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

Cheryl Wellington: Pediatric reference intervals for serum neurofilament light and glial fibrillary acidic protein using the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) cohort

Journal: Clinical Chemistry and Laboratory Medicine

Blood biomarkers have the potential to transform diagnosis and prognosis for multiple neurological indications. Establishing normative data is a critical benchmark in the analytical validation process. The current study generated pediatric reference intervals (RIs) for serum neurofilament light (NfL), an axonal marker, and glial fibrillary acidic protein (GFAP), an astrocytic marker.

Results showed there was a significant negative association between age and serum NfL and GFAP. Taken together with the literature on adults, NfL and GFAP displayed U-shaped curves with high levels in infants, decreasing levels during childhood, a plateau during adolescence and early adulthood and increasing levels in seniors. These normative data are expected to inform future pediatric studies on the importance of age on neurological blood biomarkers.


Cheryl Wellington: Age specific reference intervals for plasma biomarkers of neurodegeneration and neurotrauma in a Canadian population

Journal: Clinical Biochemistry

The current study aimed to create reference intervals (RI) using a large Canadian population-based cohort, for plasma protein biomarkers with potential utility to screen, diagnosis, prognosticate and manage a variety of neurological diseases and disorders. RIs were generated for: the ratio of amyloid beta 42 over 40 (Aβ42/40), phosphorylated tau-181 (p-tau-181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP).

From the study, the researchers concluded that discrete and continuous RIs for neurological plasma biomarkers will help refine normative cut-offs across the lifespan and improve the precision of interpretating biomarker levels. Continuous RIs are recommended for use in age groups, such as pediatrics and older adults, that experience rapid concentration changes by age.


Ruth Grunau: Prenatal serotonin reuptake inhibitor antidepressant exposure, SLC6A4 genetic variations, and cortisol activity in 6-year-old children of depressed mothers: A cohort study

Journal: Developmental Psychobiology

Prenatal exposure to maternal depression and serotonin reuptake inhibitor (SRI) antidepressants both affect the development of the hypothalamic-pituitary-adrenal (HPA) system, possibly via the neurotransmitter serotonin (5HT). In a community cohort, the researchers investigated the impact of two factors that shape prenatal 5HT signaling (prenatal SRI [pSRI] exposure and child SLC6A4 genotype) on HPA activity at age 6 years.

Generalized estimating equation (GEE) models were used to study associations between cortisol reactivity, pSRI exposure, and child SLC6A4 genotype. Cortisol decreased from arrival across both developmental assessments, and then increased across both time points following the stress challenge. pSRI-exposed children had lower cortisol levels across all time points. The findings suggest that pSRI exposure and a genetic factor associated with modulating 5HT signaling shaped HPA reactivity to a laboratory stress challenge at school age.


Catharine Winstanley, Stan Floresco: Win-paired cues modulate the effect of dopamine neuron sensitization on decision making and cocaine self-administration: divergent effects across sex

Journal: Biological Psychiatry

Both psychostimulant use and engagement with probabilistic schedules of reward sensitize the mesocorticolimbic dopamine (DA) system. Such behaviors may act synergistically to explain the high comorbidity between stimulant use and gambling disorder. The researchers sensitized ventral tegmental area DA neurons while rats learned a gambling task in the presence or absence of casino-like cues. The same rats then learned to self-administer cocaine.

The results showed in the absence of cues, sensitization promoted risk taking in both sexes. When rewards were cued, sensitization expedited the development of a risk-preferring phenotype in males while attenuating cue-induced risk taking in females. While these results provide further confirmation that ventral tegmental area DA neurons critically modulate risky decision making, they also reveal stark sex differences in the decisional impact that dopaminergic signals exert when winning outcomes are cued.


Shannon Kolind, Cornelia Laule: The CALIPR framework for highly accelerated myelin water imaging with improved precision and sensitivity

Journal: Scientific Advances

Quantitative magnetic resonance imaging (MRI) techniques are powerful tools for the study of human tissue, but, in practice, their utility has been limited by lengthy acquisition times. The current study introduces the Constrained, Adaptive, Low-dimensional, Intrinsically Precise Reconstruction (CALIPR) framework in the context of myelin water imaging (MWI); a quantitative MRI technique generally regarded as the most rigorous approach for noninvasive, in vivo measurement of myelin content. The CALIPR framework facilitates drastically improved MWI and could be similarly transformative for other quantitative MRI applications.


Neil Cashman: Shift of the insoluble content of the proteome in the aging mouse brain

Journal: Proceedings of the National Academy of Sciences of the USA

During aging, the cellular response to unfolded proteins is believed to decline, resulting in diminished proteostasis. In model organisms, such as Caenorhabditis elegans, proteostatic decline with age has been linked to proteome solubility shifts and the onset of protein aggregation. However, this correlation has not been extensively characterized in aging mammals.

The researchers analyzed the detergent-insoluble fraction of mouse brain tissue by mass spectrometry. They identified a group of 171 proteins, including the small heat shock protein α-crystallin, that become enriched in the detergent-insoluble fraction obtained from old mice. This study’s analysis suggests that age-related changes to proteome organization lead a group of proteins with specific features to become detergent-insoluble.


Janice Eng, Teresa Liu-Ambrose, Lara Boyd: Premotor and Posterior Parietal Cortex Activity is Increased for Slow, as well as Fast Walking Poststroke: An fNIRS Study

Journal: Neural Plasticity

The current study looked at individuals in the chronic stage of stroke. The participants walked at their normal pace, slower than normal, and as fast as possible. Functional near-infrared spectroscopy was used to assess bilateral prefrontal, premotor, sensorimotor, and posterior parietal cortices during walking.

The study found that brain activation is not linearly related to gait speed. Ipsilesional prefrontal cortex, bilateral premotor, and bilateral posterior parietal cortices are important areas for gait speed modulation and could be an area of interest for neurostimulation.


Ipek Oruc: Are people with autism prosopagnosic?

Journal: Autism Research

Difficulties in various face processing tasks have been well documented in autism spectrum disorder (ASD). Several studies have indicated that this population experiences a moderate degree of impairment, with a small percentage of studies failing to detect any impairment. One possible account of this mixed pattern of findings is heterogeneity in face processing abilities stemming from the presence of a subpopulation of prosopagnosic individuals with ASD alongside those with normal face processing skills.

The researchers tested this by examining three groups of participants: adults with ASD, adults with developmental prosopagnosia, and a comparison group. The results showed that the prosopagnosic subpopulation hypothesis does not account for the face impairments in the broader autism spectrum. ASD observers show a continuous and graded, rather than categorical, heterogeneity that span a range of face processing skills including many with mild to moderate deficits, inconsistent with a prosopagnosic subtype account.


Lakshmi Yatham: Cannabidiol as an Adjunctive Treatment for Acute Bipolar Depression: A Pilot Study

Journal: Canadian Journal of Psychiatry

The treatment of bipolar depression remains challenging due to the limited effective and safe therapeutic options available. The objective of the present study was to test 150 to 300 mg/day of cannabidiol as an adjunctive treatment for bipolar depression. The researchers looked at changes in the Montgomery-Åsberg Depression Rating Scale (MADRS).

Results showed MADRS scores significantly decreased from baseline to the endpoint, but there was no significant difference between the groups. Cannabidiol did not show significantly higher adverse effects than placebo. Despite the negative finding on the primary outcome, an exploratory analysis suggested that cannabidiol should be further studied in bipolar depression in higher doses of at least 300 mg/day and under research designs that could better control for high placebo response.


Teresa Liu-Ambrose: Aerobic exercise training effects on hippocampal volume in healthy older individuals: a meta-analysis of randomized controlled trials

Journal: GeroScience

The researchers conducted a meta-analysis of randomized controlled trials investigating the effects of aerobic exercise training (AET) lasting ≥ 4 weeks on hippocampal volume and cardiorespiratory fitness (CRF) in cognitively unimpaired, healthy older individuals.

From the limited number of studies, AET does not seem to impact hippocampal volume in cognitively unimpaired, healthy older individuals. Notable methodological limitations across investigations might mask the lack of effects.


Noah Silverberg, William Panenka: Catastrophizing is associated with excess cognitive symptom reporting after mild traumatic brain injury

Journal: Neuropsychology

Persistent cognitive symptoms after mild traumatic brain injury (mTBI) often do not correlate with objective neuropsychological performance. Catastrophizing (i.e., excessively negative interpretations of symptoms) may help explain this discrepancy. The researchers hypothesize that symptom catastrophizing will be associated with greater cognitive symptom reporting relative to neuropsychological test performance in people seeking treatment for mTBI.

The researchers concluded that catastrophizing is associated with misperceptions of cognitive functioning following mTBI, specifically overreporting cognitive symptoms relative to neuropsychological performance. Symptom catastrophizing may be an important determinant of cognitive symptom reporting months after mTBI.


Terrance Snutch, Brian MacVicar, Piotr Kozlowski: Chronic pregabalin treatment protects against spreading depolarization and alters hippocampal synaptic characteristics in a model of familial hemiplegic migraine-type 1

Journal: Molecular Brain

Familial hemiplegic migraine type-1 (FHM-1) is a form of migraine with aura caused by mutations in a voltage-gated calcium channel. Pregabalin inhibits calcium channel activity and recent studies suggest that it may have potential for the treatment of migraine. Spreading Depolarization (SD) is a neurophysiological phenomenon that can occur during migraine with aura by propagating a wave of silenced neuronal function through brain structures.

The results show the potential of chronic pregabalin to limit recurrent SD to subcortical brain structures during pathophysiological events in both the genetically-normal and FHM-1 brain. The work further provides insights into FHM-1 pathophysiology and the potential for chronic pregabalin treatment to prevent SD in migraineurs.


Mahmoud Pouladi: iPS-cell-derived microglia promote brain organoid maturation via cholesterol transfer

Journal: Nature

Microglia contribute to multiple aspects of brain development, but their precise roles in the early human brain remain poorly understood owing to limited access to relevant tissues. The generation of brain organoids from human induced pluripotent stem cells recapitulates some key features of human embryonic brain development. However, current approaches do not incorporate microglia or address their role in organoid maturation.

The researchers generated microglia-sufficient brain organoids by coculturing brain organoids with primitive-like macrophages generated from the same human induced pluripotent stem cells. Overall, the approach substantially advances current human brain organoid approaches by incorporating microglial cells, as illustrated by the discovery of a key pathway of lipid-mediated crosstalk between microglia and neuronal progenitor cells that leads to improved neurogenesis.


Cheryl Wellington: Roles of peripheral lipoproteins and cholesteryl ester transfer protein in the vascular contributions to cognitive impairment and dementia

Journal: Molecular Neurodegeneration

This review focuses on the role of cholesteryl ester transfer protein (CETP) and peripheral lipoproteins in the vascular contributions to cognitive impairment and dementia (VCID). Humans have a peripheral lipoprotein profile where low-density lipoproteins (LDL) represent the dominant lipoprotein fraction and high-density lipoproteins (HDL) represent a minor lipoprotein fraction. Elevated LDL-cholesterol (LDL-C) levels are well-established to cause cardiovascular disease and several LDL-C-lowering therapies are clinically available to manage this vascular risk factor.

The LDL:HDL ratio in humans is set mainly by CETP activity, which exchanges cholesteryl esters for triglycerides across lipoprotein fractions to raise LDL and lower HDL as CETP activity increases. As HDL has potent beneficial effects on endothelial cells, the naturally high HDL levels in mice protect them from vascular disorders, likely including VCID. Genetic restoration of CETP expression in mice to generate a more human-like lipid profile may increase the relevance of murine models for VCID studies. The therapeutic potential of existing and emerging LDL-lowering therapies for VCID are discussed.


Daniela Palombo: The shared and unique neural correlates of personal semantic, general semantic, and episodic memory

Journal: eLife

One of the most common distinctions in long-term memory is that between semantic (i.e., general world knowledge) and episodic (i.e., recollection of contextually specific events from one’s past). However, emerging cognitive neuroscience data suggest a surprisingly large overlap between the neural correlates of semantic and episodic memory. The current study used fMRI to record brain activity while participants verified statements concerning general facts, autobiographical facts, repeated events, and unique events.

In the multivariate analysis, all four types of memory involved activity within a common network bilaterally and some areas of the medial temporal lobe. Yet the four memory types differentially engaged this network. The data is compatible with a component process model, in which declarative memory types rely on different weightings of the same elementary processes.


Sarah Kraeutner, Lara Boyd: Frontoparietal function and underlying structure reflect capacity for motor skill acquisition during healthy aging

Journal: Neurobiology of Aging

While capacity for motor skill acquisition changes with healthy aging, there has been little consideration of how age-related changes in brain function or baseline brain structure support motor skill acquisition. The researchers examined age-dependent changes in functional reorganization related to frontoparietal regions during motor skill acquisition, and whether capacity for motor skill acquisition relates to baseline white matter microstructure in frontoparietal tracts.

Results showed frontoparietal tract microstructure was lower in healthy older versus younger adults, yet it was negatively associated with rate of skill acquisition regardless of group. Findings indicate that age-dependent alterations in frontoparietal function and baseline structure of a frontoparietal tract reflect capacity for motor skill acquisition.


Lynn Raymond: Age- and region-dependent cortical excitability in the zQ175 Huntington disease mouse model

Journal: Human Molecular Genetics

The neurodegenerative disorder, Huntington disease (HD), manifests as disorders of movement, cognition and mood. Although studies report abnormal corticostriatal synaptic function early in HD mouse models, less is known about cortical–cortical activity across brain regions and disease stages. The researchers investigated cortical excitability of zQ175 HD-model mice compared to their wild-type littermates.

Cortical pyramidal neurons (CPNs) in somatosensory cortex of zQ175 mice showed intrinsic hyper-excitability at 3–4 months, but hypo-excitability at early-manifest stage (8–9 months); reduced frequency of spontaneous excitatory postsynaptic currents (sEPSCs) was seen at both ages. In contrast, motor cortex CPNs in early-manifest zQ175 mice showed increased intrinsic excitability and sEPSC frequency.


Lynn Raymond: Activin A targets extrasynaptic NMDA receptors to ameliorate neuronal and behavioral deficits in a mouse model of Huntington disease

Journal: Neurobiology of Disease

Cortical-striatal synaptic dysfunction, including enhanced toxic signaling by extrasynaptic N-methyl-d-aspartate receptors (eNMDARs), precedes neurodegeneration in Huntington disease (HD). A previous study showed Activin A, whose transcription is upregulated by calcium influx via synaptic NMDARs, suppresses eNMDAR signaling. The current study examined the role of Activin A in the YAC128 HD mouse model, comparing it to wild-type controls.

The researchers found decreased Activin A secretion in YAC128 cortical-striatal co-cultures, while Activin A overexpression in this model rescued altered eNMDAR expression. Striatal overexpression of Activin A in vivo improved motor learning, and normalized striatal neuronal eNMDAR-mediated currents, membrane capacitance and spontaneous excitatory postsynaptic current frequency in the YAC128 mice. These results support the therapeutic potential of Activin A signaling and targeting eNMDARs to restore striatal neuronal health and ameliorate behavioral deficits in HD.