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Background Objective Methods Results Conclusion Neuromodulator injections are minimally invasive procedures performed across the globe. Despite their ubiquity, there is a dearth of information on whether and how needle tips used for neuromodulator procedures are deformed after repeated injections.We investigated the magnitude of needle tip deformation following sequential injection passes (3×, 5×, and 10×) during facial neuromodulator injections with three commonly used needle sizes (30G, 31G, and 32G).Neuromodulator was administered for four different aesthetic indications. Each collected needle was mounted and imaged in a Philips XL‐30 Scanning electron microscope. Images were processed using ImageJ photo analysis software.Forty‐five needle tips were investigated. When comparing the facial regions of interest, a statistically significant difference in deformation percentage was found when injecting 10× (p = 0.044) with greatest damage after injecting the glabella (38.4%), followed by lateral canthus (27.9%), forehead (27.5%), and midface (23.1%). Independent of facial region targeted, the mean percentage of needle deformation at 3× was 14.8%, at 5× 19.6%, and at 10× 29.2% with p < 0.001. Smaller needle size corresponded to smaller percentage of damage.Exchanging needles after more than five injection passes will minimize needle deformation and likely increase injection precision. [ABSTRACT FROM AUTHOR]

Targeted plasticity therapy (TPT) utilizes vagus nerve stimulation (VNS) to promote improvements in function following neurological injury and disease. During TPT, a brief burst of VNS induces neuromodulator release, which when paired with relevant behavioral events can influence functionally relevant neuroplasticity. Functional improvements following TPT are therefore in part mediated by neuromodulator signaling. Unfortunately, comorbidities associated with neurological disease often result in altered cognitive states that can influence neuromodulator signaling, potentially impeding neuroplasticity induced by TPT. Aside from altered cognitive states, cardiorespiratory rhythms also affect neuromodulator signaling, due to the vagus nerve’s role in relaying visceral sensory information from the cardiovascular and respiratory systems. Moreover, precise VNS delivery during specific periods of the cardiorespiratory rhythms may further improve TPT. Ultimately, understanding the impact of patient-specific states on neuromodulator signaling may likely facilitate optimized VNS delivery, paving the way for personalized neuromodulation during TPT. Overall, this review explores challenges and considerations for developing advanced TPT paradigms, focusing on altered cognitive states and cardiorespiratory rhythms. We specifically discuss the possible impact of these cognitive states and autonomic rhythms on neuromodulator signaling and subsequent neuroplasticity. Altered cognitive states (arousal deficits or pain) could affect VNS intensity, while cardiorespiratory rhythmsmay further inform optimized timing of VNS. We propose that understanding these interactions will lead to the development of personalized state dependent VNS paradigms for TPT. [ABSTRACT FROM AUTHOR]

Parabens are the most prevalent ingredients in cosmetics and personal care products (PCPs). They are colorless and tasteless and exhibit good stability when combined with other components. Because of these unique physicochemical properties, they are extensively used as antimicrobial and antifungal agents. Their release into the aquatic ecosystem poses potential threats to aquatic organisms, including fish. We conducted an electronic search in PubMed (http://www.ncbi. nlm.nih.gov/pubmed) using the search term parabens and fish and sorted 93 articles consisting of methyl paraben (MTP), ethyl paraben (ETP), propyl paraben (PPP), butyl paraben (BTP), and benzyl paraben (BNP) in several fish species. Furthermore, we confined our search to six fish species (common carp, Cyprinus carpio; fathead minnows, Pimephales promelas; Japanese medaka, Oryzias latipes; rainbow trout, Oncorhynchus mykiss; Nile tilapia, Oreochromis niloticus; and zebrafish, Danio rerio) and four common parabens (MTP, ETP, PPP, and BTP) and sorted 48 articles for review. Our search indicates that among all six fish, zebrafish was the most studied fish and the MTP was the most tested paraben in fish. Moreover, depending on the alkyl chain length and linearity, long-chained parabens were more toxic than the parabens with short chains. Parabens can be considered endocrine disruptors (EDs), targeting estrogen-androgen-thyroid-steroidogenesis (EATS) pathways, blocking the development and growth of gametes, and causing intergenerational toxicity to impact the viability of offspring/larvae. Paraben exposure can also induce behavioral changes and nervous system disorders in fish. Although the USEPA and EU limit the use of parabens in cosmetics and pharmaceuticals, their prolonged persistence in the environment may pose an additional health risk to humans. [ABSTRACT FROM AUTHOR]

The first-line management of cervical dystonia (CD) symptoms is intramuscular injection of botulinum toxin type A (BoNTA). However, a comparison of safety among BoNTAs is difficult because, per regulatory authorities, units of BoNTA activity are not interchangeable. Dysphagia and muscle weakness are widely considered two key adverse events to monitor closely in the treatment of CD. This integrated analysis compared the safety of BoNTAs approved for CD in the US by evaluating relationships between the incidence of dysphagia and muscle weakness in prescribing information and the core neurotoxin content. Coefficients The coefficients of determination (R2) and trendlines were estimated via regression-based lines of best fit. Adverse drug reaction (ADR) rates were strongly correlated with core neurotoxin amounts for conventional BoNTAs (slope coefficients: dysphagia = 0.048, R2 = 0.74; muscle weakness = 0.096, R2 = 0.82). The published ADR rates at approved doses for conventional BoNTAs were higher compared with DaxibotulinumtoxinA (DAXI; DAXXIFY®, Revance Therapeutics, Inc., Nashville, TN, USA) by core neurotoxin content. The use of a core neurotoxin amount was found to be an effective method for comparing the safety of BoNTA products. Current clinical trials suggest that DAXI, a novel BoNTA formulation, provides a potentially wider safety margin compared with other approved BoNTAs for CD. The lower amount of core neurotoxin administered at approved doses compared with conventional BoNTAs may explain low on-target ADRs like muscle weakness, whereas reduced diffusion from the injection site is thought to be responsible for low off-target ADRs like dysphagia. [ABSTRACT FROM AUTHOR]

Purpose of Review: In this manuscript, we aim to review the proposed mechanisms of the pathophysiology of functional heartburn (FH) and functional chest pain (FCP) as well as highlight the different neuromodulatory therapies available to providers and the evidence for each of them. Recent Findings: Understanding the basis for the symptoms that patients are presenting with is essential when evaluating patients with possible esophageal motility disorders or gastroesophageal reflux disease. Objective testing to understand these conditions is a key component to that understanding. Patients undergoing evaluation for heartburn or chest pain, following cardiac evaluation, often require a combination of endoscopy, esophageal manometry, and pH testing. Treatment for FH or FCP often involves some combination of neuromodulatory pharmacologic or behavioral therapies based on their understood pathophysiology. Summary: When a diagnosis of functional heartburn or functional chest pain is reached, it is important for the managing provider to understand the available therapeutic options. Often, treatment requires management with neuromodulation. [ABSTRACT FROM AUTHOR]

Context: In athletes, postural control impairment and knee muscle dysfunction are the most common disorders following anterior cruciate ligament (ACL) injury. Because of functional changes in the motor cortex following ACL injury, physiotherapy (PT) is not enough for treatment and using neuromodulators, such as trans-cranial direct current stimulation (tDCS) may be necessary. The present study focused on the effects of anodal tDCS (a-tDCS) over the primary motor cortex (M1) concurrent with PT on postural control and muscular performance in the athletes with ACL injury. Design: In this study, 34 athletes with ACL injury were randomly assigned in 2 groups of intervention group (active M1 a-tDCS concurrent with PT, n = 16) and control group (sham M1 a-tDCS concurrent with PT, n = 16). Methods: The participants of all groups received 20-minute 2 mA M1 a-tDCS with PT during 10 sessions, while tDCS was turned off after 30 seconds in the sham group. Before, immediately following, and 1 month after the interventions, the center of pressure and the average of power of flexor and extensor muscles at 2 velocities of 30°/s and 60°/s were measured by force plate and isokinetic devices, respectively. Results: One month after treatment, the displacement of center of pressure was decreased in the intervention group (P < .05), while there were no changes in the control group. Y-axis of center of pressure decreased in the intervention group relative to the control group, although average of power of flexor and extensor muscles increased immediately in both groups, but the rise in the intervention group was larger than that in the control group (P < .05). Conclusion: The findings indicated that M1 a-tDCS can induce the efficacy of PT, which has a lasting effect on the improvement of the postural control in athletes with ACL injury. [ABSTRACT FROM AUTHOR]

Vitamin D has multifaceted roles in brain function beyond its traditional role in bone health, impacting neurotransmitters, inflammation, and mood-regulating brain areas where its receptors are present. Conversely, Vitamin D deficiency is often observed in obese individuals. Metreleptin, a synthetic form of human leptin, has demonstrated efficacy in promoting weight loss and alleviating depression among obese patients. However, there is limited direct evidence linking metreleptin to depression reduction or establishing an interaction between metreleptin and Vitamin D in this context. Vitamin D’s neurotrophic and immunomodulatory properties influence neurotransmitter regulation, including serotonin, dopamine, and norepinephrine, vital for mood stability. The presence of Vitamin D Receptors (VDR) in regions of the brain linked to depression further supports its role in mood regulation. Moreover, Vitamin D’s anti-inflammatory effects contribute to mitigating brain inflammation associated with depression. Given the inverse relationship between obesity and Vitamin D levels, obese individuals are at higher risk of Vitamin D deficiency. Metreleptin, as a synthetic leptin analogue, has demonstrated significant efficacy in reducing obesity. Thus, the plausible combination of Vitamin D and metreleptin presents a potential novel strategy for managing depression in obese individuals. Though these therapies may address the intricate interplay of depression in the context of obesity, rigorous research is essential to validate their efficacy and safety in tandem.

Vitamin D has multifaceted roles in brain function beyond its traditional role in bone health, impacting neurotransmitters, inflammation, and mood-regulating brain areas where its receptors are present. Conversely, Vitamin D deficiency is often observed in obese individuals. Metreleptin, a synthetic form of human leptin, has demonstrated efficacy in promoting weight loss and alleviating depression among obese patients. However, there is limited direct evidence linking metreleptin to depression reduction or establishing an interaction between metreleptin and Vitamin D in this context. Vitamin D’s neurotrophic and immunomodulatory properties influence neurotransmitter regulation, including serotonin, dopamine, and norepinephrine, vital for mood stability. The presence of Vitamin D Receptors (VDR) in regions of the brain linked to depression further supports its role in mood regulation. Moreover, Vitamin D’s anti-inflammatory effects contribute to mitigating brain inflammation associated with depression. Given the inverse relationship between obesity and Vitamin D levels, obese individuals are at higher risk of Vitamin D deficiency. Metreleptin, as a synthetic leptin analogue, has demonstrated significant efficacy in reducing obesity. Thus, the plausible combination of Vitamin D and metreleptin presents a potential novel strategy for managing depression in obese individuals. Though these therapies may address the intricate interplay of depression in the context of obesity, rigorous research is essential to validate their efficacy and safety in tandem. [ABSTRACT FROM AUTHOR]

Herein, we briefly review the role of nicotinic acetylcholine receptors in regulating important brain activity by controlled release of acetylcholine from subcortical neuron groups, focusing on a microscopic viewpoint and considering the nonlinear dynamics of biological macromolecules associated with neuron activity and how they give rise to advanced brain functions of brain. [ABSTRACT FROM AUTHOR]

Targeted plasticity therapy (TPT) utilizes vagus nerve stimulation (VNS) to promote improvements in function following neurological injury and disease. During TPT, a brief burst of VNS induces neuromodulator release, which when paired with relevant behavioral events can influence functionally relevant neuroplasticity. Functional improvements following TPT are therefore in part mediated by neuromodulator signaling. Unfortunately, comorbidities associated with neurological disease often result in altered cognitive states that can influence neuromodulator signaling, potentially impeding neuroplasticity induced by TPT. Aside from altered cognitive states, cardiorespiratory rhythms also affect neuromodulator signaling, due to the vagus nerve’s role in relaying visceral sensory information from the cardiovascular and respiratory systems. Moreover, precise VNS delivery during specific periods of the cardiorespiratory rhythms may further improve TPT. Ultimately, understanding the impact of patient-specific states on neuromodulator signaling may likely facilitate optimized VNS delivery, paving the way for personalized neuromodulation during TPT. Overall, this review explores challenges and considerations for developing advanced TPT paradigms, focusing on altered cognitive states and cardiorespiratory rhythms. We specifically discuss the possible impact of these cognitive states and autonomic rhythms on neuromodulator signaling and subsequent neuroplasticity. Altered cognitive states (arousal deficits or pain) could affect VNS intensity, while cardiorespiratory rhythms may further inform optimized timing of VNS. We propose that understanding these interactions will lead to the development of personalized state dependent VNS paradigms for TPT.

Parabens are the most prevalent ingredients in cosmetics and personal care products (PCPs). They are colorless and tasteless and exhibit good stability when combined with other components. Because of these unique physicochemical properties, they are extensively used as antimicrobial and antifungal agents. Their release into the aquatic ecosystem poses potential threats to aquatic organisms, including fish. We conducted an electronic search in PubMed (http://www.ncbi.nlm.nih.gov/pubmed) using the search term parabens and fish and sorted 93 articles consisting of methyl paraben (MTP), ethyl paraben (ETP), propyl paraben (PPP), butyl paraben (BTP), and benzyl paraben (BNP) in several fish species. Furthermore, we confined our search to six fish species (common carp, Cyprinus carpio; fathead minnows, Pimephales promelas; Japanese medaka, Oryzias latipes; rainbow trout, Oncorhynchus mykiss; Nile tilapia, Oreochromis niloticus; and zebrafish, Danio rerio) and four common parabens (MTP, ETP, PPP, and BTP) and sorted 48 articles for review. Our search indicates that among all six fish, zebrafish was the most studied fish and the MTP was the most tested paraben in fish. Moreover, depending on the alkyl chain length and linearity, long-chained parabens were more toxic than the parabens with short chains. Parabens can be considered endocrine disruptors (EDs), targeting estrogen-androgen-thyroid-steroidogenesis (EATS) pathways, blocking the development and growth of gametes, and causing intergenerational toxicity to impact the viability of offspring/larvae. Paraben exposure can also induce behavioral changes and nervous system disorders in fish. Although the USEPA and EU limit the use of parabens in cosmetics and pharmaceuticals, their prolonged persistence in the environment may pose an additional health risk to humans.

Hong-Bin Liang,1,2 Wan-You He,2 Yan-Ping Liu,3 Han-Bing Wang1,2 1Graduate School of Guangdong Medical University, Zhanjiang, Guangdong Province, People’s Republic of China; 2Department of Anesthesiology, The First People’s Hospital of Foshan, Foshan, Guangdong Province, People’s Republic of China; 3College of Nursing, Shandong First Medical University (Shandong Academy of Medical Science), Jinan, Shandong Province, People’s Republic of ChinaCorrespondence: Han-Bing Wang, Department of Anesthesiology, The First People’s Hospital of Foshan, No. 81 North of Ling Nan Road, Foshan, Guangdong Province, People’s Republic of China, Email fswhbing@126.comAbstract: A negative correlation exists between attention and pain. The cognitive impairments linked to pain can significantly impede a patient’s healing process and everyday tasks, particularly for individuals experiencing persistent pain. Furthermore, it has been demonstrated that diversion can effectively decrease pain levels in individuals. The focus of this review is to analyze clinical trials and fundamental investigations regarding alterations in focus and persistent discomfort. Moreover, we investigated the common neuroanatomy associated with attention and pain. Furthermore, we examined the impact of various neuromodulators on the transmission of pain and processes related to attention, while also considering the potential neural mechanisms that contribute to the co-occurrence of pain and attention deficits. Further investigation in this field will enhance our comprehension of patient symptoms and the underlying pathophysiology, ultimately resulting in more objective approaches to treatment.Keywords: pain, attention deficit, brain, neuromodulator

The unraveling of the regulatory mechanisms that govern neuronal excitability is a major challenge for neuroscientists worldwide. Neurotransmitters play a critical role in maintaining the balance between excitatory and inhibitory activity in the brain. The balance controls cognitive functions and emotional responses. Glutamate and γ-aminobutyric acid (GABA) are the primary excitatory and inhibitory neurotransmitters of the brain, respectively. Disruptions in the balance between excitatory and inhibitory transmission are implicated in several psychiatric disorders, including anxiety disorders, depression, and schizophrenia. Neuromodulators such as dopamine and acetylcholine control cognition and emotion by regulating the excitatory/inhibitory balance initiated by glutamate and GABA. Dopamine is closely associated with reward-related behaviors, while acetylcholine plays a role in aversive and attentional behaviors. Although the physiological roles of neuromodulators have been extensively studied neuroanatomically and electrophysiologically, few researchers have explored the interplay between neuronal excitability and cell signaling and the resulting impact on emotion regulation. This review provides an in-depth understanding of “cell signaling crosstalk” in the context of neuronal excitability and emotion regulation. It also anticipates that the next generation of neurochemical analyses, facilitated by integrated phosphorylation studies, will shed more light on this topic. [ABSTRACT FROM AUTHOR]

Oxytocin (OXT) and OXT receptor (OXTR)-mediated signaling control excitability, firing patterns, and plasticity of hippocampal CA2 pyramidal neurons, which are pivotal in generation of brain oscillations and social memory. Nonetheless, the ionic mechanisms underlying OXTR-induced effects in CA2 neurons are not fully understood. Using slice physiology in a reporter mouse line and interleaved current-clamp and voltage-clamp experiments, we systematically identified the ion channels modulated by OXT signaling in CA2 pyramidal cells (PYRs) in mice of both sexes and explored how changes in channel conductance support altered electrical activity. Activation of OXTRs inhibits an outward potassium current mediated by inward rectifier potassium channels (I Kir) and thus favoring membrane depolarization. Concomitantly, OXT signaling also diminishes inward current mediated by hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels (I h), providing a hyperpolarizing drive. The combined reduction in both I Kir and I h synergistically elevate the membrane resistance and favor dendritic integration while the membrane potential is restrained from quickly depolarizing from rest. As a result, the responsiveness of CA2 PYRs to synaptic inputs is highly sharpened during OXTR activation. Unexpectedly, OXTR signaling also strongly enhances a tetrodotoxin-resistant (TTX-R), voltage-gated sodium current that helps drive the membrane potential to spike threshold and thus promote rhythmic firing. This novel array of OXTR-stimulated ionic mechanisms operates in close coordination and underpins OXT-induced burst firing, a key step in CA2 PYRs' contribution to hippocampal information processing and broader influence on brain circuitry. Our study deepens our understanding of underpinnings of OXT-promoted social memory and general neuropeptidergic control of cognitive states.SIGNIFICANCE STATEMENT Oxytocin (OXT) plays key roles in reproduction, parenting and social and emotional behavior, and deficiency in OXT receptor (OXTR) signaling may contribute to neuropsychiatric disorders. We identified a novel array of OXTR-modulated ion channels that operate in close coordination to retune hippocampal CA2 pyramidal neurons, enhancing responsiveness to synaptic inputs and sculpting output. OXTR signaling inhibits both potassium conductance (I Kir) and mixed cation conductance (I h), engaging opposing influences on membrane potential, stabilizing it while synergistically elevating membrane resistance and electrotonic spread. OXT signaling also facilitates a tetrodotoxin-resistant (TTX-R) Na+ current, not previously described in hippocampus (HP), engaged on further depolarization. This TTX-R current lowers the spike threshold and supports rhythmic depolarization and burst firing, a potent driver of downstream circuitry.

GBM, or glioblastoma multiforme, is a brain tumor that poses a great threat to both children and adults, being the primary cause of death related to brain tumors. GBM is often associated with epilepsy, which can be debilitating. Seizures and the development of epilepsy are the primary symptoms that have a severe impact on the quality of life for GBM patients. It is increasingly apparent that the nervous system plays an essential role in the tumor microenvironment for all cancer types, including GBM. In recent years, there has been a growing understanding of how neurotransmitters control the progression of gliomas. Evidence suggests that neurotransmitters and neuromodulators found in the tumor microenvironment play crucial roles in the excitability, proliferation, quiescence, and differentiation of neurons, glial cells, and neural stem cells. The involvement of neurotransmitters appears to play a significant role in various stages of GBM. In this review, the focus is on presenting updated knowledge and emerging ideas regarding the interplay between neurotransmitters and neuromodulators, such as glutamate, GABA, norepinephrine, dopamine, serotonin, adenosine, and their relationship with GBM and the seizures induced by this condition. The review aims to explore the current understanding and provide new insights into the complex interactions between these neurotransmitters and neuromodulators in the context of GBM‐related seizures. [ABSTRACT FROM AUTHOR]

Stress is a complex and multifaceted phenomenon that can significantly influence both aggressive behavior and sexual function. This review explores the intricate relationship between stress, neuromodulator pathways, and epigenetics, shedding light on the various mechanisms that underlie these connections. While the role of stress in both aggression and sexual behavior is well-documented, the mechanisms through which it exerts its effects are multifarious and not yet fully understood. The review begins by delving into the potential influence of stress on the Hypothalamic-Pituitary-Adrenal (HPA) axis, glucocorticoids, and the neuromodulators involved in the stress response. The intricate interplay between these systems, which encompasses the regulation of stress hormones, is central to understanding how stress may contribute to aggressive behavior and sexual function. Several neuromodulator pathways are implicated in both stress and behavior regulation. We explore the roles of norepinephrine, serotonin, oxytocin, and androgens in mediating the effects of stress on aggression and sexual function. It is important to distinguish between general sexual behavior, sexual motivation, and the distinct category of “sexual aggression” as separate constructs, each necessitating specific examination. Additionally, epigenetic mechanisms emerge as crucial factors that link stress to changes in gene expression patterns and, subsequently, to behavior. We then discuss how epigenetic modifications can occur in response to stress exposure, altering the regulation of genes associated with stress, aggression, and sexual function. While numerous studies support the association between epigenetic changes and stress-induced behavior, more research is necessary to establish definitive links. Throughout this exploration, it becomes increasingly clear that the relationship between stress, neuromodulator pathways, and epigenetics is intricate and multifaceted. The review emphasizes the need for further research, particularly in the context of human studies, to provide clinical significance and to validate the existing findings from animal models. By better understanding how stress influences aggressive behavior and sexual function through neuromodulator pathways and epigenetic modifications, this research aims to contribute to the development of innovative protocols of precision medicine and more effective strategies for managing the consequences of stress on human behavior. This may also pave way for further research into risk factors and underlying mechanisms that may associate stress with sexual aggression which finds application not only in neuroscience, but also law, ethics, and the humanities in general.

Reduced oral aperture (ROA), resulting from systemic sclerosis (SSc), is a debilitating condition with limited treatment options. Improvement in oral function has been reported with perioral administration of botulinum toxin type A. To prospectively evaluate the efficacy of onabotulinumtoxinA (onabotA) injection in improving oral opening and quality of life in SSc patients with ROA. Seventeen women with SSc and ROA were treated with 16 units of onabotA in 8 different sites around the cutaneous lips. Measurements of maximum mouth opening were taken before treatment, at 2 weeks posttreatment, and at 3 months posttreatment. Function and quality of life were also assessed via surveys. Interincisor and interlabial distances were significantly increased 2 weeks after treatment with onabotA (P <.001) but not 3 months after. Subjective improvement in quality of life was noted. This single-institution study enrolled 17 patients and did not have a placebo control group. OnabotA appears to have a strong short-term symptomatic benefit in patients with ROA due to SSc, with possible benefit to quality of life. [ABSTRACT FROM AUTHOR]

Nanomedicines are promising for delivering drugs to the central nervous system, though their precision is still being improved. Fortifying nanoparticles with vital molecules can interact with the blood–brain barrier, enabling access to brain tissue. This study summarizes recent advances in nanomedicine to treat neurological complications. The integration of nanotechnology into cell biology aids in the study of brain cells' interactions. Magnetic microhydrogels have exhibited superior neuron activation compared with superparamagnetic iron oxide nanoparticles and hold promise for neuropsychiatric disorders. Nanomaterials have shown notable results, such as tackling neurodegenerative diseases by hindering harmful protein buildup and regulating cellular processes. However, further studies of the safety and effectiveness of nanoparticles in managing neurological diseases and disorders are still required. [ABSTRACT FROM AUTHOR]

Background: Real‐world data on the outcome of routine treatment for disorders of gut‐brain interaction (DGBI) in secondary care are lacking. Method: A longitudinal study of consecutive adult patients with various DGBI attending this institution's gastroenterology clinic was conducted. Following 2 years of treatment, the proportion of patients with symptom improvement, details of clinical therapy, factors associated with and the impact of 'no symptom improvement' were determined. Results: A total of 289 patients (median age 68 years; 64.7% females; 28.4% irritable bowel syndrome (IBS), 20.1% functional dyspepsia (FD), 8.7% functional constipation (FC), 42.9% overlap syndrome) were recruited. After 2 years, 66.1% patients reported symptom improvement. Patients with overlap syndrome were less likely to have symptomatic improvement compared to those with a single DGBI (Overlap 55.6% vs IBS 74.4% vs FD 72.4% vs FC 76.0%, p = 0.014). Reassurance was associated with symptom improvement (p < 0.001). On multivariate analysis, overlap syndrome remained significantly associated with a poorer outcome (OR 2.27, 95% CI 1.22–4.25, p = 0.010), while providing reassurance was associated with a positive outcome (OR 0.30, 95% CI 0.16–0.56, p < 0.001). Only 25.6% and 14.9% of patients were referred for a low FODMAP diet and psychiatric intervention respectively. DGBI patients who had 'no improvement' were more likely to seek further GI consultations and had more work absenteeism. Conclusion: Two‐thirds of DGBI patients in secondary care showed symptom improvement. Patients who were reassured had better symptom improvement, while those with an overlap syndrome were associated with a poorer outcome, resulting in greater healthcare consultation and work absenteeism. [ABSTRACT FROM AUTHOR]

An important component of plastic surgery residency training is independent cosmetic patient management. A resident cosmetic clinic was created at Oregon Health & Science University in 2007 to expand this experience. The cosmetic clinic has traditionally been most successful in offering nonsurgical facial rejuvenation with neuromodulators and soft tissue fillers. This study focuses on the demographics of the patient population and the treatments provided over a 5-year period and compares this experience to those of the same program's attending cosmetic clinics. A retrospective chart review of all patients seen at Oregon Health & Science University's Plastic and Reconstructive Surgery Resident Cosmetic Clinic between January 1, 2017, and December 31, 2021 was performed. Patient demographics, type of injectable received (neuromodulator versus soft tissue filler), location of injection, and additional cosmetic procedures were evaluated. Two hundred patients met the study criteria, which included 114 seen in the resident clinic (RC), 31 seen in attending clinic (AC), and 55 patients seen in both. A primary analysis compared the two groups seen in the resident and attending only clinics. The average age of patients seen in the RC was younger, 45 versus 51.5 (P ≤ 0.05). There was a trend toward more patients in the RC being involved in healthcare as compared to those patients seen in the AC, but this difference was not found to be statistically significant. The median number of neuromodulator visits in the RC was 2 (1, 4) versus 1 (1, 2) in the AC (P ≤ 0.05) The most common location for neuromodulator injections in both clinics was the corrugators. Patients in the resident cosmetic clinic were younger females, most receiving neuromodulator injections. No statistically significant differences were identified in patient population, injections received, and location of injections between the two clinics, indicating a similar trainee skill set and patient care plan between the two clinics. [ABSTRACT FROM AUTHOR]

Thyrotropin-releasing hormone (TRH) is a tripeptide that regulates the neuroendocrine thyroid axis. Moreover, its widespread brain distribution has indicated that it is a relevant neuromodulator of behaviors such as feeding, arousal, anxiety, and locomotion. Importantly, it is also a neurotrophic peptide, and thus may halt the development of neurodegenerative diseases and improve mood-related disorders. Its neuroprotective actions on those pathologies and behaviors have been limited due to its poor intestinal and blood–brain barrier permeability, and because it is rapidly degraded by a serum enzyme. As new strategies such as TRH intranasal delivery emerge, a renewed interest in the peptide has arisen. TRH analogs have proven to be safe in animals and humans, while not inducing alterations in thyroid hormones' levels. In this review, we integrate research from different approaches, aiming to demonstrate the therapeutic effects of TRH, and to summarize new efforts to prolong and facilitate the peptide's actions to improve symptoms and the progression of several pathologies. [ABSTRACT FROM AUTHOR]

Background: Piper guineense and honey contain antioxidative, anti-inflammatory, and antimicrobial properties that can help restore neuronal and other cell damage. To investigate the neuromodulatory roles of p. guineense and honey against lead toxicity on the hippocampus and cerebellum, impairing social behaviors and motor activities. Methodology: Thirty Wistar rats were separated into six groups of five rats each, marked with dye. Group A served as control; B was untreated lead; C was a medium dose of the extract (50 mg/kg) and honey (1000 mg/kg); D was a high dose of the extract (80 mg/kg) and honey (1500 mg/kg); E received extract (80 mg/kg), and F received honey (1500 mg/kg). All groups received 110 mg/kg of lead orally, except the control. Social interaction, antidepressant effects, and motor activities were studied using a sociability chamber (SC), Forced Swim Test (FST), and String methods. A blood sample was used to evaluate glutathione peroxidase (GPx) and glutathione oxide transaminase (GOT), while the lipid level was estimated using cerebellar homogenate. Neuronal damage, vacuolation, necrosis, cell degeneration, and alterations in both hippocampus and cerebellum marked untreated group, with decreased GPx and GOT activities followed by impaired motor activities, social behavior, memory, and motivation. Using SCT, group B spent significantly lesser time (47.60 ± 47.60) with stranger 1 compared to A (138.20 ± 34.05), while group C spent considerably more time with stranger 1 (86.80 ± 30.32) than group B at P ≥ 0.05. The treatment increased the enzyme level and restored histoarchitecture (Figures 1–12), improving motor activities, social behavior, memory, motivation, and social affiliation (Tables 3, 4, 2, and 6). The extract and honey may be helpful as neuromodulators in lead toxicity in a dose-dependent manner.

Nicotinamide adenine dinucleotide (NAD) is a substrate of adenosine diphosphate (ADP)-ribosyl cyclase and is catalyzed to cyclic ADP-ribose (cADPR) by CD38 and/or CD157. cADPR, a Ca2+ mobilizing second messenger, is critical in releasing oxytocin from the hypothalamus into the brain. Although NAD precursors effectively play a role in neurodegenerative disorders, muscular dystrophy, and senescence, the beneficial effects of elevating NAD by NAD precursor supplementation on brain function, especially social interaction, and whether CD38 is required in this response, has not been intensely studied. Here, we report that oral gavage administration of nicotinamide riboside, a perspective NAD precursor with high bioavailability, for 12 days did not show any suppressive or increasing effects on sociability (mouse's interest in social targets compared to non-social targets) in both CD157KO and CD38KO male mice models in a threechamber test. CD157KO and CD38KO mice displayed no social preference (that is, more interest towards a novel mouse than a familiar one) behavior. This defect was rescued after oral gavage administration of nicotinamide riboside for 12 days in CD157KO mice, but not in CD38KO mice. Social memory was not observed in CD157KO and CD38KO mice; subsequently, nicotinamide riboside administration had no effect on social memory. Together with the results that nicotinamide riboside had essentially no or little effect on body weight during treatment in CD157KO mice, nicotinamide riboside is less harmful and has beneficial effect on defects in recovery from social behavioral, for which CD38 is required in mice. [ABSTRACT FROM AUTHOR]

Artificial optoelectronic synapses with flexibly regulated synaptic weight are crucial to the rapidly evolved artificial visual system. Although three‐terminal devices with transistor geometry have exhibited controllable synaptic response through applying electrical pulses on the gate terminal, the complicated device structure limits its integration with array configurations. In this work, a simple two‐terminal optoelectronic synapses array based on the ZnO/Al2O3/CdS heterojunction with tunable synaptic weight is presented. It can respond to UV and green light stimulation in a neuromorphic manner, allowing the implementation of the basic synaptic function. By introducing the piezo‐phototronic effect, the synaptic weight can be regulated in multilevels, extending the forgetting time by 30.08% and reducing training epochs for image recognition by 36.13%. In addition, the device can extract the target image from massive noisy optical inputs avoiding redundant data memorization. This work provides a novel method to regulate the synaptic weight of the simple two‐terminal device configuration through the piezo‐phototronic effect, showing potential applications for the mimicry of the human visual‐perception system. [ABSTRACT FROM AUTHOR]

The bed nuclei of the stria terminalis (BST) is recognised as a pivotal integrative centre for monitoring emotional valence. It is implicated in the regulation of diverse affective states and motivated behaviours, and decades of research have firmly established its critical role in anxiety-related behavioural processes. Researchers have recently intricately dissected the BST's dynamic activities, its connection patterns and its functions with respect to specific cell types using multiple techniques such as optogenetics, in vivo calcium imaging and transgenic tools to unmask the complex circuitry mechanisms that underlie anxiety. In this review, we principally focus on studies of anxiety-involved neuromodulators within the BST and provide a comprehensive architecture of the anxiety network--highlighting the BST as a key hub in orchestrating anxiety-like behaviour. We posit that these promising efforts will contribute to the identification of an accurate roadmap for future treatment of anxiety disorders. [ABSTRACT FROM AUTHOR]

The behavior of somatic stem cells is regulated by their niche. Interaction between hematopoietic stem cells (HSCs) and their niches are a representative model to understand stem cell‐niche interplay. Here, we provide an overview of crosstalk between HSCs and their niches in bone marrow and extramedullary organs following the life journey of HSCs from emergence, development, maturation until aging. We highlight the unique differences of HSC niches in different life stages within various organs focusing on recent literature to propose new speculations and hypotheses. [ABSTRACT FROM AUTHOR]

Nicotinamide adenine dinucleotide (NAD) is a substrate of adenosine diphosphate (ADP)-ribosyl cyclase and is catalyzed to cyclic ADP-ribose (cADPR) by CD38 and/or CD157. cADPR, a Ca2+ mobilizing second messenger, is critical in releasing oxytocin from the hypothalamus into the brain. Although NAD precursors effectively play a role in neurodegenerative disorders, muscular dystrophy, and senescence, the beneficial effects of elevating NAD by NAD precursor supplementation on brain function, especially social interaction, and whether CD38 is required in this response, has not been intensely studied. Here, we report that oral gavage administration of nicotinamide riboside, a perspective NAD precursor with high bioavailability, for 12 days did not show any suppressive or increasing effects on sociability (mouse’s interest in social targets compared to non-social targets) in both CD157KO and CD38KO male mice models in a three-chamber test. CD157KO and CD38KO mice displayed no social preference (that is, more interest towards a novel mouse than a familiar one) behavior. This defect was rescued after oral gavage administration of nicotinamide riboside for 12 days in CD157KO mice, but not in CD38KO mice. Social memory was not observed in CD157KO and CD38KO mice; subsequently, nicotinamide riboside administration had no effect on social memory. Together with the results that nicotinamide riboside had essentially no or little effect on body weight during treatment in CD157KO mice, nicotinamide riboside is less harmful and has beneficial effect on defects in recovery from social behavioral, for which CD38 is required in mice.

Abstract Artificial optoelectronic synapses with flexibly regulated synaptic weight are crucial to the rapidly evolved artificial visual system. Although three‐terminal devices with transistor geometry have exhibited controllable synaptic response through applying electrical pulses on the gate terminal, the complicated device structure limits its integration with array configurations. In this work, a simple two‐terminal optoelectronic synapses array based on the ZnO/Al2O3/CdS heterojunction with tunable synaptic weight is presented. It can respond to UV and green light stimulation in a neuromorphic manner, allowing the implementation of the basic synaptic function. By introducing the piezo‐phototronic effect, the synaptic weight can be regulated in multilevels, extending the forgetting time by 30.08% and reducing training epochs for image recognition by 36.13%. In addition, the device can extract the target image from massive noisy optical inputs avoiding redundant data memorization. This work provides a novel method to regulate the synaptic weight of the simple two‐terminal device configuration through the piezo‐phototronic effect, showing potential applications for the mimicry of the human visual‐perception system.

DaxibotulinumtoxinA for Injection (DAXI) is a novel botulinum toxin type A product containing daxibotulinumtoxinA with a stabilizing excipient peptide (RTP004). DAXI immunogenicity was assessed in three phase 3 glabellar line studies (two placebo-controlled, single-dose studies and an open-label repeat-dose safety study). Binding antibodies to daxibotulinumtoxinA and RTP004 were detected by validated ELISAs. Samples positive for daxibotulinumtoxinA-binding antibodies were evaluated further for titer and neutralizing antibodies by mouse protection assay. Overall, 2786 subjects received DAXI and 2823 subjects were exposed to RTP004 as DAXI (n = 2786) or placebo (n = 37). Treatment-related anti-daxibotulinumtoxinA binding antibodies were detected in 21 of 2737 evaluable subjects (0.8%). No subject developed neutralizing antibodies. Treatment-related anti-RTP004 binding antibodies were detected in 35 (1.3%) of 2772 evaluable subjects. Binding antibodies were generally transient, of low titer (<1:200), and no subject had binding antibodies to both daxibotulinumtoxinA and RTP004. All subjects with treatment-induced binding antibodies to daxibotulinumtoxinA or RTP004 achieved none or mild glabellar line severity at Week 4 following each DAXI cycle, indicating no impact on DAXI efficacy. No subjects with binding antibodies to daxibotulinumtoxinA or RTP004 reported immune-related adverse events. This evaluation of anti-drug antibody formation with DAXI shows low rates of antibody formation to both daxibotulinumtoxinA and RTP004. [ABSTRACT FROM AUTHOR]

The Drosophila melanogaster (fruit fly), is a crucial and straightforward model organism for researching how genetic changes affect behavior and neural activity. Drosophila is used by biologists to study the nervous system because of its genetic tractability, well-known complex behaviors, straightforward neuroanatomy, and numerous human genes orthologs. Due to the Drosophila central nervous system's diminutive size, neurochemical studies are difficult. Recently, electrochemistry-based techniques have been created to monitor the release and clearance of neurotransmitters in real time in both larvae and adults. So, in this study Drosophila models used to study neuromodulator activity were reviewed and compiled using various databases. It is possible to take a close look at the functional role of traditional neuromodulators like octopamine, serotonin, dopamine, and neuropeptides using the genetic toolkit of Drosophila. This study compiles neurotransmitter role such as dopamine, serotonin, and octopamine production in both genetically normal and mutant flies. The fly is a system that is well-suited to shed new light on the complex issue of how neuromodulation might link behavioral demands particular to a given scenario with the level of arousal in the brain. The fly has powerful genetic tools and increasingly well-defined behavioral circuits. [ABSTRACT FROM AUTHOR]

Background and objectiveLong-course (LC) antidepressants for the treatment of disorders of gut-brain interaction, such as refractory functional dyspepsia (rFD), pose patients at risk of antidepressant discontinuation syndrome (ADS). Short-course (SC) therapy of rapid-acting antidepressant may reduce discontinuation syndromes while maintaining efficacy for dyspeptic symptoms. However, the evidence-based research is lacking. This study aims to determine whether SC therapy with antidepressants could decrease the risk of ADS with comparable treatment efficacy to LC therapy in rFD.MethodsThis randomized clinical trial with rFD patients was conducted at a tertiary hospital in China. Participants (N = 240) were randomly allocated to receive flupentixol-melitracen (FM) plus omeprazole therapy for 2 (SC group) or 4 (LC group) weeks, respectively. Scores for Leeds Dyspepsia Questionnaire (LDQ), Generalized Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire-9 for Depression (PHQ-9) were assessed at baseline and every 2 weeks, ending at 4 weeks after treatment. ADS was assessed after drug cessation. Medication possession ratio (MPR) for FM was calculated.ResultsThe severity and incidence of ADS of patients in SC group were significantly lower than those in LC group (0.60 ± 0.62 vs. 1.71 ± 1.58 and 3.64 vs. 39.45%; both P < 0.0001). The MPR values for FM were significantly higher in patients of SC group than in LC group (P < 0.0001). Scores for LDQ, GAD-7 and PHQ-9 decreased in patients of both groups, and the symptom improvement in SC group was comparable to that in LC group after treatment.ConclusionsCompared to 4-week FM therapy, the 2-week FM therapy reduces the risk of ADS with non-inferior treatment efficacy in patients with rFD.Clinical trial registrationClinical trials.gov, identifier NCT05099913.

A person's smile frames the face and, arguably, is the most pleasing and meaningful facial expression, as well as a universal sign of happiness. A gummy smile can be a significant aesthetic concern. Its treatment can have a huge impact on a patient's confidence and, consequently, is highly rewarding for practitioners. A substantial improvement in a gummy smile can be achieved with both non-surgical and surgical interventions. The choice of treatment depends on the underlying aetiology, of which there can be multiple. Treatment modalities include botulinum toxin type A, dermal filler, surgical repositioning of the lip, gingivectomy, crown lengthening or a combination of the aforementioned. For each of these methods, it is important to consider its suitability depending on the underlying causes of the gummy smile and the patient's aesthetic goals, as well as any risks or downtime involved. [ABSTRACT FROM AUTHOR]

Oxytocin (OXT) and OXT receptor (OXTR)-mediated signaling control excitability, firing patterns, and plasticity of hippocampal CA2 pyramidal neurons, which are pivotal in generation of brain oscillations and social memory. Nonetheless, the ionic mechanisms underlying OXTR-induced effects in CA2 neurons are not fully understood. Using slice physiology in a reporter mouse line and interleaved current-clamp and voltage-clamp experiments, we systematically identified the ion channels modulated by OXT signaling in CA2 pyramidal cells (PYRs) in mice of both sexes and explored how changes in channel conductance support altered electrical activity. Activation of OXTRs inhibits an outward potassium current mediated by inward rectifier potassium channels (IKir) and thus favoring membrane depolarization. Concomitantly, OXT signaling also diminishes inward current mediated by hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels (Ih), providing a hyperpolarizing drive. The combined reduction in both IKir and Ih synergistically elevate the membrane resistance and favor dendritic integration while the membrane potential is restrained from quickly depolarizing from rest. As a result, the responsiveness of CA2 PYRs to synaptic inputs is highly sharpened during OXTR activation. Unexpectedly, OXTR signaling also strongly enhances a tetrodotoxin-resistant (TTX-R), voltage-gated sodium current that helps drive the membrane potential to spike threshold and thus promote rhythmic firing. This novel array of OXTR-stimulated ionic mechanisms operates in close coordination and underpins OXT-induced burst firing, a key step in CA2 PYRs' contribution to hippocampal information processing and broader influence on brain circuitry. Our study deepens our understanding of underpinnings of OXT-promoted social memory and general neuropeptidergic control of cognitive states. [ABSTRACT FROM AUTHOR]

The vertebrate nonapeptide families arginine vasopressin (AVP) and oxytocin (OXT) are considered to have evolved from a single vasopressin-like peptide present in invertebrates and termed arginine vasotocin in early vertebrate evolution. Unprecedented genome sequence availability has more recently allowed new insight into the evolution of nonapeptides and especially their receptor families in the context of whole genome duplications. In bony fish, nonapeptide homologues of AVP termed arginine vasotocin (Avp) and an OXT family peptide (Oxt) originally termed isotocin have been characterized. While reproductive roles of both nonapeptide families have historically been studied in several vertebrates, their roles in teleost reproduction remain much less understood. Taking advantage of novel genome resources and associated technological advances such as genetic modifications in fish models, we here critically review the current state of knowledge regarding the roles of nonapeptide systems in teleost reproduction. We further discuss sources of plasticity of the conserved nonapeptide systems in the context of diverse reproductive phenotypes observed in teleost fishes. Given the dual roles of preoptic area (POA) synthesized Avp and Oxt as neuromodulators and endocrine/paracrine factors, we focus on known roles of both peptides on reproductive behaviour and the regulation of the hypothalamic-pituitarygonadal axis. Emphasis is placed on the identification of a gonadal nonapeptide system that plays critical roles in both steroidogenesis and gamete maturation. We conclude by highlighting key research gaps including a call for translational studies linking new mechanistic understanding of nonapeptide regulated physiology in the context of aquaculture, conservation biology and ecotoxicology. [ABSTRACT FROM AUTHOR]

Background: Piper guineense and honey contain antioxidative, anti-inflammatory, and antimicrobial properties that can help restore neuronal and other cell damage. To investigate the neuromodulatory roles of p. guineense and honey against lead toxicity on the hippocampus and cerebellum, impairing social behaviors and motor activities. Methodology: Thirty Wistar rats were separated into six groups of five rats each, marked with dye. Group A served as control; B was untreated lead; C was a medium dose of the extract (50 mg/kg) and honey (1000 mg/kg); D was a high dose of the extract (80 mg/kg) and honey (1500 mg/kg); E received extract (80 mg/kg), and F received honey (1500 mg/kg). All groups received 110 mg/kg of lead orally, except the control. Social interaction, antidepressant effects, and motor activities were studied using a sociability chamber (SC), Forced Swim Test (FST), and String methods. A blood sample was used to evaluate glutathione peroxidase (GPx) and glutathione oxide transaminase (GOT), while the lipid level was estimated using cerebellar homogenate. Neuronal damage, vacuolation, necrosis, cell degeneration, and alterations in both hippocampus and cerebellum marked untreated group, with decreased GPx and GOT activities followed by impaired motor activities, social behavior, memory, and motivation. Using SCT, group B spent significantly lesser time (47.60 ± 47.60) with stranger 1 compared to A (138.20 ± 34.05), while group C spent considerably more time with stranger 1 (86.80 ± 30.32) than group B at P = 0.05. The treatment increased the enzyme level and restored histoarchitecture (Figures 1-12), improving motor activities, social behavior, memory, motivation, and social affiliation (Tables 3, 4, 2, and 6). The extract and honey may be helpful as neuromodulators in lead toxicity in a dose-dependent manner. [ABSTRACT FROM AUTHOR]

The vertebrate nonapeptide families arginine vasopressin (AVP) and oxytocin (OXT) are considered to have evolved from a single vasopressin-like peptide present in invertebrates and termed arginine vasotocin in early vertebrate evolution. Unprecedented genome sequence availability has more recently allowed new insight into the evolution of nonapeptides and especially their receptor families in the context of whole genome duplications. In bony fish, nonapeptide homologues of AVP termed arginine vasotocin (Avp) and an OXT family peptide (Oxt) originally termed isotocin have been characterized. While reproductive roles of both nonapeptide families have historically been studied in several vertebrates, their roles in teleost reproduction remain much less understood. Taking advantage of novel genome resources and associated technological advances such as genetic modifications in fish models, we here critically review the current state of knowledge regarding the roles of nonapeptide systems in teleost reproduction. We further discuss sources of plasticity of the conserved nonapeptide systems in the context of diverse reproductive phenotypes observed in teleost fishes. Given the dual roles of preoptic area (POA) synthesized Avp and Oxt as neuromodulators and endocrine/paracrine factors, we focus on known roles of both peptides on reproductive behaviour and the regulation of the hypothalamic-pituitary-gonadal axis. Emphasis is placed on the identification of a gonadal nonapeptide system that plays critical roles in both steroidogenesis and gamete maturation. We conclude by highlighting key research gaps including a call for translational studies linking new mechanistic understanding of nonapeptide regulated physiology in the context of aquaculture, conservation biology and ecotoxicology.

Thyrotropin-releasing hormone (TRH) is a tripeptide that regulates the neuroendocrine thyroid axis. Moreover, its widespread brain distribution has indicated that it is a relevant neuromodulator of behaviors such as feeding, arousal, anxiety, and locomotion. Importantly, it is also a neurotrophic peptide, and thus may halt the development of neurodegenerative diseases and improve mood-related disorders. Its neuroprotective actions on those pathologies and behaviors have been limited due to its poor intestinal and blood–brain barrier permeability, and because it is rapidly degraded by a serum enzyme. As new strategies such as TRH intranasal delivery emerge, a renewed interest in the peptide has arisen. TRH analogs have proven to be safe in animals and humans, while not inducing alterations in thyroid hormones’ levels. In this review, we integrate research from different approaches, aiming to demonstrate the therapeutic effects of TRH, and to summarize new efforts to prolong and facilitate the peptide’s actions to improve symptoms and the progression of several pathologies.

The influence of neuromodulators on brain activity and behaviour is undeniably profound, yet our knowledge of the underlying mechanisms, or ability to reliably reproduce effects across varying conditions, is still lacking. Oxytocin, a hormone that acts as a neuromodulator in the brain, is an example of this quandary; it powerfully shapes behaviours across nearly all mammalian species, yet when manipulated exogenously can produce unreliable or sometimes unexpected behavioural results across varying contexts. While current research is rapidly expanding our understanding of oxytocin, interactions between oxytocin and other neuromodulatory systems remain underappreciated in the current literature. This review highlights interactions between oxytocin and the opioid system that serve to influence social behaviour and proposes a parallel-mechanism hypothesis to explain the supralinear effects of combinatorial neuropharmacological approaches. This article is part of the theme issue 'Interplays between oxytocin and other neuromodulators in shaping complex social behaviours'. [ABSTRACT FROM AUTHOR]