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Early-stage detection of subclinical obesity-driven systemic changes is a challenging area of medical diagnostics, where the most popular existing measures - such as body mass index - BMI - often fall short of providing a realistic estimate of adiposity and, therefore, of ongoing pathologies at the systemic, tissue and cellular level. In the quest for identifying new more robust diagnostic markers, whole-organ analysis of chemical elements is a promising approach for identifying candidate proxies of obesity status in the system.Total Reflection X-ray fluorescence (TXRF) coupled with biochemical assays, chemometrics and statistical validation was used as a new integrated pipeline for marker identification in external ear samples of obese animals. The specimens were taken from obese animals fed a high calorie diet as well as from lean intact animals fed a standard diet.The most significant differences in the content of K, Fe, Br, and Rb between the studied groups of the animals were identified. However, with the methodology applied Rb was found the most robust biochemical discriminator of early-stage obesity effects, as validated by the logistic regression model. We observed no relationship between the levels of the elements consumed by the animals and their apparent content in the earlobe tissue samples.Our preliminary study confirms that obesity alters tissue trace metal metabolism and shows the proposed new approach as an accurate and reliable methodology for detecting tissue elemental obesity-related alterations.This result can be of practical significance for designing new point-of-care systems for obesity screening tests, taking advantage of direct/indirect Rb measurements.

Correlative Fourier Transform Infra-Red (FTIR) and hard X-Ray Fluorescence (XRF) microscopy studies of thin biological samples have recently evolved as complementary methods for biochemical fingerprinting of animal/human tissues. These are seen particularly useful for tracking the mechanisms of neurological diseases, i.e., in Alzheimer/Parkinson disease, in the brain where mishandling of trace metals (Fe, Cu, Zn) seems to be often associated with ongoing damage to molecular components via, among others, oxidative/reductive stress neurotoxicity. Despite substantial progress in state-of-the-art detection and data analysis methods, combined FTIR-XRF experiments have never benefited from correlation and co-localization analysis of molecular moieties and chemical elements, respectively. We here propose for the first time a completely novel data analysis pipeline, utilizing the idea of 2D correlation spectrometry for brain tissue analysis. In this paper, we utilized combined benchtop FTIR - synchrotron XRF mapping experiments on thin brain samples mounted on polypropylene membranes. By implementing our recently developed Multiple Linear Regression Multi-Reference (MLR-MR) algorithm, along with advanced image processing, artifact-free 2D FTIR-XRF spectra could be obtained by mitigating the impact of spectral artifacts, such as Etalon fringes and mild scattering Mie-like signatures, in the FTIR data. We demonstrated that the method is a powerful tool for co-localizing and correlating molecular arrangements and chemical elements (and vice versa) using visually attractive 2D correlograms. Moreover, the methods' applicability for fostering the identification of distinct (biological) materials, involving chemical elements and molecular arrangements, is also shown. Taken together, the 2D FTIR-XRF method opens up for new measures for in-situ investigating hidden complex biochemical correlations, and yet unraveled mechanisms in a biological sample. This step seems crucial for developing new strategies for facilitating the research on the interaction of metals/nonmetals with organic components. This is particularly important for enhancing our understanding of the diseases associated with metal/nonmetal mishandling.

A decision on how to choose the appropriate data quantification procedure lies behind the most serious methodological challenges in microbeam X-ray fluorescence imaging of tissue slices. This problem becomes particularly cumbersome whenever intermediate thickness samples must be utilized in order to increase the signal to noise ratio. Noteworthy, it is always the case when laboratory-based X-ray sources are used, which arises from their relatively limited beam flux. In our study, we put particular attention to the quantitative elemental microanalysis of dried brain tissue samples taken from the obese rats treated by the transcranial direct current stimulation. For doing so, we took advantage of tissue probing by an X-ray microscope system for accessing P, S, Cl, K, Ca, Fe, Cu, and Zn in the brain structures triggering food intake and appetite regulation. Proper data quantification schemes are presented by showing the elements whereby the radiation loss by self-absorption of fluorescence radiation is negligible. The impact of sample self-absorption correction on quantitative data is studied for the brain structures with various water fraction spanning from 75–83%. It is demonstrated that K, Ca, Fe, Cu, and Zn can effectively be quantified by the thin-sample approach, regardless sample matrix. Quantitative results demonstrate that the clinical efficacy of transcranial direct current stimulation is linked to significant changes in surface masses of elements triggering brain membrane currents: K, Cl, and also, those defining the redox state: Fe in the hunger center. Copyright © 2017 John Wiley & Sons, Ltd.

In order to push the spatial resolution limits to the nanoscale, synchrotron-based soft X-ray microscopy (XRM) experiments require higher radiation doses to be delivered to materials. Nevertheless, the associated radiation damage impacts on the integrity of delicate biological samples. Herein, the extent of soft X-ray radiation damage in popular thin freeze-dried brain tissue samples mounted onto Si3N4 membranes, as highlighted by Fourier transform infrared microscopy (FTIR), is reported. The freeze-dried tissue samples were found to be affected by general degradation of the vibrational architecture, though these effects were weaker than those observed in paraffin-embedded and hydrated systems reported in the literature. In addition, weak, reversible and specific features of the tissue–Si3N4 interaction could be identified for the first time upon routine soft X-ray exposures, further highlighting the complex interplay between the biological sample, its preparation protocol and X-ray probe.

The course of pyrolysis process of the three industrial samples of lower, middle, and higher rank coals was studied using the TG/FT-IR technique and a laboratory unit for investigation of carbonization process by X-raying. The coal samples from the zones of plastic layer were studied by scanning electron microscopy and next extracted by a mixture of chloroform and methanol. The obtained extracts were analyzed by FT-IR and UV spectroscopies and STEM-HAADF technique. It was stated that the composition of volatile products of a lower rank coal (LRC) is characterized by the greatest relative content of saturated and unsaturated hydrocarbons in comparison with a middle rank coal (MRC) and a higher rank coal (HRC). However, a higher contribution ratio of water vapour is observed in the composition of volatile matter of HRC. It is suggested that low molecular products of destruction formed inside swelling grains of MRC can react with each other and form new compounds with a greater molecular mass. These can be macromolecules of heteroorganic compounds. The STEM-HAADF images showed that there are topological structures of various types in the material of extracts from the gas-saturated zone of coals of different rank. The presence of inorganic elements in the extracted material changes depending on coal rank. Heterorganic compounds of different shape and composition can catalyze the reactions taking place during thermal destruction of coals in a selective way. In MRC, these reactions will cause a decrease in pressure inside its swelling grains and without their substantial growth in volume. Such reactions do not take place in grains of HRC. Moreover, an increased contribution of water vapour formed during destruction can cause its adsorption inside grains and an increase in volume of swelling grains. This can be the cause for an increase in generation of dangerous coking pressure in the charge of studied HRC.

Due to its high prevalence, obesity is considered an epidemic, which stimulated research on non-invasive methods to reduce excess body fat. Transcranial direct current stimulation (tDCS) is a non-invasive technique used to modulate the activity of cerebral cortex, which has already found increasing interest in medicine as a promising methodology. The aim of this study was to analyze the impact of tDCS on feeding behavior, metabolic abnormalities and neurotransmitters in certain brain areas involved in appetite control of obese rats. The male Wistar rats were divided into five subgroups depending on an effect of consumed diet (lean, obese) and tDCS type (anodal, cathodal, sham, and no stimulation). Two 10-min daily sessions of tDCS for eight consecutive days of the study were applied. Rats subjected to active tDCS (anodal right or cathodal left of the prefrontal cortex) had reduced appetite and showed lesser body weight gain than the animals subjected to sham procedure or those receiving no stimulation at all. Furthermore, tDCS contributed to reduction of epididymal fat pads and to a decrease in blood concentration of leptin. Neurochemical examination revealed that tDCS modulated serotonin pathways of the reward-related brain areas and contributed to a significant decrease in the density of D2 but not D1 dopamine receptors in the dorsal striatum, recorded 5 hours after the last stimulation. No significant effect of tDCS on dopamine and it’s metabolites in examined brain regions was observed. It seems that the hypothalamus was not affected by tDCS application as no changes in measured neurotransmitters were detected at any examined time point. However, these results do not exclude the possibility of the delayed response of the monoamines in the examined brain areas to tDCS application. Altogether, these findings imply that repeated tDCS of the prefrontal cortex may change feeding behavior of obese rats. Either right anodal or left cathodal tDCS were sufficient to decrease food intake, to reduce body adiposity and to normalize other metabolic anomalies. These beneficial effects can be at least partially explained by changes in serotoninergic and in lesser extent dopaminergic system activity within some brain areas belonging to reward system.

Obesity is a chronic, multifactorial origin disease that has recently become one of the most frequent lifestyle disorders. Unfortunately, current obesity treatments seem to be ineffective. At present, transcranial direct current brain stimulation (tDCS) represents a promising novel treatment methodology that seems to be efficient, well-tolerated and safe for a patient. Unfortunately, the biochemical action of tDCS remains unknown, which prevents its widespread use in the clinical arena, although neurobiochemical changes in brain signaling and metal metabolism are frequently reported. Therefore, our research aimed at exploring the biochemical response to tDCS in situ, in the brain areas triggering feeding behavior in obese animals. The objective was to propose a novel neurochemical (serotoninergic and dopaminergic signaling) and trace metal analysis of Fe, Cu and Zn. In doing so, we used energy-dispersive X-ray fluorescence (EDXRF) and high-performance liquid chromatography (HPLC). Anodal-type stimulation (atDCS) of the right frontal cortex was utilized to down-regulate food intake and body weight gain in obese rats. EDXRF was coupled with the external standard method in order to quantify the chemical elements within appetite-triggering brain areas. Major dopamine metabolites were assessed in the brains, based on the HPLC assay utilizing the external standard assay. Our study confirms that elemental analysis by EDXRF and brain metabolite assay by HPLC can be considered as a useful tool for the in situ investigation of the interplay between neurochemical and Fe/Cu/Zn metabolism in the brain upon atDCS. With this methodology, an increase in both Cu and Zn in the satiety center of the stimulated group could be reported. In turn, the most significant neurochemical changes involved dopaminergic and serotoninergic signaling in the brain reward system.

Understanding the pathological triggers that affect the structural and physiological integrity of biochemical milieu of neurons is crucial to extend our knowledge on brain disorders, that are in many circumstances hardly treatable. Over recently, by using sophisticated hyperspectral micro-imaging modalities, it has been placed within our reach to get an insight into high fidelity histological details along with corresponding biochemical information in a label-free fashion, without using any additional chemical fixatives. However, in order to push forwards extensive application of these methods in the clinical arena, it is viable to make further iterations in novel data analysis protocols in order to boost their sensitivity. Therefore, in our study we proposed a new combined approach utilizing both benchtop Fourier transform infrared (FTIR) and synchrotron X-ray fluorescence (SR-XRF) micro-spectroscopies coupled with multivariate data clustering using the K-means algorithm for combined molecular and elemental micro-imaging, so that these complimentary analytical tools could be used for delineating between various brain structures based on their biochemical composition. By utilizing mid-IR transmission FTIR experiments, the biochemical composition in terms of lipids, proteins and phosphodiesters became accessible. In turn, the SR-XRF experiment was carried out at the advanced IAEA X-ray spectrometry station at Elettra Sincrotrone Trieste. By measuring in vacuum and by using the primary exciting X-ray beam, monochromatized to 10.5 keV, we took advantage of accessing the characteristic X-ray lines of a variety of elements ranging from carbon to zinc. Herein, we can report that the developed methodology has high specificity for label-free discriminating between lipid- and protein-rich brain tissue areas.

Streszczenie Rtęć dość powszechnie występuje zarówno w węglu brunatnym, jak i kamiennym. Uważa się, że w substancji mineralnej węgla powiązana jest ona głównie z pirytem, a w substancji organicznej z grupami tiolowymi. Niemniej jednak spotykane są również węgle, w których rtęć w znacznych ilościach powiązana jest z węglanami i krzemianami. Można by zatem oczekiwać, że ilość występującej w węglu rtęci powinna być skorelowana z zawartością substancji mineralnej czy zawartością popiołu. Jednak w literaturze informacje na temat takiej korelacji są sprzeczne. W niektórych pracach stwierdzono, że rosnącej zawartości popiołu towarzyszy zwiększona zawartość rtęci, natomiast w innych taka prawidłowość nie była obserwowana. Celem pracy było wyjaśnienie powiązania między występowaniem rtęci i siarki w substancji mineralnej polskich węgli kamiennych. W tym celu przebadano populację odpadów z procesu wzbogacania węgli kamiennych, charakteryzujących się relatywnie niską zawartością substancji organicznej. Wyjaśnienie sposobu powiązania rtęci i siarki w substancji mineralnej posiada nie tylko aspekt poznawczy, ale może być też wykorzystane dla optymalizacji procesów usuwania rtęci z węgla, jak też może być pomocne dla opracowania i udoskonalenia aktualnie stosowanych metod zagos-podarowania odpadów górniczych. Badane odpady charakteryzowaly się zróżnicowaną zawartością rtęci w zakresie od 55 do 249 μg/kg (w przeliczeniu na stan suchy). Dla 9 spośród 14 rozpatrywanych przypadków zawartość rtęci w odpadach była wyższa niż w surowym urobku węglowym, a w pozostalych przypadkach zawartość ta była nieznacznie niższa. Analizując poszczególne operacje wzbogacania nie można sformułować zasadniczych wniosków co do występowania rtęci w odpadach. Dla każdej z analizowanych operacji wzbogacania występują zarówno odpady o niższej, jak i wyższej zawartości rtęci. Odnotowano natomiast, że zawartość rtęci w odpadach dla różnych kopalń może się dość zasadniczo różnić. Przykładowo, dla jednej z rozpatrywanych kopalń wszystkie odpady charakteryzowały się niską zawartością rtęci, podczas gdy dla innej – bardzo wysoką. Wiązać to należy z różną naturą surowego węgla z tych kopalń. Analiza statystyczna wykazała, że zawartość rtęci w odpadach istotnie skorelowana jest z zawartością siarki pirytowej, całkowitej i siarczanowej, przy czym najwyższy współczynnik determinacji R2 uzyskano dla siarki pirytowej. W świetle uzyskanych wyników można więc wnioskować, że występowanie rtęci i pirytu w substancji mineralnej badanych węgli kamiennych jest wzajemnie ze sobą powiązane. Brak istotnej korelacji z występowaniem rtęci w odpadach stwierdzono dla substancji mineralnej i popiołu. Tłumaczyć to można występowaniem rtęci w substancji mineralnej w powiązaniu nie tylko z pirytem, ale także z innymi jej składnikami, których udział może być zróżnicowany. Stwierdzono ponadto, że w przypadkach odpadów zawierających znacznie więcej rtęci niż wyjściowy urobek węglowy (powyżej 40 μg/kg), odpady te posiadały jednocześnie wysoką zawartość siarki pirytowej (powyżej 0,30%). Dla takich węgli należy więc oczekiwać skutecznej redukcji zawartości rtęci w węglu w efekcie jego wzbogacania.

Recent studies highlight that obesity may alter the electric activity in brain areas triggering appetite and craving. Transcranial direct current brain stimulation (tDCS) has recently emerged as a safe alternative for treating food addiction via modulating cortical excitability without any high-risk surgical procedure to be utilized. As for anodal-type tDCS (atDCS), we observe increased excitability and spontaneous firing of the cortical neurons, whilst for the cathodal-type tDCS (ctDCS) a significant decrease is induced. Unfortunately, for the method to be fully used in a clinical setting, its biochemical action mechanism must be precisely defined, although it is proposed that molecular remodelling processes play in concert with brain activity changes involving the ions of: Na, Cl, K and Ca. Herein, we proposed for the first time Fourier transform infrared (FTIR) and synchrotron X-ray fluorescence (SRXRF) microprobes for a combined molecular and elemental analysis in the brain areas implicated appetite control, upon experimental treatment by either atDCS or ctDCS. The study, although preliminary, shows that by stimulating the prefrontal cortex in the rats fed high-caloric nutrients, the feeding behavior can be significantly changed, resulting in significantly inhibited appetite. Both, atDCS and ctDCS produced significant molecular changes involving qualitative and structural properties of lipids, whereas atDCS was found with a somewhat more significant effect on protein secondary structure in all the brain areas investigated. Also, tDCS was reported to reduce surface masses of Na, Cl, K, and Ca in almost all brain areas investigated, although the atDCS deemed to have a stronger neuro-modulating effect. Taken together, one can report that tDCS is an effective treatment technique, and its action mechanism in the appetite control seems to involve a variety of lipid-, protein- and metal/non-metal-ion-driven biochemical changes, regardless the current polarization.

Na+ loading without Cl− fails to increase blood pressure in the DOCA model. We compared the changes in the total body (TB) effective Na+, K+, Cl−, and water (TBW) content as well as in intracellular (ICV) or extracellular (ECV) volume in rats receiving DOCA-NaCl, DOCA-NaHCO3, or DOCA-KHCO3. We divided 42 male rats into 5 groups. Group 1 was untreated, group 2 received 1% NaCl, and groups 3, 4, and 5 were treated with DOCA and received 1% NaCl, 1.44% NaHCO3, or 1.7% KHCO3 to drink. We measured mean arterial blood pressure (MAP) directly after 3 wk. Tissue electrolyte and water content was measured by chemical analysis. Compared with control rats, DOCA-NaCl increased MAP while DOCA-NaHCO3 and DOCA-KHCO3 did not. DOCA-NaCl increased TBNa+ 26% but only moderately increased TBW. DOCA-NaHCO3 led to similar TBNa+ excess, while TBW and ICV, but not ECV, were increased more than in DOCA-NaCl rats. DOCA-KHCO3 did not affect TBNa+ or volume. At a given TB(Na++K+) and TBW, MAP in DOCA-NaCl rats was higher than in control, DOCA-NaHCO3, and DOCA-KHCO3 rats, indicating that hypertension in DOCA-NaCl rats was not dependent on TB(Na++K+) and water mass balance. Skin volume retention was hypertonic compared with serum and paralleled hypertension in DOCA-NaCl rats. These rats had higher TB(Na++K+)-to-TBW ratio in accumulated fluid than DOCA-NaHCO3 rats. DOCA-NaCl rats also had increased intracellular Cl− concentrations in skeletal muscle. We conclude that excessive cellular electrolyte redistribution and/or intracellular Na+ or Cl− accumulation may play an important role in the pathogenesis of salt-sensitive hypertension.

Recent immunohistochemical studies point to the dorsal motor nucleus of the vagus nerve as the point of departure of initial changes which are related to the gradual pathological developments in the dopaminergic system. In the light of current investigations, it is likely that biochemical changes within the peripheral nervous system may influence the physiology of the dopaminergic system, suggesting a putative role for it in the development of neurodegenerative disorders. By using Fourier transform infrared microspectroscopy, coupled with statistical analysis, we examined the effect of chronic, unilateral electrical vagus nerve stimulation on changes in lipid composition and in protein secondary structure within dopamine-related brain structures in rats. It was found that the chronic vagal nerve stimulation strongly affects the chain length of fatty acids within the ventral tegmental area, nucleus accumbens, substantia nigra, striatum, dorsal motor nucleus of vagus and the motor cortex. In particular, the level of lipid unsaturation was found significantly increasing in the ventral tegmental area, substantia nigra and motor cortex as a result of vagal nerve stimulation. When it comes to changes in protein secondary structure, we could see that the mesolimbic, mesocortical and nigrostriatal dopaminergic pathways are particularly affected by vagus nerve stimulation. This is due to the co-occurrence of statistically significant changes in the content of non-ordered structure components, alpha helices, beta sheets, and the total area of Amide I. Macromolecular changes caused by peripheral vagus nerve stimulation may highlight a potential connection between the gastrointestinal system and the central nervous system in rat during the development of neurodegenerative disorders.

Pulsed electromagnetic field (PEMF) influenced the viability of proliferating in vitro peripheral blood mononuclear cells (PBMCs) isolated from Crohn’s disease patients as well as acute myeloblastic leukemia (AML) patients by induction of cell death, but did not cause any vital changes in cells from healthy donors. Experiments with lymphoid U937 and monocytic MonoMac6 cell lines have shown a protective effect of PEMF on the death process in cells treated with death inducers.The aim of the current study was to investigate the influence of PEMF on native proliferating leukocytes originating from newly diagnosed acute lymphoblastic leukemia (ALL) patients.The effects of exposure to PEMF were studied in PBMCs from 20 children with ALL. PBMCs were stimulated with three doses of PEMF (7 Hz, 30 mT) for 4 h each with 24 h intervals. After the last stimulation, the cells were double stained with annexin V and propidium iodide dye to estimate viability by flow cytometric analysis.The results indicated an increase of annexin V positive as well as double stained annexin V and propidium iodide positive cells after exposure to threefold PEMF stimulation.A low-frequency pulsed electromagnetic field induces cell death in native proliferating cells isolated from ALL patients. The increased vulnerability of proliferating PBMCs to PEMF-induced interactions may be potentially applied in the therapy of ALL.The analysis of expression of apoptosis-related genes revealed changes in mRNA of some genes engaged in the intrinsic apoptotic pathway belonging to the Bcl-2 family and the pathway with apoptosis-inducing factor (AIF) abundance upon PEMF stimulation of PBMCs.

Salt sensitivity, described as association between salt intake and blood pressure, varies among individuals. HSD contributes to salt-sensitive hypertension. Traditional view on blood pressure regulation was focused on the kidneys and ECV expansion secondary to body Na+ load. However, the latest data suggest that salt-sensitive hypertension does not primarily come about by volume-related mechanisms and other than the renal body fluid control must play an important role. Since Na+ accumulation in the body does not necessarily lead to expansion of the extracellular volume it is suggested that Na+ might be stored in an osmotically inactive form either as osmotically inactive Na+ storage in the skin and/or osmotically neutral Na+/K+ exchange in muscle. Hypertonicity in the skin interstitium compared with blood and therefore osmotic stress may be a crucial cause of interstitial Na+ accumulation and hypertension development. Dietary salt loading increases osmotically inactive skin Na+ storage and polyanionic character of the skin, leading to local hypertonicity. The response to this hypertonic internal environment in the skin interstitium involves MPS-driven and TonEBP-VEGF-C-mediated hyperplasia of lymph capillaries and increased eNOS expression. A decreased osmotically inactive storage capacity for Na+ or reduced osmotically neutral Na+/K+ exchange may predispose to marked volume retention, and therefore to rise in blood pressure.

Objective: Present studies are aimed to elucidate that pulsed electromagnetic field (PEMF) influences cell death parameters and cellular interactions in coculture model in response to inflammatory stimulus like E.coli endotoxin. Methods: We hypothesized that PEMF exposure will affect cell death rate in the experimental coculture model, composed of the human bladder microvascular endothelial cell line (HMEVEC-Bd) and MonoMac6 (MM6) cells previously activated with LPS, and exposed to PEMF (7Hz, 30mT) for three times with 24h intervals. Following the last electromagnetic exposure, we measured viability of cocultured and cultured cells by annexin V (AnV) - propidium iodide (PI) flow cytometry staining procedure to evaluate cell death parameters. The level of proinflammatory cytokine, cell adhesion molecules and vascular endothelial growth factor (IL-8, ICAM-1 and VEGF-A) was estimated by ELISA method in coculture and cell culture collected supernatants. Results: PEMF exposure of HMVEC-Bd and MM6 coculture caused decrease of measured cell death parameters (early and late apoptosis as well as necrosis) and diminished production of some inflammatory agents released in response to LPS activation, comparing to not stimulated with PEMF controls. Conclussion: Obtained results confirmed our hypothesis and showed out that PEMF exposure of HMVEC-Bd & MM6 coculture previously activated with LPS exerted an anti-inflammatory effect.

Vagus nerve as a part of brain-gut axis transmits peripheral information to the brain via vagovagal reflexes. Electric properties of the vagus are not exactly known. Analysis of electric changes in vagal nerves evoked by physiologic impulse such as stomach distention by food would facilitate applying better documented and therefore safer vagal neuromodulation. The aim of our study was analysis and interpretation of electric properties of the left vagus in vivo in fasted and satiated Wistar rats. Silver measuring electrodes connected to analog amplifier (A-M Systems 3000) were attached to the nerve in the neck region. The signal was filtered and probing by computer recording system (ADInstruments Power Lab) and additional analyses were performed using GNU Octave programme. Our resuts have shown that the higher amplitude the smaller number of counted impulses in the vagus was detected. This relationship was true only till the maximum level typical for each recording (about 15-20 dB). We note that observed inter spike interval can be approximated with log-normal distribution, and that its mu parameter is enough to characterize a particular recording. Satiated rats were characterized by higher number of spikes per second in the nerve than fasted ones (0.9 vs 0.26) indicating that food intake increased nervous activity 3-4 times comparing to fasted state. The outcomes encourage us to state that good quality characteristic of the left vagus nerve activity provides an effective tool for detection of peripheral signals which are transmitting via vagal afferents to the higher centres. Target vagal neuromodulation to obtain certain terapeutic effects may be possible.