Institut Universitaire en Santé Mentale de Québec

CONTEXT: Cognitive behavioral therapy (CBT) and hypnotic medications are efficacious for short-term treatment of insomnia, but few patients achieve complete remission with any single treatment. It is unclear whether combined or maintenance therapies would enhance outcome. OBJECTIVES: To evaluate the added value of medication over CBT alone for acute treatment of insomnia and the effects of maintenance therapies on long-term outcome. DESIGN, SETTING, AND PATIENTS: Prospective, randomized controlled trial involving 2-stage therapy for 160 adults with persistent insomnia treated at a university hospital sleep center in Canada between January 2002 and April 2005. INTERVENTIONS: Participants received CBT alone or CBT plus 10 mg/d (taken at bedtime) of zolpidem for an initial 6-week therapy, followed by extended 6-month therapy. Patients initially treated with CBT attended monthly maintenance CBT for 6 months or received no additional treatment and those initially treated with combined therapy (CBT plus 10 mg/d of zolpidem) continued with CBT plus intermittent use of zolpidem or CBT only. MAIN OUTCOME MEASURES: Sleep onset latency, time awake after sleep onset, total sleep time, and sleep efficiency derived from daily diaries (primary outcomes); treatment response and remission rates derived from the Insomnia Severity Index (secondary outcomes). RESULTS: Cognitive behavioral therapy used singly or in combination with zolpidem produced significant improvements in sleep latency, time awake after sleep onset, and sleep efficiency during initial therapy (all P<.001); a larger increase of sleep time was obtained with the combined approach (P = .04). Both CBT alone and CBT plus zolpidem produced similar rates of treatment responders (60% [45/75] vs 61% [45/74], respectively; P = .84) and treatment remissions (39% [29/75] vs 44% [33/74], respectively; P = .52) with the 6-week acute treatment, but combined therapy produced a higher remission rate compared with CBT alone during the 6-month extended therapy phase and the 6-month follow-up period (56% [43/74 and 32/59] vs 43% [34/75 and 28/68]; P = .05). The best long-term outcome was obtained with patients treated with combined therapy initially, followed by CBT alone, as evidenced by higher remission rates at the 6-month follow-up compared with patients who continued to take zolpidem during extended therapy (68% [20/30] vs 42% [12/29]; P = .04). CONCLUSION: In patients with persistent insomnia, the addition of medication to CBT produced added benefits during acute therapy, but long-term outcome was optimized when medication is discontinued during maintenance CBT. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00042146.

OBJECTIVE: The presence of anxiety disorders (AD) in schizophrenia (SZ) is attracting increasing interest. However, published studies have yielded very broad variations in prevalence rates across studies. The current meta-analysis sought to (1) investigate the prevalence of co-occurring AD in SZ by reporting pooled prevalence rates and (2) identify potential sources of variations in reported rates that could guide our efforts to identify and treat these co-occurring disorders in patients with SZ. METHODS: We performed a systematic search of studies reporting prevalence of AD in SZ and related psychotic disorders. Mean prevalence rates and 95% confidence intervals (CIs) were first computed for each disorder. We then examined the impact of potential moderators related to patient sampling or to AD assessment methods on these rates. RESULTS: Fifty-two eligible studies were identified. Pooled prevalence rates and CIs were 12.1% (7.0%-17.1%) for obsessive-compulsive disorders, 14.9% (8.1%-21.8%) for social phobia, 10.9% (2.9%-18.8%) for generalized AD, 9.8% (4.3%-15.4%) for panic disorders, and 12.4% (4.0%-20.8%) for post-traumatic stress disorders. For all disorders, we found significant heterogeneity in rates across studies. This heterogeneity could at least partially be explained by the effect of moderator variables related to patient characteristics or assessment methods. CONCLUSIONS: AD are highly prevalent in SZ, but important variations in rates are observed between studies. This meta-analysis highlights several factors that affect risk for, or detection of AD in SZ, and could, thus, have an important impact on treatment and outcome of SZ patients.

The variety of physiological functions controlled by dopamine in the brain and periphery is mediated by the D1, D2, D3, D4 and D5 dopamine GPCRs. Drugs acting on dopamine receptors are significant tools for the management of several neuropsychiatric disorders including schizophrenia, bipolar disorder, depression and Parkinson's disease. Recent investigations of dopamine receptor signalling have shown that dopamine receptors, apart from their canonical action on cAMP-mediated signalling, can regulate a myriad of cellular responses to fine-tune the expression of dopamine-associated behaviours and functions. Such signalling mechanisms may involve alternate G protein coupling or non-G protein mechanisms involving ion channels, receptor tyrosine kinases or proteins such as β-arrestins that are classically involved in GPCR desensitization. Another level of complexity is the growing appreciation of the physiological roles played by dopamine receptor heteromers. Applications of new in vivo techniques have significantly furthered the understanding of the physiological functions played by dopamine receptors. Here we provide an update of the current knowledge regarding the complex biology, signalling, physiology and pharmacology of dopamine receptors.

The growing consensus that language is distributed into large-scale cortical and subcortical networks has brought with it an increasing focus on the connectional anatomy of language, or how particular fibre pathways connect regions within the language network. Understanding connectivity of the language network could provide critical insights into function, but recent investigations using a variety of methodologies in both humans and non-human primates have provided conflicting accounts of pathways central to language. Some of the pathways classically considered language pathways, such as the arcuate fasciculus, are now argued to be domain-general rather than specialized, which represents a radical shift in perspective. Other pathways described in the non-human primate remain to be verified in humans. In this review, we examine the consensus and controversy in the study of fibre pathway connectivity for language. We focus on seven fibre pathways-the superior longitudinal fasciculus and arcuate fasciculus, the uncinate fasciculus, extreme capsule, middle longitudinal fasciculus, inferior longitudinal fasciculus and inferior fronto-occipital fasciculus-that have been proposed to support language in the human. We examine the methods in humans and non-human primate used to investigate the connectivity of these pathways, the historical context leading to the most current understanding of their anatomy, and the functional and clinical correlates of each pathway with reference to language. We conclude with a challenge for researchers and clinicians to establish a coherent framework within which fibre pathway connectivity can be systematically incorporated to the study of language.

BACKGROUND: The measurement of mechanosensitivity is a key method for the study of pain in animal models. This is often accomplished with the use of von Frey filaments in an up-down testing paradigm. The up-down method described by Chaplan et al. (J Neurosci Methods 53:55-63, 1994) for mechanosensitivity testing in rodents remains one of the most widely used methods for measuring pain in animals. However, this method results in animals receiving a varying number of stimuli, which may lead to animals in different groups receiving different testing experiences that influences their later responses. To standardize the measurement of mechanosensitivity we developed a simplified up-down method (SUDO) for estimating paw withdrawal threshold (PWT) with von Frey filaments that uses a constant number of five stimuli per test. We further refined the PWT calculation to allow the estimation of PWT directly from the behavioral response to the fifth stimulus, omitting the need for look-up tables. RESULTS: The PWT estimates derived using SUDO strongly correlated (r > 0.96) with the PWT estimates determined with the conventional up-down method of Chaplan et al., and this correlation remained very strong across different levels of tester experience, different experimental conditions, and in tests from both mice and rats. The two testing methods also produced similar PWT estimates in prospective behavioral tests of mice at baseline and after induction of hyperalgesia by intraplantar capsaicin or complete Freund's adjuvant. CONCLUSION: SUDO thus offers an accurate, fast and user-friendly replacement for the widely used up-down method of Chaplan et al.

Due to the expected decline in the working-age population, especially in European countries, people with disabilities are now more often recognized as a valuable resource in the workforce and research into disability and employment is more important than ever.This paper outlines the state of affairs of research on disability and employment.We thereby focus on one particular group of people with disabilities, that is to say people with mental disabilities.We define disability according to the International Classification of Functioning, Disability and Health (ICF) of the World Health Organization, by that recognizing that disability results from the interaction of person and environment.Key issues, including the complexity of defining disability, the legal situation in Europe and North America concerning disability at work, and barriers and enablers to employment, are discussed.For each of the topics we show important findings in the existing literature and indicate where more indepth research is needed.We finalize with a concrete research agenda on disability and employment and provide recommendations for practice.

mutant. Thus, even though results suggest that exosomes containing pathological TDP-43 may play a key role in the propagation of TDP-43 proteinopathy, a therapeutic strategy for amyotrophic lateral sclerosis based on inhibition of exosome production would seem inappropriate, as in vivo data suggest that exosome secretion plays an overall beneficial role in neuronal clearance of pathological TDP-43.

BACKGROUND: Mental health apps have great potential to help people needing support to cope with distress or specific symptoms. In fact, there is an exponential increase in the number of mental health apps available on the internet, with less than 5% being actually studied. OBJECTIVE: This study aimed to assess the quality of the available evidence regarding the use of mental health apps and to summarize the results obtained so far. METHODS: Systematic reviews and meta-analyses were searched, specifically for mobile apps on mental health issues or symptoms, and rated using the Grading of Recommendations Assessment, Development and Evaluation system. RESULTS: A total of 7 meta-analyses were carefully reviewed and rated. Although some meta-analyses looked at any mental health issue and analyzed the data together, these studies were of poorer quality and did not offer strong empirical support for the apps. Studies focusing specifically on anxiety symptoms or depressive symptoms were of moderate to high quality and generally had small to medium effect sizes. Similarly, the effects of apps on stress and quality of life tended to offer small to medium effects and were of moderate to high quality. Studies looking at stand-alone apps had smaller effect sizes but better empirical quality than studies looking at apps with guidance. The studies that included follow-ups mostly found a sustained impact of the app at an 11-week follow-up. CONCLUSIONS: This meta-review revealed that apps for anxiety and depression hold great promise with clear clinical advantages, either as stand-alone self-management or as adjunctive treatments. More meta-analyses and more quality studies are needed to recommend apps for other mental health issues or for specific populations.

The field of the neurobiology of language is experiencing a paradigm shift in which the predominant Broca-Wernicke-Geschwind language model is being revised in favor of models that acknowledge that language is processed within a distributed cortical and subcortical system. While it is important to identify the brain regions that are part of this system, it is equally important to establish the anatomical connectivity supporting their functional interactions. The most promising framework moving forward is one in which language is processed via two interacting "streams"--a dorsal and ventral stream--anchored by long association fiber pathways, namely the superior longitudinal fasciculus/arcuate fasciculus, uncinate fasciculus, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and two less well-established pathways, the middle longitudinal fasciculus and extreme capsule. In this article, we review the most up-to-date literature on the anatomical connectivity and function of these pathways. We also review and emphasize the importance of the often overlooked cortico-subcortical connectivity for speech via the "motor stream" and associated fiber systems, including a recently identified cortical association tract, the frontal aslant tract. These pathways anchor the distributed cortical and subcortical systems that implement speech and language in the human brain.

There are still important gaps in our knowledge regarding the intergenerational transmission of attachment from mother to child, especially in mothers with childhood histories of abuse and neglect (CA&N). This study examined the contributions of reflective function concerning general attachment relationships, and specifically concerning trauma, as well as those of maternal attachment states of mind to the prediction of infant attachment disorganization in a sample of mothers with CA&N and their infants, using a 20-month follow-up design. Attachment and reflective functioning were assessed during pregnancy with the Adult Attachment Interview. Infant attachment was evaluated with the Strange Situation Procedure. The majority (83%) of infants of abused and neglected mothers were classified as insecure, and a significant proportion (44%) manifested attachment disorganization. There was a strong concordance between mother and child attachment, indicative of intergenerational transmission of attachment in parents with CA&N and their infants. Both unresolved trauma and trauma-specific reflective function made significant contributions to explaining variance in infant attachment disorganization. The findings of this study highlight the importance of trauma-specific mentalization in the intergenerational transmission of attachment by mothers with a history of childhood maltreatment, and provide new evidence of the importance of the absence of mentalization regarding trauma for infant attachment. Aún existen importantes vacíos en nuestro conocimiento sobre la transmisión intergeneracional de la afectividad de madre a niño, sobre todo en las madres con historial de abuso y negligencia en su niñez (CA&N). Este estudio examina las contribuciones de la función de reflexión con respecto a las relaciones generales de afectividad (RF-G) y específicamente con respecto al trauma (RF-T), así como de los estados mentales de la afectividad maternal, a la predicción de la desorganización de la afectividad del infante en un grupo muestra con CA&N y sus infantes, usando un modelo con seguimiento a los 20 meses. La afectividad y el funcionamiento de reflexión fueron evaluados durante el embarazo con la Entrevista de la Afectividad del Adulto. La afectividad del infante fue evaluada con el Procedimiento de la Situación Extraña. A la mayoría (83%) de los infantes de madres con historial de abuso y negligencia se les clasificó como inseguros y una proporción significativa (44%) reveló desorganización en la afectividad. Se dio una fuerte concordancia entre la afectividad de la madre y la del niño, lo cual es indicativo de la transmisión intergeneracional de la afectividad en progenitores con CA&N y sus infantes. La función de reflexión en ambos el trauma no resuelto y el trauma específico contribuyeron significativamente a explicar la variación en la desorganización de la afectividad del infante. Los resultados de este estudio resaltan la importancia de la mentalización de trauma específico en la transmisión intergeneracional de la afectividad en madres con historial de malos tratos en la niñez, y proveen nueva evidencia de la importancia de la falta de mentalización con respecto al trauma para la afectividad del infante. Il existe encore des écarts important dans nos connaissances en ce qui concerne la transmission intergénérationnelle de l'attachement de mère à enfant, surtout chez les mères ayant un passé d'abus et de négligence dans leur enfance (abrégé en anglais CA&N). Cette étude a examiné les contributions de la fonction réflective pour ce qui concerne la relation générale d'attachement (RF-G) et plus spécifiquement ce qui concerne le trauma (RF-T), ainsi que des états d'esprit d'attachement maternel, tout comme la prédiction de la désorganisation de l'attachement du bébé chez un échantillon de mères avec un CA&N et leurs bébés, en utilisant un suivi de 20 mois. L'attachement et le fonctionnement réflectif ont été évalués durant la grossesse avec un Entretien d'Attachement Adulte. L'attachement du bébé a été évalué au moyen d'une Procédure de Situation Etrange. La majorité (83%) des bébés de mères abusées ou négligées ont été classifiés comme évitants et une grande proportion (44%) ont fait preuve de désorganisation de l'attachement. Nous avons trouvé une concordance forte entre l'attachement de la mère de l'enfant, indiquant une transmission intergénérationnelle de l'attachement chez les parents avec un CA&N et leurs bébés. Le trauma sans résolution et la fonction réflective spécifique au trauma ont tous deux fortement contribué à expliquer la variance dans la désorganisation de l'attachement. Les résultats de cette étude mettent en lumière l'importance de la mentalisation spécifique au trauma dans la transmission intergénérationnelle de l'attachement chez les mères ayant un passé de maltraitance durant l'enfance, et offrent de nouvelles preuves de l'importance de l'absence de mentalisation spécifique au trauma pour l'attachement du bébé. Es gibt immer noch wichtige Wissenslücken über die intergenerationale Transmission der Bindung von Mutter zu Kind, vor allem bei Müttern mit KIndheitserfahrungen, die von Missbrauch (childhood abuse = CA) und Vernachlässigung (neglect = N) geprägt sind. Im Rahmen eines Follow-up-Designs von 20-Monaten untersuchte diese Studie den Beitrag der Reflexiven Funktion bezüglich allgemeiner Bindungsbeziehungen (RF-G), speziell in Bezug auf Trauma (RF-T) und bezüglich der mütterlichen mentalen Zustände hinsichtlich Bindung für die Vorhersage von kindlicher Bindungs-Desorganisation anhand einer Stichprobe von Müttern mit CA & N und ihren Säuglingen. Die Bindung und die reflexive Funktion wurden während der Schwangerschaft mit dem Adult Attachment Interview beurteilt. Die Bindung des Säuglings wurde mit dem Fremde-Situations-Test eingeschätzt. Die Mehrheit (83%) der Kinder der missbrauchten und vernachlässigten Mütter wurde als unsicher eingestuft und ein erheblicher Anteil (44%) äußerte Bindungs-Desorganisation. Es gab eine starke Übereinstimmung zwischen Mutter- und Kind-Bindung, was auf eine intergenerationale Transmission der Bindung von Eltern mit CA & N und ihren Kindern hinweist. Sowohl ungelöste Traumata und traumaspezifisches reflexives Funktionieren leisteten einen signifikanten Beitrag zur Varianzerklärung von Bindungs-Desorganisation bei den Säuglingen. Die Ergebnisse dieser Studie unterstreichen die Bedeutung der traumaspezifischen Mentalisierung in der intergenerationalen Transmission der Bindung bei Müttern mit Misshandlungserfahrungen in der Kindheit und liefern neue Beweise für die Bedeutung fehlender Mentalisierung in Bezug auf Trauma für die kindliche Bindung. 抄録：親から子どもへの愛着の世代間伝達についての私たちの知識には、とくに、子ども時代の虐待とネグレクト（CA&N）の歴史のある母親においては、まだ重要なギャップがある。この研究では、全般的な愛着関係に関するリフレクティブな機能（RF-G）と、特にトラウマに関するリフレクティブな機能（RF-T）、および母親の愛着の心的状態が、乳児の愛着の解体infant attachment disorganizationの予測に寄与するかを、CA&Nの母親とその乳児を対象に、20か月のフォローアップデザインを用いて調査した。愛着とリフレクティブな機能は、妊娠中にAdult Attachment Interviewで評価された。乳児の愛着は、Strange Situation Procedureで評価された。虐待されネグレクトされた母親の乳児の大多数（83%）は不安定な愛着に分類され、有意な割合（44%）が愛着の解体を表した。母親と子どもの愛着の間には、強い一致concordanceがあった。これは、CA&Nの母親とその乳児における愛着の世代間伝達を示していた。未解決のトラウマと、トラウマに特異的なリフレクティブな機能の両者が、乳児の愛着の解体の分散の説明に、有意に寄与していた。この研究の所見は、子ども時代の虐待の歴史がある母親において、トラウマに特異的なメンタライゼーションが、愛着の世代間伝達に重要であることを強調し、トラウマに関するメンタライゼーションの欠如が、乳児の愛着に重要であることの新たなエビデンスを提供する。 母親和孩子依附關係的代際傳遞，特別是在童年時被虐待和忽視（CA＆N）的母親當中,我們仍然有重要的知識差距。本研究分析關於一般的依附關係（RF-G），特別涉及創傷（RF-T），以及母親依附關係心態的思考功能對預測嬰兒依附關係混亂的作用。研究採用一個CA＆N母親和嬰兒的樣本和20個月的跟進設計。“成人依附關係訪問” 用以評估母親懷孕時的依附關係和思考功能。“陌生情境程序”用以評估嬰兒依附關係。被虐待和忽視的母親所生的嬰兒大部分（83％）被列為不安全依附型，有顯著的比例（44％）表現依附關係混亂。母子依附關係有很強的一致性，表明CA＆N的母親與其嬰兒之間有依附關係的代際傳遞。懸而未決的創傷和特定創傷思考功能都對解釋嬰兒依附混亂差異有重要的貢獻。研究結果突出特定創傷心理化,在曾被虐待母親的依附關係之代際傳遞的重要性，並提供新的證據，指出有關嬰兒依附關係創傷缺乏心理化的重要性。

Microglia-neuron interactions play a crucial role in several neurological disorders characterized by altered neural network excitability, such as epilepsy and neuropathic pain. While a series of potential messengers have been postulated as substrates of the communication between microglia and neurons, including cytokines, purines, prostaglandins, and nitric oxide, the specific links between messengers, microglia, neuronal networks, and diseases have remained elusive. Brain-derived neurotrophic factor (BDNF) released by microglia emerges as an exception in this riddle. Here, we review the current knowledge on the role played by microglial BDNF in controlling neuronal excitability by causing disinhibition. The efforts made by different laboratories during the last decade have collectively provided a robust mechanistic paradigm which elucidates the mechanisms involved in the synthesis and release of BDNF from microglia, the downstream TrkB-mediated signals in neurons, and the biophysical mechanism by which disinhibition occurs, via the downregulation of the K⁺-Cl⁻ cotransporter KCC2, dysrupting Cl⁻ homeostasis, and hence the strength of GABA(A)- and glycine receptor-mediated inhibition. The resulting altered network activity appears to explain several features of the associated pathologies. Targeting the molecular players involved in this canonical signaling pathway may lead to novel therapeutic approach for ameliorating a wide array of neural dysfunctions.

BACKGROUND: The availability of less resource-intensive alternatives to home visits for rehabilitation following orthopaedic surgeries is important, given the increasing need for home care services and the shortage of health resources. The goal of this trial was to determine whether an in-home telerehabilitation program is not clinically inferior to a face-to-face home visit approach (standard care) after hospital discharge of patients following a total knee arthroplasty. METHODS: Two hundred and five patients who had a total knee arthroplasty were randomized before hospital discharge to the telerehabilitation group or the face-to-face home visit group. Both groups received the same rehabilitation intervention for two months after hospital discharge. Patients were evaluated at baseline (before total knee arthroplasty), immediately after the rehabilitation intervention (two months after discharge), and two months later (four months after discharge). The primary outcome measure was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire at the last follow-up evaluation. Secondary outcome measures included the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire, functional and strength tests, and knee range of motion. The noninferiority margin was set at 9% for the WOMAC. RESULTS: The demographic and clinical characteristics of the two groups of patients were similar at baseline. At the last follow-up evaluation, the mean differences between the groups with regard to the WOMAC gains, adjusted for baseline values, were near zero (for 182 patients in the per-protocol analysis): -1.6% (95% confidence interval [CI]: -5.6%, 2.3%) for the total score, -1.6% (95% CI: -5.9%, 2.8%) for pain, -0.7% (95% CI: -6.8%, 5.4%) for stiffness, and -1.8% (95% CI: -5.9%, 2.3%) for function. The confidence intervals were all within the predetermined zone of noninferiority. The secondary outcomes had similar results, as did the intention-to-treat analysis, which was conducted afterward for 198 patients. CONCLUSIONS: Our results demonstrated the noninferiority of in-home telerehabilitation and support its use as an effective alternative to face-to-face service delivery after hospital discharge of patients following a total knee arthroplasty. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

The chemokine receptor CXCR4 is a widely expressed G protein-coupled receptor that has been implicated in a number of diseases including human immunodeficiency virus, cancer, and WHIM syndrome, with the latter two involving dysregulation of CXCR4 signaling. To better understand the role of phosphorylation in regulating CXCR4 signaling, tandem mass spectrometry and phospho-specific antibodies were used to identify sites of agonist-promoted phosphorylation. These studies demonstrated that Ser-321, Ser-324, Ser-325, Ser-330, Ser-339, and two sites between Ser-346 and Ser-352 were phosphorylated in HEK293 cells. We show that Ser-324/5 was rapidly phosphorylated by protein kinase C and G protein-coupled receptor kinase 6 (GRK6) upon CXCL12 treatment, whereas Ser-339 was specifically and rapidly phosphorylated by GRK6. Ser-330 was also phosphorylated by GRK6, albeit with slower kinetics. Similar results were observed in human astroglia cells, where endogenous CXCR4 was rapidly phosphorylated on Ser-324/5 by protein kinase C after CXCL12 treatment, whereas Ser-330 was slowly phosphorylated. Analysis of CXCR4 signaling in HEK293 cells revealed that calcium mobilization was primarily negatively regulated by GRK2, GRK6, and arrestin3, whereas GRK3, GRK6, and arrestin2 played a primary role in positively regulating ERK1/2 activation. In contrast, GRK2 appeared to play a negative role in ERK1/2 activation. Finally, we show that arrestin association with CXCR4 is primarily driven by the phosphorylation of far C-terminal residues on the receptor. These studies reveal that site-specific phosphorylation of CXCR4 is dynamically regulated by multiple kinases resulting in both positive and negative modulation of CXCR4 signaling.

mutation, suggesting that Src/c-Abl may be a potentially useful target for developing new drugs to treat ALS.

BACKGROUND: Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of the underlying pathophysiology is needed to improve treatment options. We did a meta-analysis of genome-wide association studies (GWASs) to identify potential molecular targets. METHODS: ) were tested for replication in an independent GWAS of 30 770 cases and 286 913 controls, followed by a joint analysis of the discovery and replication stages. We did gene annotation, pathway, and gene-set-enrichment analyses and studied the genetic correlations between restless legs syndrome and traits of interest. FINDINGS: We identified and replicated 13 new risk loci for restless legs syndrome and confirmed the previously identified six risk loci. MEIS1 was confirmed as the strongest genetic risk factor for restless legs syndrome (odds ratio 1·92, 95% CI 1·85-1·99). Gene prioritisation, enrichment, and genetic correlation analyses showed that identified pathways were related to neurodevelopment and highlighted genes linked to axon guidance (associated with SEMA6D), synapse formation (NTNG1), and neuronal specification (HOXB cluster family and MYT1). INTERPRETATION: Identification of new candidate genes and associated pathways will inform future functional research. Advances in understanding of the molecular mechanisms that underlie restless legs syndrome could lead to new treatment options. We focused on common variants; thus, additional studies are needed to dissect the roles of rare and structural variations. FUNDING: Deutsche Forschungsgemeinschaft, Helmholtz Zentrum München-Deutsches Forschungszentrum für Gesundheit und Umwelt, National Research Institutions, NHS Blood and Transplant, National Institute for Health Research, British Heart Foundation, European Commission, European Research Council, National Institutes of Health, National Institute of Neurological Disorders and Stroke, NIH Research Cambridge Biomedical Research Centre, and UK Medical Research Council.

Disruption of the blood-brain and blood-spinal cord barriers (BBB and BSCB, respectively) and immune cell infiltration are early pathophysiological hallmarks of multiple sclerosis (MS), its animal model experimental autoimmune encephalomyelitis (EAE), and neuromyelitis optica (NMO). However, their contribution to disease initiation and development remains unclear. In this study, we induced EAE in lys-eGFP-ki mice and performed single, nonterminal intravital imaging to investigate BSCB permeability simultaneously with the kinetics of GFP(+) myeloid cell infiltration. We observed a loss in BSCB integrity within a day of disease onset, which paralleled the infiltration of GFP(+) cells into the CNS and lasted for ∼4 d. Neutrophils accounted for a significant proportion of the circulating and CNS-infiltrating myeloid cells during the preclinical phase of EAE, and their depletion delayed the onset and reduced the severity of EAE while maintaining BSCB integrity. We also show that neutrophils collected from the blood or bone marrow of EAE mice transmigrate more efficiently than do neutrophils of naive animals in a BBB cell culture model. Moreover, using intravital videomicroscopy, we demonstrate that the IL-1R type 1 governs the firm adhesion of neutrophils to the inflamed spinal cord vasculature. Finally, immunostaining of postmortem CNS material obtained from an acutely ill multiple sclerosis patient and two neuromyelitis optica patients revealed instances of infiltrated neutrophils associated with regions of BBB or BSCB leakage. Taken together, our data provide evidence that neutrophils are involved in the initial events that take place during EAE and that they are intimately linked with the status of the BBB/BSCB.

The level of prediction error in the brain age estimation frameworks is associated with the authenticity of statistical inference on the basis of regression models. In this paper, we present an efficacious and plain bias-adjustment scheme using chronological age as a covariate through the training set for downgrading the prediction bias in a Brain-age estimation framework. We applied proposed bias-adjustment scheme coupled by a machine learning-based brain age framework on a large set of metabolic brain features acquired from 675 cognitively unimpaired adults through fluorodeoxyglucose positron emission tomography data as the training set to build a robust Brain-age estimation framework. Then, we tested the reliability of proposed bias-adjustment scheme on 75 cognitively unimpaired adults, 561 mild cognitive impairment patients as well as 362 Alzheimer's disease patients as independent test sets. Using the proposed method, we gained a strong R2 of 0.81 between the chronological age and brain estimated age, as well as an excellent mean absolute error of 2.66 years on 75 cognitively unimpaired adults as an independent set; whereas an R2 of 0.24 and a mean absolute error of 4.71 years was achieved without bias-adjustment. The simulation results demonstrated that the proposed bias-adjustment scheme has a strong capability to diminish prediction error in brain age estimation frameworks for clinical settings.

BACKGROUND: Cocaine use disorder is associated with cognitive deficits. However, the literature remains somewhat ambiguous with respect to which distinct cognitive functions are the most impaired in cocaine use disorder and to how duration of abstinence affects cognitive recovery. Here, we performed a meta-analysis to determine the cognitive domains impaired in cocaine abuse/dependence and the duration of abstinence necessary to achieve cognitive recovery. METHODS: A literature search yielded 46 studies that assessed cognitive dysfunction in subjects with cocaine abuse/dependence. Effect-size estimates were calculated using the Comprehensive Meta-Analysis V2, for the following 11 cognitive domains: attention, executive functions, impulsivity, speed of processing, verbal fluency/language, verbal learning and memory, visual learning and memory, visuospatial abilities, and working memory. Within these 11 domains, effect-size estimates were calculated on the basis of abstinence duration: short- (positive for drugs urine screening), intermediate- (≤12 weeks), and long-term (≥20 weeks) abstinence. RESULTS: Findings revealed moderate impairment across 8 cognitive domains during intermediate abstinence. The most impaired domains were attention, impulsivity, verbal learning/memory, and working memory. For some domains (attention, speed of processing, and verbal learning/memory), impairments were smaller during short-term abstinence than during intermediate abstinence. Finally, small effect-size estimates were found for long-term abstinence. DISCUSSION: These results suggest significant impairment across multiple cognitive domains in cocaine abusers, and that some of these deficits may be partially masked by the residual or acute withdrawal effects of cocaine. Cognitive dysfunctions remain stable during the first months of abstinence and may abate after 5 months of sobriety.

Importance: Insomnia is a significant public health problem, but there is little information on its natural history. Objective: To assess the incidence, persistence, and remission rates of insomnia over a 5-year naturalistic follow-up period. Design, Setting, and Participants: This cohort study included participants with and without sleep problems selected from the adult population in Canada from August 2007 to June 2014. Participants completed an annual survey about their sleep and health status for 5 consecutive years. Exposure: Using validated algorithms, participants were classified at each assessment as being good sleepers (n = 1717), having an insomnia disorder (n = 538), or having subsyndromal insomnia (n = 818). Main Outcomes and Measures: Survival analyses were used to derive incidence rates of new insomnia among the subgroup of good sleepers at baseline and persistence and remission rates among those with insomnia at baseline. Sleep trajectories were examined by looking at year-person transitions between each consecutive year summed over the 5-year follow-up period. All inferential analyses were weighted according to normalized sampling weights. Results: The sample included 3073 adults (mean [SD] age, 48.1 [15.0] years; range, 18.0-95.0 years; 1910 [62.2%] female). Overall, 13.9% (95% CI, 11.0%-17. 5%) of initial good sleepers developed an insomnia syndrome during the 5-year follow-up period, and incidence rates were higher among women than among men (17.6% [95% CI, 13.6%-22.7%] vs 10.1% [95% CI, 6.6%-15.3%; χ2 = 4.43; P = .03). A total of 37.5% (95% CI, 32.6%-42.5%) of participants with insomnia at baseline reported insomnia persisting at each of the 5 annual follow-up times. For subsyndromal insomnia, rates were 62.5% at 1 year to 26.5% at 5 years. For syndromal insomnia, rates were 86.0% at 1 year to 59.1% at 5 years. Conversely, remission rates among those with subsyndromal insomnia were almost double the rates among those with an insomnia syndrome at 1 year (37.5% [95% CI, 31.7%-44.0%] vs 14.0% [95% CI, 9.3%-20.8%]), 3 years (62.7% [95% CI, 56.7%-68.7%] vs 27.6% [95% CI, 20.9%-35.9%]), and 5 years (73.6% [95% CI, 68.0%-78.9%%] vs 40.9% [95% CI, 32.7%-50.4%]). Yearly trajectories showed that individuals who were good sleepers at baseline were 4.2 (95% CI, 3.51-4.89) times more likely to stay good sleepers in the subsequent year, but once they developed insomnia, they were equally likely to report symptoms (47% probability) than to return to a good sleeper status (53% probability) 1 year later. Similarly, those with an insomnia syndrome at any given assessment were more likely (adjusted odds ratio, 1.60; 95% CI, 1.19-2.60) to remain in that status (persistence) than to improve (remittance) at the next assessment; even among those who improved, the odds of relapse were greater (adjusted odds ratio, 2.04; 95% CI, 1.23-3.37) than those to improve in the following year. Conclusions and Relevance: The findings suggest that insomnia is often a persistent condition. Considering the long-term adverse outcomes associated with persistent insomnia, these findings may have important implication for the prognosis and management of insomnia.

Even after several decades of quiescent storage in the ovary, the female germ cell is capable of reinitiating transcription to build the reserves that are essential to support early embryonic development. In the current model of mammalian oogenesis, there exists bilateral communication between the gamete and the surrounding cells that is limited to paracrine signaling and direct transfer of small molecules via gap junctions existing at the end of the somatic cells' projections that are in contact with the oolemma. The purpose of this work was to explore the role of cumulus cell projections as a means of conductance of large molecules, including RNA, to the mammalian oocyte. By studying nascent RNA with confocal and transmission electron microscopy in combination with transcript detection, we show that the somatic cells surrounding the fully grown bovine oocyte contribute to the maternal reserves by actively transferring large cargo, including mRNA and long noncoding RNA. This occurrence was further demonstrated by the reconstruction of cumulus-oocyte complexes with transfected cumulus cells transferring a synthetic transcript. We propose selective transfer of transcripts occurs, the delivery of which is supported by a remarkable synapselike vesicular trafficking connection between the cumulus cells and the gamete. This unexpected exogenous contribution to the maternal stores offers a new perspective on the determinants of female fertility.