Papers of the month: February 2025

Check out some of the papers that were recently published by DMCBH members:

Judy Illes: Far from Home: Managing Incidental Findings in Field Research with Portable MRI 

Journal: Journal of Law, Medicine & Ethics 

Portable MRI is a new technology expanding neuroimaging research into remote field settings, allowing the examination of populations previously excluded from research and marginalized in health care. However, the lack of access to health care and medical institutions raises ethical questions involving incidental findings. Incidental findings are unexpected findings unrelated to the original aim of the imaging, such as tumours or aneurysms, and may have clinical significance. Researchers should not withhold information about incidental findings when participants consent to receive it, and instead should facilitate access to information and clinical care.  

Judy Illes: The Realization of Portable MRI for Indigenous Communities in the USA and Canada 

Journal: Journal of Law, Medicine & Ethics 

Native American People in the USA and Indigenous People in Canada are historically underrepresented in neuroimaging research to date. Consequently, there is a scarcity of existing baseline data for understanding neurologic health and the effects of injury on people from Indigenous populations. This paper explores how portable MRI can change this for the better. It discusses pathways to engage local leadership, encourage participation of communities and empower field-based researchers to bring the holistic worldview embraced by Indigenous communities to neuroimaging research.  

Erik Pioro: Modeling ALS with Patient-Derived iPSCs: Recent Advances and Future Potentials 

Journal: Brain Sciences 

Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of upper and lower motor neurons in the brain and spinal cord, leading to the progressive weakness of muscles. 10-15% of cases are familial, but the majority is sporadic with no known cause, for which there are no effective animal models. More sophisticated models of ALS disease are needed to understand this complex disease. Human-derived pluripotent stem cell (hiPSC) technology offers an opportunity to model diverse human cell types in a culture dish. The present review focuses on hiPSC-derived ALS neuronal and non-neuronal models to examine the research progress of current 2D monocultures, co-cultures and 3D-model organoids.  

Jason Snyder, Fidel Vila-Rodriguez: Electroconvulsive shock and transcranial magnetic stimulation do not alter the survival or spine density of adult-born striatal neurons 

Journal: PLoS One 

Adult neurogenesis has been widely studied in the hippocampus and subventricular zone-olfactory bulb. Relatively little is known about the properties of newly born neurons in non-canonical areas such as the striatum. Although adult-born striatal neurons have been described in both rodents and humans, the regulation of them is poorly understood. Since striatal dysfunction occurs in Parkinson’s disease, researchers investigated whether neurostimulation therapies such as electroconvulsive shock (ECS) or transcranial magnetic stimulation (rTMS) would affect neuroplasticity of adult-born striatal neurons. Adult born cells were labelled in transgenic mice and after 8 days, mice were given 10 stimulations over the course of 3 weeks. Adult-born medium spiny neuron phenotypes were observed in all groups. However, neither ECS nor rTMS altered the number of new neurons and both treatments had no effect on the density of dendritic spines. These results suggest that neither ESC nor eTMS alter early neuronal survival or plasticity in the striatum.  

Deborah Giaschi, Miriam Spering: Poor fixation stability does not account for motion perception deficits in amblyopia 

Journal: Scientific Reports 

Amblyopia, colloquially known as lazy eye, is associated with deficits in global motion detection, especially at slow speeds. These observers also have unstable visual fixation when viewing stationary targets. It is possible that poor fixation stability may interfere with visual input to the motion-sensitive neurons in the visual cortex, thus leading to these deficits. Researchers assessed motion coherence thresholds in adults with amblyopia while measuring fixation stability. Participants with amblyopia showed global motion perception deficits and elevated fixation stability relative to controls. Fixation stability was not related to visual acuity, suggesting that motion perception deficits might not be a result of poor visual input due to unstable fixation – it may be due to processing deficits in the visual cortex.  

Freda Miller, David Kaplan: Single cell approaches define neural stem cell niches and identify microglial ligands that can enhance precursor-mediated oligodendrogenesis 

Journal: Cell Reports 

Researchers used single cell RNA sequencing and single cell spatial transcriptomics to characterize the forebrain neural stem cell (NSC) niche under normal and injured conditions. The dorsal and lateral ventricular-subventricular zones (V-SVZs) were defined as separate neighbourhoods. After white matter injury, NSCs were activated to make oligodendrocytes dorsally for remyelination. This corresponds with an increase in distinct microglia in the dorsal V-SVZ niche. Insulin growth factor 1 and oncostain M were found to promote precursor proliferation and oligodendrogenesis, even in the lateral V-SVZ where neuroblasts are normally made. These data support a model where gliogenesis is determined by the local NSC neighbourhood and where injury-induced alterations promote NSC activation.  

Teresa Liu-Ambrose: Gait Speed Modifies Efficacy of Home-Based Exercise for Falls in Older Adults with a Previous Fall: Secondary Analysis of a Randomized Controlled Trial 

Journal: Physical Therapy 

While exercise has been shown to be an effective strategy for preventing falls in older adults, its efficacy may vary based on individual characteristics like gait speed. This study investigated whether baseline gait speed affected the effects of home-based exercise on subsequent falls. A secondary analysis of a 12-month randomized controlled trial in community-dwelling adults older than 70 who had fallen within the past year. Participants were randomized to either 12 months of home-based exercise or standard care. For participants with slow gait speed, exercise reduced fall rates by 44% at 6 months, while participants with normal gait speed did not show any significant effect of exercise on fall rates. Older adults with slow gait speed may be a target population for exercise-based fall prevention.  

Daniel Vigo: Effective Treatment for Mental and Substance Use Disorders in 21 Countries 

Journal: JAMA Psychiatry  

This cross-sectional study examined the proportion of mental and substance use disorders receiving guideline-consistent treatment in 21 countries. Among 56,927 respondents, the proportion of 12-month person-disorders receiving effective treatment was 6.9%. The biggest barriers to effective treatment were low perceived need (46.5%), low treatment contact given perceived need (34.1%), and low effective treatment given minimally adequate treatment (47%). It is important to train primary care treatment clinicians for recognition and treatment of mental disorders, improve the continuum of care and bridge the effective treatment gap for men and those with lower education.  

Liisa Galea: Sex-specific influences of APOEε4 genotype on hippocampal neurogenesis and progenitor cells in middle-aged rats 

Journal: Biology of Sex Differences 

Alzheimer’s disease (AD) disproportionally affects females, with sex differences further exacerbated by the top genetic risk factor for late-onset AD, Apolipoprotein (APOE) ε4 alleles. This study explored how APOEε4 affects hippocampal neurogenesis and microglia in middle-aged rats. Relative to healthy controls, male rats with the humanized APOEε4 genotype showed reduced neural stem cell-like cells and new adult-born brain cells and increased microglia (marker of inflammation in the brain) at middle age. In contrast, female rats with hAPOEε4 genotype showed increased new adult-born neurons, but no changes in the other cell types, suggesting a possible compensatory response to the effects of hAPOEε4 at this time point.  It is crucial to examine the influence of sex on AD endophenotypes as it may reveal sex-specific pathways and protective mechanisms with implications for improving care for both sexes.  

Judy Illes: Two-Eyed Seeing and other Indigenous perspectives for neuroscience 

Journal:  Nature  

Integrating Indigenous perspectives and knowledge with biomedical approaches in neurosciences can expand our understanding of the human brain. Drawing upon the writings of Elders in Canada, this integration is termed “Two-Eyed Seeing”. In this review article, researchers discuss how Two-Eyed seeing can bring both breadth of knowledge and humility to the research development process, including both academic and non-academic traditions and the work of Indigenous scholars. This paper offered broad strategies for allyship, humility and universalism, situating them in four specific examples involving disability, suicide, migration and the environment. Read more here. 

Helen Tremlett: Evaluating the Role of High-Dimensional Proxy Data in Confounding Adjustment in Multiple Sclerosis Research: A Case Study 

Journal: Pharmacoepidemiology and drug safety  

Silke Appel-Cresswell: Sex and gender differences in the molecular etiology of Parkinson’s disease: considerations for study design and data analysis 

Journal: Biology of Sex Differences 

Parkinson’s disease (PD) is more common in men than women and displays different clinical features in each sex. Although these differences are well known, females are underrepresented in clinical and experimental studies of PD, with much unknown about the origins of sex differences. This review summarizes known contributors to sex differences in PD throughout the lifespan with a focus on neurological development, gene regulation, hormones and lifestyle factors. It also discusses how researchers can consider sex and gender in future studies to enhance our understanding of how PFD develops, and to inform prevention and therapeutic strategies tailored to each sex.  

Kota Mizumoto: Comparison among bright green fluorescent proteins in C. elegans 

Journal: microPublication Biology  

Green fluorescent proteins (GFPs) are important tools used for visualizing cells and proteins across model systems. Efforts have been made to generate brighter fluorescent proteins such as eGFP, GFPnovo2, mNeonGreen and mStayGold. In this study, researchers generated single-copy knock-in C. Elephans strains for these GFP variants, directly comparing their brightness and photo stability. It was found that mStayGold was brighter and more photo stable than the other three, suggesting that it may hold advantages over other GFP variants in experiments.  

Mark Cembrowski: Atypical hippocampal excitatory neurons express and govern object memory 

Journal: Nature Communications 

The hippocampus is traditionally thought to flexibly encode both spatial and non-spatial information through pyramidal cells. However, recent findings suggest that distinct excitatory neuron types shape hippocampal function. In mice, researchers identified a non-pyramidal excitatory neuron, the “ovoid” neuron, located near subiculum pyramidal cells but differing in gene expression, electrophysiology, morphology, and connectivity. Ovoid neurons exhibit sustained activity in response to novel objects but not familiar ones, even months after single-trial learning. Silencing these neurons impairs non-spatial object learning without affecting spatial learning, while activation shifts behavior from novel-object seeking to familiar-object seeking. This function is distinct from pyramidal neurons, which influence spatial but not non-spatial learning. These findings highlight cell-type-specific control of non-spatial memory and behavioral preference in the hippocampal circuit. Read more here.  

Brian MacVicar: Brain pericytes and perivascular fibroblasts are stromal progenitors with dual functions in cerebrovascular regeneration after stroke 

Journal: Nature Neuroscience  

A stroke occurs when blood flow to part of the brain is interrupted, causing widespread cell death. Recovery requires the remodeling and regeneration of blood vessels around the site of injury. Stromal progenitor cells (SPCs) are critical for tissue regeneration following injury, but their role in the brain is not clearly known. Researchers show that brain SPCs include pericytes and perivascular fibroblasts, which help regenerate blood vessels following experimental stroke in mice. These two cell types are distinct subpopulations of SPCs in the adult brain that coordinate revascularization and scar formation after injury. Read more here.  

Lynn Raymond, Tim Murphy: Home cage-based insights into motor learning and strategy adaptation in a Huntington disease mouse model 

Journal: PLoS One  

Huntington disease (HD) is a genetic neurodegenerative disorder characterized by progressive motor dysfunction, cognitive decline and neuropsychiatric symptoms. Traditional behavioural tasks are limited in assessing early motor skill deficits in HD mouse models. A home cage-based lever-pulling task was used to evaluate motor learning in 6–7-month-old zQ175 knock-in HD mice in a more naturalistic environment. During this task, mice learn to pull a lever for a water reward, needing to hold the lever within a specific goal range for a required hold time. As the mice improved, the required hold time increased. Both wild type and zQ175 mice initially showed similar task engagement, but zQ175 mice failed to adjust and adapt to increasing hold time. Post-task neural assessments revealed that wild type mice developed experience-mediated synaptic plasticity in the left striatum while zQ175 mice showed no significant changes, suggesting that they have corticostriatal plasticity impairments. Group-housed, home cage-based assessments appear to be effective for evaluating motor learning and adaptation in HD mouse models.  

William Gibson: Minimally Humanized Ezh2 Exon-18 Mouse Cell Lines Validate Preclinical CRISPR/Cas9 Approach to Treat Weaver Syndrome 

Journal: Human Gene Therapy 

Weaver syndrome is a rare neurodevelopmental disorder characterized by macrocephaly, tall stature, obesity, brain anomalies and increased susceptibility to cancer. This dominant monogenic disorder is caused by germline variants in the enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2). There are no existing effective treatments for Weaver syndrome. This study tests, for the first time, whether CRISPR/Cas9 gene-editing strategies may be able to “correct” a Weaver syndrome at the level of DNA. In this study, researchers humanized the region around a common patient-variant location in mouse embryonic stem cells (ESCs) to better translate DNA-binding strategies to human cells. They then introduced a variant of the EZH2 gene associated with Weaver syndrome (c.2035C>T p.Arg684Cys) into the ESCs and found a significant reduction in EZH2 enzymatic activity, confirming previous studies. Interestingly, the variant caused a hypomorphic effect rather than a complete loss of function. They tested four CRISPR gene-editing strategies, with Streptococcus pyogenes Cas9 (SpCas9) showing the highest correction but also significant alterations of the nonvariant allele. In contrast, Staphylococcus aureus Cas9 (SaCas9) provided a similar correction rate with much lower off-target effects, making it the optimal strategy for correcting the Weaver syndrome variant in therapy.