The Douglas Mental Health University Institute (French: Institut universitaire en santé mentale Douglas; formerly the Douglas Hospital and originally the Protestant Hospital for the Insane) is a Canadian psychiatric hospital located in the borough of Verdun in the city of Montreal, Quebec. It is also a teaching hospital affiliated with McGill University. The nearest Montreal Metro station is Monk.
Until the discovery of white matter neurons (WMN) in the 19th century, white matter (WM) was considered to be completely devoid of neuronal cell bodies. Despite evidence consistently showing neuronal soma within cortical WM and their purported implication in neuropsychiatric disorders, these neurons are understudied and have not been characterized in human long-range WM tracts. Using postmortem human brain tissue, we investigated the presence, densities and proportions of excitatory/inhibitory neurons in the uncinate fasciculus (UF) and corpus callosum (CC). We also investigated the ventromedial prefrontal cortex (vmPFC) to validate our methods by comparing our results with previously reported densities of neurons in cortical WM. To identify WMN, we employed fluorescence in situ hybridization with excitatory (SLC17A7) and inhibitory (GAD1) neuronal markers and subsequently validated these neurons at the protein level with NeuN immunohistochemistry. We found that the density of WMN in the vmPFC corresponded with previous independent estimates. The UF displayed a similar, though slightly lower density of WMN compared to the vmPFC, while the CC had a far lower density of WMN than both of these regions. Due to the higher-than-expected density of WMN in the UF, we validated the findings at a second location along the UF temporal segment and confirmed the presence of substantial numbers of WMN in this tract. This research constitutes the first ever validated observation of WMN in human long-range WM tracts, laying the foundation for future research on the phenotype and function of these neurons, and how they may be affected in brain disorders.
OBJECTIVES:This World Federation of Societies of Biological Psychiatry (WFSBP) consensus paper aims to summarise and evaluate the published study results on objectively measurable biological markers associated with anorexia nervosa (AN). METHODS:The relevant literature was reviewed by the WFSBP Task Forces on Eating Disorders and on Biological Markers, and a consensus regarding the significance of the published evidence was reached. RESULTS:Candidate biological markers that have been associated with AN include clinical (e.g. body weight), molecular (e.g. genetic, epigenetic, hormonal, immunological, metabolomic), cellular (e.g. leukocytes), neuroimaging (e.g. structure, function, connectivity), digital, cardiac and neurophysiological parameters. Some clinical and laboratory parameters are risk markers in clinical practice. Biological markers have pathophysiological relevance in understanding the biological and metabolic pathophysiology of AN and its physical health consequences. Few studies have examined pharmacogenetics or therapeutic drug monitoring as tools to monitor and guide the treatment of AN. CONCLUSIONS:Biological markers will hopefully soon enable clinicians to intervene earlier in a more targeted manner to mitigate treatment resistance. However, the current scientific basis for most biological markers are group comparisons only. Studies on sensitivity, specificity and the prognostic value of these markers are lacking.
Pragmatic language impairments—difficulties using language effectively in social contexts—are common in adults suffering from severe mental illnesses (SMIs) such as schizophrenia spectrum disorders (SSD), major depressive disorder (MDD), and bipolar disorder (BD). These impairments hinder social functioning and recovery but have been explored most widely using comprehension tasks, with pragmatic production being poorly described. We undertook a systematic review and meta-analysis of studies assessing expressive pragmatic language in adults with SMIs versus healthy controls. 18 items were tested, including Coherence, Cohesion, Gricean maxims, figurative language, Prosody, and Turn-Taking. The searches were PRISMA-compliant and were conducted in PubMed and Scopus. 51 studies were included; 28 were meta-analyzed. Results showed significant impairments in Cooperativity, Anaphora and Cohesion, moderate impairments in Coherence, and low impairments in Metaphor. No significant moderator was detected. Our results emphasize the need for standardized pragmatic testing and intervention for language production in clinical settings.
White matter hyperintensities (WMHs) are neuroimaging markers widely interpreted as caused by cerebral small vessel disease, yet emerging evidence suggests that a subset may have a neurodegenerative etiology. Current imaging methods have lacked the specificity to disentangle biological processes underlying WMHs in vivo. Here, we used voxel-level normative modeling and seven microstructural MRI markers with complementary biophysical sensitivities to generate single-subject high-resolution WMH pathophysiology maps in a large cohort (n=32,526). We calculated data-driven spatial patterns of similar WMHs, revealing distinct periventricular, posterior, and anterior clusters. We identified a reproducible WMH signature linked to dementia and Alzheimer's disease, characterized by a posterior predominance and a pathophysiological pattern indicative of selective fiber degeneration. Posterior WMHs connected cortical regions vulnerable to tau pathology. Our framework distinguishes vascular and neurodegenerative contributions of WMHs in vivo, which could alter the course of treatment strategies and provide nuanced interpretations of research findings.
BACKGROUND:Major depressive disorder (MDD) is a debilitating condition that is commonly treated with antidepressants. However, many people do not respond to treatment, and the molecular mechanisms underlying antidepressant response remain poorly understood. Baseline DNA methylation differences have been observed between individuals who respond to treatment compared to those who do not respond; however, little is known regarding DNA methylation changes that occur during treatment or how they may relate to clinical response. METHODS:We assessed peripheral levels of DNA methylation and gene expression at baseline and after 8 weeks of treatment in 154 individuals with MDD who were treated with escitalopram or desvenlafaxine, using the Infinium MethylationEPIC Beadchip and RNA sequencing. We identified methylation sites whose levels changed over time in relation to changes in depressive symptoms, as well as corresponding changes to gene expression levels after 8 weeks of treatment. RESULTS:We identified 2 sites, in sodium voltage-gated channel alpha subunit 7 and IQ Motif and ankyrin repeat containing 1, whose methylation changes over time were correlated with changes in depressive symptoms at the epigenome-wide level. Gene ontology analyses of genes displaying response-related methylation changes highlighted several processes previously implicated in depression, including small GTPase-related signaling and the Wnt signaling pathway. Additionally, we identified methylation sites in 10 genes that displayed significant changes in methylation over time in relation to improvement of depressive symptoms, whose expression levels at week 8 were correlated with the level of depressive symptoms, and for which methylation levels were functionally related to gene expression. CONCLUSIONS:Antidepressant treatment response is associated with changes in peripheral DNA methylation over time, as well as corresponding alterations in gene expression. Significance Statement Major depressive disorder (MDD) is commonly treated with antidepressants; however, many people do not respond to treatment. In order to better understand the molecular changes that occur during antidepressant treatment, we analyzed DNA methylation and gene expression in the blood of 154 individuals with MDD who were treated with escitalopram or desvenlafaxine. We found 10 methylation sites within 10 genes whose methylation levels changed over time in relation to clinical improvement, and whose levels of expression were related to both methylation and antidepressant response.
