Right temporoparietal junction transcranial direct current stimulation in the treatment of functional dissociative seizures: a case series.

Functional dissociative seizures (FDSs) are clinical events that resemble epileptic seizures but are not associated with abnormal brain electrical discharges or other physiological problems. In this pilot case series, ten adults with FDSs were recruited from our psychiatry department after being referred by a neurologist who made the diagnosis of FDS based on video EEG results. Each subject received ten sessions of cathodal tDCS focused on the right temporoparietal junction. A significant decrease in weekly seizure frequency was seen in all participants between baseline (30.2 ± 70.3 events) and 1 month after tDCS treatment (0.2 ± 0.3events) (p = 0.006). Main predisposing factors were unchanged after treatment.

Four Questions Nurses Can Ask to Predict PTSD 1 Year After a Motor Vehicle Crash.

BACKGROUND: The role of nurses in screening for posttraumatic stress disorder is crucial in trauma units. OBJECTIVES: To create and evaluate an easy and brief tool for nurses to predict chronic posttraumatic stress disorder 1 year after a motor vehicle crash. METHODS: We performed a 1-year follow-up multicenter study from 2007 to 2015, including 274 patients injured in a motor vehicle crash who were hospitalized in an orthopedic trauma unit. Nurses administered the DEPITAC questionnaire. Posttraumatic stress disorder was measured by the Post-Traumatic Stress Disorder Checklist of symptoms during the first year following the crash. A multivariable logistic regression model was implemented to select items significantly associated with posttraumatic stress disorder to improve the DEPITAC questionnaire. Predictive performance to predict posttraumatic stress disorder 1 year after the motor vehicle crash was examined for these different models. RESULTS: Of 274 patients studied, a total of 75.9% completed the questionnaire at 1 year of follow-up. We found that only two questions and two simple elements of the patient's medical record (other injury or a person dying during the crash, perception of vital threat, number of children, and length of stay in trauma) predicted posttraumatic stress disorder 1 year after a motor vehicle crash. CONCLUSIONS: The brevity of this evaluation, simple scoring rules, and screening test performance suggest that this new screening tool can be easily administered in the acute care setting by nurses.

Is electroconvulsive therapy an evidence-based treatment for catatonia? A systematic review and meta-analysis.

We aimed to review and discuss the evidence-based arguments for the efficacy of electroconvulsive therapy (ECT) in the treatment of catatonia. Randomized controlled trials (RCTs) and observational studies focusing on the response to ECT in catatonia were selected in PubMed, the Cochrane Library, Embase, ClinicalTrials.gov and Current Controlled Trials through October 2016 and qualitatively described. Trials assessing pre-post differences using a catatonia or clinical improvement rating scale were pooled together using a random effect model. Secondary outcomes were adverse effects of anesthesia and seizure. 564 patients from 28 studies were included. RCTs were of low quality and were heterogeneous; therefore, it was not possible to combine their efficacy results. An improvement of catatonic symptoms after ECT treatment was evidenced in ten studies (SMD = -3.14, 95% CI [-3.95; -2.34]). The adverse effects that were reported in seven studies included mental confusion, memory loss, headache, or adverse effects associated with anesthesia. ECT protocols were heterogeneous. The literature consistently describes improvement in catatonic symptoms after ECT. However, the published studies fail to demonstrate efficacy and effectiveness. It is now crucial to design and perform a quality RCT to robustly validate the use of ECT in catatonia.Prospero registration information: PROSPERO 2016: CRD42016041660.

fMRI capture of auditory hallucinations: Validation of the two-steps method.

Our purpose was to validate a reliable method to capture brain activity concomitant with hallucinatory events, which constitute frequent and disabling experiences in schizophrenia. Capturing hallucinations using functional magnetic resonance imaging (fMRI) remains very challenging. We previously developed a method based on a two-steps strategy including (1) multivariate data-driven analysis of per-hallucinatory fMRI recording and (2) selection of the components of interest based on a post-fMRI interview. However, two tests still need to be conducted to rule out critical pitfalls of conventional fMRI capture methods before this two-steps strategy can be adopted in hallucination research: replication of these findings on an independent sample and assessment of the reliability of the hallucination-related patterns at the subject level. To do so, we recruited a sample of 45 schizophrenia patients suffering from frequent hallucinations, 20 schizophrenia patients without hallucinations and 20 matched healthy volunteers; all participants underwent four different experiments. The main findings are (1) high accuracy in reporting unexpected sensory stimuli in an MRI setting; (2) good detection concordance between hypothesis-driven and data-driven analysis methods (as used in the two-steps strategy) when controlled unexpected sensory stimuli are presented; (3) good agreement of the two-steps method with the online button-press approach to capture hallucinatory events; (4) high spatial consistency of hallucinatory-related networks detected using the two-steps method on two independent samples. By validating the two-steps method, we advance toward the possible transfer of such technology to new image-based therapies for hallucinations. Hum Brain Mapp 38:4966-4979, 2017. © 2017 Wiley Periodicals, Inc.

Effect of growth hormone and IgG aggregates on dendritic cells activation and T-cells polarization.

Patients treated with therapeutic biological products (BP) frequently develop anti-drug antibodies (ADA) with potential neutralizing capacities leading to loss of clinical response or serious side effects. BP aggregates have been suggested to promote immunogenicity, thus enhancing ADA production. Dendritic cells (DC) are key effectors in T-cell and B-cell fates, and the subsequent generation of immunogenicity. The objective of this work was to determine if BP aggregates can participate to DC maturation and T-cell activation. We compared aggregates from three different proteins: human growth hormone (hGH), Rituximab, a chimeric anti-CD20 antibody and a serum-purified human IgG1. All three proteins underwent a stir stress, generating comparable populations of aggregated particles. Maturation of human monocyte-derived DC (moDC) upon exposure to native BPs or aggregates was evaluated in vitro. Results showed that hGH aggregates induced an increased expression of moDC co-stimulation markers, and augmented levels of IL-6, IL-8, IL-12p40, CCL2, CCL3, CCL4 and CXCL10. Both antibodies aggregates were also able to modify DC phenotype, but cytokine and chemokine productions were seen only with IL-6, IL-8, IL-12p40 and CXCL10. Aggregates-treated moDC enhanced allogenic T-cell proliferation and cytokines production, suggesting Th1 polarization with hGH, and mixed T-cell responses with antibodies aggregates. These results showed that BP aggregates provoked DC maturation, thus driving adaptive T-cell responses and polarization.

A Proline-Tryptophan Turn in the Intrinsically Disordered Domain 2 of NS5A Protein Is Essential for Hepatitis C Virus RNA Replication.

Hepatitis C virus (HCV) nonstructural protein 5A (NS5A) and its interaction with the human chaperone cyclophilin A are both targets for highly potent and promising antiviral drugs that are in the late stages of clinical development. Despite its high interest in regards to the development of drugs to counteract the worldwide HCV burden, NS5A is still an enigmatic multifunctional protein poorly characterized at the molecular level. NS5A is required for HCV RNA replication and is involved in viral particle formation and regulation of host pathways. Thus far, no enzymatic activity or precise molecular function has been ascribed to NS5A that is composed of a highly structured domain 1 (D1), as well as two intrinsically disordered domains 2 (D2) and 3 (D3), representing half of the protein. Here, we identify a short structural motif in the disordered NS5A-D2 and report its NMR structure. We show that this structural motif, a minimal Pro(314)-Trp(316) turn, is essential for HCV RNA replication, and its disruption alters the subcellular distribution of NS5A. We demonstrate that this Pro-Trp turn is required for proper interaction with the host cyclophilin A and influences its peptidyl-prolyl cis/trans isomerase activity on residue Pro(314) of NS5A-D2. This work provides a molecular basis for further understanding of the function of the intrinsically disordered domain 2 of HCV NS5A protein. In addition, our work highlights how very small structural motifs present in intrinsically disordered proteins can exert a specific function.

Network dynamics during the different stages of hallucinations in schizophrenia.

The majority of patients with schizophrenia suffer from hallucinations. While the triple-network model, which includes the default mode network (DMN), the central executive network (CEN) and the salience network (SAL), has recently been applied to schizophrenia, how this framework could explain the emergence of hallucinations remains unclear. Therefore, complementary brain regions that have been linked to hallucinations, such as the left hippocampus, should also be considered and added to this model. Accordingly, the present study explored the effective connectivity across these four components (i.e., the quadripartite model) during the different stages of hallucinations. Twenty-five patients with schizophrenia participated in a single session of resting-state functional magnetic resonance imaging to capture hallucinatory experiences. Based on the participants' self-report of the psychosensory experiences that occurred during scanning, hallucinatory experiences were identified and divided into four stages: periods without hallucination ("OFF"), periods with hallucination ("ON"), transition periods between "OFF" and "ON", and the extinction of the hallucinatory experience ("END"). Using stochastic dynamic causal modeling analysis, this study first confirmed that the SAL played a critical and causal role in switching between the CEN and the DMN in schizophrenia. In addition, effective connectivity within the quadripartite model depended on the hallucinatory stage. In particular, "ON" periods were linked to memory-based sensory input from the hippocampus to the SAL, while "END" periods were associated with a takeover of the CEN in favor of a voluntary process. Finally, the pathophysiological and therapeutic implications of these findings are critically discussed. Hum Brain Mapp 37:2571-2586, 2016. © 2016 Wiley Periodicals, Inc.

Functional and structural analysis of HicA3-HicB3, a novel toxin-antitoxin system of Yersinia pestis.

The mechanisms involved in the virulence of Yersinia pestis, the plague pathogen, are not fully understood. In previous research, we found that a Y. pestis mutant lacking the HicB3 (YPO3369) putative orphan antitoxin was attenuated for virulence in a murine model of bubonic plague. Toxin-antitoxin systems (TASs) are widespread in prokaryotes. Most bacterial species possess many TASs of several types. In type II TASs, the toxin protein is bound and neutralized by its cognate antitoxin protein in the cytoplasm. Here we identify the hicA3 gene encoding the toxin neutralized by HicB3 and show that HicA3-HicB3 constitutes a new functional type II TAS in Y. pestis. Using biochemical and mutagenesis-based approaches, we demonstrate that the HicA3 toxin is an RNase with a catalytic histidine residue. HicB3 has two functions: it sequesters and neutralizes HicA3 by blocking its active site, and it represses transcription of the hicA3B3 operon. Gel shift assays and reporter fusion experiments indicate that the HicB3 antitoxin binds to two operators in the hicA3B3 promoter region. We solved the X-ray structures of HicB3 and the HicA3-HicB3 complex; thus, we present the first crystal structure of a TA complex from the HicAB family. HicB3 forms a tetramer that can bind two HicA3 toxin molecules. HicA3 is monomeric and folds as a double-stranded-RNA-binding domain. The HicB3 N-terminal domain occludes the HicA3 active site, whereas its C-terminal domain folds as a ribbon-helix-helix DNA-binding motif.

Half a Century of Research on Posttraumatic Stress Disorder: A Scientometric Analysis.

We conducted a scientometric analysis to outline clinical research on posttraumatic stress disorder (PTSD). Our primary objective was to perform a broad-ranging scientometric analysis to evaluate key themes and trends over the past decades. Our secondary objective was to measure research network performance. We conducted a systematic search in the Web of Science Core Collection up to 15 August 2022 for publications on PTSD. We identified 42,170 publications published between 1945 and 2022. We used CiteSpace to retrieve the co-cited reference network (1978-2022) that presented significant modularity and mean silhouette scores, indicating highly credible clusters (Q = 0.915, S = 0.795). Four major trends of research were identified: 'war veterans and refugees', 'treatment of PTSD/neuroimaging', 'evidence syntheses', and 'somatic symptoms of PTSD'. The largest cluster of research concerned evidence synthesis for genetic predisposition and environmental exposures leading to PTSD occurrence. Research on war-related trauma has shifted from battlefield-related in-person exposure trauma to drone operator trauma and is being out published by civilian-related trauma research, such as the 'COVID-19' pandemic impact, 'postpartum', and 'grief disorder'. The focus on the most recent trends in the research revealed a burst in the 'treatment of PTSD' with the development of Mhealth, virtual reality, and psychedelic drugs. The collaboration networks reveal a central place for the USA research network, and although relatively isolated, a recent surge of publications from China was found. Compared to other psychiatric disorders, we found a lack of high-quality randomized controlled trials for pharmacological and nonpharmacological treatments. These results can inform funding agencies and future research.

Domain 3 of NS5A protein from the hepatitis C virus has intrinsic alpha-helical propensity and is a substrate of cyclophilin A.

Nonstructural protein 5A (NS5A) is essential for hepatitis C virus (HCV) replication and constitutes an attractive target for antiviral drug development. Although structural data for its in-plane membrane anchor and domain D1 are available, the structure of domains 2 (D2) and 3 (D3) remain poorly defined. We report here a comparative molecular characterization of the NS5A-D3 domains of the HCV JFH-1 (genotype 2a) and Con1 (genotype 1b) strains. Combining gel filtration, CD, and NMR spectroscopy analyses, we show that NS5A-D3 is natively unfolded. However, NS5A-D3 domains from both JFH-1 and Con1 strains exhibit a propensity to partially fold into an α-helix. NMR analysis identifies two putative α-helices, for which a molecular model could be obtained. The amphipathic nature of the first helix and its conservation in all genotypes suggest that it might correspond to a molecular recognition element and, as such, promote the interaction with relevant biological partner(s). Because mutations conferring resistance to cyclophilin inhibitors have been mapped into NS5A-D3, we also investigated the functional interaction between NS5A-D3 and cyclophilin A (CypA). CypA indeed interacts with NS5A-D3, and this interaction is completely abolished by cyclosporin A. NMR heteronuclear exchange experiments demonstrate that CypA has in vitro peptidyl-prolyl cis/trans-isomerase activity toward some, but not all, of the peptidyl-prolyl bonds in NS5A-D3. These studies lead to novel insights into the structural features of NS5A-D3 and its relationships with CypA.

Structural characterization by nuclear magnetic resonance of the impact of phosphorylation in the proline-rich region of the disordered Tau protein.

Phosphorylation of the neuronal Tau protein is implicated in both the regulation of its physiological function of microtubule stabilization and its pathological propensity to aggregate into the fibers that characterize Alzheimer's diseased neurons. However, how specific phosphorylation events influence both aspects of Tau biology remains largely unknown. In this study, we address the structural impact of phosphorylation of the Tau protein by Nuclear Magnetic Resonance (NMR) spectroscopy on a functional fragment of Tau (Tau[Ser208-Ser324] = TauF4). TauF4 was phosphorylated by the proline-directed CDK2/CycA3 kinase on Thr231 (generating the AT180 epitope), Ser235, and equally on Thr212 and Thr217 in the Proline-rich region (Tau[Ser208-Gln244] or PRR). These modifications strongly decrease the capacity of TauF4 to polymerize tubulin into microtubules. While all the NMR parameters are consistent with a globally disordered Tau protein fragment, local clusters of structuration can be defined. The most salient result of our NMR analysis is that phosphorylation in the PRR stabilizes a short α-helix that runs from pSer235 till the very beginning of the microtubule-binding region (Tau[Thr245-Ser324] or MTBR of TauF4). Phosphorylation of Thr231/Ser235 creates a N-cap with helix stabilizing role while phosphorylation of Thr212/Thr217 does not induce modification of the local transient secondary structure, showing that the stabilizing effect is sequence specific. Using paramagnetic relaxation experiments, we additionally show a transient interaction between the PRR and the MTBR, observed in both TauF4 and phospho-TauF4.

Towards understanding the phosphorylation code of tau.

We describe our efforts to combine in vitro enzymatic reactions with recombinant kinases to phosphorylate the neuronal tau protein, and NMR spectroscopy to unravel the resulting phosphorylation pattern in both qualitative and quantitative manners. This approach, followed by functional assays with the same samples, gives access to the complex phosphorylation code of tau. As a result, we propose a novel hypothesis for the link between tau (hyper)phosphorylation and aggregation.

Intrusive experiences in posttraumatic stress disorder: Treatment response induces changes in the directed functional connectivity of the anterior insula.

BACKGROUND: One of the core features of posttraumatic stress disorder (PTSD) is re-experiencing trauma. The anterior insula (AI) has been proposed to play a crucial role in these intrusive experiences. However, the dynamic function of the AI in re-experiencing trauma and its putative modulation by effective therapy need to be specified. METHODS: Thirty PTSD patients were enrolled and exposed to traumatic memory reactivation therapy. Resting-state functional magnetic resonance imaging (fMRI) scans were acquired before and after treatment. To explore AI-directed influences over the rest of the brain, we referred to a mixed model using pre-/posttreatment Granger causality analysis seeded on the AI as a within-subject factor and treatment response as a between-subject factor. To further identify correlates of re-experiencing trauma, we investigated how intrusive severity affected (i) causality maps and (ii) the spatial stability of other intrinsic brain networks. RESULTS: We observed changes in AI-directed functional connectivity patterns in PTSD patients. Many within- and between-network causal paths were found to be less influenced by the AI after effective therapy. Insular influences were found to be positively correlated with re-experiencing symptoms, while they were linked with a stronger default mode network (DMN) and more unstable central executive network (CEN) connectivity. CONCLUSION: We showed that directed changes in AI signaling to the DMN and CEN at rest may underlie the degree of re-experiencing symptoms in PTSD. A positive response to treatment further induced changes in network-to-network anticorrelated patterns. Such findings may guide targeted neuromodulation strategies in PTSD patients not suitably improved by conventional treatment.

Spectroscopic studies of GSK3{beta} phosphorylation of the neuronal tau protein and its interaction with the N-terminal domain of apolipoprotein E.

Alzheimer disease neurons are characterized by extraneuronal plaques formed by aggregated amyloid-ß peptide and by intraneuronal tangles composed of fibrillar aggregates of the microtubule-associated Tau protein. Tau is mostly found in a hyperphosphorylated form in these tangles. Glycogen synthase kinase 3ß (GSK3ß) is a proline-directed kinase generally considered as one of the major players that (hyper)phosphorylates Tau. The kinase phosphorylates mainly (Ser/Thr)-Pro motifs and is believed to require a priming activity by another kinase. Here, we use an in vitro phosphorylation assay and NMR spectroscopy to characterize in a qualitative and quantitative manner the phosphorylation of Tau by GSK3ß. We find that three residues can be phosphorylated (Ser-396, Ser-400, and Ser-404) by GSK3ß alone, without priming. Ser-404 is essential in this process, as its mutation to Ala prevents all activity of GSK3ß. However, priming enhances the catalytic efficacy of the kinase, as initial phosphorylation of Ser-214 by the cAMP-dependent protein kinase (PKA) leads to the rapid modification by GSK3ß of four regularly spaced additional sites. Because the regular incorporation of negative charges by GSK3ß leads to a potential parallel between phospho-Tau and heparin, we investigated its interaction with the heparin/low density lipoprotein receptor binding domain of human apolipoprotein E. We indeed observed an interaction between the GSK3ß-promoted regular phospho-pattern on Tau and the apolipoprotein E fragment but none in the absence of phosphorylation or the presence of an irregular phosphorylation pattern by the prolonged activity of PKA. Apolipoprotein E is therefore able to discriminate and interact with specific phosphorylation patterns of Tau.

Mental health among medical, healthcare, and other university students during the first COVID-19 lockdown in France.

Background The COVID-19 pandemic has raised concerns regarding its psychological effect on university students, especially healthcare students. We aimed at assessing the risk of mental health problems according to the type of university studies, by adjusting for potential confounders. Methods We used data from the COSAMe study, a national cross-sectional survey including 69,054 French university students during the first quarantine. The mental health outcomes evaluated were suicidal thoughts, severe self-reported distress (as assessed by the Impact of Events Scale-Revised), stress (Perceived Stress Scale), anxiety (State-Trait Anxiety Inventory, State subscale), and depression (Beck Depression Inventory). Multivariable logistic regression analyzes were performed to test the association between the type of university studies (healthcare studies: medical and non-medical, and non-healthcare studies) and poor mental health outcomes, adjusted for sociodemographic characteristics, precariousness indicators, health-related data, quality of social relationships, and data about media consumption. Results Compared to non-healthcare students (N = 59,404), non-medical healthcare (N = 5,431) and medical students (N = 4,193) showed a lower risk of presenting at least one poor mental health outcome (adjusted OR [95%CI] = 0.86[0.81-0.92] and 0.87[0.81-0.93], respectively). Compared to non-healthcare students, medical students were at lower risk of suicidal thoughts (0.83[0.74-0.93]), severe self-reported distress (0.75[0.69-0.82]) and depression (0.83[0.75-0.92]). Non-medical healthcare students were at lower risk of severe selfreported distress (0.79[0.73-0.85]), stress (0.92[0.85-0.98]), depression (0.83[0.76-0.91]), and anxiety (0.86[0.80-0.92]). Limitations This is a large but not representative cross-sectional study, limited to the first confinement. Conclusions Being a healthcare student is a protective factor for mental health problems among confined students. Mediating factors still need to be explored.

NMR spectroscopy of the neuronal tau protein: normal function and implication in Alzheimer's disease.

NMR spectroscopy was used to explore the different aspects of the normal and pathological functions of tau, but proved challenging because the protein contains 441 amino acids and has poor signal dispersion. We have set out to dissect the phosphorylation patterns of tau in order to understand better its role in the aggregation process and microtubule-binding regulation. Our current knowledge on the functional consequences of specific phosphorylations is still limited, mainly because producing and assessing quantitatively phosphorylated tau samples is far from straightforward, even in vitro. We use NMR spectroscopy as a proteomics tool to characterize the phosphorylation patterns of tau, after in vitro phosphorylation by recombinant kinases. The phosphorylated tau can next be use for functional assays or interaction assays with phospho-dependent protein partners, such as the prolyl cis-trans isomerase Pin1.

Reward anticipation in schizophrenia: A coordinate-based meta-analysis.

Reward processing impairments have been linked with positive and negative symptoms of schizophrenia. Here, we performed a coordinate-based meta-analysis that combined eleven BOLD-fMRI studies comparing reward anticipation signals between schizophrenia patients and healthy controls. We observed a reduced difference in activation in schizophrenia patients within a frontal-striatal network. Meta-regressions revealed that this functional signature was linked to the severity of psychotic symptoms and persisted even after controlling for the dose of antipsychotic medications.

Loxoscelism: Advances and Challenges in the Design of Antibody Fragments with Therapeutic Potential.

Envenoming due to Loxosceles spider bites still remains a neglected disease of particular medical concern in the Americas. To date, there is no consensus for the treatment of envenomed patients, yet horse polyclonal antivenoms are usually infused to patients with identified severe medical conditions. It is widely known that venom proteins in the 30-35 kDa range with sphingomyelinase D (SMasesD) activity, reproduce most of the toxic effects observed in loxoscelism. Hence, we believe that monoclonal antibody fragments targeting such toxins might pose an alternative safe and effective treatment. In the present study, starting from the monoclonal antibody LimAb7, previously shown to target SMasesD from the venom of L. intermedia and neutralize its dermonecrotic activity, we designed humanized antibody V-domains, then produced and purified as recombinant single-chain antibody fragments (scFvs). These molecules were characterized in terms of humanness, structural stability, antigen-binding activity, and venom-neutralizing potential. Throughout this process, we identified some blocking points that can impact the Abs antigen-binding activity and neutralizing capacity. In silico analysis of the antigen/antibody amino acid interactions also contributed to a better understanding of the antibody's neutralization mechanism and led to reformatting the humanized antibody fragment which, ultimately, recovered the functional characteristics for efficient in vitro venom neutralization.

Psychogenic non-epileptic seizures treated with guided transcranial direct current stimulation: A case report.

INTRODUCTION: Psychogenic non-epileptic seizures (PNES) are paroxysms of either altered subjective or objective manifestations that may mimic epileptic seizures (ES), without abnormal neuronal epileptiform activity. In this report, we present the case of a 39-year-old woman with PNES and functional movement disorders, who was successfully treated with neuro-guided transcranial direct current stimulation (tDCS). METHODS: We used a PET-guided tDCS approach, as a hypometabolism of the frontal region was revealed by FDG TEP scan. TDCs was performed 5 days/week, 2 times/day, during 3 weeks. All clinical manifestations were reported in a seizure diary. We also assessed dissociation, depression, alexithymia, psychotraumatic scales, and involuntary movements. RESULTS: The treatment was followed by a decrease of both psychogenic involuntary movements and PNES at 5 weeks. At the same time, PTSD symptoms, dissociative symptoms, depression and alexithymia improved. CONCLUSION: PET-scan and tDCS seems to be promising tools for the evaluation and treatment of PNES in clinical practice, and may have a specific role on dissociative symptoms.