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Pharmacological Reviews Jun 2024The orexin system consists of the peptide transmitters orexin-A and -B and the G protein-coupled orexin receptors OX and OX Orexin receptors are capable of coupling to...
The orexin system consists of the peptide transmitters orexin-A and -B and the G protein-coupled orexin receptors OX and OX Orexin receptors are capable of coupling to all four families of heterotrimeric G proteins, and there are also other complex features of the orexin receptor signaling. The system was discovered 25 years ago and was immediately identified as a central regulator of sleep and wakefulness; this is exemplified by the symptomatology of the disorder narcolepsy with cataplexy, in which orexinergic neurons degenerate. Subsequent translation of these findings into drug discovery and development has resulted to date in three clinically used orexin receptor antagonists to treat insomnia. In addition to sleep and wakefulness, the orexin system appears to be a central player at least in addiction and reward, and has a role in depression, anxiety and pain gating. Additional antagonists and agonists are in development to treat, for instance, insomnia, narcolepsy with or without cataplexy and other disorders with excessive daytime sleepiness, depression with insomnia, anxiety, schizophrenia, as well as eating and substance use disorders. The orexin system has thus proved an important regulator of numerous neural functions and a valuable drug target. Orexin prepro-peptide and orexin receptors are also expressed outside the central nervous system, but their potential physiological role there remains unknown. The orexin system was discovered 25 years ago and immediately emerged as an essential sleep-wakefulness regulator. This discovery has tremendously increased the understanding of these processes and has thus far resulted in the market approval of three orexin receptor antagonists, which promote more physiological sleep than previous hypnotics. Further, orexin receptor agonists and antagonists with different pharmacodynamic properties are in development since research has revealed additional potential therapeutic indications. Orexin receptor signaling is complex and may represent novel features.
PubMed: 38902035
DOI: 10.1124/pharmrev.123.000953 -
Psychophysiology Jun 2024Transcranial magnetic stimulation (TMS) is pivotal in the field of major depressive disorder treatment. Due to its unsatisfied response rate, an increasing number of...
Transcranial magnetic stimulation (TMS) is pivotal in the field of major depressive disorder treatment. Due to its unsatisfied response rate, an increasing number of researchers have turned their attention towards optimizing TMS site localization. Since the influence of TMS in reducing heart rate (HR) offers insights into its regulatory impact on the autonomic nervous system, a novel approach, called neurocardiac-guided TMS (NCG-TMS), has been proposed to pinpoint the brain region eliciting the maximal individual reduction in HR as a personalized optimal stimulation target. The present study intends to systematically explore the effects of stimulation frequency, left and right hemispheres, stimulation positions, and individual differences on HR modulation using the NCG-TMS method. In experiment 1, low-frequency TMS was administered to 30 subjects, and it was found that low-frequency NCG-TMS significantly downregulated HR, with more significant effects in the right hemisphere than in the left hemisphere and the prefrontal cortex than in other brain areas. In experiment 2, high-frequency NCG-TMS stimulation was administered to 30 subjects, showing that high-frequency NCG-TMS also downregulated HR and had the greatest modulatory effect in the right prefrontal region. Simultaneously, both experiments revealed sizeable individual variability in the optimal stimulation site, which in turn validated the feasibility of the NCG-TMS method. In conclusion, the present experiments independently replicated the effect of NCG-TMS, provided an effect of high-/low-frequency TMS stimulation to downregulate HR, and identified a right lateralization of the HR modulation effect.
PubMed: 38898649
DOI: 10.1111/psyp.14631 -
Journal of Clinical Medicine Jun 2024The rising prevalence of cardiovascular disease underscores the growing significance of heart failure (HF). Pathophysiological insights into HF highlight the... (Review)
Review
The rising prevalence of cardiovascular disease underscores the growing significance of heart failure (HF). Pathophysiological insights into HF highlight the dysregulation of the autonomic nervous system (ANS), characterized by sympathetic overactivity and diminished vagal tone, impacting cardiovascular function. Heart rate recovery (HRR), a metric measuring the heart's ability to return to its baseline rate post-exertion, plays a crucial role in assessing cardiovascular health. Widely applied across various cardiovascular conditions including HF, coronary artery disease (CAD), and arterial hypertension (HTN), HRR quantifies the difference between peak and recovery heart rates. Given its association with elevated sympathetic tone and exercise, HRR provides valuable insights into the perspective of HF, beyond effort tolerance, reaching toward prognostic and mortality indicators. Incorporating HRR into cardiovascular evaluations enhances our understanding of autonomic regulation in HF, offering potential implications for prognostication and patient management. This review addresses the significance of HRR in HF assessment, analyzing recently conducted studies, and providing a foundation for further research and clinical application.
PubMed: 38893039
DOI: 10.3390/jcm13113328 -
International Journal of Molecular... Jun 2024The autonomic nervous system plays an integral role in motion and sensation as well as the physiologic function of visceral organs. The nervous system additionally plays... (Review)
Review
The autonomic nervous system plays an integral role in motion and sensation as well as the physiologic function of visceral organs. The nervous system additionally plays a key role in primary liver diseases. Until recently, however, the impact of nerves on cancer development, progression, and metastasis has been unappreciated. This review highlights recent advances in understanding neuroanatomical networks within solid organs and their mechanistic influence on organ function, specifically in the liver and liver cancer. We discuss the interaction between the autonomic nervous system, including sympathetic and parasympathetic nerves, and the liver. We also examine how sympathetic innervation affects metabolic functions and diseases like nonalcoholic fatty liver disease (NAFLD). We also delve into the neurobiology of the liver, the interplay between cancer and nerves, and the neural regulation of the immune response. We emphasize the influence of the neuroimmune axis in cancer progression and the potential of targeted interventions like neurolysis to improve cancer treatment outcomes, especially for hepatocellular carcinoma (HCC).
Topics: Humans; Liver Neoplasms; Neuroimmunomodulation; Animals; Carcinoma, Hepatocellular; Liver; Non-alcoholic Fatty Liver Disease; Autonomic Nervous System
PubMed: 38892423
DOI: 10.3390/ijms25116237 -
Open Heart Jun 2024Neurocardiogenic syncope is a common condition with significant associated psychological and physical morbidity. The effectiveness of therapeutic options for... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Neurocardiogenic syncope is a common condition with significant associated psychological and physical morbidity. The effectiveness of therapeutic options for neurocardiogenic syncope beyond placebo remains uncertain.
METHODS
The primary endpoint was the risk ratio (RR) of spontaneously recurring syncope following any therapeutic intervention. We also examined the effect of blinding on treatment efficacy. We identified all randomised trials which evaluated the effect of any pharmacological, device-based or supportive intervention on patients with a history of syncope. A systematic search was conducted on Medline, Embase, PubMed databases and Cochrane Central Register for Controlled Trials from 1950 to 25 April 2023. Event rates, their RRs and 95% CIs were calculated, and a random-effects meta-analysis was conducted for each intervention. Data analysis was performed in R using RStudio.
RESULTS
We identified 47 eligible trials randomising 3518 patients. Blinded trials assessing syncope recurrence were neutral for beta blockers, fludrocortisone and conventional dual-chamber pacing but were favourable for selective serotonin reuptake inhibitors (SSRIs) (RR 0.40, 95% CI 0.26 to 0.63, p<0.001), midodrine (RR 0.70, 95% CI 0.53 to 0.94, p=0.016) and closed-loop stimulation (CLS) pacing (RR 0.15, 95% CI 0.07 to 0.35, p<0.001). Unblinded trials reported significant benefits for all therapy categories other than beta blockers and consistently showed larger benefits than blinded trials.
CONCLUSIONS
Under blinded conditions, SSRIs, midodrine and CLS pacing significantly reduced syncope recurrence. Future trials for syncope should be blinded to avoid overestimating treatment effects.
PROSPERO REGISTRATION NUMBER
CRD42022330148.
Topics: Humans; Syncope, Vasovagal; Randomized Controlled Trials as Topic; Treatment Outcome; Recurrence
PubMed: 38890128
DOI: 10.1136/openhrt-2024-002669 -
Chest Jun 2024Obstructive Sleep Apnea (OSA) is diagnosed and managed by a metric called the apnea- hypopnea index (AHI). The AHI quantifies total number of respiratory events (apnea... (Review)
Review
Obstructive Sleep Apnea (OSA) is diagnosed and managed by a metric called the apnea- hypopnea index (AHI). The AHI quantifies total number of respiratory events (apnea or hypopnea), disregarding important information on the characteristics and physiological consequences of respiratory events, including, degrees of ventilatory deficit and associated hypoxemia, cardiac autonomic response, and cortical activity. The oversimplification of the disorder by the AHI is considered one of the reasons for divergent findings on the associations of OSA and cardiovascular disease (CVD) in observational and randomized controlled trial studies. Prospective observational cohort studies have demonstrated strong associations of OSA with several cardiovascular diseases while randomized controlled trials of continuous positive airway pressure (CPAP) intervention have not been able to detect a benefit of CPAP to reduce the risk of CVD. Over the last several years, novel methodologies have been proposed to better quantify the magnitude of OSA-related breathing disturbance and its physiological consequences. As a result, stronger associations with cardiovascular and neurocognitive outcomes have been observed. In this review, we focus on the methods that capture polysomnographic heterogeneity of OSA.
PubMed: 38885898
DOI: 10.1016/j.chest.2024.05.028 -
PloS One 2024Heart rate variability (HRV), an important marker of autonomic nervous system activity, is usually determined from electrocardiogram (ECG) recordings corrected for...
BACKGROUND
Heart rate variability (HRV), an important marker of autonomic nervous system activity, is usually determined from electrocardiogram (ECG) recordings corrected for extrasystoles and artifacts. Especially in large population-based studies, computer-based algorithms are used to determine RR intervals. The Modular ECG Analysis System MEANS is a widely used tool, especially in large studies. The aim of this study was therefore to evaluate MEANS for its ability to detect non-sinus ECG beats and artifacts and to compare HRV parameters in relation to ECG processing. Additionally, we analyzed how ECG processing affects the statistical association of HRV with cardiovascular disease (CVD) risk factors.
METHODS
20-min ECGs from 1,674 subjects of the population-based CARLA study were available for HRV analysis. All ECGs were processed with the ECG computer program MEANS. A reference standard was established by experienced clinicians who visually inspected the MEANS-processed ECGs and reclassified beats if necessary. HRV parameters were calculated for 5-minute segments selected from the original 20-minute ECG. The effects of misclassified typified normal beats on i) HRV calculation and ii) the associations of CVD risk factors (sex, age, diabetes, myocardial infarction) with HRV were modeled using linear regression.
RESULTS
Compared to the reference standard, MEANS correctly classified 99% of all beats. The averaged sensitivity of MEANS across all ECGs to detect non-sinus beats was 76% [95% CI: 74.1;78.5], but for supraventricular extrasystoles detection sensitivity dropped to 38% [95% CI: 36.8;38.5]. Time-domain parameters were less affected by false sinus beats than frequency parameters. Compared to the reference standard, MEANS resulted in a higher SDNN on average (mean absolute difference 1.4ms [95% CI: 1.0;1.7], relative 4.9%). Other HRV parameters were also overestimated as well (between 6.5 and 29%). The effect estimates for the association of CVD risk factors with HRV did not differ between the editing methods.
CONCLUSION
We have shown that the use of the automated MEANS algorithm may lead to an overestimation of HRV due to the misclassification of non-sinus beats, especially in frequency domain parameters. However, in population-based studies, this has no effect on the observed associations of HRV with risk factors, and therefore an automated ECG analyzing algorithm as MEANS can be recommended here for the determination of HRV parameters.
Topics: Humans; Heart Rate; Electrocardiography; Female; Male; Middle Aged; Aged; Cohort Studies; Algorithms; Cardiovascular Diseases; Risk Factors
PubMed: 38885223
DOI: 10.1371/journal.pone.0304893 -
Harefuah Jun 2024Post-Covid Syndrome, Sick Building Syndrome, Silicone Breast Syndrome, Choric Fatigue Syndrome, Fibromyalgia -Autoimmunity to the Autonomic Nervous System.
Post-Covid Syndrome, Sick Building Syndrome, Silicone Breast Syndrome, Choric Fatigue Syndrome, Fibromyalgia -Autoimmunity to the Autonomic Nervous System.
Topics: Humans; Fibromyalgia; Female; COVID-19; Silicones; Post-Acute COVID-19 Syndrome; Autonomic Nervous System; Breast Implants; Autoimmunity; Autonomic Nervous System Diseases
PubMed: 38884297
DOI: No ID Found -
Critical Reviews in Biomedical... 2024The study aims to enhance the standard of medical care for individuals working in the electric power industry who are exposed to industrial frequency electromagnetic... (Review)
Review
Fuzzy-Based Bioengineering System for Predicting and Diagnosing Diseases of the Nervous System Triggered by the Interaction of Industrial Frequency Electromagnetic Fields.
The study aims to enhance the standard of medical care for individuals working in the electric power industry who are exposed to industrial frequency electromagnetic fields and other relevant risk factors. This enhancement is sought through the integration of fuzzy mathematical models with contemporary information and intellectual technologies. The study addresses the challenges of forecasting and diagnosing illnesses within a specific demographic characterized by a combination of poorly formalized issues with interconnected conditions. To tackle this complexity, a methodological framework was developed for synthesizing hybrid fuzzy decision rules. This approach combines clinical expertise with artificial intelligence methodologies to promote innovative problem-solving strategies. Additionally, the researchers devised an original method to evaluate the body's protective capacity, which was integrated into these decision rules to enhance the precision and efficacy of medical decision-making processes. The research findings indicate that industrial frequency electromagnetic fields contribute to illnesses of societal significance. Additionally, it highlights that these effects are worsened by other risk factors such as adverse microclimates, noise, vibration, chemical exposure, and psychological stress. Diseases of the neurological, immunological, cardiovascular, genitourinary, respiratory, and digestive systems are caused by these variables in conjunction with unique physical traits. The development of mathematical models in this study makes it possible to detect and diagnose disorders in workers exposed to electromagnetic fields early on, especially those pertaining to the autonomic nervous system and heart rhythm regulation. The results can be used in clinical practice to treat personnel in the electric power industry since expert evaluation and modeling showed high confidence levels in decision-making accuracy.
Topics: Humans; Electromagnetic Fields; Fuzzy Logic; Nervous System Diseases; Bioengineering; Occupational Exposure
PubMed: 38884210
DOI: 10.1615/CritRevBiomedEng.2024053240 -
Drug Development Research Jun 2024Schizophrenia (SZ) is a serious, destructive neurodevelopmental disorder. Antipsychotic medications are the primary therapy approach for this illness, but it's important...
Schizophrenia (SZ) is a serious, destructive neurodevelopmental disorder. Antipsychotic medications are the primary therapy approach for this illness, but it's important to pay attention to the adverse effects as well. Clinical studies for SZ are currently in phase ΙΙΙ for SEP-363856 (SEP-856)-a new antipsychotic that doesn't work on dopamine D receptors. However, the underlying action mechanism of SEP-856 remains unknown. This study aimed to evaluate the impact and underlying mechanisms of SEP-856 on SZ-like behavior in a perinatal MK-801 treatment combined with social isolation from the weaning to adulthood model (MK-SI). First, we created an animal model that resembles SZ that combines the perinatal MK-801 with social isolation from weaning to adulthood. Then, different classical behavioral tests were used to evaluate the antipsychotic properties of SEP-856. The levels of proinflammatory cytokines (tumor necrosis factor-α, interleukin-6, and interleukin-1β), apoptosis-related genes (Bax and Bcl-2), and synaptic plasticity-related genes (brain-derived neurotrophic factor [BDNF] and PSD-95) in the hippocampus were analyzed by quantitative real-time PCR. Hematoxylin and eosin staining were used to observe the morphology of neurons in the hippocampal DG subregions. Western blot was performed to detect the protein expression levels of BDNF, PSD-95, Bax, Bcl-2, PI3K, p-PI3K, AKT, p-AKT, GSK-3β, p-GSK-3β in the hippocampus. MK-SI neurodevelopmental disease model studies have shown that compared with sham group, MK-SI group exhibit higher levels of autonomic activity, stereotyped behaviors, withdrawal from social interactions, dysregulated sensorimotor gating, and impaired recognition and spatial memory. These findings imply that the MK-SI model can mimic symptoms similar to those of SZ. Compared with the MK-SI model, high doses of SEP-856 all significantly reduced increased activity, improved social interaction, reduced stereotyping behavior, reversed sensorimotor gating dysregulation, and improved recognition memory and spatial memory impairment in MK-SI mice. In addition, SEP-856 can reduce the release of proinflammatory factors in the MK-SI model, promote the expression of BDNF and PSD-95 in the hippocampus, correct the Bax/Bcl-2 imbalance, turn on the PI3K/AKT/GSK-3β signaling pathway, and ultimately help the MK-SI mice's behavioral abnormalities. SEP-856 may play an antipsychotic role in MK-SI "dual-hit" model-induced SZ-like behavior mice by promoting synaptic plasticity recovery, decreasing death of hippocampal neurons, lowering the production of pro-inflammatory substances in the hippocampal region, and subsequently initiating the PI3K/AKT/GSK-3β signaling cascade.
Topics: Animals; Schizophrenia; Proto-Oncogene Proteins c-akt; Signal Transduction; Mice; Disease Models, Animal; Phosphatidylinositol 3-Kinases; Glycogen Synthase Kinase 3 beta; Male; Neuroprotective Agents; Antipsychotic Agents; Female; Dizocilpine Maleate; Hippocampus; Behavior, Animal; Mice, Inbred C57BL; Social Isolation
PubMed: 38879781
DOI: 10.1002/ddr.22225