Check out some of the papers that were recently published by DMCBH members:
Paul Pavlidis: Thiorphan reprograms neurons to promote functional recovery after spinal cord injury
Journal: Nature
Researchers previously identified an embryonic shift in the corticospinal motor neuronal transcriptome after spinal cord injury associated with successful axonal regeneration. The current study used in silico screens to identify small molecules that generate similar effects, identifying thiorphan (a neutral endopeptidase inhibitor) as a lead candidate. It increased neurite outgrowth 1.8-fold. When infused into the central nervous system and combined with a neural stem cell graft, thiorphan elicited significant improvements in forelimb function and corticospinal regeneration. Extending clinical relevance, thiorphan significantly increased neurite outgrowth in primary cortical neuronal cultures from a 56-year-old human. These findings represented a new path for drug discovery, starting from in silico screens to proof-of-concept in adult human brain cultures.
Journal: Brain Communications
Clinical diagnosis of amyotrophic lateral sclerosis (ALS) depends on evidence of upper motor neuron (UMN) and lower motor neuron (LMN) degeneration. T2- and proton density-weighted images reveal intracranial corticospinal tract (CST) hyperintensity in some UMN-predominant ALS patients. A past study identified CST fiber tract truncation in a subset of UMN-predominant ALS patients, and the present study aimed to investigate the underlying cause of this truncation. In CST-truncated ALS patients, the fibres deviated from their normal trajectory and entered the superior longitudinal fasciculus, resulting in apparent shortening. This truncation was unlikely to be due to axonal or myelin degeneration, inflammation or edema. Researchers hypothesized that impaired axonal guidance mechanisms or dysfunction of the glymphatic system may contribute to this truncation in ALS.
Lauren Emberson: Neural bases of sustained attention during naturalistic parent-infant interactions
Journal: Scientific reports
Sustained attention is the ability to maintain focus on a particular location or object for an extended period, and it is a fundamental skill during development. It lets the developing child acquire information about their environment, facilitating information processing and supporting memory. The present study developed and assessed the validity of a novel fNIRS protocol to study visual sustained attention within naturalistic contexts. Results indicated that the left temporo-parietal areas were involved in sustained attention during infancy. Moreover, validation of the protocol demonstrated that different attentional states can effectively serve as baselines for studying specific components of attention.
Liisa Galea: Sex-specific factors and APOEε4 genotype alter functional connectivity at middle age
Journal: Psychoneuroendocrinology
Cognitive aging is influenced by sex and sex-specific factors. Indeed, research has shown that parity (pregnancy and parenthood) changes biomarkers of brain health in middle age depending on Alzheimer’s disease (AD) risk. This study investigated functional connectivity changes and network dynamics at middle age based on parity and hAPOEε4 genotype in rats. Rats which birthed one litter with the hAPOEε4 genotype exhibited widespread reductions in neural activation, particularly in the dorsal striatum, nucleus accumbens, frontal cortex, and retrosplenial cortex. Network analyses further revealed that wildtype rats with one litter had the most cohesive and efficient functional connectivity networks. Activation of hippocampal new neurons in conjunction with the dorsal striatum, frontal cortex, and retrosplenial cortex dynamically predicted cognitive performance depending on parity and hAPOEε4 genotype. These findings underscored the importance of considering sex-specific factors in aging and AD research.
Erik Pioro: Shared burden of ultra-rare genetic variants across a spectrum of motor neuron diseases
Journal: Translational neurodegeneration
Researchers analyzed the genetics of motor neuron diseases, focusing on ALS and HSP, using whole-genome sequencing from a diverse cohort. They found that pathogenic ultra-rare variants were more common in familial cases, with key contributions from known genes like C9orf72, ATXN2, SPAST, and SPG7. Importantly, rare variants in HSP genes were also enriched in sporadic ALS, revealing significant genetic overlap between these diseases. Additional analyses identified new candidate genes and mechanisms, highlighting the complex architecture of MND risk and demonstrating a new rare-variant analysis approach for understanding heritability in these neurodegenerative disorders.
Journal: Journal of Alzheimer’s disease
The abnormal extracellular accumulation of amyloid-beta plaques and intracellular tau are hallmarks of early events in the pathogenesis of Alzheimer’s disease (AD). The present study reported changes in dopamine receptors (DR), Aβ, and astrocyte distribution in the cortex and hippocampus of 5XFAD mice. Researchers examined DR1-DR5 expression and localization in the cortex and hippocampus of 5XFAD mice using immunohistochemistry, qPCR, and western blot. In AD brains, Gs-coupled DR1 and DR5 were upregulated, while Gi-coupled receptors were downregulated. In the cortex, receptor alterations were implicated in increased CDK5 and tau phosphorylation. The cortex showed greater vulnerability to Aβ-associated degeneration, whereas the hippocampus was more susceptible to inflammation and tau pathology. Overall, findings revealed a role for dopamine receptor subtypes in regulating tau phosphorylation and CDK5, with implications for AD-related cognitive dysfunction.
Catharine Winstanley: Histone deacetylase inhibitor sodium butyrate increases risk-taking during acquisition of the rat gambling task
Journal: Psychopharmacology
Pairing casino-esque audiovisual cues with reward delivery significantly increases risky decision-making in laboratory-based gambling tasks across rats and humans. The neurocognitive effects underlying this effect are unclear. Rodent research suggested that win-paired cues promoted habitual control of decision-making. Past literature showed that inhibiting histamine deacetylase enzymes (HDACs) can accelerate habit formation. Researchers hypothesized that risky decision making in the cued rat gambling task could be enhanced by administering the non-specific class I HDAC inhibitor sodium butyrate (NaBut). NaBut-treated rats developed a bias towards risky options more rapidly during the first five training sessions, with immunohistochemical analyses showing increased histone acetylation in the striatum and prelimbic frontal cortex. However, once training was complete, NaBut-treated rats were just as sensitive as controls were to the omission of reward. These findings suggested that development of a maladaptive, risky strategy while learning the cued rGT can be facilitated through HDAC inhibition but didn’t conclusively demonstrate that such treatment results in greater habitual control over behaviour.
Catharine Winstanley: Ventral striatal cholinergic interneurons regulate decision making or motor impulsivity differentially across learning and biological sex
Journal: The journal of neuroscience
Impairments in decision making and impulsivity are central to psychiatric conditions such as addiction, ADHD, and impulse control disorders. Understanding how these behaviours are regulated in the brain, and why they differ across individuals and sexes, is critical for developing targeted treatments. This study identifies ventral striatal cholinergic interneurons as important modulators of both impulsivity and risk-based decision making, with their influence depending on learning stage and biological sex. These results show how acetylcholine and dopamine systems interact to shape behaviour in flexible and individualized ways. By revealing circuit-level mechanisms that may underlie sex-specific vulnerabilities and stage-specific treatment outcomes, this work lays the groundwork for more personalized approaches to treating disorders involving poor impulse control and risky decision making.
John Kramer, Helen Tremlett: Safety reporting quality in multiple sclerosis clinical trials: A review of phase III clinical trials included in FDA approval of disease-modifying treatments
Journal: Multiple Sclerosis journal – experimental, translational and clinical
Evaluating the safety of emerging interventions is important in clinical trials. This study examined safety reporting in pivotal trials of disease-modifying therapies in patients with multiple sclerosis (MS). 30 published phase III clinical trials from 1995 to 2022 included in FDA approval material for MS disease-modifying therapies were reviewed by two independent examiners. Overall, safety reporting quality was fair, with small molecule trials associated with higher quality reporting than biologic interventions. More recent publications were also associated with higher quality reporting. Items related to laboratory-defined toxicity and defining adverse events were among reporting items notably lacking. While the reporting of phase III clinical trials for DMTs for the treatment of MS has improved with time, there remain gaps and opportunities for further improvement.
Journal: Behavioural brain research
Developmental coordination disorder (DCD) is a neurodevelopmental disorder affecting motor control, motor learning and coordination. This study investigated brain activation associated with a virtual decision-making task in children with and without DCD. Children completed a fMRI session where they responded to a virtual task using controllers to indicate the direction a virtual person was travelling, and how they would avoid the person. Children with DCD had greater neural activation during the avoidance task in the visual cortices and right middle frontal gyrus compared to their peers. Children with DCD were also less accurate at responding correctly to the person-direction task than their peers. Overall, children with DCD required greater attentional resources to complete a decision-making task compared to neurotypical children, potentially due to visuomotor processing deficits.
Wolfram Tetzlaff: Age-impaired remyelination is associated with dysregulated microglial transitions
Journal: Nature communications
Multiple sclerosis (MS) is a chronic inflammatory condition characterized by neurodegeneration and demyelination. The lost myelin may be regenerated in people with MS through remyelination, although this process is prone to failure and impaired with age. The present study profiled the microglial response during remyelination in the lysolecithin mouse model using single-cell RNA sequencing, discovering several distinct microglial states which merged into a resolved state. Researchers also observed a delay in the appearance of several microglial states with age, in concordance with delayed remyelination. This multi-faceted microglial response during efficient remyelination provides the basis of multi-faceted microglia-specific targets for future MS therapies.
Philip Barker: A systematic review of the potential neurotoxicity of micro-and nanoplastics: the known and unknown
Journal: Particle and fibre toxicology
The escalating accumulation of micro- and nanoplastics (MNPs) in the environment has raised significant concerns regarding their neurotoxic potential in vertebrates. This critical review synthesized evidence from 234 original research articles across aquatic and terrestrial models, as well as in vitro systems, to evaluate the impacts of MNPs on the brain. Emerging data suggest that MNPs may reach the brain via olfactory translocation or by penetrating the blood-brain barrier. Neurologic outcomes varied widely depending on particle size, shape, polymer type, exposure concentration and species. The review presented limitations in current studies, noting poor ecological and translatability. Researchers recommended comprehensive physicochemical characterization of MNPs, adoption of environmentally relevant exposure scenarios, inclusion of diverse polymer types and shapes, and mechanistic integration through multi-omics and adverse outcome pathway frameworks.
Haakon Nygaard, Brian MacVicar: Generation of 3D Human iPSC-Derived Multi-Cell Type Neurospheres for Studying Neuron, Astrocyte, and Microglia Crosstalk
Journal: Bio-protocol
Three-dimensional human brain tissue models derived from induced pluripotent stem cells (iPSCs) have transformed the study of neural development and disease. This paper outlined a detailed, reproducible protocol for generating multi-cell type 3D neurospheres that incorporate neurons, astrocytes and optionally microglia. The system supports a range of downstream applications, including functional confocal live imaging of GCaMP6f after adeno-associated virus (AAV) transduction of neurospheres or immunofluorescence staining after fixation. Moreover, it has been successfully implemented across multiple laboratories, showing robustness and translational potential for studying neuron-glia interactions and modeling neurodegenerative processes.
Teresa Liu-Ambrose: Reply to the letter: To consider the exercise density in the dose-response relationship: the idea is promising, the operationalization tricky!
Journal: European journal of applied physiology
The authors responded to a commentary by Desgorces on their recent publication about physical activity (PA) and brain health. They noted that Desgorces agreed with their view of PA density, which is a measure of how activity is distributed over time. Authors argued that PA density was an important factor for analyzing and prescribing exercise to support brain health. However, Desgorces also highlighted that measuring PA density is challenging due to differing definitions, methods, and interpretations. In their reply, the authors took the opportunity to clarify their perspective, address the points raised, and reinforce their original conclusions about the significance of PA density in understanding and applying exercise interventions for brain health.
Vesna Sossi, Jon Stoessl: Novel insights into relationships between metabolic covariance patterns of FDG-PET data and clinical status in Parkinson’s disease using partial least squares correlation analysis
Journal: Journal of Parkinson’s disease
Researchers examined brain-imaging data to understand how patterns of brain metabolism were linked to different aspects of Parkinson’s disease (PD), including how the disease began, how it progressed, and how it overlapped with normal aging. They combined clinical information such as age and disease duration with an analytical method designed to uncover shared metabolic patterns. When they analyzed people with PD alongside healthy controls, they recovered the well-known metabolic signature associated with PD. When they analyzed only individuals with PD, they saw a pattern marked by increasing metabolic activity in the putamen and less involvement of the cerebellum. Finally, when they allowed clinical variables to influence the groups differently, they identified a metabolic pattern present in both PD and healthy aging: higher metabolism in the basal ganglia, brainstem, and white matter, and lower metabolism in the frontal cortex. In healthy participants, this pattern was linked only to age, but in individuals with PD it related to both age and disease duration. Overall, the study identified metabolic signatures connected to PD onset, PD progression, and normal aging, and highlighted age-related metabolic changes that may increase vulnerability to developing PD.
Neil Cashman: Development of a targeted BioPROTAC degrader selective for misfolded SOD1
Journal: Nature communications
Researchers investigated a new therapeutic approach for amyotrophic lateral sclerosis (ALS), a disease in which the buildup of misfolded proteins—such as harmful variants of the SOD1 protein—contributes to nerve cell damage. They designed a biological proteolysis-targeting chimera (BioPROTAC), which combined a SOD1-specific intrabody with an enzyme that marks proteins for degradation, with the goal of selectively removing misfolded SOD1 from cells. After screening different intrabodies and enzymes, they identified a BioPROTAC that successfully degraded several disease-linked SOD1 variants and prevented them from forming toxic aggregates in cells. They then created a genetically engineered mouse line that expressed this BioPROTAC and found that it delayed disease progression in the SOD1G93A ALS mouse model. This delay was linked to protection of motor neurons, reduced buildup of insoluble SOD1, and better preservation of neuromuscular junctions. Overall, the study provided proof-of-concept evidence that BioPROTACs could offer a targeted way to eliminate misfolded, neurotoxic proteins in neurodegenerative diseases.
Thalia Field: Types and Rates of Major Adverse Cardiovascular Events in Antithrombotic Trials: A Systematic Review and Meta-Analysis
Journal: Canadian journal of cardiology
Researchers reviewed large clinical trials of antithrombotic therapies to understand how major adverse cardiovascular events (MACE) were defined and how often they occurred across different patient groups. Across more than 400,000 participants, they found that stroke occurred much more frequently in stroke-focused trials, while heart attacks were far more common in cardiovascular trials. Rates of major bleeding and death were similar across all groups. Their analysis also showed that trials with more female participants had higher annual rates of stroke and death, while longer studies tended to report lower event rates. Importantly, they found that definitions of MACE and bleeding varied widely between trials, making comparisons difficult. Overall, the study showed that different disease populations experience different types of recurrent events, highlighting the need for disease-specific prevention strategies and more standardized outcome definitions in clinical research.
Tim Murphy: Mouse Hippocampal Sharp-Wave Ripple Dataset Curated From Public Neuropixels Datasets
Journal: Scientific data
Researchers worked with large open-access datasets from the Allen Brain Institute and the International Brain Laboratory, which included detailed recordings of brain activity and behavior from mice performing tasks with Neuropixels probes. These probes often passed through the hippocampus, allowing the researchers to study sharp-wave ripples (SWRs), brief high-frequency bursts in the hippocampal local field potential that are important for memory and coordination of neural activity. Because no standard existed for sharing SWR data, the team extracted and curated SWR events from these datasets using established field criteria and organized them into a consistent, shareable format that integrates with the projects’ existing APIs. In total, they compiled and released more than 967,000 SWR events from 210 mice, along with the code used to process the data. This work created a unified resource for analyzing SWRs across large-scale mouse neuroscience datasets and supports more accessible and reproducible research.
Alexander Rauscher, David Li: C-FLAIR: Fluid-attenuated Inversion Recovery with Controlled Artifact Suppression in Brain MRI
Journal: Radiology
Researchers aimed to reduce common artifacts in a routine brain MRI sequence called FLAIR, which can produce misleading signals when the magnetic or radiofrequency fields are uneven. They designed a new inversion pulse using optimal control methods to make the sequence more robust to these field inhomogeneities. In tests using a specialized phantom with strong field variations and in scans from 14 participants—including healthy volunteers and individuals with multiple sclerosis, concussion symptoms, or white matter changes—the optimized sequence, called C-FLAIR, produced much cleaner images. It showed nearly complete suppression of unwanted fluid signals even in challenging regions, effectively eliminating artifacts without altering the visibility of multiple sclerosis lesions or other white matter abnormalities. Overall, C-FLAIR successfully removed artifacts caused by incomplete inversion while preserving diagnostic image quality.
Daniela Palombo: Neural patterns reflect shared emotional history
Journal: The journal of neuroscience
Researchers investigated how the emotional context of experiences influences memory and brain activity. They proposed that events encoded with a similar emotional “hue,” particularly negative emotions, would show similar patterns of brain activation when later recalled. To test this, they used fMRI while the participants completed a two-phase memory task. During encoding, participants viewed pairs of images: a neutral object paired with either a negative or neutral emotional scene. Later, participants saw the neutral objects again and rated their pleasantness, implicitly recalling the emotional context. Using advanced analyses, the researchers examined brain areas linked to emotion and memory, including the ventral visual stream (VVS), hippocampus, and ventromedial prefrontal cortex (vmPFC). They found that the VVS consistently reflected the shared negative emotional context of events, showing similar activation patterns for negative experiences. The hippocampus and vmPFC contributed in a more nuanced way. Overall, the study revealed that the brain encodes emotional context as part of memory, allowing shared emotional experiences to shape how we remember events and highlighting the brain’s flexibility in integrating affective content into mnemonic representations.
Teresa Liu-Ambrose: Epigenetic age predicts depressive symptoms during the COVID-19 pandemic in the Canadian Longitudinal Study on Aging: importance of biological sex
Journal: Aging
Researchers examined whether biological age, measured through epigenetic markers, could predict changes in depressive symptoms among older adults during the COVID-19 pandemic. Using data from the Canadian Longitudinal Study on Aging, they measured participants’ epigenetic age at baseline (2012–2015) and tracked depressive symptoms across four time points, including two surveys conducted during 2020. Surprisingly, they found that women with a younger epigenetic age experienced greater increases in depressive symptoms from the pre-pandemic follow-up to the COVID-19 Baseline survey. In contrast, higher epigenetic age was not linked to changes in depressive symptoms during this period. These findings suggest that epigenetic age may help identify women who are particularly vulnerable to the mental health effects of major life stressors.
