Effects of hunger, satiety and oral glucose on effective connectivity between hypothalamus and insular cortex.

The hypothalamus and insular cortex play an essential role in the integration of endocrine and homeostatic signals and their impact on food intake. Resting-state functional connectivity alterations of the hypothalamus, posterior insula (PINS) and anterior insula (AINS) are modulated by metabolic states and caloric intake. Nevertheless, a deeper understanding of how these factors affect the strength of connectivity between hypothalamus, PINS and AINS is missing. This study investigated whether effective (directed) connectivity within this network varies as a function of prandial states (hunger vs. satiety) and energy availability (glucose levels and/or hormonal modulation). To address this question, we measured twenty healthy male participants of normal weight twice: once after 36 â€‹h of fasting (except water consumption) and once under satiated conditions. During each session, resting-state functional MRI (rs-fMRI) and hormone concentrations were recorded before and after glucose administration. Spectral dynamic causal modeling (spDCM) was used to assess the effective connectivity between the hypothalamus and anterior and posterior insula. Using Bayesian model selection, we observed that the same model was identified as the most likely model for each rs-fMRI recording. Compared to satiety, the hunger condition enhanced the strength of the forward connections from PINS to AINS and reduced the strength of backward connections from AINS to PINS. Furthermore, the strength of connectivity from PINS to AINS was positively related to plasma cortisol levels in the hunger condition, mainly before glucose administration. However, there was no direct relationship between glucose treatment and effective connectivity. Our findings suggest that prandial states modulate connectivity between PINS and AINS and relate to theories of interoception and homeostatic regulation that invoke hierarchical relations between posterior and anterior insula.

New Approaches in the Management of Sudden Cardiac Death in Patients with Heart Failure-Targeting the Sympathetic Nervous System.

Cardiovascular diseases (CVDs) have been considered the most predominant cause of death and one of the most critical public health issues worldwide. In the past two decades, cardiovascular (CV) mortality has declined in high-income countries owing to preventive measures that resulted in the reduced burden of coronary artery disease (CAD) and heart failure (HF). In spite of these promising results, CVDs are responsible for ~17 million deaths per year globally with ~25% of these attributable to sudden cardiac death (SCD). Pre-clinical data demonstrated that renal denervation (RDN) decreases sympathetic activation as evaluated by decreased renal catecholamine concentrations. RDN is successful in reducing ventricular arrhythmias (VAs) triggering and its outcome was not found inferior to metoprolol in rat myocardial infarction model. Registry clinical data also suggest an advantageous effect of RDN to prevent VAs in HF patients and electrical storm. An in-depth investigation of how RDN, a minimally invasive and safe method, reduces the burden of HF is urgently needed. Myocardial systolic dysfunction is correlated to neuro-hormonal overactivity as a compensatory mechanism to keep cardiac output in the face of declining cardiac function. Sympathetic nervous system (SNS) overactivity is supported by a rise in plasma noradrenaline (NA) and adrenaline levels, raised central sympathetic outflow, and increased organ-specific spillover of NA into plasma. Cardiac NA spillover in untreated HF individuals can reach ~50-fold higher levels compared to those of healthy individuals under maximal exercise conditions. Increased sympathetic outflow to the renal vascular bed can contribute to the anomalies of renal function commonly associated with HF and feed into a vicious cycle of elevated BP, the progression of renal disease and worsening HF. Increased sympathetic activity, amongst other factors, contribute to the progress of cardiac arrhythmias, which can lead to SCD due to sustained ventricular tachycardia. Targeted therapies to avoid these detrimental consequences comprise antiarrhythmic drugs, surgical resection, endocardial catheter ablation and use of the implantable electronic cardiac devices. Analogous NA agents have been reported for single photon-emission-computed-tomography (SPECT) scans usage, specially the 123I-metaiodobenzylguanidine (123I-MIBG). Currently, HF prognosis assessment has been improved by this tool. Nevertheless, this radiotracer is costly, which makes the use of this diagnostic method limited. Comparatively, positron-emission-tomography (PET) overshadows SPECT imaging, because of its increased spatial definition and broader reckonable methodologies. Numerous ANS radiotracers have been created for cardiac PET imaging. However, so far, [11C]-meta-hydroxyephedrine (HED) has been the most significant PET radiotracer used in the clinical scenario. Growing data has shown the usefulness of [11C]-HED in important clinical situations, such as predicting lethal arrhythmias, SCD, and all-cause of mortality in reduced ejection fraction HF patients. In this article, we discussed the role and relevance of novel tools targeting the SNS, such as the [11C]-HED PET cardiac imaging and RDN to manage patients under of SCD risk.

Five weeks of intermittent transcutaneous vagus nerve stimulation shape neural networks: a machine learning approach.

Invasive and transcutaneous vagus nerve stimulation [(t)-VNS] have been used to treat epilepsy, depression and migraine and has also shown effects on metabolism and body weight. To what extent this treatment shapes neural networks and how such network changes might be related to treatment effects is currently unclear. Using a pre-post mixed study design, we applied either a tVNS or sham stimulation (5 h/week) in 34 overweight male participants in the context of a study designed to assess effects of tVNS on body weight and metabolic and cognitive parameters resting state (rs) fMRI was measured about 12 h after the last stimulation period. Support vector machine (SVM) classification was applied to fractional amplitude low-frequency fluctuations (fALFF) on established rs-networks. All classification results were controlled for random effects and overfitting. Finally, we calculated multiple regressions between the classification results and reported food craving. We found a classification accuracy (CA) of 79 % in a subset of four brainstem regions suggesting that tVNS leads to lasting changes in brain networks. Five of eight salience network regions yielded 76,5 % CA. Our study shows tVNS' post-stimulation effects on fALFF in the salience rs-network. More detailed investigations of this effect and their relationship with food intake seem reasonable for future studies.

Female Gender Is Associated with Higher Susceptibility of Weight Induced Arterial Stiffening and Rise in Blood Pressure.

Arterial stiffness is an important predictor of cardiovascular events, independent of traditional risk factors. Stiffening of arteries, though an adaptive process to hemodynamic load, results in substantial increase in the pulsatile hemodynamic forces that detrimentally affects the microcirculation perfusing the vital organs such as the brain, heart and kidneys. Studies have proposed that arterial stiffness precedes and may contribute to the development of hypertension in individuals with obesity. Our study sought to determine the gender-based effects on arterial stiffening in obesity which may predispose to the development of hypertension. We found female sex is associated with higher susceptibility of weight-related arterial stiffening and rise in blood pressure in obesity. Women had significantly higher carotid-femoral pulse wave velocity (CF-PWV) with higher body mass index (BMI) status (normal: 7.9 ± 2 m/s; overweight: 9.1 ± 2 m/s; obese: 9 ± 2 m/s, p < 0.001), whereas it was similar in males across all BMI categories. The linear association between arterial stiffness and BMI following adjustment for age and brachial systolic and diastolic blood pressure (BP), remained significant in females (ß = 0.06; 95% CI 0.01 to 0.1; p < 0.05) but not in males (ß = 0.04; 95% CI -0.01 to 0.1; p > 0.05). The mean CF-PWV values increased by 0.1 m/s for every 1 kg/m2 increase in BMI in the female subjects in the age adjusted linear model, while such effect was not seen in the male subjects. In line with arterial stiffening, the overweight and obese females demonstrated significantly higher systolic brachial BP. (BP difference: ΔBP 9-11 mmHg, p < 0.01) and central systolic pressure (ΔBP 8-10 mmHg, p < 0.05) compared to their lean counterparts, unlike the male subjects. Our results suggest that female gender is associated with higher susceptibility of weight-related arterial stiffening and rise in blood pressure.

Retinal capillary rarefaction is associated with arterial and kidney damage in hypertension.

Microvascular disease and rarefaction are key pathological hallmarks of hypertension. The retina uniquely allows direct, non-invasive investigation of the microvasculature. Recently developed optical coherence tomography angiography now allows investigation of the fine retinal capillaries, which may provide a superior marker of overall vascular damage. This was a prospective cross-sectional study to collect retinal capillary density data on 300 normal eyes from 150 hypertensive adults, and to investigate possible associations with other organ damage markers. The average age of participants was 54 years and there was a greater proportion of males (85; 57%) than females. Multivariate, confounder adjusted linear regression showed that retinal capillary rarefaction in the parafovea was associated with increased pulse wave velocity (ß = - 0.4, P = 0.04), log-albumin/creatinine ratio (ß = - 0.71, P = 0.003), and with reduced estimated glomerular filtration rate (ß = 0.04, P = 0.02). Comparable significant associations were also found for whole-image vascular-density, for foveal vascular-density significant associations were found with pulse wave velocity and estimated glomerular filtration rate only. Our results indicate that retinal capillary rarefaction is associated with arterial stiffness and impaired kidney function. Retinal capillary rarefaction may represent a useful and simple test to assess the integrated burden of hypertension on the microvasculature irrespective of current blood pressure levels.

Impact of Hunger, Satiety, and Oral Glucose on the Association Between Insulin and Resting-State Human Brain Activity.

To study the interplay of metabolic state (hungry vs. satiated) and glucose administration (including hormonal modulation) on brain function, resting-state functional magnetic resonance imaging (rs-fMRI) and blood samples were obtained in 24 healthy normal-weight men in a repeated measurement design. Participants were measured twice: once after a 36 h fast (except water) and once under satiation (three meals/day for 36 h). During each session, rs-fMRI and hormone concentrations were recorded before and after a 75 g oral dose of glucose. We calculated the amplitude map from blood-oxygen-level-dependent (BOLD) signals by using the fractional amplitude of low-frequency fluctuation (fALFF) approach for each volunteer per condition. Using multiple linear regression analysis (MLRA) the interdependence of brain activity, plasma insulin and blood glucose was investigated. We observed a modulatory impact of fasting state on intrinsic brain activity in the posterior cingulate cortex (PCC). Strikingly, differences in plasma insulin levels between hunger and satiety states after glucose administration at the time of the scan were negatively related to brain activity in the posterior insula and superior frontal gyrus (SFG), while plasma glucose levels were positively associated with activity changes in the fusiform gyrus. Furthermore, we could show that changes in plasma insulin enhanced the connectivity between the posterior insula and SFG. Our results indicate that hormonal signals like insulin alleviate an acute hemostatic energy deficit by modifying the homeostatic and frontal circuitry of the human brain.

Modulation of brain activity by hormonal factors in the context of ingestive behaviour.

INTRODUCTION: Metabolic and hormonal signals have been shown to be associated with brain activity in the context of ingestive behaviour. However, this has mostly been seen in studies using external administration of hormones or glucose. We therefore studied endocrine-brain interaction in a physiological setting with hormone levels determined by metabolic conditions such as normal food intake vs. prolonged fasting. METHODS: 24 healthy, normal weight men participated in two sessions, one involving a 38-hour fasting period and one a non-fasting control condition with standardized meals. Functional magnetic resonance imaging was performed at the end of the experiment with participants being required to rate pictures of food. Brain activation was compared between conditions in predefined regions of interest (ROIs). Multiple blood samples were taken to determine levels of insulin, C-peptide, cortisol, ACTH, glucose and adiponectin. These were used as a predictor variable in a regression analysis on brain activations in the different ROIs. RESULTS: Food pictures were rated as more desirable in the fasting condition. Univariate analysis of ROI activations revealed mainly effects of food rating and no significant effects of the metabolic state. Multiple regression analysis revealed associations between orbitofrontal cortex activation and blood glucose in the non-fasting condition. In the fasting condition adiponectin was associated with the signal from the caudate nucleus and insulin and C-peptide were associated with functional activity of orbitofrontal regions. DISCUSSION: Associations of endocrine signals and functional neural regions could be demonstrated in a realistic setting without external administration of hormones. As the current approach was correlational, further studies need to address the causal role of hormonal signals.

Endocrine responses and food intake in fasted individuals under the influence of glucose ingestion.

INTRODUCTION: Different metabolic conditions can affect what and how much we eat. Hormones of glucose metabolism and adipokines such as adiponectin take part in the control of these decisions and energy balance of the body. However, a comprehensive understanding of how these endocrine and metabolic factors influence food intake has not been reached. We hypothesised that the amount of food a person consumes differs substantially after a fasting period even after the energy deficit was partially removed by glucose ingestion and endocrine signals like insulin and C-peptide indicated a high glucose metabolic status. Furthermore, the macronutrient composition of the consumed food and a possible association with adiponectin under the influence of glucose ingestion was assessed. METHODS: In a within-subject design, 24 healthy males participated in both a fasting (42 h) and control (non-fasting) condition. A total of 20 blood samples from each subject were collected during each condition to assess serum levels of adiponectin, insulin, C-peptide, cortisol and ACTH. At the end of each condition food intake was measured with an ad libitum buffet after the acute energy deficit was compensated using a carbohydrate-rich drink. RESULTS: The total amount of caloric intake and single macronutrients was higher after the fasting intervention after replenishment with glucose. All recorded hormone levels, except for adiponectin, were significantly different for at least one of the study intervals. The relative proportions of the macronutrient composition of the consumed food were stable in both conditions under the influence of glucose ingestion. In the non-fasting condition, the relative amount of protein intake correlated with adiponectin levels during the experiment. DISCUSSION AND CONCLUSION: An anabolic glucose metabolism after glucose ingestion following a fasting intervention did not even out energy ingestion compared to a control group with regular food intake and glucose ingestion. Anorexigenic hormones like insulin in this context were not able despite higher levels than in the control condition to ameliorate the drive for food intake to normal or near normal levels. Relative macronutrient intake remains stable under these varying metabolic conditions and glucose influence. Serum adiponectin levels showed a positive association with the relative protein intake in the non-fasting condition under the influence of glucose although adiponectin levels overall did not differ in between the conditions.

Sympathetic Activation in Hypertensive Chronic Kidney Disease - A Stimulus for Cardiac Arrhythmias and Sudden Cardiac Death?

Studies have revealed a robust and independent correlation between chronic kidney disease (CKD) and cardiovascular (CV) events, including death, heart failure, and myocardial infarction. Recent clinical trials extend this range of adverse CV events, including malignant ventricular arrhythmias and sudden cardiac death (SCD). Moreover, other studies point out that cardiac structural and electrophysiological changes are a common occurrence in this population. These processes are likely contributors to the heightened hazard of arrhythmias in CKD population and may be useful indicators to detect patients who are at a higher SCD risk. Sympathetic overactivity is associated with increased CV risk, specifically in the population with CKD, and it is a central feature of the hypertensive state, occurring early in its clinical course. Sympathetic hyperactivity is already evident at the earliest clinical stage of CKD and is directly related to the progression of renal failure, being most pronounced in those with end-stage renal disease. Sympathetic efferent and afferent neural activity in kidney failure is a crucial facilitator for the perpetuation and evolvement of the disease. Here, we will revisit the role of the feedback loop of the sympathetic neural cycle in the context of CKD and how it may aggravate several of the risk factors responsible for causing SCD. Targeting the overactive sympathetic nervous system therapeutically, either pharmacologically or with newly available device-based approaches, may prove to be a pivotal intervention to curb the substantial burden of cardiac arrhythmias and SCD in the high-risk population of patients with CKD.