Central Action Research Articles

I don’t know about you, but I’m feeling IL-22

Defense of the human body against damaging and pathogenic insults is a heavily regulated affair. A primary mechanism of defense at sites of insult are soluble mediators whose defensive maneuvers increase barrier integrity and promote pro-reparative and resolution processes. IL-22 is a cytokine in the IL-10 cytokine family that has garnered increased attention in recent years due to its intimate link in promoting resolution of inflammatory insults, while simultaneously being over expressed in certain fibrotic and chronic inflammatory-skewed diseases. The spatial action of IL-22 centers around the barrier sites of the body, including the skin, lungs, and gut mucosa. As such, a detailed understanding of the role of this cytokine, the producers and responders, and the diseases resulting from over- or under-expression have prominent impacts on a variety of disease outcomes. Herein we present a comprehensive review of IL-22; from historical perspectives and initial discovery, as well as more recent data that dramatically expands on the cellular sources and impact of this cytokine. We aim to showcase the duality of IL-22 and highlight addressable gaps in the field of IL-22 crosstalk and impacts at the ever-important mucosal and tissue barrier sites.

Regional distribution of unbound eletriptan and sumatriptan in the CNS and PNS in rats: implications for a potential central action

BackgroundTriptans are potent 5-HT1B/1D/1F receptor agonists used in migraine therapy, thought to act through peripheral mechanisms. It remains unclear whether triptans cross the blood-brain barrier (BBB) sufficiently to stimulate central 5-HT1B/1D/1F receptors. This study investigates the disposition of eletriptan and sumatriptan in central nervous system (CNS) and peripheral nervous system (PNS) regions and predicts regional 5-HT1B/1D/1F receptor occupancies at clinically relevant concentrations.MethodsUsing the Combinatory Mapping Approach (CMA) for regions of interest (ROI), we assessed the unbound tissue-to-plasma concentration ratio (Kp, uu, ROI) in rats at steady state across CNS (hypothalamus, brain stem, cerebellum, frontal cortex, parietal cortex, striatum, hippocampus, whole brain, and spinal cord) and PNS (trigeminal ganglion and sciatic nerve) regions. We used Kp, uu, ROI values to estimate unbound target-site concentrations and 5-HT1B/1D/1F receptor occupancies in humans.ResultsWe observed heterogenous triptan transport across CNS and PNS regions with the highest extent of unbound drug transport across the blood-nerve barrier in the trigeminal ganglion (Kp, uu, TG: eletriptan: 0.519, and sumatriptan: 0.923). Both drugs displayed restricted entry across the BBB (Kp, uu, whole brain: eletriptan: 0.058, and sumatriptan: 0.045) combined with high inter-regional variability. We estimated near-complete receptor occupancy in the trigeminal ganglion, while lower occupancies were observed in the whole brain, irrespective of the drug or receptor subtype. For instance, eletriptan was predicted to achieve 84% 5-HT1B receptor occupancy in the trigeminal ganglion and 37% in the whole brain at clinically relevant concentrations.ConclusionsThis study suggests that despite low BBB transport, both eletriptan and sumatriptan achieve unbound concentrations sufficient to stimulate 5-HT1B, 5-HT1D, and 5-HT1F receptors not only in the trigeminal ganglion, but also in the CNS. Further research is needed to determine whether central mechanisms contribute to triptan’s antimigraine effect and/or side effects.Graphical

Magnesium sulphate: Current application in anaesthesia

The role of magnesium in medicine has advanced considerably over the two decades. It is now generally accepted that magnesium is a crucial nutrient, and its deficiency has adverse effects on a variety of physiological processes. Magnesium deficiency should be avoided in the perioperative period. Magnesium has been developed as a drug with various clinical uses. It is a key cation in physiological processes, and its homeostasis is essential for the normal function of human body organs. Magnesium sulphate is a mineral pharmaceutical preparation of magnesium. It has a high therapeutic index and cost-effectiveness. Magnesium sulphate is readily available, affordable and its use in clinical practice is associated with less complications. Recently, the potentiation of effects of muscle relaxation and perioperative analgesia has drawn the attention of anaesthetists to the use of magnesium sulphate in anaesthesia and pain management. The characteristics features of magnesium sulphate as a vasodilator, ability to protect the blood brain barrier, reduction of cerebral oedema and central anticonvulsant action make it very useful in intensive care.

12248 Leptin Signaling Deficiency At The Central Nervous System Reduces Hepatic Glucagon Sensibility Disturbing Liver Amino Acid Metabolism Leading To Hyperaminoacidemia And Hyperglucagonemia In Male Adult Rats

Abstract Disclosure: C. Pintado Losa: None. L. Mazuecos Fernández-Pacheco: None. Ó. Gómez Torres: None. S. Artigas Jerónimo: None. E. Burgos Ramos: None. I. Ramos: None. J. Poveda Colado: None. C. Arribas Mocoroa: None. A. Andres: None. N. Gallardo: None. Leptin regulates glucagon secretion, but the contribution of central leptin resistance to circulating glucagon levels and hepatic glucagon signaling is poorly studied. To analyze the effects of deficient hypothalamic leptin signaling on glucagon levels and hepatic glucagon signaling, we infused intracerebroventricularly a rat-specific leptin receptor antagonist SLA (0,2 µg/day) for 21 days to male 3-month-old Wistar rats (n=12) or PBS (n=12). At day 21 of treatment and 30 min before sacrifice, a glucagon challenge (100 µg/kg) was performed in 16h fasted rats. After sacrifice, blood and liver samples were collected for analysis. Serum hormones, urea, and total and branched-chain amino acids (BCAA) levels were determined using commercial kits and by RP-HPLC. Hepatic neutral lipid was extracted and quantified using an enzymatic kit and the hepatic content of mRNA and proteins involved in lipid and amino acid metabolism were measured by RT-PCR and Western-Blot. Additionally, the HOMA-IR and glucagon-alanine index were determined in all rats. Blocking central leptin signaling led to impaired fat oxidation and triglyceride export capacity in the liver, resulting in a 50% increase in hepatic triglyceride content in SLA-treated rats. Glucagonemia increased in SLA-treated rats, indicating impaired hepatic glucagon sensitivity. In fact, in response to exogenous glucagon, the hepatic phosphorylation of CREB was reduced by 55% in SLA-infused compared to control rats. Importantly, SLA treatment significantly decreases the expression and the activity of BCKDH (branched-chain alpha-keto acid dehydrogenase) in the liver, leading to a reduction in the BCAA degradation in SLA-treated rats, hyperaminoacidemia, and decreased serum urea levels. In conclusion, deficient hypothalamic leptin signaling alters glucose, lipid, and amino acid homeostasis, highlighting the relevance of central leptin action in the control of peripheral metabolism and glucagon sensitivity. Funding: Work supported by Ministerio de Ciencia, Innovación y Universidades under project grants RTI2018-098643-B-I00, PID2021-128243OB-I00, and from the University of Castilla-La Mancha and the European Regional Development Fund (FEDER) under project grant 2023- GRIN-34280. Presentation: 6/1/2024

Cortical actions of thyroid hormone: An exploration and metabolism crossroad

Classically, the central actions of thyroid hormones (THs) on metabolism occur within the hypothalamus. A recent article published in Cell by Sabatini and colleagues demonstrates that TH modulates cerebral cortical circuits of male mice, which might integrate exploratory behavior and whole-body metabolism.

Interference with Systemic Negative Feedback Regulation as a Potential Mechanism for Nonmonotonic Dose-Responses of Endocrine-Disrupting Chemicals.

Endocrine-disrupting chemicals (EDCs) often exhibit nonmonotonic dose-response (NMDR) relationships, posing significant challenges to health risk assessment and regulations. Several molecular mechanisms operating locally in cells have been proposed, including opposing actions via different receptors, mixed-ligand heterodimer formation, and receptor downregulation. Systemic negative feedback regulation of hormone homeostasis, which is a common feature of many endocrine systems, has also been invoked as a mechanism; however, whether and how exactly such global feedback structure may underpin NMDRs is poorly understood. We hypothesize that an EDC may compete with the endogenous hormone for receptors (i) at the central site to interfere with the feedback regulation thus altering the physiological hormone level, and (ii) at the peripheral site to disrupt the hormone action; this dual-action may oppose each other, producing nonmonotonic endocrine effects. The objective here is to explore - through computational modeling - how NMDRs may arise through this potential mechanism and the relevant biological variabilities that enable susceptibility to nonmonotonic effects. We constructed a dynamical model of a generic hypothalamic-pituitary-endocrine (HPE) axis with negative feedback regulation between a pituitary hormone and a terminal effector hormone (EH). The effects of model parameters, including receptor binding affinities and efficacies, on NMDR were examined for EDC agonists and antagonists. Monte Carlo human population simulations were then conducted to systemically explore biological parameter conditions that engender NMDR. When an EDC interferes sufficiently with the central feedback action of EH, the net endocrine effect at the peripheral target site can be opposite to what is expected of an agonist or antagonist at low concentrations. J/U or Bell-shaped NMDRs arise when the EDC has differential binding affinities and/or efficacies, relative to EH, for the peripheral and central receptors. Quantitative relationships between these biological variabilities and associated distributions were discovered, which can distinguish J/U and Bell-shaped NMDRs from monotonic responses. The ubiquitous negative feedback regulation in endocrine systems can act as a universal mechanism for counterintuitive and nonmonotonic effects of EDCs. Depending on key receptor kinetic and signaling properties of EDCs and endogenous hormones, some individuals may be more susceptible to these complex endocrine effects.

Эффективность применения Контрапаина-10® (нефопама гидрохлорида) при мультимодальной анальгезии собак

Purpose of the research: to estimate the effectiveness of nefopam hydrochloride (Contrapain-10®) as a part of multimodal analgesia in pre- and intraoperative period of dogs, and to find out whether this medicine will reduce the number of anesthetics used during the intraoperative period. Materials and methods: the study included 34 dogs; 2 groups (n = 17) were formed from patients with diagnosed herniated discs of varying severity in different departments. All animals were subject to surgical treatment: group A (control group with nefopam hydrochloride) and B (experimental group without nefopam hydrochloride). For group A dogs in the preoperative period a non-opioid analgesic of central action, nefopam hydrochloride, was introduced into the multimodal analgesia scheme at a dosage of 0.3…0.5 mg/kg of body weight intramuscularly with an assessment of the analgesic effect. For dogs of group B (control) A standard multimodal analgesia protocol was used without the nefopam hydrochloride. During the intraoperative period, patients' pain levels were assessed using numerical hardware parameters (the main components of monitoring are ECG, frequency of respiratory movements, heart rate, noninvasive blood pressure, pulse oximetry, thermometry), as well as visual monitoring. Physiological parameters, pain and degree of sedation were assessed during the whole surgical operation and intermediate results were recorded every 30, 60, 90, 120, 150, 180 minutes. Estimation of clinical effectiveness of the medicine was evaluated based on the results of the pain assessment (from 1 to 5), general condition and values of vital parameters recorded during surgery. Results: Contrapain-10® promotes high-quality and safe anesthesia of patients both during surgery and in the postoperative period. At the same time, the consumption of opioid and non-opioid analgesics is minimal.

Machine Learning-based Categorization of Airbnb Listings in NYC

This research focuses into creating a machine-learning-driven system to categorize Airbnb listings in New York City (NYC) based on neighborhood attributes and listing features. Utilizing data scraped from InsideAirbnb.com, including custom attributes such as median household income, craft beer and specialty coffee counts, and a connectivity score, KMeans clustering was applied to classify listings into four groups. These groups, named Normal People, The 2%, Central Action, and Hip Kids, offer insights into the city’s diverse landscape of Airbnb offerings. The classification model’s accuracy was validated using various semi-supervised learning techniques, resulting in 100% accuracy for some models. Dropping significant features like income in validation tests reduced accuracy to 66-78%, showing the importance of feature selection. The study demonstrates the potential of machine learning in enhancing Airbnb’s understanding of customer preferences and refining inventory management.

Central Actions of Leptin Induce an Atrophic Pattern and Improves Heart Function in Lean Normoleptinemic Rats via PPARβ/δ Activation.

Leptin, acting centrally or peripherally, has complex effects on cardiac remodeling and heart function. We previously reported that central leptin exerts an anti-hypertrophic effect in the heart via cardiac PPARβ/δ activation. Here, we assessed the impact of central leptin administration and PPARβ/δ inhibition on cardiac function. Various cardiac properties, including QRS duration, R wave amplitude, heart rate (HR), ejection fraction (EF), end-diastolic left ventricular mass (EDLVM), end-diastolic volume (EDV), and cardiac output (CO) were analyzed. Central leptin infusion increased cardiac PPARβ/δ protein content and decreased HR, QRS duration, and R wave amplitude. These changes induced by central leptin suggested a decrease in the ventricular wall growth, which was confirmed by MRI. In fact, the EDLVM was reduced by central leptin while increased in rats co-treated with leptin and GSK0660, a selective antagonist of PPARβ/δ activity. In summary, central leptin plays a dual role in cardiac health, potentially leading to ventricular atrophy and improving heart function when PPARβ/δ signaling is intact. The protective effects of leptin are lost by PPARβ/δ inhibition, underscoring the importance of this pathway. These findings highlight the therapeutic potential of targeting leptin and PPARβ/δ pathways to combat cardiac alterations and heart failure, particularly in the context of obesity.

Retrospective comparative analysis of two medical evacuation systems for Ukrainian patients affected by war

IntroductionCoordinated medical evacuations represent an important strategy for emergency response when healthcare systems are impaired by armed conflict, particularly for patients diagnosed with life-threatening conditions such as cancer. In this study, we compare the experiences of two parallel medical evacuation systems developed to meet the medical needs of Ukrainians affected by war. MethodsThis retrospective study compared outcomes of two medical evacuation systems, developed by the European Union Emergency Response Coordination Centre (ERCC) and Supporting Action for Emergency Response in Ukraine (SAFER Ukraine) collaborative, in the first 10 months after the war’s intensification in Ukraine (February 24 to December 21, 2022). Each groups’ respective registries served as data sources. Patient demographics and allocation data were summarized descriptively. Median time for patient referral were analyzed statistically. ResultsThe ERCC pathway evacuated 1385 patients (median age: 36 [0 − 85] years) to 16 European countries; 78.7 % (n = 1091) suffered from trauma-related injuries and 13.4 % (n = 185) from cancer. SAFER Ukraine evacuated 550 patients (median age: 9 [0 − 22] years) to 14 European and North American countries; 97.1 % (n = 534) were children diagnosed with cancer or blood disorders. The median evacuation time for the SAFER Ukraine cohort was shorter than the ERCC cohort (p < 0.001), though comparable (six versus seven days). ConclusionThe ERCC and SAFER Ukraine collaborative successfully developed medical evacuation pathways to meet the needs of Ukrainian patients impacted by war. System comparison provides opportunity to identify strategies for parallel system harmonization and a pragmatic example of how to anticipate support of these patients in future armed conflicts.

Light-responsive adipose-hypothalamus axis controls metabolic regulation

Light is fundamental for biological life, with most mammals possessing light-sensing photoreceptors in various organs. Opsin3 is highly expressed in adipose tissue which has extensive communication with other organs, particularly with the brain through the sympathetic nervous system (SNS). Our study reveals a new light-triggered crosstalk between adipose tissue and the hypothalamus. Direct blue-light exposure to subcutaneous white fat improves high-fat diet-induced metabolic abnormalities in an Opsin3-dependent manner. Metabolomic analysis shows that blue light increases circulating levels of histidine, which activates histaminergic neurons in the hypothalamus and stimulates brown adipose tissue (BAT) via SNS. Blocking central actions of histidine and denervating peripheral BAT blunts the effects of blue light. Human white adipocytes respond to direct blue light stimulation in a cell-autonomous manner, highlighting the translational relevance of this pathway. Together, these data demonstrate a light-responsive metabolic circuit involving adipose-hypothalamus communication, offering a potential strategy to alleviate obesity-induced metabolic abnormalities.

Effects of chronic treatment with metformin on brain glucose hypometabolism and central insulin actions in transgenic mice with tauopathy

Brain glucose hypometabolism and insulin alterations are common features of many neurological diseases. Herein we sought to corroborate the brain glucose hypometabolism that develops with ageing in 12-months old Tau-VLW transgenic mice, a model of tauopathy, as well as to determine whether this model showed signs of altered peripheral glucose metabolism. Our results demonstrated that 12-old months Tau mice exhibited brain glucose hypometabolism as well as basal hyperglycemia, impaired glucose tolerance, hyperinsulinemia, and signs of insulin resistance. Then, we further studied the effect of chronic metformin treatment (9 months) in Tau-VLW mice from 9 to 18 months of age. Longitudinal PET neuroimaging studies revealed that chronic metformin altered the temporal profile in the progression of brain glucose hypometabolism associated with ageing. Besides, metformin altered the content and/or phosphorylation of key components of the insulin signal transduction pathway in the frontal cortex leading to significant changes in the content of the active forms. Thus, metformin increased the expression of pAKT-Y474 while reducing pmTOR-S2448 and pGSK3β. These changes might be related, at least partially, to a slow progression of ageing, neurological damage, and cognitive decline. Metformin also improved the peripheral glucose tolerance and the ability of the Tau-VLW mice to maintain their body weight through ageing. Altogether our study shows that the tau-VLW mice could be a useful model to study the potential interrelationship between tauopathy and central and peripheral glucose metabolism alterations. More importantly our results suggest that chronic metformin treatment may have direct beneficial central effects by post-transcriptional modulation of key components of the insulin signal transduction pathway.

How Interactions Among Peripheral and Central Actors Shape Action in Health Innovation Ecosystems.

How Interactions Among Peripheral and Central Actors Shape Action in Health Innovation Ecosystems.

New findings about neuropathological outcomes in the PKU mouse throughout lifespan

Phenylketonuria (PKU, OMIM 261600) is a genetic disorder caused by a deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH). If left untreated, PKU leads to systemic phenylalanine (Phe) accumulation, which can result in irreversible brain damage and intellectual disabilities. In the last 60 years, early and strict dietary restriction of phenylalanine (Phe) intake proved to prevent the severe clinical phenotype of untreated PKU. While the specific mechanisms through which phenylalanine causes brain damage are still poorly understood, preclinical models have been deeply explored to characterize the neurotoxic effect of Phe on neurodevelopmental processes. At the same time, that on the aging brain still needs to be explored. In the brain of untreated PAHEnu2(−/−) mouse, we previously reported a reduction of myelin basic protein (MBP) during postnatal development up to 60 PND. Later in the diseased mouse's life, a spontaneous and persistent restoration of MBP was detected. In this present longitudinal study, ranging from 14 to 540 post-natal days (PND) of untreated PAHEnu2(−/−) mice, we further investigated: a) the long-life consistency of two Phe-related brain metabolic alterations, such as large neutral amino acids (LNAA) and biogenic amine neurotransmitters' depletion; b) the outcome of locomotor functions during the same life span; c) the integrity of myelin as assessed ex vivo by central (hippocampus) and peripheral (extensor digitorum longus-sciatic nerve) action potential conduction velocities. In contrast with the results of other studies, brain Leu, Ile, and Val concentrations were not significantly altered in the brain PAHEnu2(−/−) mouse. On the other hand, 3-O-Methyldopa (3-OMD, a biomarker of L-DOPA), serotonin, and its associated metabolites were reduced throughout most of the considered time points, with consistent reductions observed prevalently from 14 to 60 PND. Normal saltatory conduction was restored after 60 PND and remained normal at the last examination at 360 PND, resulting nonetheless in a persistent locomotor impairment throughout a lifetime. These new findings contribute to laying the foundations for the preclinical characterization of aging in PKU, confirming neurotransmitter defects as consistent metabolic traits. LNAAs have a minor role, if any, in brain damage pathogenesis. Transient myelin synthesis failure may impact brain connectivity during postnatal development but not nervous signal conduction.

Governance of automated mobilities transition in Aotearoa New Zealand

This paper explores how political-institutional factors influence the transition towards automated vehicles (AVs) in New Zealand (NZ). Using the lens of ‘mobilities paradigm’ and analysing policy documents along with interviews data from government officials, the findings reveal the complexity of governing AVs transition due to fragmented responsibility, contested visions, and high interdependency across government agencies. The findings suggest that strong political leadership coupled with infrastructure investments and building regulators’ capability are important catalysts of change towards AVs transition in NZ. The paper concludes that the complex governance environment, and the central government action and inaction to set priority for the AVs agenda, may hinder or facilitate a smooth transition towards AVs in NZ. This paper contributes to the mobilities paradigm by enriching our understanding of the political-institutional challenges associated with the emergence of AVs and offers illuminating policy guidance to better inform decision-making around governing the future transition towards AVs.

Unraveling the Hippocampal Molecular and Cellular Alterations behind Tramadol and Tapentadol Neurobehavioral Toxicity.

Tramadol and tapentadol are chemically related opioids prescribed for the analgesia of moderate to severe pain. Although safer than classical opioids, they are associated with neurotoxicity and behavioral dysfunction, which arise as a concern, considering their central action and growing misuse and abuse. The hippocampal formation is known to participate in memory and learning processes and has been documented to contribute to opioid dependence. Accordingly, the present study assessed molecular and cellular alterations in the hippocampal formation of Wistar rats intraperitoneally administered with 50 mg/kg tramadol or tapentadol for eight alternate days. Alterations were found in serum hydrogen peroxide, cysteine, homocysteine, and dopamine concentrations upon exposure to one or both opioids, as well as in hippocampal 8-hydroxydeoxyguanosine and gene expression levels of a panel of neurotoxicity, neuroinflammation, and neuromodulation biomarkers, assessed through quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemical analysis of hippocampal formation sections showed increased glial fibrillary acidic protein (GFAP) and decreased cluster of differentiation 11b (CD11b) protein expression, suggesting opioid-induced astrogliosis and microgliosis. Collectively, the results emphasize the hippocampal neuromodulator effects of tramadol and tapentadol, with potential behavioral implications, underlining the need to prescribe and use both opioids cautiously.

1523-P: Anorexia Induced by the Central Action of Fibroblast Growth Factor 1 (FGF1) Is Dependent on Activation of Parabrachial CGRP Neurons

1523-P: Anorexia Induced by the Central Action of Fibroblast Growth Factor 1 (FGF1) Is Dependent on Activation of Parabrachial CGRP Neurons

Evidence for peripheral and central actions of codeine to dysregulate swallowing in the anesthetized cat

Systemic administration of opioids has been associated with aspiration and swallow dysfunction in humans. We speculated that systemic administration of codeine would induce dysfunctional swallowing and that this effect would have a peripheral component. Experiments were conducted in spontaneously breathing, anesthetized cats. The animals were tracheotomized and electromyogram (EMG) electrodes were placed in upper airway and chest wall respiratory muscles for recording swallow related motor activity. The animals were allocated into three groups: vagal intact (VI), cervical vagotomy (CVx), and supra-nodose ganglion vagotomy (SNGx). A dose response to intravenous codeine was performed in each animal. Swallowing was elicited by injection of 3 mL of water into the oropharynx. The number of swallows after vehicle was significantly higher in the VI group than in SNGx. Codeine had no significant effect on the number of swallows induced by water in any of the groups. However, the magnitudes of water swallow-related EMGs of the thyropharyngeus muscle were significantly increased in the VI and CVx groups by 2–4 fold in a dose-related manner. In the CVx group, the geniohyoid muscle EMG during water swallows was significantly increased. There was a significant dose-related increase in spontaneous swallowing in each group from codeine. The spontaneous swallow number at the 10 mg/kg dose of codeine was significantly larger in the CVx group than that in the SNGx group. During water-evoked swallows, intravenous codeine increased upper airway motor drive in a dose-related manner, consistent with dysregulation. The data support the existence of both central and peripheral actions of codeine on spontaneous swallowing. At the highest dose of codeine, the reduced spontaneous swallow number in the SNGx group relative to CVx is consistent with a peripheral excitatory action of codeine either on pharyngeal/laryngeal receptors or in the nodose ganglion itself. The higher number of swallows in the CVx group than the VI group supports disinhibition of this behavior by elimination of inhibitory vagal sensory afferents.

Early effect of onabotulinumtoxinA on EEG-based functional connectivity in patients with chronic migraine: A pilot study.

In this pilot prospective cohort study, we aimed to evaluate, using high-density electroencephalography (HD-EEG), the longitudinal changes in functional connectivity (FC) in patients with chronic migraine (CM) treated with onabotulinumtoxinA (OBTA). OBTA is a treatment for CM. Several studies have shown the modulatory action of OBTA on the central nervous system; however, research on migraine is limited. This study was conducted at the Neurology Unit of "Policlinico Tor Vergata," Rome, Italy, and included 12 adult patients with CM treated with OBTA and 15 healthy controls (HC). Patients underwent clinical scales at enrollment (T0) and 3 months (T1) from the start of treatment. HD-EEG was recorded using a 64-channel system in patients with CM at T0 and T1. A source reconstruction method was used to identify brain activity. FC in δ-θ-α-β-low-γ bands was analyzed using the weighted phase-lag index. FC changes between HCs and CM at T0 and T1 were assessed using cross-validation methods to estimate the results' reliability. Compared to HCs at T0, patients with CM showed hyperconnected networks in δ (p = 0.046, area under the receiver operating characteristic curve [AUC: 0.76-0.98], Cohen's κ [0.65-0.93]) and β (p = 0.031, AUC [0.68-0.95], Cohen's κ [0.51-0.84]), mainly involving orbitofrontal, occipital, temporal pole and orbitofrontal, superior temporal, occipital, cingulate areas, and hypoconnected networks in α band (p = 0.029, AUC [0.80-0.99], Cohen's κ [0.42-0.77]), predominantly involving cingulate, temporal pole, and precuneus. Patients with CM at T1, compared to T0, showed hypoconnected networks in δ band (p = 0.032, AUC [0.73-0.99], Cohen's κ [0.53-0.90]) and hyperconnected networks in α band (p = 0.048, AUC [0.58-0.93], Cohen's κ [0.37-0.78]), involving the sensorimotor, orbitofrontal, cingulate, and temporal cortex. These preliminary results showed that patients with CM presented disrupted EEG-FC compared to controls restored by a single session of OBTA treatment, suggesting a primary central modulatory action of OBTA.

Effect of acute intranasal insulin administration on muscle sympathetic nerve activity in healthy young adults.

Systemic insulin increases muscle sympathetic nerve activity (MSNA) via both central actions within the brainstem and peripheral activation of the arterial baroreflex. Augmented MSNA during hyperinsulinemia likely restrains peripheral vasodilation and contributes to the maintenance of blood pressure (BP). However, in the absence of insulin action within the peripheral vasculature, whether central insulin stimulation increases MSNA and influences peripheral hemodynamics in humans remains unknown. Herein, we hypothesized intranasal insulin administration would increase MSNA and BP in healthy young adults. Participants were assigned to time control [TC, n = 13 (5 females/8 males), 28 ± 1 yr] or 160 IU of intranasal insulin administered over 5 min [n = 15 (5 females/10 males), 26 ± 2 yr]; five (1 female/4 males) participants completed both conditions. MSNA (fibular microneurography), BP (finger photoplethysmography), and leg blood flow (LBF, femoral Doppler ultrasound) were assessed at baseline, and 15 and 30 min following insulin administration. Leg vascular conductance [LVC = (LBF ÷ mean BP) × 100] was calculated. Venous insulin and glucose concentrations remained unchanged throughout (P > 0.05). Following intranasal insulin administration, MSNA (burst frequency; baseline = 100%; minute 15, 121 ± 8%; minute 30, 118 ± 6%; P = 0.009, n = 7) and mean BP (baseline = 100%; minute 15, 103 ± 1%; minute 30, 102 ± 1%; P = 0.003) increased, whereas LVC decreased (baseline = 100%; minute 15, 93 ± 3%; minute 30, 99 ± 3%; P = 0.03). In contrast, MSNA, mean BP, and LVC were unchanged in TC participants (P > 0.05). We provide the first evidence that intranasal insulin administration in healthy young adults acutely increases MSNA and BP and decreases LVC. These results enhance mechanistic understanding of the sympathetic and peripheral hemodynamic response to insulin.NEW & NOTEWORTHY Systemic insulin increases muscle sympathetic nerve activity (MSNA) via central actions within the brainstem and peripheral activation of the arterial baroreflex. In the absence of peripheral insulin action, whether central insulin stimulation increases MSNA and influences peripheral hemodynamics in humans was unknown. We provide the first evidence that intranasal insulin administration increases MSNA and blood pressure and reduces leg vascular conductance. These results enhance mechanistic understanding of the sympathetic and hemodynamic response to insulin.