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European Journal of Translational... Mar 2022Neuromuscular disorders are a heterogeneous group of acquired or hereditary conditions that affect striated muscle function. The resulting decrease in muscle strength...
Neuromuscular disorders are a heterogeneous group of acquired or hereditary conditions that affect striated muscle function. The resulting decrease in muscle strength and motility irreversibly impacts quality of life. In addition to directly affecting skeletal muscle, pathogenesis can also arise from dysfunctional crosstalk between nerves and muscles, and may include cardiac impairment. Muscular weakness is often progressive and paralleled by continuous decline in the ability of skeletal muscle to functionally adapt and regenerate. Normally, the skeletal muscle resident stem cells, named satellite cells, ensure tissue homeostasis by providing myoblasts for growth, maintenance, repair and regeneration. We recently defined 'Satellite Cell-opathies' as those inherited neuromuscular conditions presenting satellite cell dysfunction in muscular dystrophies and myopathies (doi:10.1016/j.yexcr.2021.112906). Here, we expand the portfolio of Satellite Cell-opathies by evaluating the potential impairment of satellite cell function across all 16 categories of neuromuscular disorders, including those with mainly neurogenic and cardiac involvement. We explore the expression dynamics of myopathogenes, genes whose mutation leads to skeletal muscle pathogenesis, using transcriptomic analysis. This revealed that 45% of myopathogenes are differentially expressed during early satellite cell activation (0 - 5 hours). Of these 271 myopathogenes, 83 respond to Pax7, a master regulator of satellite cells. Our analysis suggests possible perturbation of satellite cell function in many neuromuscular disorders across all categories, including those where skeletal muscle pathology is not predominant. This characterisation further aids understanding of pathomechanisms and informs on development of prognostic and diagnostic tools, and ultimately, new therapeutics.
PubMed: 35302338
DOI: 10.4081/ejtm.2022.10064 -
Cannabis and Cannabinoid Research Aug 2022The endocannabinoid (eCB) system plays a key role in maintaining homeostasis, including the regulation of metabolism and stress responses. Chronic stress may blunt eCB... (Meta-Analysis)
Meta-Analysis
The endocannabinoid (eCB) system plays a key role in maintaining homeostasis, including the regulation of metabolism and stress responses. Chronic stress may blunt eCB signaling, and disruptions in eCB signaling have been linked to stress-related psychiatric disorders and physical health conditions, including anxiety, depression, post-traumatic stress disorder (PTSD), diabetes, and obesity. Pharmacological and nonpharmacological behavioral interventions (e.g., exercise) that target the eCB system may be promising therapeutic approaches for the prevention and treatment of stress-related diseases. In this study, we perform a systematic review and the first meta-analysis to examine the impact of exercise on circulating eCB concentrations. We performed a review of the MEDLINE (PubMed) database for original articles examining the impact of exercise on eCBs in humans and animal models. A total of 262 articles were screened for initial inclusion. Thirty-three articles (reporting on 57 samples) were included in the systematic review and 10 were included in the meta-analysis. The majority of samples that measured anandamide (AEA) showed a significant increase in AEA concentrations following acute exercise (74.4%), whereas effects on 2-arachidonoylglycerol (2-AG) were inconsistent. The meta-analysis, however, revealed a consistent increase in both AEA and 2-AG following acute exercise across modalities (e.g., running, cycling), species (e.g., humans, mice), and in those with and without pre-existing health conditions (e.g., PTSD, depression). There was substantial heterogeneity in the magnitude of the effect across studies, which may relate to exercise intensity, physical fitness, timing of measurement, and/or fasted state. Effects of chronic exercise were inconsistent. Potential interpretations and implications of exercise-induced mobilization of eCBs are discussed, including refilling of energy stores and mediating analgesic and mood elevating effects of exercise. We also offer recommendations for future work and discuss therapeutic implications for exercise in the prevention and treatment of stress-related psychopathology.
Topics: Affect; Animals; Anxiety; Endocannabinoids; Humans; Mice; Running; Stress Disorders, Post-Traumatic
PubMed: 34870469
DOI: 10.1089/can.2021.0113 -
Journal of Thoracic Disease Feb 2019Lung contusion resulting from chest trauma may be present various clinical pictures. It quite often remains unrecognized and is only suspected later when severe... (Review)
Review
Lung contusion resulting from chest trauma may be present various clinical pictures. It quite often remains unrecognized and is only suspected later when severe complications have developed. Lung contusion may present in association with chest trauma but may also occur alone. It has to be emphasized, that lung contusion as a clinical identity does not necessarily require a blunt or penetrating chest to be in the background. Nowadays, as a result of traffic accidents, following high energy deceleration, lung contusion may present without an actual tissue damage in the chest wall as a condition initiating an independent, life-threatening generalised process. Although lung contusion shows similarities to blast injury of the lung with respect to clinical consequences, other factors play a role in its aetiology and pathology. Its description and recognition as an independent pathology is not simple. Several approaches exist: thoracic trauma, pulmonary contusion, pulmonary laceration, lung contusion; although these may show similar clinical signs, manifest in different pathologies. Pathologies with similar meaning and possibly similar clinical course cannot, actually, be differentiated; they may accompany other injuries to the trunk, skull or extremities, which, alone, are associated with high morbidity and mortality. Generally, it can be declared that besides high energy, blunt injuries affecting the trunk, lung contusion, has been an often neglected additional radiological finding attached to the main report, despite the fact, that its late consequences crucially determine the prospects of the injured.
PubMed: 30906578
DOI: 10.21037/jtd.2018.11.53 -
The Journal of Neuroscience : the... Oct 2022Humans routinely learn the value of actions by updating their expectations based on past outcomes - a process driven by reward prediction errors (RPEs). Importantly,...
Humans routinely learn the value of actions by updating their expectations based on past outcomes - a process driven by reward prediction errors (RPEs). Importantly, however, implementing a course of action also requires the investment of effort. Recent work has revealed a close link between the neural signals involved in effort exertion and those underpinning reward-based learning, but the behavioral relationship between these two functions remains unclear. Across two experiments, we tested healthy male and female human participants ( = 140) on a reinforcement learning task in which they registered their responses by applying physical force to a pair of hand-held dynamometers. We examined the effect of effort on learning by systematically manipulating the amount of force required to register a response during the task. Our key finding, replicated across both experiments, was that greater effort increased learning rates following positive outcomes and decreased them following negative outcomes, which corresponded to a differential effect of effort in boosting positive RPEs and blunting negative RPEs. Interestingly, this effect was most pronounced in individuals who were more averse to effort in the first place, raising the possibility that the investment of effort may have an adaptive effect on learning in those less motivated to exert it. By integrating principles of reinforcement learning with neuroeconomic approaches to value-based decision-making, we show that the very act of investing effort modulates one's capacity to learn, and demonstrate how these functions may operate within a common computational framework. Recent work suggests that learning and effort may share common neurophysiological substrates. This raises the possibility that the very act of investing effort influences learning. Here, we tested whether effort modulates teaching signals in a reinforcement learning paradigm. Our results showed that effort resulted in more efficient learning from positive outcomes and less efficient learning from negative outcomes. Interestingly, this effect varied across individuals, and was more pronounced in those who were more averse to investing effort in the first place. These data highlight the importance of motivational factors in a common framework of reward-based learning, which integrates the computational principles of reinforcement learning with those of value-based decision-making.
Topics: Humans; Male; Female; Decision Making; Reinforcement, Psychology; Reward; Motivation; Affect
PubMed: 36096671
DOI: 10.1523/JNEUROSCI.2223-21.2022 -
Journal of Affective Disorders Mar 2021Inadequate treatment response and emotional blunting are common challenges with selective serotonin reuptake inhibitors/serotonin-noradrenaline reuptake inhibitors...
INTRODUCTION
Inadequate treatment response and emotional blunting are common challenges with selective serotonin reuptake inhibitors/serotonin-noradrenaline reuptake inhibitors (SSRIs/SNRIs) for major depressive disorder (MDD). We investigated the effectiveness of vortioxetine on emotional blunting in patients with partial response to treatment with SSRIs/SNRIs.
METHODS
Patients with MDD who experienced a partial response to SSRI/SNRI monotherapy at adequate dose for ≥6 weeks were switched to 8 weeks of vortioxetine treatment 10-20 mg/day (Study NCT03835715). Key inclusion criteria were Montgomery-Åsberg Depression Rating Scale (MADRS) total score >21 and <29, current major depressive episode <12 months, Oxford Depression Questionnaire (ODQ) total score ≥50, and confirmation of emotional blunting by standardized screening question. Emotional blunting was assessed by ODQ and depressive symptoms by MADRS. Other outcomes assessed included motivation and energy (Motivation and Energy Inventory [MEI]), cognitive performance (Digit Symbol Substitution Test [DSST]), and overall functioning (Sheehan Disability Scale [SDS]).
RESULTS
At week 8, patients (N=143) had improved by -29.8 points (p<0.0001) in ODQ total score; 50% reported no emotional blunting in response to standardized screening question. Significant improvements were observed on the DSST, MEI, and SDS at all time points assessed, and 47% of patients were in remission (MADRS total score ≤10) at week 8. The most common treatment-emergent adverse events included nausea, headache, dizziness, vomiting, and diarrhea.
LIMITATIONS
No prospective phase before medication switch.
CONCLUSION
Vortioxetine 10-20 mg effectively improved emotional blunting, overall functioning, motivation and energy, cognitive performance, and depressive symptoms in patients with MDD with partial response to SSRI/SNRI therapy and emotional blunting.
Topics: Depressive Disorder, Major; Double-Blind Method; Humans; Selective Serotonin Reuptake Inhibitors; Serotonin and Noradrenaline Reuptake Inhibitors; Treatment Outcome; Vortioxetine
PubMed: 33516560
DOI: 10.1016/j.jad.2020.11.106 -
Schizophrenia Research Nov 2014Deficits in nonverbal vocal expression (e.g., blunted vocal affect, alogia) are a hallmark of schizophrenia and are a focus of the Research Domain Criteria initiative... (Meta-Analysis)
Meta-Analysis Review
Deficits in nonverbal vocal expression (e.g., blunted vocal affect, alogia) are a hallmark of schizophrenia and are a focus of the Research Domain Criteria initiative from the National Institute of Mental Health. Results from studies using symptom rating scales suggest that these deficits are profound; on the order of four to six standard deviations. To complement this endeavor, we conducted a meta-analysis of studies employing objective analysis of natural speech in patients with schizophrenia and nonpsychiatric controls. Thirteen studies, collectively including 480 patients with schizophrenia and 326 nonpsychiatric controls, were identified. There was considerable variability across studies in which aspects of vocal communication were examined and in the magnitudes of deficit. Overall, speech production (reflecting alogia) was impaired at a large effects size level (d=-.80; k=13), whereas speech variability (reflecting blunted affect) was much more modest (d=-.36; k=2). Regarding the former, this was largely driven by measures of pause behavior, as opposed to other aspects of speech (e.g., number of words/utterances). On the other hand, ratings of negative symptoms across these studies suggested profound group differences (d=3.54; k=4). These data suggest that only certain aspects of vocal expression are affected in schizophrenia, and highlight major discrepancies between symptom rating and objective-based measures. The discussion centers on advancing objective analysis for understanding vocal expression in schizophrenia and for identifying and defining more homogenous patient subsets for study.
Topics: Affective Symptoms; Aphasia; Humans; Schizophrenia; Speech Production Measurement
PubMed: 25261880
DOI: 10.1016/j.schres.2014.09.013 -
Neuropharmacology May 2021Blunted stress reactivity resulting from early exposure to stress during childhood and adolescence may increase vulnerability to addiction. Early life adversity (ELA)... (Review)
Review
Blunted stress reactivity resulting from early exposure to stress during childhood and adolescence may increase vulnerability to addiction. Early life adversity (ELA) affects brain structure and function and results in blunted stress axis reactivity. In this review, we focus on the underlying neurobiological mechanisms associated with a blunted response to stress, ELA, and risk for addictive disorders. ELA and blunted reactivity are accompanied by unstable mood regulation, impulsive behaviors, and reduced cognitive function. Neuroimaging studies reveal cortical and subcortical changes in persons exposed to ELA and those who have a genetic disposition for addiction. We propose a model in which blunted stress reactivity may be a marker of risk for addiction through an altered motivational and behavioral reactivity to stress that contribute to disinhibited behavioral reactivity and impulsivity leading in turn to increased vulnerability for substance use. Evidence supporting this hypothesis in the context of substance use initiation, maintenance, and risk for relapse is presented. The effects of ELA on persons at risk for addiction may lead to early experimentation with drugs of abuse. Early adoption of drug intake may alter neuroregulation in such vulnerable persons leading to a permanent dysregulation of motivational responses consistent with dependence. This article is part of the special issue on 'Vulnerabilities to Substance Abuse'.
Topics: Adaptation, Psychological; Adolescent; Adverse Childhood Experiences; Behavior, Addictive; Child; Cognition; Humans; Impulsive Behavior; Stress, Psychological; Substance-Related Disorders
PubMed: 33711348
DOI: 10.1016/j.neuropharm.2021.108519 -
Current Treatment Options in Allergy 2014Current asthma therapies can effectively control symptoms and the on-going inflammatory process; however, they do not affect the underlying, dysregulated immune... (Review)
Review
Current asthma therapies can effectively control symptoms and the on-going inflammatory process; however, they do not affect the underlying, dysregulated immune response. Thus, they are limited to blunting the progression of the disease, which relapses on ceasing the treatment. Allergen-specific immunotherapy (AIT) is the only etiology-based treatment capable of disease modification. Recent evidence provided a plausible explanation for its multiple mechanisms inducing both rapid desensitization and long-term allergen-specific immune tolerance, as well as the suppression of allergic inflammation in the affected tissues. Although the current guideline documents give both subcutaneous (SCIT) and sublingual (SLIT) immunotherapy a conditional recommendation in allergic asthma due to the moderate and low quality of evidence, respectively, a growing body of evidence from double-blind, placebo-controlled studies shows that both SLIT and SCIT are effective in reducing symptom scores and medication use, improving quality of life, and inducing favorable changes in specific immunologic markers. Due to the very limited evidence from head-to-head comparative studies and variability of the end-point used in different studies, it is currently not possible to assess superiority of either route of vaccine administration.
PubMed: 24900950
DOI: 10.1007/s40521-014-0013-1