Glucagon-like peptide-1 analogues: a new way to quit smoking? (SKIP)-a structured summary of a study protocol for a randomized controlled study.

BACKGROUND: Cigarette smoking is the leading preventable cause of premature death. Despite dedicated programmes, quit rates remain low due to barriers such as nicotine withdrawal syndrome or post-cessation weight gain. Glucagon-like peptide-1 (GLP-1) analogues reduce energy intake and body weight and seem to modulate addictive behaviour. These GLP-1 properties are of major interest in the context of smoking cessation. The aim of this study is to evaluate the GLP-1 analogue dulaglutide as a new therapy for smoking cessation. METHODS: This is a placebo-controlled, double-blind, parallel group, superiority, single-centre randomized study including 255 patients. The intervention consists of a 12-week dulaglutide treatment phase with 1.5 mg once weekly or placebo subcutaneously, in addition to standard of care (behavioural counselling and pharmacotherapy with varenicline). A 40-week non-treatment phase follows. The primary outcome is the point prevalence abstinence rate at week 12. Smoking status is self-reported and biochemically confirmed by end-expiratory exhaled carbon monoxide measurement. Further endpoints include post-cessational weight gain, nicotine craving analysis, glucose homeostasis and long-term nicotine abstinence. Two separate substudies assess behavioural, functional and structural changes by functional magnetic resonance imaging and measures of energy metabolism (i.e. resting energy expenditure, body composition). DISCUSSION: Combining behavioural counselling and medical therapy, e.g. with varenicline, improves abstinence rates and is considered the standard of care. We expect a further increase in quit rates by adding a second component of medical therapy and assume a dual effect of dulaglutide treatment (blunting nicotine withdrawal symptoms and reducing post-cessational weight gain). This project is of high relevance as it explores novel treatment options aimed at preventing the disastrous consequences of nicotine consumption and obesity. TRIAL REGISTRATION: ClinicalTrials.gov NCT03204396 . Registered on June 26, 2017.

Affordable IgY-based antiviral prophylaxis for resource-limited settings to address epidemic and pandemic risks.

Background: The COVID-19 pandemic caused by SARS-CoV-2 exposed a global problem, as highly effective vaccines are challenging to produce and distribute, particularly in regions with limited resources and funding. As an alternative, immunoglobulins produced in eggs of immunized hens (IgY) can be a simple and inexpensive source for a topical and temporary prophylaxis. Here, we developed a method to extract and purify IgY antibodies from egg yolks of hens immunized against viral pathogen-derived proteins using low-cost, readily available materials, for use in resource-limited settings. Methods: Existing protocols for IgY purification and equipment were modified, including extraction from yolks and separation of water-soluble IgY using common household reagents and tools. A replacement for a commercial centrifuge was developed, using a home food processor equipped with a 3D printed adapter to enable IgY precipitation. IgY purification was verified using standard gel electrophoresis and Western blot analyses. Results: We developed a step-by-step protocol for IgY purification for two settings in low- and middle-income countries (LMIC): a local laboratory, where commercial centrifuges are available, or a more rural setting, where an alternative for expensive centrifuges can be used. Gel electrophoresis and Western blot analyses confirmed that the method produced highly enriched IgY preparation; each commercial egg produced ~ 90 mg of IgY. We also designed a kit for IgY production in these two settings and provided a cost estimate of the kit. Conclusion: IgY purified from eggs of immunized local hens can offer a fast and affordable prophylaxis, provided that purification can be performed in a resource-limited setting. Here, we created a low-cost method that can be used anywhere where electricity is available using inexpensive, readily available materials in place of costly, specialized laboratory equipment and chemicals. This procedure can readily be used now to make an anti-SARS-CoV-2 prophylaxis in areas where vaccines are unavailable, and can be modified to combat future threats from viral epidemics and pandemics.

A randomized controlled trial of the GLP-1 receptor agonist dulaglutide in primary polydipsia.

BackgroundPrimary polydipsia, characterized by excessive fluid intake, carries the risk of water intoxication and hyponatremia, but treatment options are scarce. Glucagon-like peptide 1 (GLP-1) reduces appetite and food intake. In experimental models, GLP-1 has also been shown to play a role in thirst and drinking behavior. The aim of this trial was to investigate whether GLP-1 receptor agonists reduce fluid intake in patients with primary polydipsia.MethodsIn this randomized, double-blind, placebo-controlled, 3-week crossover trial, 34 patients with primary polydipsia received weekly dulaglutide (1.5 mg, Trulicity) in one treatment segment and placebo (0.9% sodium chloride) in the other. During the last treatment week, patients attended an 8-hour evaluation visit with free access to water. The primary endpoint was total fluid intake during the evaluation visits. Treatment effects were estimated using linear mixed-effects models. In a subset of 15 patients and an additional 15 matched controls, thirst perception and neuronal activity in response to beverage pictures were assessed by functional MRI.RESULTsPatients on dulaglutide reduced their fluid intake by 490 mL (95% CI: -780, -199; P = 0.002), from 2950 mL (95% CI: 2435, 3465) on placebo to 2460 mL (95% CI: 1946, 2475) on dulaglutide (model estimates), corresponding to a relative reduction of 17%. Twenty-four-hour urinary output was reduced by -943 mL (95% CI: -1473, -413; P = 0.001). Thirst perception in response to beverage pictures was higher for patients with primary polydipsia than for controls, and lower for patients on dulaglutide versus placebo, but functional activity was similar among groups and treatments.CONCLUSIONSGLP-1 receptor agonists reduce fluid intake and thirst perception in patients with primary polydipsia and could therefore be a treatment option for these patients.Trial registrationClinicaltrials.gov NCT02770885.FundingSwiss National Science Foundation (grant 32473B_162608); University Hospital and University of Basel; Young Talents in Clinical Research grant from the Swiss Academy of Medical Sciences and the Gottfried & Julia Bangerter-Rhyner Foundation; Top-up Grant from the PhD Programme in Health Sciences, University of Basel.

Acute Effects of Glucose and Fructose Administration on the Neural Correlates of Cognitive Functioning in Healthy Subjects: A Pilot Study.

The present randomized double-blinded cross-over study aims to extensively study the neural correlates underpinning cognitive functions in healthy subjects after acute glucose and fructose administration, using an integrative multimodal neuroimaging approach. Five minutes after glucose, fructose, or placebo administration through a nasogastric tube, 12 participants underwent 3 complementary neuroimaging techniques: 2 task-based functional magnetic resonance imaging (fMRI) sequences to assess working memory (N-back) and response inhibition (Go/No-Go) and one resting state fMRI sequence to address the cognition-related fronto-parietal network (FPN) and salience network (SN). During working memory processing, glucose intake decreased activation in the anterior cingulate cortex (ACC) relative to placebo, while fructose decreased activation in the ACC and sensory cortex relative to placebo and glucose. During response inhibition, glucose and fructose decreased activation in the ACC, insula and visual cortex relative to placebo. Resting state fMRI indicated increased global connectivity strength of the FPN and the SN during glucose and fructose intake. The results demonstrate that glucose and fructose lead to partially different partially overlapping changes in regional brain activities that underpin cognitive performance in different tasks.

Predicting neurodevelopmental outcome in preterm born infants using auditory event-related potentials: A systematic review.

Prematurity is a known risk factor for later cognitive deficits. At present there are neither behavioral nor neurological tests available to detect those preterm infants who would benefit most from early interventions. Neurophysiologic methods, and more specifically, auditory event-related potentials (AERPs) are convenient tools to investigate early cognitive functioning. However, the capability of AERPs as a prognostic factor for mental development in preterm infants remains unclear. The present systematic search of the literature yielded 1016 articles, out of which 13 were included. Both prospective and cross-sectional studies reported a relationship between AERPs and cognitive outcome. Our results show that larger amplitudes and shorter latencies of late AERPs are related to better cognitive outcomes. Additional studies are needed to corroborate our findings regarding this potential use of AERPs in the individual evaluation of preterm born infants.

Shoulder apprehension: A multifactorial approach.

Shoulder apprehension is related to changes in functional cerebral networks induced by dislocations, peripheral neuromuscular lesions and persistent mechanical glenohumeral instability consisting of micro-motion.All the damage to the osseous and soft-tissue stabilizers of the shoulder, as well as neurologic impairment persisting even after stabilization, must be properly identified in order to offer the best possible treatment to the patient.There is growing evidence supporting the use of a global multimodal approach, involving, on the one hand, shoulder 'reafferentation', including proprioception, mirror therapy and even cognitive behavioural approaches, and, on the other hand, surgical stabilization techniques and traditional physical therapy in order to minimize persistent micro-motion, which may help brain healing. This combined management could improve return to sport and avoid dislocation arthropathy in the long term. Cite this article: EFORT Open Rev 2018;3:550-557. DOI: 10.1302/2058-5241.3.180007.

Acute Effects of Methylphenidate, Modafinil, and MDMA on Negative Emotion Processing.

Background: Stimulants such as methylphenidate and modafinil are frequently used as cognitive enhancers in healthy people, whereas 3,4-methylenedioxymethamphetamine (ecstasy) is proposed to enhance mood and empathy in healthy subjects. However, comparative data on the effects of methylphenidate and modafinil on negative emotions in healthy subjects have been partially missing. The aim of this study was to compare the acute effects of methylphenidate and modafinil on the neural correlates of fearful face processing using 3,4-methylenedioxymethamphetamine as a positive control. Methods: Using a double-blind, within-subject, placebo-controlled, cross-over design, 60 mg methylphenidate, 600 mg modafinil, and 125 mg 3,4-methylenedioxymethamphetamine were administrated to 22 healthy subjects while performing an event-related fMRI task to assess brain activation in response to fearful faces. Negative mood states were assessed with the State-Trait Anxiety Inventory and subjective ratings. Results: Relative to placebo, modafinil, but not methylphenidate or 3,4-methylenedioxymethamphetamine, increased brain activation within a limbic-cortical-striatal-pallidal-thalamic circuit during fearful face processing. Modafinil but not methylphenidate also increased amygdala responses to fearful faces compared with 3,4-methylenedioxymethamphetamine. Furthermore, activation in the middle and inferior frontal gyrus in response to fearful faces correlated positively with subjective feelings of fearfulness and depressiveness after modafinil administration. Conclusions: Despite the cognitive enhancement effects of 600 mg modafinil in healthy people, potential adverse effects on emotion processing should be considered.

Decreased Fronto-Parietal and Increased Default Mode Network Activation is Associated with Subtle Cognitive Deficits in Elderly Controls.

BACKGROUND: Cognitive functions progressively deteriorate during aging and neurodegenerative diseases. The present study aims at investigating differences in working memory performance as well as functional brain changes during the earliest stages of cognitive decline in health elderly individuals. METHODS: 62 elderly individuals (41 females), including 41 controls (35 females) and 21 middle cognitive impairment subjects (6 females), underwent neuropsychological assessment at baseline and an fMRI examination in a N-back paradigm contrasting 2-back vs. 0-back condition. Upon a 18 months follow-up, we identified stable controls (sCON) with preserved cognition and deteriorating controls (dCON) with -1SD decrease of performances in at least two neuropsychological tests. Data analyses included accuracy and reaction time (RT) for the 2-back condition and general linear model (GLM) for the fMRI sequence. RESULTS: At the behavioral level, sCON and dCON performed better than MCI in terms of accuracy and reaction time. At the brain level, functional differences in regions of the fronto-parietal network (FPN) and of the Default Mode Network (DFM) were observed. Significantly lower neural activations in the bilateral inferior and middle frontal gyri were found in MCI versus both dCON / sCON and for dCON versus sCON. Significantly increased activations in the anterior cingulate cortex and posterior cingulate cortex and bilateral insula were found in MCI versus both dCON / sCON and in dCON versus sCON. CONCLUSION: The present study suggests that brain functional changes in FPN and DMN anticipate differences in cognitive performance in healthy elderly individuals with subsequent subtle cognitive decline.

Detecting Perfusion Pattern Based on the Background Low-Frequency Fluctuation in Resting-State Functional Magnetic Resonance Imaging Data and Its Influence on Resting-State Networks: An Iterative Postprocessing Approach.

Resting-state functional magnetic resonance imaging (RS-fMRI) is based on the assumption that the vascular response and the blood oxygenation level-dependent response are homogenous across the entire brain. However, this a priori hypothesis is not consistent with the well-known variability of cerebral vascular territories. To explore whether the RS networks are influenced by varied vascular speed in different vascular territories, we assessed the time-shift maps that give an estimate of the local timing of the vascular response and checked whether local differences in this timing have an impact on the estimates of RS networks. Two hundred seventeen elderly (≥60 years), healthy participants (73.74 ± 4.41 years, 143 females, 203 right handed) underwent one MRI examination, including an RS-fMRI session. After preprocessing, statistical analyses included time-shift analyses and RS-fMRI analyses using as regressor the delay maps obtained from the time-shift analyses. The functional connectivity map of default mode network (DMN) of each participant was then calculated by using the seed-to-voxel analysis in the REST toolbox. Faster cerebrovascular responses were notably present in the primary motor and somatosensory and peri-insular cortex, while slower responses were present in various regions, including notably the posterior cingulate cortex (PCC). Moreover, significant changes notably in the DMN, including medial prefrontal cortex (t = 11.95), PCC (t = 11.52), right middle temporal lobe (t = 10.72), and right angular gyrus (t = 10.88), were observed also taking into account the cerebrovascular delayed maps. As the most prominent example of the RS networks, DMN activation patterns change as a function of the cerebrovascular delay. These data suggest that a group correction for vascular maps in RS-fMRI measurements is essential to correctly depict functional differences and exclude potential confounding effects, notably in the elderly with increasing prevalence of vascular comorbidity.

Green tea effects on cognition, mood and human brain function: A systematic review.

BACKGROUND: Green tea (Camellia sinensis) is a beverage consumed for thousands of years. Numerous claims about the benefits of its consumption were stated and investigated. As green tea is experiencing a surge in popularity in Western culture and as millions of people all over the world drink it every day, it is relevant to understand its effects on the human brain. PURPOSE: To assess the current state of knowledge in the literature regarding the effects of green tea or green tea extracts, l-theanine and epigallocatechin gallate both components of green tea-on general neuropsychology, on the sub-category cognition and on brain functions in humans. METHODS: We systematically searched on PubMed database and selected studies by predefined eligibility criteria. We then assessed their quality and extracted data. We structured our effort according to the PRISMA statement. OUTCOME: We reviewed and assessed 21 studies, 4 of which were randomised controlled trials, 12 cross-over studies (both assessed with an adapted version of the DELPHI-list), 4 were cross-sectional studies and one was a cohort study (both assessed with an adapted version of the Newcastle-Ottawa assessment scale). The average study quality as appraised by means of the DELPHI-list was good (8.06/9); the studies evaluated with the Newcastle-Ottawa-scale were also good (6.7/9). CONCLUSIONS: The reviewed studies presented evidence that green tea influences psychopathological symptoms (e.g. reduction of anxiety), cognition (e.g. benefits in memory and attention) and brain function (e.g. activation of working memory seen in functional MRI). The effects of green tea cannot be attributed to a single constituent of the beverage. This is exemplified in the finding that beneficial green tea effects on cognition are observed under the combined influence of both caffeine and l-theanine, whereas separate administration of either substance was found to have a lesser impact.

The impact of gut hormones on the neural circuit of appetite and satiety: A systematic review.

The brain-gut-axis is an interdependent system affecting neural functions and controlling our eating behaviour. In recent decades, neuroimaging techniques have facilitated its investigation. We systematically looked into functional and neurochemical brain imaging studies investigating how key molecules such as ghrelin, glucagon-like peptide-1 (GLP-1), peptide tyrosine-tyrosine (PYY), cholecystokinin (CCK), leptin, glucose and insulin influence the function of brain regions regulating appetite and satiety. Of the 349 studies published before July 2016 identified in the database search, 40 were included (27 on healthy and 13 on obese subjects). Our systematic review suggests that the plasma level of ghrelin, the gut hormone promoting appetite, is positively correlated with activation in the pre-frontal cortex (PFC), amygdala and insula and negatively correlated with activation in subcortical areas such as the hypothalamus. In contrast, the plasma levels of glucose, insulin, leptin, PYY, GLP-1 affect the same brain regions conversely. Our study integrates previous investigations of the gut-brain matrix during food-intake and homeostatic regulation and may be of use for future meta-analyses of brain-gut interactions.

Comparative Effects of Methylphenidate, Modafinil, and MDMA on Response Inhibition Neural Networks in Healthy Subjects.

Background: Psychostimulants such as methylphenidate and modafinil are increasingly used by healthy people for cognitive enhancement purposes, whereas the acute effect of 3,4-methylenedioxymethamphetamine (ecstasy) on cognitive functioning in healthy subjects remains unclear. This study directly compared the acute effects of methylphenidate, modafinil, and 3,4-methylenedioxymethamphetamine on the neural mechanisms underlying response inhibition in healthy subjects. Methods: Using a double-blind, within-subject, placebo-controlled, cross-over design, methylphenidate, modafinil, and 3,4-methylenedioxymethamphetamine were administrated to 21 healthy subjects while performing a go/no-go event-related functional magnetic resonance imaging task to assess brain activation during motor response inhibition. Results: Relative to placebo, methylphenidate and modafinil but not 3,4-methylenedioxymethamphetamine improved inhibitory performance. Methylphenidate significantly increased activation in the right middle frontal gyrus, middle/superior temporal gyrus, inferior parietal lobule, presupplementary motor area, and anterior cingulate cortex compared with placebo. Methylphenidate also induced significantly higher activation in the anterior cingulate cortex and presupplementary motor area and relative to modafinil. Relative to placebo, modafinil significantly increased activation in the right middle frontal gyrus and superior/inferior parietal lobule, while 3,4-methylenedioxymethamphetamine significantly increased activation in the right middle/inferior frontal gyrus and superior parietal lobule. Conclusions: Direct comparison of methylphenidate, modafinil, and 3,4-methylenedioxymethamphetamine revealed broad recruitment of fronto-parietal regions but specific effects of methylphenidate on middle/superior temporal gyrus, anterior cingulate cortex, and presupplementary motor area activation, suggesting dissociable modulations of response inhibition networks and potentially the superiority of methylphenidate in the enhancement of cognitive performance in healthy subjects.

Hippocampal and Amygdala Gray Matter Loss in Elderly Controls with Subtle Cognitive Decline.

In contrast to the idea that hippocampal and amygdala volume loss occur in late phases of neurodegeneration, recent contributions point to the relevance of preexisting structural deficits that are associated with aging and are independent of amyloid deposition in preclinical Alzheimer disease cases. The present work explores GM hippocampal and amygdala volumes in elderly controls displaying the first signs of cognitive decline. 455 subjects (263 females), including 374 controls (228 females) and 81 middle cognitive impairment subjects (35 females), underwent two neuropsychological evaluations (baseline and 18 months follow-up) and a MRI-T1 examination (only baseline). Clinical assessment included Mini-Mental State Examination (MMSE), Clinical Dementia Rating scale, Hospitalized Anxiety and Depression scale, the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery and RI-48 Cued Recall Test (RI-48) for episodic memory. Based on their cognitive performance, we defined the controls as stable controls (sCON) and deteriorating controls (dCONs). Analyses included volumetric assessment, shape analyses and linear regressions between GM volume loss and differences in clinical scores between baseline and follow-up. Significant GM volume decrease in hippocampus bilaterally and right amygdala was found in dCON compared to sCON (p < 0.05). Lower right amygdala volumes were measured in mild cognitive impairment (MCI) compared to sCON (p < 0.05). Shape analyses revealed that atrophy was more pronounced at the superior- posterior lateral side of the hippocampus and amygdala. Significant correlations were found between GM volume of left hippocampus and the delta of MMSE and RI-48 scores in dCON and MCI groups separately. Decreased hippocampal and right amygdala volumes precede the first signs of cognitive decline in healthy elderly controls at the pre-MCI state. Left hippocampus volume may also predict short-term changes of overall cognition in these vulnerable cases.

Brain activity in the right-frontal pole and lateral occipital cortex predicts successful post-operatory outcome after surgery for anterior glenoumeral instability.

Shoulder apprehension is more complex than a pure mechanical problem of the shoulder, creating a scar at the brain level that prevents the performance of specific movements. Surgery corrects for shoulder instability at the physical level, but a re-dislocation within the first year is rather common. Predicting which patient will be likely to have re-dislocation is therefore crucial. We hypothesized that the assessment of neural activity at baseline and follow-up is the key factor to predict the post-operatory outcome. 13 patients with shoulder apprehension (30.03 ± 7.64 years) underwent clinical and fMRI examination before and one year after surgery for shoulder dislocation contrasting apprehension cue videos and control videos. Data analyses included task-related general linear model (GLM) and correlations imaging results with clinical scores. Clinical examination showed decreased pain and increased shoulder functions for post-op vs. pre-op. Coherently, GLM results show decreased activation of the left pre-motor cortex for post-surgery vs. pre-surgery. Right-frontal pole and right-occipital cortex activity predicts good recovery of shoulder function measured by STT. Our findings demonstrate that beside physical changes, changes at the brain level also occur one year after surgery. In particular, decreased activity in pre-motor and orbito-frontal cortex is key factor for a successful post-operatory outcome.

Structural white matter and functional connectivity alterations in patients with shoulder apprehension.

Previous functional magnetic resonance imaging (fMRI) findings indicate that shoulder apprehension is more complex than a pure mechanical problem of the shoulder, showing a direct modification in functional brain networks associated with motor inhibition and emotional regulation. The current study extends these findings by investigating further structural alterations in patients with shoulder apprehension compared to controls. 14 aged patients with shoulder apprehension (27.3 ± 2.0 years) and 10 matched healthy controls (29.6 ± 1.3 years) underwent clinical and fMRI examination including fMRI and diffusion tensor imaging (DTI). Tract-based spatial statistics procedure was used to analyze white matter (WM) alterations. Functional images were analyzed investigating resting state network connectivity. DTI results were correlated with different shoulder clinical scores and functional connectivity networks. Fractional anisotropy (FA), representing white matter integrity, is increased in the left internal capsule and partially in the thalamus in patients compared to controls. Moreover, FA correlates negatively with simple shoulder test (SST) scores (p < .05) and positively with a functional connectivity network qualitatively replicating previous results (p < .01). This study extends previous findings, showing that in addition to functional changes, structural white matter changes are also present in patients with shoulder apprehension.

Sex Effects on Smoking Cue Perception in Non-Smokers, Smokers, and Ex-Smokers: A Pilot Study.

INTRODUCTION: Recent neuroimaging research suggests sex-related brain differences in smoking addiction. In the present pilot study, we assessed gender-related differences in brain activation in response to cigarette-related video cues, investigating non-smokers, smokers, and ex-smokers. METHODS: First, we compared 29 females (28.6 ± 5.3) vs. 23 males (31.5 ± 6.4), regardless of current smoking status to assess global gender-related effects. Second, we performed a post hoc analysis of non-smokers (9 females and 8 males), smokers (10 females and 8 males), and ex-smokers (10 females and 7 males). Participants performed a block-design functional magnetic resonance imaging paradigm contrasting smoking with control cue video exposures. Data analyses included task-related general linear model, voxel-based morphometry of gray matter (GM), and tract-based spatial statistics of white matter (WM). RESULTS: First, the global effect regardless of current smoking status revealed higher activation in the bilateral superior frontal gyrus and anterior cingulate cortex (ACC) for females compared to males. Second, the analysis according to current smoking status demonstrated higher activation in female vs. male smokers vs. non-smokers in the superior frontal gyrus, anterior and posterior cingulate cortex, and precuneus, and higher activation in female vs. male ex-smokers vs. non-smokers in the right precentral gyrus, in the right insula and ACC. No structural differences were found in GM or WM. CONCLUSION: The current study identifies gender-related brain functional differences in smokers and ex-smokers compared to non-smokers. The current work can be considered as a starting point for future investigations into gender differences in brain responses to cigarette-related cues.

Differential effects of L-tryptophan and L-leucine administration on brain resting state functional networks and plasma hormone levels.

Depending on their protein content, single meals can rapidly influence the uptake of amino acids into the brain and thereby modify brain functions. The current study investigates the effects of two different amino acids on the human gut-brain system, using a multimodal approach, integrating physiological and neuroimaging data. In a randomized, placebo-controlled trial, L-tryptophan, L-leucine, glucose and water were administered directly into the gut of 20 healthy subjects. Functional MRI (fMRI) in a resting state paradigm (RS), combined with the assessment of insulin and glucose blood concentration, was performed before and after treatment. Independent component analysis with dual regression technique was applied to RS-fMRI data. Results were corrected for multiple comparisons. In comparison to glucose and water, L-tryptophan consistently modifies the connectivity of the cingulate cortex in the default mode network, of the insula in the saliency network and of the sensory cortex in the somatosensory network. L-leucine has lesser effects on these functional networks. L-tryptophan and L-leucine also modified plasma insulin concentration. Finally, significant correlations were found between brain modifications after L-tryptophan administration and insulin plasma levels. This study shows that acute L-tryptophan and L-leucine intake directly influence the brain networks underpinning the food-reward system and appetite regulation.

Gut Taste Stimulants Alter Brain Activity in Areas Related to Working Memory: a Pilot Study.

BACKGROUND/AIMS: Taste perception is one of the most important primary oral reinforcers, driving nutrient and energy intake as well as toxin avoidance. Taste receptors in the gastrointestinal tract might as well impact appetitive or aversive behavior and thus influence learning tasks and a close relation of neural taste processing and working memory networks seems plausible. METHODS: In the present pilot study, we determined the effects of five taste qualities "bitter" (quinine), "sweet" (glucose), "sour" (citric acid), "salty" (NaCl) and "umami" (monosodium glutamate, MSG) on working memory processing using functional MRI and their effect on plasma insulin and glucose levels. On six separate occasions, subjects received one of the following test substances dissolved in 200 mL tap water via a nasogastric tube (to circumvent the oral cavity): 1) 2g citric acid corresponding to 52 mM, 2) 2g NaCl; 171 mM, 3) 0.017g quinine; 0.26 mM, 4) 1g monosodium glutamate; 30 mM, 5) 25g glucose; 694 mM and 6) 200 mL tap water (placebo). RESULTS: The taste qualities "bitter" and "umami" significantly altered brain activation patterns in the primary gustatory cortex as well as in subcortical structures, previously reported to be involved in emotional learning and memory. In contrast, glucose did not reveal any statistically significant brain activation difference. Working memory performance was not different over the six treatments. Plasma insulin and glucose levels were not affected by the different taste substances (MSG, quinine, NaCl and citric acid). CONCLUSIONS: in this pilot trial, we demonstrate that acute intragastric administration of different taste substances does not affect working memory performance in humans. However, "umami" and "bitter" have effects on brain areas involved in neural working memory, overpowering the effects of "sweet", "salty" and "sour" reception.

Extreme Mountain Ultra-Marathon Leads to Acute but Transient Increase in Cerebral Water Diffusivity and Plasma Biomarkers Levels Changes.

Background: Pioneer studies demonstrate the impact of extreme sport load on the human brain, leading to threatening conditions for athlete's health such as cerebral edema. The investigation of brain water diffusivity, allowing the measurement of the intercellular water and the assessment of cerebral edema, can give a great contribution to the investigation of the effects of extreme sports on the brain. We therefore assessed the effect of supra-physiological effort (extreme distance and elevation changes) in mountain ultra-marathons (MUMs) athletes combining for the first time brain magnetic resonance imaging (MRI) and blood parameters. Methods:This longitudinal study included 19 volunteers (44.2 ± 9.5 years) finishing a MUM (330 km, elevation + 24000 m). Quantitative measurements of brain diffusion-weighted images (DWI) were performed at 3 time-points: Before the race, upon arrival and after 48 h. Multiple blood biomarkers were simultaneously investigated. Data analyses included brain apparent diffusion coefficient (ADC) and physiological data comparisons between three time-points. Results:The whole brain ADC significantly increased from baseline to arrival (p = 0.005) and then significantly decreased at recovery (p = 0.005) to lower values than at baseline (p = 0.005). While sodium, potassium, calcium, and chloride as well as hematocrit (HCT) changed over time, the serum osmolality remained constant. Significant correlations were found between whole brain ADC changes and osmolality (p = 0.01), cholesterol (p = 0.009), c-reactive protein (p = 0.04), sodium (p = 0.01), and chloride (p = 0.002) plasma level variations. Conclusions:These results suggest the relative increase of the inter-cellular volume upon arrival, and subsequently its reduction to lower values than at baseline, indicating that even after 48 h the brain has not fully recovered to its equilibrium state. Even though serum electrolytes may only indirectly indicate modifications at the brain level due to the blood brain barrier, the results concerning osmolality suggest that body water might directly influence the change in cerebral ADC. These findings establish therefore a direct link between general brain inter-cellular water content and physiological biomarkers modifications produced by extreme sport.

Cigarette smoking leads to persistent and dose-dependent alterations of brain activity and connectivity in anterior insula and anterior cingulate.

Although many smokers try to quit smoking, only about 20-25 percent will achieve abstinence despite 6 months or more of gold-standard treatment. This low success rate suggests long-term changes in the brain related to smoking, which remain poorly understood. We compared ex-smokers to both active smokers and non-smokers using functional magnetic resonance imaging (fMRI) to explore persistent modifications in brain activity and network organization. This prospective and consecutive study includes 18 non-smokers (29.5 ± 6.7 years of age, 11 women), 14 smokers (≥10 cigarettes a day >2 years of smoking, 29.3 ± 6.0 years of age, 10 women) and 14 ex-smokers (>1 year of quitting 30.5 ± 5.7 years of age, 10 women). Participants underwent a block-design fMRI study contrasting smoking cue with control (neutral cue) videos. Data analyses included task-related general linear model, seed-based functional connectivity, voxel-based morphometry (VBM) of gray matter and tract-based spatial statistics (TBSS) of white matter. Smoking cue videos versus control videos activated the right anterior insula in ex-smokers compared with smokers, an effect correlating with cumulative nicotine intake (pack-years). Moreover, ex-smokers had a persistent decrease in functional connectivity between right anterior insula and anterior cingulate cortex (ACC) compared with control participants, but similar to active smokers. Potentially confounding alterations in gray or white matter were excluded in VBM and TBSS analyses. In summary, ex-smokers with long-term nicotine abstinence have persistent and dose-dependent brain network changes notably in the right anterior insula and its connection to the ACC.