Check out some of the papers that were recently published by DMCBH members:
Lakshmi Yatham, Trisha Chakrabarty, Kamyar Keramatian: Duration of untreated or undiagnosed bipolar disorder and clinical characteristics and outcomes: systematic review and meta-analysis
Journal: The British journal of psychiatry: the journal of mental science
Despite its high prevalence and large disability burden, bipolar disorder often goes unrecognized and therefore untreated for several years. The duration of undiagnosed or untreated bipolar disorder (DUBD) is a rising research interest. This systematic review and meta-analysis found that the pooled mean DUBD across all studies was 9.10 years. Early onset, depression as the first mood episode, lifetime suicide attempts, comorbid anxiety and alcohol use disorders and family history of bipolar disorder were associated with significantly longer DUBD, whereas diagnosis of bipolar I disorder and lifetime psychotic symptoms were associated with shorter DUBD. DUBD may be associated with certain adverse outcomes. It’s important to adopt a more comprehensive approach to assessing mood disorders, with an emphasis on prioritising early screening for bipolar disorder.
Lakshmi Yatham, Kamyar Keramatian: Early Psychoeducational Intervention for Youth and Young Adults at Risk for Bipolar Disorder: A Feasibility Study: Intervention psychoéducative précoce pour les adolescents et les jeunes adultes à risque de trouble bipolaire : Une étude de faisabilité
Journal: The Canadian journal of psychiatry
Bipolar disorder (BD) often goes unrecognized and untreated for several years, leading to serious consequences. Researchers recently developed a manualized telehealth-based group psychoeducational and resilience enhancement program for individuals at high risk for bipolar disorder (PREP-BD). This study assessed the feasibility of implementing PREP-BD to enhance help-seeking intentions among high-risk individuals. Findings indicated excellent feasibility as shown by timely recruitment, 100% sign-up rate, and 76.19% completion rate (defined as attending at least 75% of group sessions). The intervention showed preliminary improvements in help-seeking intentions, particularly for a hypomanic scenario. Quality of life also demonstrated significant improvement, while resilience and self-stigma showed non-significant trends toward improvement. These results suggested the feasibility of implementing psychoeducation as an early identification strategy in individuals at risk for BD.
Helen Tremlett: Health Care Use Before Multiple Sclerosis Symptom Onset
Journal: JAMA Network Open
This study aimed to determine the patterns in health care use 25 years before the clinical onset of multiple sclerosis (MS). In this cohort study of 2038 patients with MS and a matched cohort of 10 182 individuals without MS, all-cause physician visits were elevated 14 years before MS onset. Mental health–related visits and visits for ill-defined symptoms and signs were elevated 14 to 15 years before MS onset, followed by neurology and ophthalmology consultations (8-9 years before onset) and musculoskeletal, sensory, and nervous system visits (4-8 years before onset). These findings suggested that MS may begin much earlier than previously recognized, with mental health–related issues as early indicators, highlighting opportunities for earlier identification and intervention.
Teresa Liu-Ambrose: 24-hour activity cycle behaviors and gray matter volume in mild cognitive impairment
Journal: Alzheimer’s & Dementia
The 24-hour activity cycle (24-HAC) includes physical activity, sedentary behavior, and sleep. The 24-HAC composition and brain health relationship in adults with mild cognitive impairment remains underexplored. Researchers examined associations between 24-HAC composition and gray matter volume. Higher moderate-to-vigorous physical activity relative to remaining behaviors was associated with greater right inferior temporal gyrus volume. Higher sedentary behaviour relative to remaining behaviors was associated with lower volume in the same region. Reallocating 30 min from sedentary behaviour to the physical activity predicted 2.1% greater volume, while the opposite predicted 2.8% lower volume. Increasing moderate-to-vigorous physical activity at the expense of sedentary behaviour may protect gray matter in regions prone to Alzheimer’s disease-related atrophy.
Journal: American Journal of medical genetics
Neurodevelopmental disorder-risk copy number variations (NDD CNVs) are genes associated with complex neuropsychiatric phenotypes. These CNVs additionally confer risk to different medical outcomes in adults, but the long-term health consequences in the context of comorbid psychiatric illness have not been well documented. Twenty-four psychiatric inpatients with treatment-resistant psychosis were identified as carriers of NDD CNVs. Phenotypes examined across the cohort indicated comorbid medical manifestations across multiple organ systems. Cardiovascular disorders were present in 96% of patients and motor disorders in 92%. All patients had multiple organ system involvement, and most organ systems (12/17 systems) were affected in 50% or more of patients, culminating in a high degree of individual-level multimorbidity.
Robert Stowe: Delineating lifetime multimorbidity associated with 16p13.11 duplication: A literature review, meta-analysis, and case study
Journal: Progress in Neuro-Psychopharmacology and Biological Psychiatry
The 16p13.11 duplication is a rare copy number variation (CNV) that appears to increase risk for multimorbidity across the life span. Initial reports implicated the duplication in autism spectrum disorder, intellectual disability, and various congenital anomalies; however, it was also observed in “phenotypically normal” individuals suggesting incomplete penetrance or non-pathogenicity. Recent studies suggest that duplication carriers often present with multimorbidity, but more data are needed to clarify the full range of associated phenotypes. Lifetime multimorbidity remains unclear, and no reviews summarizing this literature currently exist. Researchers reported a systematic literature review and meta-analysis of published phenotypic characteristics. Speech delays, developmental delays, intellectual disability, learning disability, and autistic symptoms were reported in >30 % of cases. Musculoskeletal abnormalities and cardiovascular disorders were commonly reported. Included is a lifespan case report of a 71-year-old female with a history of behavioral disturbance and treatment-resistant schizophrenia, identified as being a 16p13.11 duplication carrier.
Haakon Nygaard: Geometrical constraints dictate assembly and phenotype of human iPSC-derived motoneuronal spheroids
Journal: Stem cell research & therapy
Neuronal spheroids represent an easy and versatile solution to model neuronal tissue in vitro. However, conventional approaches to generate spheroids lack accurate size control, scalability, and customizability. This is even more exacerbated in case of pluripotent stem cell (PSC) derived spheroids, which remain challenging to standardize. Microwell devices address these limitations, providing an optimal balance between accessibility and scalability. With the aim of optimizing culture conditions, researchers parametrically investigated the role of microwell geometry on the formation and maturation of iPSC-derived motor neuron precursor (MNP) spheroids. Results indicated that spheroid size is significantly influenced by the microwell geometry, reliably due to cell partitioning at the seeding stage. Expression of proliferation and differentiation markers, such as motor neuron and pancreas homeobox 1 and Islet-1 transcription factors, is also dependent on microwell geometry and spheroid morphological descriptors.
Khaled Abdelrahman: Breaking free from opioids: A turning point in acute pain management
Journal: The Journal of Pharmacology and Experimental Therapeutics
Pain management is one of the most pressing challenges in modern medicine, impacting millions of lives worldwide. Although opioids remain a cornerstone for managing pain, broad use may contribute to the broader crisis of addiction, overdose, and misuse. As such, it’s important to develop safer and more efficacious alternatives. In January 2025, the FDA approval of suzetrigine, which targets sodium channels, marked a shift towards the development of other analgesics, underscoring the importance of a multidisciplinary approach that integrates basic pain research, pharmacology, and drug development. The FDA approval of this new class of analgesics highlights the enthusiasm and support for alternative analgesic targets. This editorial described the history of sodium channels in analgesic development and outlined future considerations.
Sarah Kraeutner, Lara Boyd: Females versus males exhibit greater brain activation in sensorimotor regions during motor imagery after stroke
Journal: Neuroscience
Motor imagery (MI) activates sensorimotor regions in the brain, providing the basis for its effectiveness as an intervention for motor recovery after stroke. However, the impact of biological sex on MI-related brain activation is unexplored. This study investigated sex-related differences in MI-related brain activation after store, and explored associations between questionnaire-based MI ability and actual brain activation. Brain activation was captured using functional magnetic resonance imaging (fMRI). MI-related brain activation was observed across sensorimotor regions. Yet, group-level contrasts revealed greater activation in sensorimotor regions for females vs. males, while greater activation in the cerebellar and parietal regions was noted in males vs. females. Females also recruited greater ipsilesional regions vs. males. Questionnaire-based MI ability was associated with brain activation localized to occipital regions. Findings suggested that females and males may respond differently to MI-based tasks. Further, researchers did not find a relationship between questionnaire-based data and activity in sensorimotor regions. Therefore, multiple measures of MI may be needed to assess its impact. Overall, this work informs the use of MI after stroke.
Sarah Kraeutner: Motor imagery improves force control in older and young females
Journal: Brain research
Motor imagery training (MIT) is the mental rehearsal of a motor task with no overt movement that enhances physical performance through adaptations in neural excitability. In older adults, with physical practice, force steadiness improves and changes are related to improved performance of functional tasks, and associated with adaptations in neural excitability. The purpose of this study was to determine if one session of MIT influences corticospinal excitability and improves force steadiness of isometric elbow flexion contractions in young and older female adults. Researchers found that in older females, MIT primes the motor system and improves force steadiness earlier and to a greater extent than in young females.
Mahmoud Pouladi: The role of oligodendroglial dysfunction in Huntington’s disease
Journal: Journal of Huntington’s disease
Huntington’s disease (HD) is a fatal neurodegenerative disorder characterized by progressive motor, cognitive, and psychiatric symptoms. This review synthesized recent findings on oligodendroglial dysfunction in HD, showing that white matter abnormalities arise early in disease progression, often preceding gray matter changes and clinical symptoms. Recognizing the role of these mechanisms provides potential biomarkers for early detection and therapeutic targets aimed at preserving both neuronal and glial function in HD.
Freda Miller, Brian MacVicar, David Kaplan: Single cell approaches define the murine leptomeninges: cortical brain interface as a distinct cellular neighborhood comprised of neural and nonneural cell types
Journal: eNeuro
The interface barrier between the brain surface and the adjacent meninges is important for regulating exchanges of fluid, protein, and immune cells between the CNS and periphery. However, the cell types that form this important interface are not yet fully defined. To address this limitation, researchers used single-cell RNA sequencing and single-cell spatial transcriptomics together with morphological lineage tracing and immunostaining to describe the cell types forming the interface barrier of the adult murine cortex. Researchers show that the cortical interface is composed of three major cell types, leptomeningeal cells, border astrocytes, and tissue-resident macrophages. Their data provide a molecular/cellular resource describing the brain interface cell types and their interactions, thereby enabling future studies investigating how this distinct cellular compartment regulates CNS:periphery interactions.
Helen Tremlett: Access to therapy for children and adolescents with multiple sclerosis: global considerations in preventing disease progression
Journal: The Lancet: Child and Adolescent health
Paediatric-onset multiple sclerosis comprises approximately 1·5% of prevalent multiple sclerosis cases and is associated with higher disease burden, early and progressive motor and cognitive disability in young adulthood, and high levels of depression and fatigue. Observational data and randomised controlled trials have shown marked effects of multiple sclerosis disease-modifying therapies on MRI activity and long-term outcomes, including disease progression, in the paediatric population. Researchers present a comprehensive review of published literature focused on issues of access to therapy in children and adolescents with paediatric-onset multiple sclerosis. In this Review, researchers identify regional variability in availability of multiple sclerosis therapies and examine issues, such as differences in access to care and time to diagnosis, criteria for regulatory approval, availability of insurance, and government supports. Finally, they outline specific future directions that should be taken to address these barriers and ensure better and equal therapy access for all children and adolescents with multiple sclerosis.
Mahmoud Pouladi: Special issue: Glia and non-neuronal cells in Huntington’s disease
Journal: Journal of Huntington’s disease
Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin gene. While much of the foundational research in HD has focused on medium spiny neurons in the striatum of the basal ganglia and neuronal mechanisms, there is growing recognition that non-neuronal cell types, including astrocytes, microglia, and oligodendrocytes, play critical roles in disease pathogenesis. This special issue of the Journal of Huntington’s Disease compiles a set of expert reviews that synthesize emerging insights into how glial and other non-neuronal cells shape HD pathology as well as novel possibilities for therapeutic intervention.
Teresa Liu-Ambrose: Running ahead of the evidence: The need for research on exercise and brain health in perimenopause
Journal: Maturitas
Women make up roughly two-thirds of all Alzheimer’s disease cases, and this disparity is not explained by longevity alone. The menopause transition, or perimenopause, is increasingly recognized as a time of vulnerability for the brain, potentially contributing to women’s elevated lifetime risk of dementia. Exercise is widely promoted as a protective strategy for brain health, especially during midlife, yet there is currently no randomized controlled trial evidence to support its benefits for cognition or brain outcomes in perimenopausal women. This absence of rigorous research underscores a major gap in the field. Establishing whether exercise can mitigate perimenopause-related brain changes is an urgent priority that could inform both prevention strategies and clinical guidelines for women’s brain health.
Robin Hsiung: High inter-rater reliability in consensus diagnoses and overall assessment in the Asian Cohort for Alzheimer’s Disease Study
Journal: NPJ Dementia
The Asian Cohort for Alzheimer’s Disease (ACAD) study is a collaborative investigation of genetic and non-genetic risk factors for AD among Asian Americans and Canadians. Harmonization of diagnostic procedures across recruiting sites will be key to the dataset’s efficacy. Forty-two participants who completed the consensus process across seven ACAD recruiting sites were re-reviewed by two further impartial raters. Cohen’s Kappa coefficient was used to evaluate inter-rater agreement. The findings reveal the highest level of observed agreement at 88% and a Cohen’s Kappa of 0.835, among site consensus participants and two levels of external review, affirming the reliability of our protocol. ACAD has developed a data collection and diagnostic process that allows consistency among sites that serve Asians speaking Korean, Chinese, and Vietnamese languages.
Joanne Matsubara: Potential roles of extracellular granzyme B in corneal and conjunctival diseases: A narrative review
Journal: Experimental eye research
The cornea and conjunctiva are vulnerable to a variety of inflammatory diseases that collectively impaired vision for millions of people worldwide. Despite their prevalence, the complex biology of these conditions made them difficult to treat effectively. Researchers found that Granzyme B (GrB), a serine protease traditionally recognized for killing infected or cancerous cells, also played extracellular roles that contributed to inflammation, tissue remodeling, barrier dysfunction, fibrosis, and cell death. Elevated levels of GrB were reported in several ocular surface disorders, including herpes simplex keratitis, corneal graft rejection, Stevens-Johnson syndrome, pterygium, and keratoconus. This review highlighted how GrB may drive disease mechanisms on the ocular surface by integrating ocular findings with systemic research. Understanding these pathways could inform new therapeutic strategies targeting GrB in corneal and conjunctival disease.
Janet Werker, Lara Boyd, Sarah Kraeutner: Examining the influence of musical sophistication, cognitive performance, and social skills on the Brain Age Gap Estimate (BrainAGE)
Journal: Brain structure and function
Brain age, a measure of biological brain aging derived from neuroimaging, has been linked to cognition and related factors. Researchers investigated how cognitive ability, musical sophistication, and social skills influenced Brain Age Gap Estimate (BrainAGE) in 81 healthy participants who underwent high-resolution MRI and completed assessments of cognition, music, and social skills. Using structural equation modeling, they examined cognitive ability via the Delis–Kaplan Executive Function System, California Verbal Learning Test, and Wechsler Adult Intelligence Scale; musical sophistication using the Goldsmiths Musical Sophistication Index; and social skills with the Social Skills Inventory. The study found that none of these factors significantly predicted BrainAGE. These results highlighted the complexity of cognitive and social influences on brain aging and emphasized the need for further research into their interactive effects on neurobiological aging.
Ian Mackenzie: Brain transcriptomics highlight abundant gene expression and splicing alterations in non-neuronal cells in aFTLD-U
Journal: Acta Pathologica
Atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U) is a rare form of FTLD characterized by FET protein inclusions, but its underlying biology has remained poorly understood. Researchers performed bulk RNA sequencing on frontal cortex tissue from 21 aFTLD-U patients and 20 controls to examine transcriptomic changes. They found a loss of excitatory neurons and an increased proportion of astrocytes in aFTLD-U brains. Differential gene expression and co-expression network analyses revealed dysregulation of mitochondrial pathways, transcriptional regulators, and upregulation of Sonic hedgehog (Shh) signaling, including the GLI1 transcription factor. Splicing analysis showed significant alterations in oligodendrocyte-enriched genes such as myelin basic protein, and immunohistochemistry confirmed reduced myelin levels in aFTLD-U patients. These findings highlighted a central role for glial cells in the disease, implicating disruptions in mitochondrial function, RNA metabolism, Shh signaling, and myelination as potential mechanisms. This study provided the first transcriptomic insight into aFTLD-U and suggested new avenues for research into FTLD-FET.
Rebecca Todd: Valenced tactile information is evoked by neutral visual cues following emotional learning
Journal: Imaging Neuroscience
Researchers investigated how the brain encodes sensory and affective features of stimuli during appetitive and aversive conditioning. Using fMRI and representational similarity analysis (RSA), they examined whether conditioned stimuli (CS) reactivated neural patterns associated with unconditioned stimuli (US), such as soft touch or painful touch. The study found that, after conditioning, CS reactivated US-related patterns in high-order brain regions, including the dorsal anterior cingulate cortex. These results suggested that the brain carries forward the affective associations of experiences, highlighting how affective salience and sensory information are represented during learning. This work provided new insight into the neural mechanisms underlying appetitive and aversive conditioning.
Cheryl Wellington: The normative modelling framework for traumatic brain injury
Journal: Brain
Researchers reviewed the principles and applications of normative modelling as a tool to address longstanding challenges in traumatic brain injury (TBI) research and management. TBI affects over 50–60 million people worldwide and presents with high clinical heterogeneity due to diverse causes, injury mechanisms, and pathophysiological processes. Traditional approaches, including classification scales like the Glasgow Coma Scale and case-control study designs, often obscure individual differences by grouping patients into broad categories. Normative modelling offers a framework to assess each patient against a reference cohort, capturing individual variability and moving beyond mean-based group comparisons. The review highlighted how this approach could improve patient selection for clinical trials, enable more personalized treatment strategies, and enhance translation of research findings into clinical practice. By emphasizing individual differences rather than group averages, normative modelling promises to advance both research and care for TBI patients.
Judy Illes: Toward Prognostic Humility for Unrepresented Patients at the End of Life
Journal: The American Journal of Bioethics
Decision-making regarding the withdrawal or continuation of life-sustaining treatment (WLST) is marked by uncertainty and profound moral responsibility, especially for patients without advance directives or surrogate decision-makers. Researchers highlighted that structurally marginalized groups—including the elderly, homeless, incarcerated, cognitively disabled, mentally ill, substance-dependent, and socially isolated—are disproportionately unrepresented in these contexts. Existing ethical frameworks for WLST have limitations, and current practices may not fully capture the values, interests, and priorities of unrepresented patients. The study emphasized the importance of critically reflecting on ethical standards and adopting patient-centered approaches to ensure that WLST decisions respect individual needs and circumstances.
Alexander Rauscher: MRI R2* and quantitative susceptibility mapping in brain tissue with extreme iron overload
Journal: European radiology experimental
Researchers investigated how R2* and quantitative susceptibility mapping (QSM) perform in assessing brain iron in patients with aceruloplasminemia (ACP), a condition causing extreme iron accumulation. They compared six algorithms each for R2* and QSM in three ACP patients and three healthy controls, analyzing iron in the caudate nucleus, putamen, globus pallidus, and thalamus. Results showed that both R2* and QSM measurements varied significantly depending on algorithm choice, with R2* variability especially pronounced in the putamen. For QSM, the choice of reference region strongly influenced susceptibility values, with whole-brain referencing yielding lower values than cerebrospinal fluid referencing in ACP patients. The study highlighted that extreme iron overload amplifies measurement variability and that careful selection of algorithms and reference regions is crucial for accurate clinical interpretation. These findings suggest that QSM, when properly processed, can provide reliable brain iron maps even in cases of severe iron accumulation, whereas R2* mapping may be less robust in regions with extremely high iron content.
Thiviya Selvanathan, Steven Miller, Ruth Grunau: Association of Early-Life or Term-Equivalent White Matter Injury With Neurodevelopmental Outcomes in Very Preterm Infants
Journal: Neurology
Researchers investigated how white matter injury (WMI) severity and location on early-life versus term-equivalent age (TEA) MRI related to neurodevelopment at 36 months in very preterm infants. A total of 393 neonates underwent MRI scans and were assessed for moderate-to-severe WMI and anterior or posterior location. Neurodevelopment was evaluated using the Bayley Scales of Infant Development, Third Edition. The study found that early-life moderate-severe and anterior WMI were associated with higher odds of cognitive and motor delays at 36 months, whereas TEA MRI findings were not significantly associated with outcomes. These results suggested that MRI conducted early in life may provide a more sensitive indicator of future neurodevelopmental risk, highlighting an optimal time window for assessing WMI in very preterm infants.
Freda Miller, Brian MacVicar, David Kaplan: Single-Cell Approaches Define the Murine Leptomeninges: Cortical Brain Interface as a Distinct Cellular Neighborhood Composed of Neural and Non-neural Cell Types
Journal: eNeuro
Researchers investigated the cellular composition of the interface between the brain surface and adjacent meninges, a key barrier regulating fluid, protein, and immune cell exchange between the central nervous system (CNS) and periphery. Using single-cell RNA sequencing, spatial transcriptomics, lineage tracing, and immunostaining in adult murine cortex, they identified three major cell types forming the interface: leptomeningeal cells, border astrocytes, and tissue-resident macrophages. On the nonparenchymal side, PDGFRα-positive leptomeningeal cells intermingled with macrophages, while a layer of transcriptionally distinct border astrocytes lined the interface. Layer 1 of the cortex contained neurons and glia that were mostly not closely associated with the interface, suggesting that secreted ligands mediate communication between the interface and underlying parenchyma. The study provided a detailed molecular and cellular map of the brain–meninges interface, creating a resource for future investigations into how this compartment regulates CNS–periphery interactions.
Timothy Murphy: Real-Time Closed-Loop Feedback System For Mouse Mesoscale Cortical Signal And Movement Control: CLoPy
Journal: eLife
Researchers implemented an open-source closed-loop neurofeedback (CLNF) and closed-loop movement feedback (CLMF) system to study cortical activity and motor learning in mice. In CLNF, cortical mesoscale activity was measured using GCaMP6s, and graded auditory feedback was provided based on changes in dorsal-cortical activity within selected regions of interest (ROIs). Mice successfully modulated activity in rule-specific ROIs to increase rewards over days and adapted to changes in ROI rules. In CLMF, feedback was based on specific body movements, with rewards delivered when movements reached a threshold. Mice receiving graded auditory feedback performed significantly better than controls, quickly learning task rules and adapting to changes in targeted body parts. Offline analyses revealed changes in neural activity (ΔF/F0) and movement parameters, with increased performance accompanied by decreased task latency and cortical activation, indicating more efficient neural processing as the task became familiar. This study demonstrated the efficacy of closed-loop feedback systems for both neural and motor training in mice.
