The impact of magnesium biotinate and arginine silicate complexes on metabolic dysfunctions, antioxidant activity, inflammation, and neuromodulation in high-fat diet-fed rats.

Biotin and arginine play crucial roles in lipid metabolism and may offer promising interventions against obesity. This study examined the combined effect of magnesium biotinate (MgB) and inositol-stabilized arginine silicate complex (ASI) on obesity-related oxidative imbalance, inflammation, lipid metabolism and neuromodulation in rats on a high-fat diet (HFD). Forty rats were divided into five groups: (a) control: rats were fed a standard diet containing 12% of energy from fat; (b) HFD: rats were fed the HFD with 42% of energy from fat; (c) HFD + MgB: rats were fed the HFD and given 0.31 mg/kg body weight (BW) MgB, (d) HFD + ASI: rats were fed the HFD and were given 12.91 mg/kg BW ASI), and (e) HFD + MgB + ASI: rats were fed the HFD and given 0.31 mg/kg BW MgB and 12.91 mg/kg BW ASI). The combined administration of MgB and ASI reduced the levels of serum cholesterol, free fatty acid (FFA), and malondialdehyde (MDA), as well as liver inflammatory cytokines, sterol regulatory element-binding protein 1-c (SREBP-1c), and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) proteins (P < 0.001) compared to HFD rats without supplementation. Moreover, this combination increased the activities of antioxidant enzymes (P < 0.05) and boosted the brain-derived neurotrophic factor (BDNF), serotonin, dopamine (P < 0.001), as well as liver insulin receptor substrate 1 (IRS-1) and peroxisome proliferator-activated receptor gamma (PPAR-γ) (P < 0.001). These findings suggest that combining MgB and ASI could deter liver fat accumulation and enhance lipid metabolism in HFD-fed rats by modulating various metabolic pathways and neuromodulators related to energy metabolism. This combination demonstrates potential in addressing obesity and its related metabolic dysfunctions.

Adaptive robustness through incoherent signaling mechanisms in a regenerative brain.

Animal behavior emerges from collective dynamics of neurons, making it vulnerable to damage. Paradoxically, many organisms exhibit a remarkable ability to maintain significant behavior even after large-scale neural injury. Molecular underpinnings of this extreme robustness remain largely unknown. Here, we develop a quantitative pipeline to measure long-lasting latent states in planarian flatworm behaviors during whole-brain regeneration. By combining >20,000 animal trials with neural network modeling, we show that long-range volumetric peptidergic signals allow the planarian to rapidly restore coarse behavior output after large perturbations to the nervous system, while slow restoration of small-molecule neuromodulator functions refines precision. This relies on the different time and length scales of neuropeptide and small-molecule transmission to generate incoherent patterns of neural activity that competitively regulate behavior. Controlling behavior through opposing communication mechanisms creates a more robust system than either alone and may serve as a generalizable approach for constructing robust neural networks.

AGA Clinical Practice Update on Diagnosis and Management of Cyclic Vomiting Syndrome: Commentary.

DESCRIPTION: The purpose of this American Gastroenterological Association (AGA) Institute Clinical Practice Update (CPU) is to review the available evidence and provide expert advice regarding the diagnosis and management of cyclic vomiting syndrome. METHODS: This CPU was commissioned and approved by the AGA Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the CPUC and external peer review through standard procedures of Gastroenterology. This expert commentary incorporates important as well as recently published studies in this field, and it reflects the experiences of the authors who are experts in treating patients with cyclic vomiting syndrome.

Outcomes of a step-up approach to the treatment of neurogenic cough.

INTRODUCTION: Neurogenic cough (NC) is thought to be related to sensory neuropathy in the hypopharynx and larynx. Defined as a cough persisting longer than 8 weeks refractory to standard therapy, it is a diagnosis of exclusion when other common etiologies (asthma, gastroesophageal reflux disease (GERD), medication side effects) are ruled out. It affects roughly 11 % of Americans and can negatively impact quality of life. METHODS: Following institutional review board approval, we evaluated the medical records of adult patients seen at the University of Arizona's tertiary laryngology center from 2018 to 2023. Patients were included if their cough persisted for >8 weeks, and they either did not respond to prior proton pump inhibitor and asthma therapy or had GERD and asthma ruled out. These patients underwent a progressive escalation of therapy, which included neuromodulators with or without cough suppression therapy, superior laryngeal nerve (SLN) block, and laryngeal botulinum toxin injections. The primary outcome was patient-reported improvement in cough symptoms rated on a 1-5 scale: 1 = no response, 2 = mild improvement, 3 = moderate improvement, 4 = significant improvement, 5 = complete resolution. RESULTS: A total of 56 patients were included. Mean (SD) age was 64.6 (14.8) years, and 66 % were female. Overall, 42 patients (75.0 %) responded to treatment. Among responders, 7 (16.7 %) experienced mild improvement, 14 (33.3 %) experienced moderate improvement, 17 (40.5 %) experienced significant improvement, and 4 (9.5 %) experienced complete resolution of their cough. 33 patients (58.9 %) were managed exclusively with neuromodulators ± cough suppression therapy; 27 responded, with an average response rating of 3.0 (SD = 1.2). 11 patients (19.6 %) failed medical therapy and underwent SLN block without subsequent botox treatment; 7 responded, with an average response rating of 2.5 (SD = 1.4). 9 patients (16.1 %) failed all previous therapies and underwent laryngeal botulinum toxin injections; 6 responded with an average response rating of 2.4 (SD = 1.3). The remaining 3 patients underwent cough suppression therapy alone, with 2 responding and an average response rating of 3.3 (SD = 1.7). CONCLUSIONS: Neurogenic cough can be effectively treated with a stepwise multimodal approach, including neuromodulators, cough suppression therapy, SLN block, and laryngeal botulinum toxin injections.

Neuromodulation of safety and surprise in the early stages of infant development: affective homeostatic regulation in bodily and mental functions.

Developing a sense of internal safety and security depends mainly on others: numerous neuromodulators play a significant role in the homeostatic process, regulating the importance of proximity to a caregiver and experiencing feelings that enable us to regulate our interdependence with our conspecifics since birth. This array of neurofunctional structures have been called the SEPARATION DISTRESS system (now more commonly known as the PANIC/ GRIEF system). This emotional system is mainly involved in the production of depressive symptoms. The disruption of this essential emotional balance leads to the onset of feelings of panic followed by depression. We will focus on the neuropeptides that play a crucial role in social approach behavior in mammals, which enhance prosocial behavior and facilitate the consolidation of social bonds. We propose that most prosocial behaviors are regulated through the specific neuromodulators acting on salient intersubjective stimuli, reflecting an increased sense of inner confidence (safety) in social relationships. This review considers the neurofunctional link between the feelings that may ultimately be at the base of a sense of inner safety and the central neuromodulatory systems. This link may shed light on the clinical implications for the development of early mother-infant bonding and the depressive clinical consequences when this bond is disrupted, such as in post-partum depression, depressive feelings connected to, addiction, neurofunctional disorders, and psychological trauma.

Central neuromodulators for patients with functional esophageal disorders: A systematic review and meta-analysis.

BACKGROUD: The use of neuromodulators is prevalent in various functional gastrointestinal disease. However, data concerning the outcomes of these treatments in functional esophageal disorders (FED) remains limited and inadequate. AIMS: The aim of the present study is to examine the efficacy of central neuromodulators in FED. METHODS: We searched PubMed, EMBASE, and the Cochrane library databases from inception to April 2023. Randomized controlled trials that compared the effects of neuromodulators and placebos on FED are included. Primary outcome is the symptom improvement, and Rome IV criteria is used to assess eligible studies. RESULTS: Eleven randomized controlled studies (three for functional chest pain, four for reflux hypersensitivity/functional heartburn, three for globus, and one for functional dysphagia) were included in the final analysis. Neuromodulators reduced chest pain by 52%-71% in patients with functional chest pain, and alleviated symptom by 46%-75% in patients with globus (n = 3, Odds ratio 6.30, 95% confidence interval 4.17-9.50). However, the results were inconsistent for reflux hypersensitivity and functional heartburn. There was a lack of convincing evidence to support the use of neuromodulators for functional dysphagia. The use of neuromodulators did not have a significant impact on the quality of life. CONCLUSIONS: Functional chest pain and globus may potentially benefit from the use of neuromodulators, but their effectiveness for functional dysphagia, functional heartburn and reflux hypersensitivity remains controversial. More controlled trials are needed to confirm the therapeutic effects on these conditions.

Greater physical fitness ( VO 2 max ) in healthy older adults associated with increased integrity of the locus coeruleus-noradrenergic system.

AIM: Physical activity (PA) is a key component for brain health and Reserve, and it is among the main dementia protective factors. However, the neurobiological mechanisms underpinning Reserve are not fully understood. In this regard, a noradrenergic (NA) theory of cognitive reserve (Robertson, 2013) has proposed that the upregulation of NA system might be a key factor for building reserve and resilience to neurodegeneration because of the neuroprotective role of NA across the brain. PA elicits an enhanced catecholamine response, in particular for NA. By increasing physical commitment, a greater amount of NA is synthetised in response to higher oxygen demand. More physically trained individuals show greater capabilities to carry oxygen resulting in greater Vo 2 max - a measure of oxygen uptake and physical fitness (PF). METHODS: We hypothesized that greater Vo 2 max would be related to greater Locus Coeruleus (LC) MRI signal intensity. In a sample of 41 healthy subjects, we performed Voxel-Based Morphometry analyses, then repeated for the other neuromodulators as a control procedure (Serotonin, Dopamine and Acetylcholine). RESULTS: As hypothesized, greater Vo 2 max related to greater LC signal intensity, and weaker associations emerged for the other neuromodulators. CONCLUSION: This newly established link between Vo 2 max and LC-NA system offers further understanding of the neurobiology underpinning Reserve in relationship to PA. While this study supports Robertson's theory proposing the upregulation of the NA system as a possible key factor building Reserve, it also provides ground for increasing LC-NA system resilience to neurodegeneration via Vo 2 max enhancement.

Where Top-Down Meets Bottom-Up: Cell-Type Specific Connectivity Map of the Whisker System.

Sensorimotor computation integrates bottom-up world state information with top-down knowledge and task goals to form action plans. In the rodent whisker system, a prime model of active sensing, evidence shows neuromodulatory neurotransmitters shape whisker control, affecting whisking frequency and amplitude. Since neuromodulatory neurotransmitters are mostly released from subcortical nuclei and have long-range projections that reach the rest of the central nervous system, mapping the circuits of top-down neuromodulatory control of sensorimotor nuclei will help to systematically address the mechanisms of active sensing. Therefore, we developed a neuroinformatic target discovery pipeline to mine the Allen Institute's Mouse Brain Connectivity Atlas. Using network connectivity analysis, we identified new putative connections along the whisker system and anatomically confirmed the existence of 42 previously unknown monosynaptic connections. Using this data, we updated the sensorimotor connectivity map of the mouse whisker system and developed the first cell-type-specific map of the network. The map includes 157 projections across 18 principal nuclei of the whisker system and neuromodulatory neurotransmitter-releasing. Performing a graph network analysis of this connectome, we identified cell-type specific hubs, sources, and sinks, provided anatomical evidence for monosynaptic inhibitory projections into all stages of the ascending pathway, and showed that neuromodulatory projections improve network-wide connectivity. These results argue that beyond the modulatory chemical contributions to information processing and transfer in the whisker system, the circuit connectivity features of the neuromodulatory networks position them as nodes of sensory and motor integration.

Identifying Practice Gaps Among Otolaryngology Providers for the Treatment of Chronic Cough.

Objective: Increasing evidence over the last decade suggests that many cases of unexplained chronic cough (UCC) have a neurogenic etiology, with laryngeal hypersensitivity (LH) being identified as a key mechanism. Official guidelines since 2015 have adopted use of neuromodulators and adjuvant speech therapy as a result, but historically implementation of guidelines is slow. Our survey aimed to investigate gaps in diagnosis and management practices of otolaryngology providers in caring for patients with UCC. Study Design: Cross-sectional study. Setting: Survey. Methods: 12-item survey was distributed to 110 otolaryngology practitioners experienced in diagnosis and treatment of chronic cough at a regional otolaryngology continuing education conference. Statistical analysis included Kendall's Tau Rank Correlation to measure the ordinal association between responses to questions, and Fisher's exact test to determine if there were associations between responses and years of career experience. Results: Forty eligible respondents underwent subsequent analysis. There was no association between frequency of identifying LH as a primary etiology and use of neuromodulators (τ = 0.23, P = .10). However, there was a significant correlation between LH and referrals to speech therapy (τ = 0.27, P = .05). Fisher's exact test did not reveal any significant differences among any responses based on practitioner experience. Conclusion: Our results indicate a possible disparity in treatment of UCC with neuromodulators and the utilization of speech therapy despite guideline recommendations advocating for neuromodulators with adjuvant speech therapy. Further research with larger sample sizes and more specific inquiries is necessary to elucidate this association and control for any regional differences.

AGA Clinical Practice Update on Pain Management in Inflammatory Bowel Disease: Commentary.

DESCRIPTION: Pain is a common symptom among patients with inflammatory bowel disease (IBD). Although pain typically occurs during episodes of inflammation, it is also commonly experienced when intestinal inflammation is quiescent. Many gastroenterologists are at a loss how to approach pain symptoms when they occur in the absence of gut inflammation. We provide guidance in this area as to the evaluation, diagnosis, and treatment of pain among patients with IBD. METHODS: This CPU was commissioned and approved by the AGA Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership and underwent internal peer review by the CPUC and external peer review through standard procedures of Gastroenterology. This expert commentary incorporates important as well as recently published studies in this field, and it reflects the experiences of the authors. Formal ratings regarding the quality of evidence or strength of the presented considerations were not included because systematic reviews were not performed.

The efficacy and safety of neubotulinumtoxinA for the treatment of forehead horizontal lines in Asians - A clinical, prospective, interventional, split-face study.

BACKGROUND: Botulinum toxin injections are widely sought after in the field of medical aesthetics, offering consumers a variety of brand choices. Two commonly available botulinum toxin products, onabotulinumtoxinA and neubotulinumtoxinA, are featured in numerous clinics, leading many to question whether there are discernible differences in results, given their varying price ranges. OBJECTIVE: To evaluate the efficacy and safety of neubotulinumtoxinA for the treatment of forehead horizontal lines. METHODS: A 12-week prospective, single-centre, interventional split-face study was conducted, including 30 subjects. These enrolled subjects received a single treatment session, with neubotulinumtoxinA applied to the left side of the forehead and onabotulinumtoxinA to the right side. A superficial injection was performed in all individuals, where the product was injected subdermally in the frontalis muscle. Evaluation was conducted at baseline, 7 days, 14, days and 4, 8, and 12 weeks after treatment, both when the eyebrows were at maximum lift and in a resting position. Treatment efficacy was assessed by two physicians and self-assessed by the patients, using the Fitzpatrick Wrinkle Classification system. Adverse events were documented to evaluate safety. RESULTS: The study found no statistically significant difference in the efficacy of neubotulinum and onabotulinum for treating forehead wrinkles, as indicated by p-values above 0.05 for both static and dynamic conditions. No safety and adverse events were observed in both formulations. CONCLUSION: This study has demonstrated that neither formulation is inferior to each other in the treatment of forehead horizontal lines.

Long-term disruption of tissue levels of glutamate and glutamatergic neurotransmission neuromodulators, taurine and kynurenic acid induced by amphetamine.

RATIONALE: Chronic amphetamine (AMPH) use leading to addiction results in adaptive changes within the central nervous system that persist well beyond the drug's elimination from the body and can precipitate relapse. Notably, alterations in glutamatergic neurotransmission play a crucial role in drug-associated behaviours. OBJECTIVES: This study aimed to identify changes induced by amphetamine in glutamate levels and the neuromodulators of glutamatergic neurotransmission (taurine and kynurenic acid) observable after 14 and 28 days of abstinence in key brain regions implicated in addiction: the cortex (Cx), nucleus accumbens (Acb), and dorsolateral striatum (CPu-L). METHODS: The rats were administered 12 doses of amphetamine (AMPH) intraperitoneally (i.p.) at 1.5 mg/kg. The behavioural response was evaluated through ultrasonic vocalizations (USV). High-performance liquid chromatography (HPLC) was used to measure the levels of glutamate, taurine, and kynurenic acid in the Cx, Acb, and CPu-L after 14 and 28 days of abstinence. RESULTS: AMPH administration led to sensitisation towards AMPH's rewarding effects, as evidenced by changes in USV. There was a noticeable decrease in kynurenic acid levels and an increase in both taurine and glutamate in the CPu-L, along with an increase in glutamate levels in the Cx, 28 days following the final AMPH injection. CONCLUSIONS: The most significant changes in the tissue levels of glutamate, taurine, and kynurenic acid were seen in the CPu-L 28 days after the last dose of AMPH. The emergence of these changes exclusively after 28 days suggests that the processes initiated by AMPH use and subsequent abstinence take time to become apparent and may be enduring. This could contribute to the incubation of craving and the risk of relapse. Developing pharmacological strategies to counteract the reduction in kynurenic acid induced by psychostimulants may provide new avenues for therapy development.

Antineuropathic Pain Management After Orthopedic Surgery: A Systematic Review.

Background: The opioid crisis has become a present concern in the medical field. In an effort to address these complications, antineuropathic pain medications have been considered as alternatives to prescribed opioids. Objective: This review focuses on the analgesic effects of neuromodulators, such as gabapentin, duloxetine, and pregabalin, that provide room for less dependence on narcotic analgesics following orthopedic surgery. Methods: During the database searches, 1,033 records were identified as a preliminary result. After duplicates were removed, an initial screen of each article was completed which identified records to be removed due to absence of a full-text article. Articles were excluded if they were not either prospective or retrospective, showcased an irrelevant medication (such as tricyclic antidepressants) which are not pertinent to this review, or deemed to be unrelated to the topic. Results: Ultimately, 19 articles were selected. Three different drugs, gabapentin, pregabalin, and duloxetine, were analyzed to compile data on the effectiveness of preventing opioid overuse and addiction following hand surgery. This review identifies potential evidence that peri-operative gabapentin, pregabalin, and duloxetine administration decreases post-operative pain and lowers opioid dependency. Conclusion: Gabapentin, pregabalin, and duloxetine have potential to further decrease post-operative pain and lower opioid dependency. This review creates an opening for further research in hand surgery to assess an updated protocol for pain management to reduce opioid dependency.

Olfactory Critical Periods: How Odor Exposure Shapes the Developing Brain in Mice and Flies.

Neural networks have an extensive ability to change in response to environmental stimuli. This flexibility peaks during restricted windows of time early in life called critical periods. The ubiquitous occurrence of this form of plasticity across sensory modalities and phyla speaks to the importance of critical periods for proper neural development and function. Extensive investigation into visual critical periods has advanced our knowledge of the molecular events and key processes that underlie the impact of early-life experience on neuronal plasticity. However, despite the importance of olfaction for the overall survival of an organism, the cellular and molecular basis of olfactory critical periods have not garnered extensive study compared to visual critical periods. Recent work providing a comprehensive mapping of the highly organized olfactory neuropil and its development has in turn attracted a growing interest in how these circuits undergo plasticity during critical periods. Here, we perform a comparative review of olfactory critical periods in fruit flies and mice to provide novel insight into the importance of early odor exposure in shaping neural circuits and highlighting mechanisms found across sensory modalities.

Sound-evoked adenosine release in cooperation with neuromodulatory circuits permits auditory cortical plasticity and perceptual learning.

Meaningful auditory memories are formed in adults when acoustic information is delivered to the auditory cortex during heightened states of attention, vigilance, or alertness, as mediated by neuromodulatory circuits. Here, we identify that, in awake mice, acoustic stimulation triggers auditory thalamocortical projections to release adenosine, which prevents cortical plasticity (i.e., selective expansion of neural representation of behaviorally relevant acoustic stimuli) and perceptual learning (i.e., experience-dependent improvement in frequency discrimination ability). This sound-evoked adenosine release (SEAR) becomes reduced within seconds when acoustic stimuli are tightly paired with the activation of neuromodulatory (cholinergic or dopaminergic) circuits or periods of attentive wakefulness. If thalamic adenosine production is enhanced, then SEAR elevates further, the neuromodulatory circuits are unable to sufficiently reduce SEAR, and associative cortical plasticity and perceptual learning are blocked. This suggests that transient low-adenosine periods triggered by neuromodulatory circuits permit associative cortical plasticity and auditory perceptual learning in adults to occur.

Lessons from lonely flies: Molecular and neuronal mechanisms underlying social isolation.

Animals respond to changes in the environment which affect their internal state by adapting their behaviors. Social isolation is a form of passive environmental stressor that alters behaviors across animal kingdom, including humans, rodents, and fruit flies. Social isolation is known to increase violence, disrupt sleep and increase depression leading to poor mental and physical health. Recent evidences from several model organisms suggest that social isolation leads to remodeling of the transcriptional and epigenetic landscape which alters behavioral outcomes. In this review, we explore how manipulating social experience of fruit fly Drosophila melanogaster can shed light on molecular and neuronal mechanisms underlying isolation driven behaviors. We discuss the recent advances made using the powerful genetic toolkit and behavioral assays in Drosophila to uncover role of neuromodulators, sensory modalities, pheromones, neuronal circuits and molecular mechanisms in mediating social isolation. The insights gained from these studies could be crucial for developing effective therapeutic interventions in future.

Bistable perception, precision and neuromodulation.

Bistable perception follows from observing a static, ambiguous, (visual) stimulus with two possible interpretations. Here, we present an active (Bayesian) inference account of bistable perception and posit that perceptual transitions between different interpretations (i.e. inferences) of the same stimulus ensue from specific eye movements that shift the focus to a different visual feature. Formally, these inferences are a consequence of precision control that determines how confident beliefs are and change the frequency with which one can perceive-and alternate between-two distinct percepts. We hypothesized that there are multiple, but distinct, ways in which precision modulation can interact to give rise to a similar frequency of bistable perception. We validated this using numerical simulations of the Necker cube paradigm and demonstrate the multiple routes that underwrite the frequency of perceptual alternation. Our results provide an (enactive) computational account of the intricate precision balance underwriting bistable perception. Importantly, these precision parameters can be considered the computational homologs of particular neurotransmitters-i.e. acetylcholine, noradrenaline, dopamine-that have been previously implicated in controlling bistable perception, providing a computational link between the neurochemistry and perception.

No changes in triple network engagement following (combined) noradrenergic and glucocorticoid stimulation in healthy men.

Successful recovery from stress is integral for adaptive responding to the environment. At a cellular level, this involves (slow genomic) actions of cortisol, which alter or reverse rapid effects of noradrenaline and cortisol associated with acute stress. At the network scale, stress recovery is less well understood but assumed to involve changes within salience-, executive control-, and default mode networks. To date, few studies have investigated this phase and directly tested these assumptions. Here, we present results from a double-blind, placebo-controlled, between-group paradigm (N = 165 healthy males) administering 10 mg oral yohimbine and/or 10 mg oral hydrocortisone two hours prior to resting state scanning. We found no changes in within-network connectivity of the three networks, both after single and combined drug administration. We further report the results of Bayesian parameter inference to provide evidence for the null hypothesis. Our results contrast with previous findings, which may be attributable to systematic differences between paradigms, highlighting the need to isolate paradigm-specific effects from those related to stress.

Illuminating the brain-genetically encoded single wavelength fluorescent biosensors to unravel neurotransmitter dynamics.

Understanding how neuronal networks generate complex behavior is one of the major goals of Neuroscience. Neurotransmitter and Neuromodulators are crucial for information flow between neurons and understanding their dynamics is the key to unravel their role in behavior. To understand how the brain transmits information and how brain states arise, it is essential to visualize the dynamics of neurotransmitters, neuromodulators and neurochemicals. In the last five years, an increasing number of single-wavelength biosensors either based on periplasmic binding proteins (PBPs) or on G-protein-coupled receptors (GPCR) have been published that are able to detect neurotransmitter release in vitro and in vivo with high spatial and temporal resolution. Here we review and discuss recent progress in the development of these sensors, their limitations and future directions.

Neuromodulators can promote nerve regeneration and accelerate functional recovery after peripheral nerve injury: A systematic review.

Peripheral nerve injuries (PNIs) are debilitating injuries that are also challenging to treat. With several different techniques being investigated to optimize nerve regeneration, we performed this systematic review aiming to evaluate and synthesize the available peer-reviewed literature regarding PNIs and the research that has been done to optimize peripheral nerve regeneration. Two research databases were searched, and abstracts were reviewed for relevance. The abstracts that met screening criteria then underwent full-text review. Out of 6,128 unique citations, 164 publications were ultimately included in this review. Evidence supports many potential options for the management of PNIs, including surgical treatment and systemic and local administration of various pharmacological agents. Some of the reported benefits of treatment with such agents include faster nerve regeneration, improved functional recovery, neuroma prevention, and decreased scar formation. However, much of the research reviewed has been performed in animal models, not human trails. Additionally, the safety profile of some agents makes systemic treatment difficult. Further translational and clinical studies are needed to fill these remaining gaps in knowledge to make evidence-based recommendations regarding the most effective treatment for PNIs.