Network-targeted transcranial direct current stimulation of the hypothalamus appetite-control network: a feasibility study.

The hypothalamus is the key regulator for energy homeostasis and is functionally connected to striatal and cortical regions vital for the inhibitory control of appetite. Hence, the ability to non-invasively modulate the hypothalamus network could open new ways for the treatment of metabolic diseases. Here, we tested a novel method for network-targeted transcranial direct current stimulation (net-tDCS) to influence the excitability of brain regions involved in the control of appetite. Based on the resting-state functional connectivity map of the hypothalamus, a 12-channel net-tDCS protocol was generated (Neuroelectrics Starstim system), which included anodal, cathodal and sham stimulation. Ten participants with overweight or obesity were enrolled in a sham-controlled, crossover study. During stimulation or sham control, participants completed a stop-signal task to measure inhibitory control. Overall, stimulation was well tolerated. Anodal net-tDCS resulted in faster stop signal reaction time (SSRT) compared to sham (p = 0.039) and cathodal net-tDCS (p = 0.042). Baseline functional connectivity of the target network correlated with SSRT after anodal compared to sham stimulation (p = 0.016). These preliminary data indicate that modulating hypothalamus functional network connectivity via net-tDCS may result in improved inhibitory control. Further studies need to evaluate the effects on eating behavior and metabolism.

Exposure to gestational diabetes mellitus in utero impacts hippocampal functional connectivity in response to food cues in children.

Objectives: Intrauterine exposure to gestational diabetes mellitus (GDM) increases the risk of obesity in the offspring, but little is known about the underlying neural mechanisms. The hippocampus is crucial for food intake regulation and is vulnerable to the effects of obesity. The purpose of the study was to investigate whether GDM exposure affects hippocampal functional connectivity during exposure to food cues using functional magnetic resonance imaging. Methods: Participants were 90 children age 7-11 years (53 females) who underwent an fMRI-based visual food cue task in the fasted state. Hippocampal functional connectivity (FC) was examined using generalized psychophysiological interaction in response to high-calorie food versus non-food cues. Food-cue induced hippocampal FC was compared between children with and without GDM exposure, while controlling for possible confounding effects of age, sex and waist-to-hip ratio. Results: Children with GDM exposure exhibited stronger hippocampal FC to the insula and striatum (i.e., putamen, pallidum and nucleus accumbens) compared to unexposed children, while viewing high caloric food cues. Conclusions: Intrauterine exposure to GDM was associated with higher food-cue induced hippocampal FC to reward processing regions. Future studies with longitudinal measurements are needed to clarify whether increased hippocampal FC to reward processing regions may raise the risk of the development of metabolic diseases later in life.

Influence of insulin sensitivity on food cue evoked functional brain connectivity in children.

Objective: Insulin resistance during childhood is a risk factor for developing type 2 diabetes and other health problems later in life. Studies in adults have shown that insulin resistance affects regional and network activity in the brain which are vital for behavior, e.g. ingestion and metabolic control. To date, no study has investigated whether brain responses to food cues in children are associated with peripheral insulin sensitivity. Methods: We included 53 children (36 girls) between the age of 7-11 years, who underwent an oral Glucose Tolerance Test (oGTT) to estimate peripheral insulin sensitivity (ISI). Brain responses were measured using functional magnetic resonance imaging (fMRI) before and after glucose ingestion. We compared food-cue task-based activity and functional connectivity (FC) between children with low and high ISI, adjusted for age and BMIz. Results: Independent of prandial state (i.e., glucose ingestion), children with lower ISI showed higher FC between the anterior insula and caudate and lower FC between the posterior insula and mid temporal cortex than children with higher ISI. Sex differences were found based on prandial state and peripheral insulin sensitivity in the insular FC. No differences were found on whole-brain food-cue reactivity. Conclusions: Children with low peripheral insulin sensitivity showed differences in food cue evoked response particularly in insula functional connectivity. These differences might influence eating behavior and future risk of developing diabetes.

Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase.

Insulin action in the human brain modulates eating behaviour, whole-body metabolism and body fat distribution1,2. In particular, brain insulin action increases whole-body insulin sensitivity, but these studies were mainly performed in lean men3,4. Here we investigate metabolic and hypothalamic effects of brain insulin action in women with a focus on the impact of menstrual cycle ( ClinicalTrials.gov registration: NCT03929419 ).Eleven women underwent four hyperinsulinemic-euglycemic clamps, two in the follicular phase and two in the luteal phase. Brain insulin action was introduced using nasal insulin spray5-7 and compared to placebo spray in a fourfold crossover design with change in glucose infusion rate as the primary endpoint. Here we show that during the follicular phase, more glucose has to be infused after administration of nasal insulin than after administration of placebo. This remains significant after adjustment for blood glucose and insulin. During the luteal phase, no significant influence of brain insulin action on glucose infusion rate is detected after adjustment for blood glucose and insulin (secondary endpoint). In 15 other women, hypothalamic insulin sensitivity was assessed in a within-subject design by functional magnetic resonance imaging with intranasal insulin administration8. Hypothalamus responsivity is influenced by insulin in the follicular phase but not the luteal phase.Our study therefore highlights that brain insulin action improves peripheral insulin sensitivity also in women but only during the follicular phase. Thus, brain insulin resistance could contribute to whole-body insulin resistance in the luteal phase of the menstrual cycle.

Sweet taste preference is associated with greater hypothalamic response to glucose and longitudinal weight gain.

The hypothalamus has an abundant expression of sweet taste receptors that play a role in glucose sensing and energy homeostasis. Evidence suggests that liking "sweets" can be associated with weight gain, but the relationship between sweet taste preference and hypothalamic regulation of appetite is unknown. This study tested the hypothesis that sweet taste preference is associated with increased hypothalamic activation in response to glucose (a purported neural marker for weight gain risk) and greater longitudinal increases in body mass index (BMI). Fifty-four adults aged 18-35 years with a mean (± SD) BMI of 27.99 ± 5.32 kg/m2 completed the study. Height and weight were measured at baseline and 6-12 months later in a subset of 36 participants. Sweet taste preference was assessed via the Monell 2-series, forced-choice tracking procedure. Arterial spin labeling magnetic resonance imaging was performed before and after oral glucose ingestion to determine hypothalamic blood flow response to glucose. Linear models were used to examine relationships between sweet taste preference and the hypothalamic response to glucose and longitudinal changes in BMI, adjusting for age, sex, and baseline BMI. Sweet taste preference was positively associated with glucose-linked hypothalamic blood flow (beta = 0.017, p = 0.043), adjusted for age, sex and BMI. We also observed a positive association between sweet taste preference and longitudinal change in BMI (beta = 0.088, p = 0.015), adjusted for age, sex and baseline BMI. These findings suggest that heightened sweet taste preference is associated with glucose-linked hypothalamic activation and may be linked to increased susceptibility for weight gain.

Brain insulin responsiveness is linked to age and peripheral insulin sensitivity.

AIMS: Insulin action in the brain influences cognitive processes, peripheral metabolism and eating behaviour. However, the influence of age and peripheral insulin sensitivity on brain insulin action remains unclear. MATERIALS AND METHODS: We used intranasal administration of insulin and functional magnetic resonance imaging in a randomized, placebo-controlled within-subject design in 110 participants (54 women, body mass index 18-49 kg/m2 , age 21-74 years). Cerebral blood flow was measured before and after nasal spray application to assess brain insulin action. Peripheral insulin sensitivity was assessed by a five-point oral glucose tolerance test. Linear regressions were used to investigate associations between age and peripheral insulin sensitivity with brain insulin action in predefined region of interests (i.e. insulin-sensitive brain regions). RESULTS: We found significant negative associations between age and insulin action in the hippocampus (ß = -0.215; p = .017) and caudate nucleus (ß = -0.184; p = .047); and between peripheral insulin sensitivity and insulin action in the amygdala (ß = -0.190, p = .023). Insulin action in the insular cortex showed an interaction effect between age and peripheral insulin sensitivity (ß = -0.219 p = .005). Furthermore, women showed the strongest negative association between age and hippocampal insulin action, while men showed the strongest associations with peripheral insulin sensitivity and age in reward-related brain regions. CONCLUSION: We could show a region-specific relationship between brain insulin responsiveness, age and peripheral insulin sensitivity. Our findings underline the need to study brain insulin action in both men and women and further substantiate that brain insulin sensitivity is a possible link between systemic metabolism and neurocognitive functions.

The effect of hunger state on hypothalamic functional connectivity in response to food cues.

The neural underpinnings of the integration of internal and external cues that reflect nutritional status are poorly understood in humans. The hypothalamus is a key integrative area involved in short- and long-term energy intake regulation. Hence, we examined the effect of hunger state on the hypothalamus network using functional magnetic resonance imaging. In a multicenter study, participants performed a food cue viewing task either fasted or sated on two separate days. We evaluated hypothalamic functional connectivity (FC) using psychophysiological interactions during high versus low caloric food cue viewing in 107 adults (divided into four groups based on age and body mass index [BMI]; age range 24-76 years; BMI range 19.5-41.5 kg/m2 ). In the sated compared to the fasted condition, the hypothalamus showed significantly higher FC with the bilateral caudate, the left insula and parts of the left inferior frontal cortex. Interestingly, we observed a significant interaction between hunger state and BMI group in the dorsolateral prefrontal cortex (DLPFC). Participants with normal weight compared to overweight and obesity showed higher FC between the hypothalamus and DLPFC in the fasted condition. The current study showed that task-based FC of the hypothalamus can be modulated by internal (hunger state) and external cues (i.e., food cues with varying caloric content) with a general enhanced communication in the sated state and obesity-associated differences in hypothalamus to DLPFC communication. This could potentially promote overeating in persons with obesity.

Exercise restores brain insulin sensitivity in sedentary adults who are overweight and obese.

BACKGROUNDInsulin resistance of the brain can unfavorably affect long-term weight maintenance and body fat distribution. Little is known if and how brain insulin sensitivity can be restored in humans. We aimed to evaluate the effects of an exercise intervention on insulin sensitivity of the brain and how this relates to exercise-induced changes in whole-body metabolism and behavior.METHODSIn this clinical trial, sedentary participants who were overweight and obese underwent an 8-week supervised aerobic training intervention. Brain insulin sensitivity was assessed in 21 participants (14 women, 7 men; age range 21-59 years; BMI range 27.5-45.5 kg/m2) using functional MRI, combined with intranasal administration of insulin, before and after the intervention.RESULTSThe exercise program resulted in enhanced brain insulin action to the level of a person of healthy weight, demonstrated by increased insulin-induced striatal activity and strengthened hippocampal functional connectivity. Improved brain insulin action correlated with increased mitochondrial respiration in skeletal muscle, reductions in visceral fat and hunger, as well as improved cognition. Mediation analyses suggest that improved brain insulin responsiveness helps mediate the peripheral exercise effects leading to healthier body fat distribution and reduced perception of hunger.CONCLUSIONOur study demonstrates that an 8-week exercise intervention in sedentary individuals can restore insulin action in the brain. Hence, the ameliorating benefits of exercise toward brain insulin resistance may provide an objective therapeutic target in humans in the challenge to reduce diabetes risk factors.TRIAL REGISTRATIONClinicalTrials.gov (NCT03151590).FUNDINGBMBF/DZD 01GI0925.

Sex differences in central insulin action: Effect of intranasal insulin on neural food cue reactivity in adults with normal weight and overweight.

BACKGROUND/OBJECTIVES: Central insulin action influences cognitive processes, peripheral metabolism, and eating behavior. However, the contribution of obesity and sex on central insulin-mediated neural food cue processing still remains unclear. SUBJECTS/METHODS: In a randomized within-participant design, including two visits, 60 participants (30 women, BMI 18-32 kg/m2, age 21-69 years) underwent a functional MRI task measuring blood oxygen level-dependent (BOLD) signal in response to visual food cues after intranasal insulin or placebo spray administration. Central insulin action was defined as the neural BOLD response to food cues after insulin compared to placebo administration. Afterwards, participants were asked to rate the food cues for desire to eat (i.e., wanting rating). For statistical analyses, participants were grouped according to BMI and sex. RESULTS: Food cue reactivity in the amygdala showed higher BOLD activation in response to central insulin compared to placebo. Furthermore, women with overweight and obesity and men of normal weight showed higher BOLD neural food cue responsivity to central insulin compared to placebo. Higher central insulin action in the insular cortex was associated with better peripheral insulin sensitivity and higher cognitive control. Moreover, central insulin action in the dorsolateral prefrontal cortex (DLPFC) revealed significant sex differences. In response to central insulin compared to placebo, men showed lower DLPFC BOLD activity, whereas women showed higher DLPFC activity in response to highly desired food cues. On behavioral level, central insulin action significantly reduced hunger, whereas the desire to eat, especially for low caloric food cues was significantly higher with central insulin than with placebo. CONCLUSIONS: Obesity and sex influenced the central insulin-mediated neural BOLD activity to visual food cues in brain regions implicated in reward and cognitive control. These findings show that central insulin action regulates food response differentially in men and women, which may have consequences for metabolism and eating behavior.

Short-Term Variability of Proton Density Fat Fraction in Pancreas and Liver Assessed by Multiecho Chemical-Shift Encoding-Based MRI at 3 T.

BACKGROUND: Quantification of pancreatic fat (PF) and intrahepatic lipids (IHL) is of increasing interest in subjects at risk for metabolic diseases. There is limited data available on short- and medium-term variability of PF/IHL and on their dependence on nutritional status. PURPOSE: To assess short-term intraday variations of PF/IHL after a high-fat meal as well as medium-term changes after 5 days of high-caloric diet. STUDY TYPE: Prospective cohort study. SUBJECTS: A total of 12 subjects (six males) for intraday variations study, 15 male subjects for medium-term high-caloric diet study and 11 age- and body mass index (BMI)-matched controls. FIELD STRENGTH/SEQUENCE: A 3 T; chemical-shift encoded multiecho gradient echo sequence. ASSESSMENT: For the intraday study, subjects were scanned after overnight fasting and after a high fat meal on the same day. For the medium-term study, 26 subjects were scanned after overnight fasting with 15/11 rescanned after 5 days of high-calorie diet/isocaloric diet. Proton density fat fraction (PDFF) maps were generated inline on the scanner. Regions of interest were manually drawn in head, body, and tail of pancreas and in the liver by a medical physicist and a doctoral student (26/4 years of experience). PF was calculated as the average of the head, body, and tail measurements. STATISTICAL TESTS: Repeated measurements ANOVA for assessing changes in PF/IHL, linear correlation analyses for assessing relationships of PF/IHL with BMI. Significance level P < 0.05 for all. RESULTS: Nonsignificant changes in PF (2.6 ± 1.0 vs. 2.7 ± 0.9% after high-fat meal, 1.4 ± 0.8 vs. 1.5 ± 0.6% [high-caloric diet] and 1.5 ± 0.8 vs. 1.8 ± 1.0% [isocaloric control group]), nonsignificant changes in IHL after high-fat meal (2.6 ± 1.3 vs. 2.5 ± 0.9%) and in the control group (1.1 ± 0.6 vs. 1.2 ± 1.1%), significantly increased IHL after high-caloric diet (1.7 ± 2.2% vs. 2.7 ± 3.6%). Nonsignificant changes in PF (2.6 ± 1.0 vs. 2.7 ± 0.9% after high-fat meal, 1.4 ± 0.8 vs. 1.5 ± 0.6% [high-caloric diet] and 1.5 ± 0.8 vs. 1.8 ± 1.0% [isocaloric control group]), nonsignificant changes in IHL after high-fat meal (2.6 ± 1.3 vs. 2.5 ± 0.9%) and in the control group (1.1 ± 0.6 vs. 1.2 ± 1.1%), significantly increased IHL after 5-days of high-caloric diet (1.7 ± 2.2% vs. 2.7 ± 3.6%). DATA CONCLUSION: Time of day and nutritional status have no significant influence on PF/IHL and are therefore not likely to be major confounders in epidemiologic or clinical studies. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.

The TUDID Study - Background and Design of a Prospective Cohort.

Prevalence of both type 1 and type 2 diabetes mellitus is growing worldwide and one major cause for morbidity and mortality. However, not every patient develops diabetes-related complications, but causes for the individual susceptibility are still not fully understood. As a platform to address this, we initiated the TUDID (TUebingen DIabetes Database) study, a prospective, monocentric, observational study that includes adults with diabetes mellitus who are treated in the inpatient clinic of a University Hospital in southern Germany. Besides a thorough clinical examination and extensive laboratory tests (with integrated biobanking), major study focuses are the kidneys, the eyes, the vasculature as well as cognition and mood where standardized investigations for early stages for diabetes complications are performed. Analyses of the data generated by this precise characterization of diabetes-related complications will contribute to our understanding of the development and course of such complications, and thus facilitate the implementation of tailored treatment options that can reduce the risk and severity of diabetes-related complications.

Empagliflozin Improves Insulin Sensitivity of the Hypothalamus in Humans With Prediabetes: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial.

OBJECTIVE: Insulin action in the human brain reduces food intake, improves whole-body insulin sensitivity, and modulates body fat mass and its distribution. Obesity and type 2 diabetes are often associated with brain insulin resistance, resulting in impaired brain-derived modulation of peripheral metabolism. So far, no pharmacological treatment for brain insulin resistance has been established. Since sodium-glucose cotransporter 2 (SGLT2) inhibitors lower glucose levels and modulate energy metabolism, we hypothesized that SGLT2 inhibition may be a pharmacological approach to reverse brain insulin resistance. RESEARCH DESIGN AND METHODS: In this randomized, double-blind, placebo-controlled clinical trial, 40 patients (mean ± SD; age 60 ± 9 years; BMI 31.5 ± 3.8 kg/m2) with prediabetes were randomized to receive 25 mg empagliflozin every day or placebo. Before and after 8 weeks of treatment, brain insulin sensitivity was assessed by functional MRI combined with intranasal administration of insulin to the brain. RESULTS: We identified a significant interaction between time and treatment in the hypothalamic response to insulin. Post hoc analyses revealed that only empagliflozin-treated patients experienced increased hypothalamic insulin responsiveness. Hypothalamic insulin action significantly mediated the empagliflozin-induced decrease in fasting glucose and liver fat. CONCLUSIONS: Our results corroborate insulin resistance of the hypothalamus in humans with prediabetes. Treatment with empagliflozin for 8 weeks was able to restore hypothalamic insulin sensitivity, a favorable response that could contribute to the beneficial effects of SGLT2 inhibitors. Our findings position SGLT2 inhibition as the first pharmacological approach to reverse brain insulin resistance, with potential benefits for adiposity and whole-body metabolism.

Neurobiological regulation of eating behavior: Evidence based on non-invasive brain stimulation.

The prefrontal cortex is appreciated as a key neurobiological player in human eating behavior. A special focus is herein dedicated to the dorsolateral prefrontal cortex (DLPFC), which is critically involved in executive function such as cognitive control over eating. Persons with obesity display hypoactivity in this brain area, which is linked to overconsumption and food craving. Contrary to that, higher activity in the DLPFC is associated with successful weight-loss and weight-maintenance. Transcranial direct current stimulation (tDCS) is a non-invasive neurostimulation tool used to enhance self-control and inhibitory control. The number of studies using tDCS to influence eating behavior rapidly increased in the last years. However, the effectiveness of tDCS is still unclear, as studies show mixed results and individual differences were shown to be an important factor in the effectiveness of non-invasive brain stimulation. Here, we describe the current state of research of human studies using tDCS to influence food intake, food craving, subjective feeling of hunger and body weight. Excitatory stimulation of the right DLPFC seems most promising to reduce food cravings to highly palatable food, while other studies provide evidence that stimulating the left DLPFC shows promising effects on weight loss and weight maintenance, especially in multisession approaches. Overall, the reported findings are heterogeneous pointing to large interindividual differences in tDCS responsiveness.

Slow deep breathing modulates cardiac vagal activity but does not affect peripheral glucose metabolism in healthy men.

Parasympathetic nervous system innervates peripheral organs including pancreas, hepatic portal system, and gastrointestinal tract. It thereby contributes to the regulation of whole-body glucose metabolism especially in the postprandial state when it promotes secretion of insulin and enhances its action in major target organs. We now aimed to evaluate the effect of parasympathetic modulation on human glucose metabolism. We used slow deep breathing maneuvers to activate the parasympathetic nervous system and tested for effects on metabolism during an oral glucose tolerance test in a randomized, controlled, cross-over trial in 15 healthy young men. We used projections towards the heart as a readout for parasympathetic activity. When analyzing heart rate variability, there was a significant increase of RMSSD (root mean square of successive differences) when participants performed slow deep breathing compared to the control condition, indicating a modulation of parasympathetic activity. However, no statistically significant effects on peripheral glucose metabolism or energy expenditure after the glucose tolerance test were detected. Of note, we detected a significant association between mean heart rate and serum insulin and C-peptide concentrations. While we did not find major effects of slow deep breathing on glucose metabolism, our correlational results suggest a link between the autonomic nervous system and insulin secretion after oral glucose intake. Future studies need to unravel involved mechanisms and develop potential novel treatment approaches for impaired insulin secretion in diabetes.

Resting-state functional connectivity of the human hypothalamus.

Communication pathways of the hypothalamus with other brain regions and the periphery are critical to successfully control key physiological and psychological processes. With advanced functional magnetic resonance imaging (fMRI) techniques, it is possible to target hypothalamic function and infer discrete hypothalamus networks. Resting-state functional connectivity (RSFC) is a promising tool to study the functional organization of the brain and may act as a marker of individual differences and dysfunctions. Based on recent fMRI findings, the hypothalamus is mostly connected to parts of the striatum, midbrain, thalamus, insula, frontal, cingulate, and temporal cortices and the cerebellum. There is a strong interplay of the hypothalamus with these regions in response to different metabolic, hormonal, and nutritional states. In a state of hunger, hypothalamus RSFC increases with a strong shift to reward-related brain regions, especially in person with excessive weight. Nutrient signals and hormones, as insulin, act on these same connections conveying reward and internal signals to regulate homeostatic control. Moreover, dysfunctional hypothalamus communication has been documented in persons with neurological and psychiatric diseases. The results implicate that patients with depression, epilepsy, and neurodegenerative diseases show mostly a reduction in hypothalamus RSFC, whereas patients with migraine and headache display predominantly increased hypothalamus RSFC. The extent of these changes and regions affected depend on the disorder and symptom severity. Whether hypothalamus RSFC can serve as a marker for disease states or is a prodromal neurobiological feature still needs to be investigated.

Diminished prefrontal cortex activation in patients with binge eating disorder associates with trait impulsivity and improves after impulsivity-focused treatment based on a randomized controlled IMPULS trial.

BACKGROUND: Behavioral and cognitive control are vital for healthy eating behavior. Patients with binge eating disorder (BED) suffer under recurrent binge eating episodes accompanied by subjective loss of control that results, among other factors, from increased impulsivity. METHODS: In the current study, we investigated the frontal network using functional near-infrared spectroscopy (fNIRS) during a food specific go/nogo task to assess response inhibition in 24 patients with BED (BMI range 22.6-59.7 kg/m2) compared to 12 healthy controls (HC) (BMI range 20.9-27 kg/m2). Patients with BED were invited to undergo fNIRS measurements before an impulsivity-focused cognitive behavioral group treatment, directly after this treatment and 3 months afterwards. As this was a planned subgroup analysis of the randomized controlled IMPULS trial, patients with BED were randomized either to the treatment group (n = 14) or to a control group (n = 10). The treatment group received 8 weekly sessions of the IMPULS treatment. RESULTS: We found a significant response inhibition effect (nogo minus go), in terms of an increased oxygenated hemoglobin response in the bilateral prefrontal cortex in both groups. The greatest response was observed when participants were instructed to go for healthy and withhold their response to unhealthy high caloric food cues. The healthy nogo condition failed to show a significant prefrontal inhibitory response, which was probably related to the task design, as the condition was considered more demanding. BED patients, especially those with higher trait impulsivity, showed a weaker activation of the prefrontal cortex during response inhibition, predominantly in the right hemisphere. Interestingly, three months after the treatment, patients of the treatment group increased their right prefrontal cortex activity during response inhibition. Likewise, increased prefrontal cortex activation correlated with decreased trait impulsivity after treatment. CONCLUSIONS: Our results suggest that patients with BED have limited resources to activate the prefrontal cortex when asked to inhibit a reaction onto food-specific stimuli. However, this effect could be partly driven by differences in BMI between the HC and BED group. Cognitive-behavioral therapy targeting impulsive eating behavior may improve prefrontal cortex recruitment during response inhibition.