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

Joanne Matsubara: Purinergic signaling via P2X receptors and mechanisms of unregulated ATP release in the outer retina and age-related macular degeneration

Journal: Frontiers in Neuroscience

Age-related macular degeneration (AMD) is a chronic and progressive inflammatory disease of the retina characterized by photoreceptor loss and significant central visual impairment. The pathophysiology of AMD is complex and multifactorial. Known contributors to AMD, such as the complement cascade and inflammasome activation, and other biological systems, such as purinergic signaling, have not been fully characterized. In this review, the researchers explored the interactions between purinergic signaling, ATP release, and known contributors to AMD pathogenesis including complement dysregulation and inflammasome activation.

The research team found that the purinergic system accelerates AMD pathogenesis leading to apoptotic and pyroptotic cell death in retinal cells. More research is needed to improve our understanding of the mechanisms that drive AMD pathogenesis which is critical in developing treatment strategies that prevent or slow progression of the disease.


Annie Ciernia: Histone deacetylase 3 regulates microglial function through histone deacetylation

Journal: Epigenetics

As the primary innate immune cells of the brain, microglia respond to damage and disease through pro-inflammatory release of cytokines and neuroinflammatory molecules. Histone acetylation is an activating transcriptional mark that regulates inflammatory gene expression. Inhibition of histone deacetylase 3 (Hdac3) has been utilized in pre-clinical models of depression, stroke, and spinal cord injury to improve recovery following injury, but the molecular mechanisms underlying Hdac3’s regulation of inflammatory gene expression in microglia is not well understood.

The researchers examined how pharmacological inhibition of Hdac3 in an immortalized microglial cell line (BV2) impacted histone acetylation and gene expression of pro- and anti-inflammatory genes in response to immune challenge with lipopolysaccharide (LPS). The findings suggest Hdac3 serves as a regulator of microglial inflammation, and that inhibition of Hdac3 facilitates the microglial response to inflammation. This work provides new mechanistic insights into therapeutic applications of Hdac3 inhibition.


Christian Schutz: The effectiveness of oxytocin in the treatment of stimulant use disorders: a systematic review

Journal: Behavioural Pharmacology

Despite stimulant use disorder being a major public health concern, there are no validated pharmacological treatments. Psychosocial interventions show limited effectiveness especially in the more severe cases of stimulant use disorder, whereas animal models suggest that oxytocin may be a useful treatment. The purpose of the review was to examine human study evidence on the effectiveness of oxytocin in the stimulant use disorder population.

Results found although oxytocin was well tolerated across studies, no study showed a statistically significant reduction in reported cocaine use or cravings. Available research does not support the use of oxytocin in the management of stimulant use disorder; however, included studies are small in sample size and limited in number. Considering the limited data available at this time, further studies are required before any definitive conclusions can be made regarding the use of oxytocin in stimulant use disorder management.


Lakshmi Yatham: Duration of Adjunctive Antidepressant Maintenance in Bipolar I Depression

Journal: The New England Journal of Medicine

Antidepressants are used to treat acute depression in patients with bipolar I disorder, but their effect as maintenance treatment after the remission of depression has not been well studied. The researchers conducted a multisite, double-blind, randomized, placebo-controlled trial of maintenance of treatment with adjunctive escitalopram or bupropion XL as compared with discontinuation of antidepressant therapy in patients with bipolar I disorder who had recently had remission of a depressive episode.

The results found adjunctive treatment with escitalopram or bupropion XL that continued for 52 weeks did not show a significant benefit as compared with treatment for 8 weeks in preventing relapse of any mood episode. The trial was stopped early owing to slow recruitment and funding limitations.


Kamyar Keramatian: Caring for youth with co-occurring substance use and severe psychiatric disorders: diagnostic challenges and clinical implications

Journal: Journal of the Canadian Academy of Child and Adolescent Psychiatry

Substance use disorder is a common comorbidity during the early stages of mood and psychotic disorders that further heightens acute risks and is considered a negative prognostic factor. New presentations of mood and psychotic symptoms with co-occurring substance use are inherently challenging to formulate due to the uncertainty surrounding the relative impact of multiple intrinsic and extrinsic factors.

Given such uncertainty, it is natural for clinicians to rely on heuristics to guide assessment and management. These heuristics however may bring about premature diagnostic closure by favouring the primacy of substance use, which in turn can result in a missed window of opportunity for a timely and appropriate intervention. The present study cautions clinicians against over-attributing early symptoms of mood and psychotic disorders to substances use alone.


Fidel Vila-Rodriguez, Tamara Vanderwal: Subgenual cingulate connectivity as a treatment predictor during low-frequency right dorsolateral prefrontal rTMS: A concurrent TMS-fMRI study

Journal: Brain Stimulation

Repetitive transcranial magnetic stimulation (rTMS) to the dorsolateral prefrontal cortex (DLPFC) is effective in alleviating treatment-resistant depression (TRD). It has been proposed that regions within the left DLPFC that are anti-correlated with the right subgenual anterior cingulate cortex (sgACC) may represent optimal individualized target sites for high-frequency left rTMS (HFL). This study aimed to explore the effects of low-frequency right rTMS (LFR) on left sgACC connectivity during concurrent TMS-fMRI.

The results showed when TMS-fMRI increased left sgACC functional connectivity to parietal regions within the ventral attention network, differences were not significantly associated with clinical improvements. In contrast to studies that targeted the left DLPFC, higher anti-correlation was not shown to be associated with clinical outcomes. The results suggest that the antidepressant mechanism of action of LFR to the right DLPFC may be different than for HFL.


Ipek Oruc: Learning from small data: Classifying sex from retinal images via deep learning

Journal: PLoS ONE

Deep learning (DL) techniques have seen tremendous interest in medical imaging, particularly in the use of convolutional neural networks (CNNs) for the development of automated diagnostic tools. Recent work in the analysis of fundus images using CNNs relies on access to massive datasets for training and validation, composed of hundreds of thousands of images. However, data residency and data privacy restrictions hinder the applicability of this approach in medical settings where patient confidentiality is a mandate.

Here, the research team showcases results for the performance of DL on small datasets to classify patient sex from fundus images. The models developed using a 25% decrease in performance despite a nearly 1000-fold decrease in the dataset size compared to prior results in the literature. The results show that binary classification, even with a hard task such as sex categorization from retinal fundus images, is possible with very small datasets.


Joanne Matsubara: Ligand-independent activation of platelet-derived growth factor receptor β promotes vitreous-induced contraction of retinal pigment epithelial cells

Journal: BMC Ophthalmology

Epiretinal membranes in patients with proliferative vitreoretinopathy (PVR) consist of extracellular matrix and a number of cell types including retinal pigment epithelial (RPE) cells and fibroblasts. In RPE cells depletion of platelet-derived growth factor (PDGF) receptor (PDGFR)β suppresses vitreous-induced Akt activation, whereas in fibroblasts Akt activation through indirect activation of PDGFRα by growth factors outside the PDGF family (non-PDGFs) plays an essential role in experimental PVR. Whether non-PDGFs in the vitreous, however, were also able to activate PDGFRβ in RPE cells remained elusive.

Results of the study found expression of a truncated PDGFRβ lacking a PDGF-binding domain in the RPEM cells whose PDGFRB gene has been silent using CRISPR/Cas9 technology restores vitreous-induced Akt activation as well as cell proliferation. This suggests that in RPE cells PDGFRβ can be activated indirectly by non-PDGFs in the vitreous to facilitate the development of PVR, thereby providing novel opportunities for PVR therapeutics.


Douglas Altshuler: From the eye to the wing: neural circuits for transforming optic flow into motor output in avian flight

Journal: Journal of Comparative Physiology A

Avian flight is guided by optic flow—the movement across the retina of images of surfaces and edges in the environment due to self-motion. In all vertebrates, there is a short pathway for optic flow information to reach pre-motor areas. Electrophysiological and tract tracing studies are revealing the functional connectivity of a more elaborate circuit through the avian cerebellum, which integrates optic flow with other sensory signals.

Here the research team reviews the research supporting this framework and identifies the cerebellar output centres, the lateral (CbL) and medial (CbM) cerebellar nuclei, as two key nodes with potentially distinct roles in flight control. The CbM receives bilateral optic flow information and suggests a primary role for flight control over time. The CbL receives monocular optic flow and provides feedback to sensory areas throughout the brain. This arrangement suggests primary roles for the CbL in the control of wing morphing and for rapid maneuvers.


Janet Werker: Babies, bugs and brains: How the early microbiome associates with infant brain and behavior development

Journal: PLoS ONE

Growing evidence is demonstrating the connection between the microbiota gut-brain axis and neurodevelopment. It has been hypothesized that the early microbiome interactions along the gut-brain axis evolved to promote advanced cognitive functions and behaviors. Here, the researchers performed a pilot study with a multidisciplinary approach to test if the microbiota composition of infants is associated with measures of early cognitive development, in particular neural rhythm tracking; language versus non-language discrimination; and social joint attention.

Results found infants who succeeded at the Point and Gaze test tended to have increased Actinobacteria and reduced Firmicutes. Measurements of neural rhythm tracking associated negatively to the abundance of Bifidobacterium and positively to the abundance of Clostridium and Enterococcus. No associations were found for language discrimination.


Kiran Soma, Stan Floresco: Neurosteroids and the mesocorticolimbic system

Journal: Neuroscience & Biobehavioral Reviews

The mesocorticolimbic system coordinates executive functions, such as working memory and behavioral flexibility. This circuit includes dopaminergic projections from the ventral tegmental area to the nucleus accumbens and medial prefrontal cortex. In this review, the researchers summarize evidence that cells in multiple nodes of the mesocorticolimbic system produce neurosteroids and express steroid receptors.

The research team focuses on on neuroandrogens, neuroestrogens, and androgen and estrogen receptors. They also summarize how neuroandrogens and neuroestrogens affect dopamine signaling in the mesocorticolimbic system and regulate executive functions. Taken together, the data suggest that steroids produced in the gonads and locally in the brain modulate higher-order cognition and executive functions.


Daniela Palombo: Emotion in the mind’s eye: Imagination for adaptive cognition

Journal: Annuals of the New York Academy of Science

In a complex world, we are constantly faced with environmental stimuli that shape our moment-to-moment experiences. But just as rich and complex as the external world is the internal milieu—our imagination. Imagination offers a powerful vehicle for playing out hypothetical experiences in the mind’s eye. Imagined experiences tend to be emotion-laden. Based on psychological findings, the researchers highlight the importance of imagination for emotional aspects of cognition and behavior, namely in the generation and regulation of emotions.

The research team identifies putative neural networks that are critical for emotional imagination, with a focus on the default mode network. They also highlight the possible functional implications of individual differences in imagination. Overall, the researchers hope to address why humans have the capacity to simulate hypothetical emotional experiences and how this ability can be harnessed in adaptive (and sometimes maladaptive) ways.


Kamyar Keramatian: Neuroanatomical predictors of problematic alcohol consumption in adolescents: a systematic review of longitudinal studies

Journal: Alcohol and Alcoholism

This study aimed to systematically review the literature on neuroanatomical predictors of future problematic drinking in adolescents. Out of 1412 studies identified, 19 studies met the criteria, consisting of 11 gray matter, 5 white matter, and 3 assessing both. Neuroanatomical predictors of future problematic drinking in adolescents were reported to be distributed across various brain regions such as the orbitofrontal cortex and paralimbic regions. However, the findings were largely heterogeneous.

This is the first systematic review to map out the existing literature on neuroanatomical predictors of problematic drinking in adolescents. Future research should focus on the aforementioned regions to determine their role in predicting future problematic drinking with more certainty.


Lakshmi Yatham: Treatment options for acute bipolar depression: an urgent unmet clinical need 

Journal: The Lancet Psychiatry

Depression is a major cause of disability and mortality and is the predominant mood state in people with bipolar disorders. Currently, only five pharmacological treatments are approved by the US Food and Drug Administration (FDA) for acute bipolar depression. By contrast, over 30 FDA-approved unique medications are available for the treatment of major depressive disorder. Off-label medications often prescribed for bipolar depression are those primarily used to treat mania or psychosis, or major depressive disorder.

Although pragmatic treatment guidelines for bipolar disorder exist, clinicians have scant data on direct comparisons of medications to guide treatment selection for patients with acute bipolar depression. This can lead to an ad hoc approach to sequential pharmacotherapy, resulting in the use of untested polypharmacy, which could in part explain high rates of treatment-resistant bipolar depression.


Noah Silverberg, Daniela Palombo, Rebecca Todd: Factors perpetuating functional cognitive symptoms after mild traumatic brain injury

Journal: Journal of Clinical and Experimental Neuropsychology

Self-reported memory difficulties often persist long after a mild traumatic brain injury (mTBI), despite normal neuropsychological test performance. This clinical presentation may be a manifestation of a functional cognitive disorder (FCD). This study aims to explore perpetuating factors in mTBI, to advance our understanding of why memory symptoms frequently persist following mTBI.

Results found participants with mTBI performed similarly to controls on objective measures of memory ability but reported experiencing much more frequent memory lapses in daily life. Contrary to expectations, metacognitive efficiency did not differentiate the mTBI and control groups and was not associated with functional memory symptoms. Depression and checking behaviors were greater in the mTBI group compared to the control group and were associated with greater functional memory symptoms within the mTBI group.


Miriam Spering: Rapid audiovisual integration guides predictive actions

Journal: eNeuro

Natural movements, such as catching a ball or capturing prey, typically involve multiple senses. Yet, laboratory studies on human movements commonly focus solely on vision and ignore sound. Here, the research team is interested in how visual and auditory signals are integrated to guide interceptive movements. Human observers tracked the brief launch of a simulated baseball, randomly paired with batting sounds of varying intensities, and made a quick pointing movement at the ball.

Movement end points revealed systematic overestimation of target speed when the ball launch was paired with a loud versus a quiet sound. Amplitude of the first catch-up saccade revealed early integration of audiovisual information for trajectory estimation. This sound-induced bias was reversed during later predictive saccades. The findings suggest that auditory and visual signals are integrated to guide interception and that this integration process must occur early at a neural site that receives auditory and visual signals within an ultrashort time span.