Nils B. Kroemer

(Still) longing for food: Insulin reactivity modulates response to food pictures

Overweight and obesity pose serious challenges to public health and are promoted by our food‐rich environment. We used functional magnetic resonance imaging (fMRI) to investigate reactivity to food cues after overnight fasting and following a standardized caloric intake (i.e., a 75 g oral glucose tolerance test, OGTT) in 26 participants (body mass index, BMI between 18.5 and 24.9 kg m−2). They viewed pictures of palatable food and low‐level control stimuli in a block design and rated their current appetite after each block. Compared to control pictures, food pictures activated a large bilateral network typically involved in homeostatically and hedonically motivated food processing. Glucose ingestion was followed by decreased activation in the basal ganglia and paralimbic regions and increased activation in parietal and occipital regions. Plasma level increases in insulin correlated with cue‐induced appetite at the neural and behavioral level. High insulin increases were associated with reduced activation in various bilateral regions including the fusiform gyrus, the superior temporal gyrus, the medial frontal gyrus, and the limbic system in the right hemisphere. In addition, they were accompanied by lower subjective appetite ratings following food pictures and modulated the neural response associated with it (e.g., in the fusiform gyrus). We conclude that individual insulin reactivity is critical to reduce food‐cue responsivity after an initial energy intake and thereby may help to counteract overeating. Hum Brain Mapp 34:2367–2380, 2013.

Fasting levels of ghrelin covary with the brain response to food pictures

Ghrelin figures prominently in the regulation of appetite in normal‐weighed individuals. The apparent failure of this mechanism in eating disorders and the connection to addictive behavior in general demand a deeper understanding of the endogenous central‐nervous processes related to ghrelin. Thus, we investigated processing of pictures showing palatable food after overnight fasting and following a standardized caloric intake (i.e. a 75‐g oral glucose tolerance test) using functional magnetic resonance imaging and correlated it with blood plasma levels of ghrelin. Twenty‐six healthy female and male volunteers viewed food and control pictures in a block design and rated their appetite after each block. Fasting levels of ghrelin correlated positively with food‐cue reactivity in a bilateral network of visual processing‐, reward‐ and taste‐related regions, including limbic and paralimbic regions. Notably, among those regions were the hypothalamus and the midbrain where ghrelin receptors are densely concentrated. In addition, high fasting ghrelin levels were associated with stronger increases of subjective appetite during the food‐cue‐reactivity task. In conclusion, brain activation and subjective appetite ratings suggest that ghrelin elevates the hedonic effects of food pictures. Thereby, fasting ghrelin levels may generally enhance subjective craving when confronted with reward cues.

Balancing reward and work: anticipatory brain activation in NAcc and VTA predict effort differentially.

Complex decision-making involves anticipation of future rewards to bias effort for obtaining it. Using fMRI, we investigated 50 participants employing an instrumental-motivation task that cued reinforcement levels before the onset of the motor-response phase. We extracted timecourses from regions of interest (ROI) in the mesocorticolimbic system and used a three-level hierarchical model to separate anticipatory brain responses predicting value and subsequent effort on a trial-by-trial basis. Whereas all ROIs scaled positively with value, higher effort was predicted by higher anticipatory activation in nucleus accumbens (NAcc) but lower activation in ventral tegmental area/substantia nigra (VTA/SN). Moreover, anticipatory activation in the dorsal striatum predicted average effort whereas higher activation in the amygdala predicted above-average effort. Thus, anticipatory activation entails the appetitive drive towards reinforcement that requires effort in order to be obtained. Our results support the role of NAcc as the main hub supported by the salience network operating on a trial-by-trial basis, while the dorsal striatum incorporates habitual responding.

Acute and chronic nicotine effects on behaviour and brain activation during intertemporal decision making

Previous studies demonstrated higher discount rates for delayed rewards in smokers than non‐smokers. We performed this study to determine whether those differences in intertemporal choice are due to pharmacological effects of nicotine and to track related brain regions. Thirty‐three non‐smokers and 27 nicotine‐dependent smokers underwent functional magnetic resonance imaging while performing an intertemporal choice task consisting of 40 sets of monetary reward options that varied by delay to delivery. Smokers were investigated in a state of nicotine satiation. Non‐smokers were investigated twice, receiving nicotine (2 mg) and placebo gums in a double‐blinded, randomized cross‐over design. Smokers displayed steeper temporal discounting than non‐smokers. Those behavioural differences were reflected in the brain response during the decision between two alternative money/time pairs: smokers showed less activation in parietal and occipital areas (e.g. precuneus) than non‐smokers under placebo. A single dose of nicotine in non‐smokers led to a similar effect on brain activation but did not impact behaviour. Processing of the reward magnitude of money/time pairs differed between smokers and non‐smokers: smokers showed decreased reactivity of the ventral striatum. Moreover, there was an acute nicotine effect in non‐smokers on processing of the reward magnitude: nicotine increased the correlation of blood oxygen level‐dependent response and mean amount in the left hippocampus, amygdala and anterior insula. We conclude that cross‐sectional differences between smokers and non‐smokers are only, in part, due to the acute pharmacological effects of nicotine. Longitudinal studies are needed to investigate pre‐drug group characteristics as well as consequences of smoking on discounting behaviour and its neural correlates.

The personality trait self-directedness predicts the amygdala’s reaction to appetizing cues in fMRI☆

Personality and neural response to food cues in various mesolimbic brain structures have been linked to eating disorders. We investigated the question of whether personality traits in healthy individuals correlate with the brain activation induced on confrontation with appetizing visual stimuli. Personality was assessed in 27 normal-weight participants (14 women, mean age=26.0, SD=3.3 years) with the Temperament and Character Inventory (TCI). After an overnight fast, participants viewed blocks of pictures, half containing appetizing food and the other half showing scrambled pictures as control. After each block, participants rated their appetite. Brain activation was measured using a 3T MR scanner. Food compared to control stimuli elicited a significantly higher appetite rating, as well as strong activation in the ventral and dorsal visual stream, the fusiform gyrus and consecutive limbic centres such as the parahippocampal gyrus, the amygdala, the thalamus, the insula, the ventral striatum and the orbitofrontal cortex. In a region-of-interest analysis, the TCI trait self-directedness was negatively correlated with mean blood oxygenation level dependent (BOLD) signal change in the right amygdala (r=-.43, p=.025). Ultimately, amygdala reactivity might provide a risk factor for the development of eating disorders.

Nicotine enhances modulation of food-cue reactivity by leptin and ghrelin in the ventromedial prefrontal cortex

Endocrine signals such as ghrelin and leptin are known to modulate the mesocorticolimbic dopaminergic system and, consequently, show associations with food and drug reward. In animal models, nicotine was demonstrated to reduce body weight by attenuating food intake and effects of leptin and ghrelin are partly modulated by nicotinic acetylcholine receptors which hint at potential interactions. However, the neuropharmacological modulation of endocrine signals by nicotine in healthy humans remains to be tested experimentally. We used functional magnetic resonance imaging to investigate food‐cue reactivity after an overnight fast and following a caloric load (oral glucose tolerance test, OGTT) in 26 healthy normal‐weight never‐smokers. Moreover, we administered either nicotine (2 mg) or placebo gums using a randomized cross‐over design and assessed blood plasma levels of ghrelin and leptin. During fasting, nicotine administration decreased correlations with ghrelin levels in the mesocorticolimbic system whereas correlations with leptin were increased. After the OGTT, nicotine increased the modulatory effects of ghrelin and leptin on food‐cue reactivity, particularly in the ventromedial prefrontal cortex (vmPFC) and the amygdala. Critically, this led to an indirect modulation of the behavioral ‘appetizer effect’ (i.e. cue‐induced increases in subjective appetite) by homeostatic feedback signals via food‐cue reactivity in vmPFC. We conclude that nicotine enhances the effect of ghrelin and leptin in the valuation and relevance network which might, in turn, reduce appetite. This highlights that amplifying the impact of homeostatic signals such as ghrelin and leptin in normal‐weight individuals might hint at a mechanism contributing to nicotines anorexic potential.

Personality and Substance Use: Psychometric Evaluation and Validation of the Substance Use Risk Profile Scale (SURPS) in English, Irish, French, and German Adolescents

BACKGROUND The aim of the present longitudinal study was the psychometric evaluation of the Substance Use Risk Profile Scale (SURPS). METHODS We analyzed data from N = 2,022 adolescents aged 13 to 15 at baseline assessment and 2 years later (mean interval 2.11 years). Missing data at follow-up were imputed (N = 522). Psychometric properties of the SURPS were analyzed using confirmatory factor analysis. We examined structural as well as convergent validity with other personality measurements and drinking motives, and predictive validity for substance use at follow-up. RESULTS The hypothesized 4-factorial structure (i.e., anxiety sensitivity, hopelessness, impulsivity [IMP], and sensation seeking [SS]) based on all 23 items resulted in acceptable fit to empirical data, acceptable internal consistencies, low to moderate test-retest reliability coefficients, as well as evidence for factorial and convergent validity. The proposed factor structure was stable for both males and females and, to lesser degree, across languages. However, only the SS and the IMP subscales of the SURPS predicted substance use outcomes at 16 years of age. CONCLUSIONS The SURPS is unique in its specific assessment of traits related to substance use disorders as well as the resulting shortened administration time. Test-retest reliability was low to moderate and comparable to other personality scales. However, its relation to future substance use was limited to the SS and IMP subscales, which may be due to the relatively low-risk substance use pattern in the present sample.

Nicotine Alters Food–Cue Reactivity via Networks Extending From the Hypothalamus

Obesity and smoking constitute two of the main causes of preventable deaths in the developed countries today. Many smokers motivate consumption as a means to control their body weight because smoking cessation increases the risk to gain weight. Although it is well established that nicotine reduces feeding in animals and that smoking is associated with reduced body weight in quasi-experimental studies of humans, acute nicotine effects are mixed and little is known about the brain networks supporting these effects. Thus, we investigated 26 normal-weighted never-smokers who received either nicotine (2 mg) or placebo gums following a double-blinded randomized cross-over design. We used functional magnetic resonance imaging (fMRI) to investigate reactivity to palatable food cues after both overnight fasting and following a standardized caloric intake (75 g oral glucose tolerance test (OGTT)). Participants viewed food or low-level control pictures in a block design and rated their current appetite after each block. Nicotine had a small- to medium-sized effect on subjective appetite and significantly altered food–cue reactivity in a region sensitive to caloric intake that extended from the right hypothalamus to the basal ganglia. During placebo sessions, the OGTT reduced functional coupling of this region with a ‘salience network’ (ie, amygdala, ventromedial prefrontal cortex) in processing of food pictures. Furthermore, nicotine reduced coupling with the nucleus accumbens and the OGTT reduced coupling with an ‘interoceptive network’ (ie, insula, operculum) instead. We conclude that locally restricted acute effects of nicotine in the hypothalamic area have profound effects on food-processing networks.

Amygdala-Function Perturbations in Healthy Mid-Adolescents With Familial Liability for Depression

OBJECTIVE Functional magnetic resonance imaging (fMRI) studies have identified increased amygdala responses to negative stimuli as a risk marker of depression in adults, and as a state marker of depression in adults and adolescents. Hyperreactivity of the amygdala has been linked to negatively biased emotional processing in depression. However, no study has elucidated whether similar amygdala perturbations can be found in healthy mid-adolescents with familial liability for depression. We hypothesized that healthy 14-year-olds with relatives with depression would demonstrate increased amygdala responses to negative stimuli, as compared with their peers with no family history of mental disorders. METHOD We investigated a community-based sample of 164 typically developing 14-year-olds without record of past or current mental disorders. Of these individuals, 28 fulfilled criteria for family history of depression, and 136 served as controls. Groups did not differ with regard to cognitive ability, depressive symptomatology, and anxiety. During fMRI they performed a perceptual discrimination task in which visual target and distractor stimuli varied systematically with regard to emotional valence. RESULTS Both a hypothesis-driven region-of-interest analysis and a whole-brain analysis of variance revealed that negative distractors elicited greater amygdala activation in adolescents with a family history of depression compared to controls. Amygdala responses also differed during the processing of negative target stimuli, but effects were reversed. CONCLUSION Our study demonstrates that familial liability for depression is associated with correlates of negatively biased emotional processing in healthy adolescents. Amygdala perturbations during the processing of negative stimuli might reflect an early and subtle risk marker for depression.

No association of goal-directed and habitual control with alcohol consumption in young adults

Alcohol dependence is a mental disorder that has been associated with an imbalance in behavioral control favoring model‐free habitual over model‐based goal‐directed strategies. It is as yet unknown, however, whether such an imbalance reflects a predisposing vulnerability or results as a consequence of repeated and/or excessive alcohol exposure. We, therefore, examined the association of alcohol consumption with model‐based goal‐directed and model‐free habitual control in 188 18‐year‐old social drinkers in a two‐step sequential decision‐making task while undergoing functional magnetic resonance imaging before prolonged alcohol misuse could have led to severe neurobiological adaptations. Behaviorally, participants showed a mixture of model‐free and model‐based decision‐making as observed previously. Measures of impulsivity were positively related to alcohol consumption. In contrast, neither model‐free nor model‐based decision weights nor the trade‐off between them were associated with alcohol consumption. There were also no significant associations between alcohol consumption and neural correlates of model‐free or model‐based decision quantities in either ventral striatum or ventromedial prefrontal cortex. Exploratory whole‐brain functional magnetic resonance imaging analyses with a lenient threshold revealed early onset of drinking to be associated with an enhanced representation of model‐free reward prediction errors in the posterior putamen. These results suggest that an imbalance between model‐based goal‐directed and model‐free habitual control might rather not be a trait marker of alcohol intake per se.