and limited to a possible reduction in symptoms. In the suicidal risk associated with mood disorders, the interest of rTMS is still to demonstrate, as well as in catatonia. The current place of the rTMS is no longer disputed in the curative treatment of major depressive disorder, preferentially used after one or two lines of antidepressants upstream. Further studies are needed to confirm preliminary positive findings in other aspects of mood disorders.