Genetically-predicted prefrontal DRD4 gene expression modulates differentiated brain responses to food cues in adolescent girls and boys

The dopamine receptor 4 (DRD4) in the prefrontal cortex (PFC) acts to modulate behaviours including cognitive control and motivation, and has been implicated in behavioral inhibition and responsivity to food cues. Adolescence is a sensitive period for the development of habitual eating behaviors and obesity risk, with potential mediation by development of the PFC. We previously found that genetic variations influencing DRD4 function or expression were associated with measures of laboratory and real-world eating behavior in girls and boys. Here we investigated brain responses to high energy–density (ED) and low-ED food cues using an fMRI task conducted in the satiated state. We used the gene-based association method PrediXcan to estimate tissue-specific DRD4 gene expression in prefrontal brain areas from individual genotypes. Among girls, those with lower vs. higher predicted prefrontal DRD4 expression showed lesser activation to high-ED and low-ED vs. non-food cues in a distributed network of regions implicated in attention and sensorimotor processing including middle frontal gyrus, and lesser activation to low-ED vs non-food cues in key regions implicated in valuation including orbitofrontal cortex and ventromedial PFC. In contrast, males with lower vs. higher predicted prefrontal DRD4 expression showed minimal differences in food cue response, namely relatively greater activation to high-ED and low-ED vs. non-food cues in the inferior parietal lobule. Our data suggest sex-specific effects of prefrontal DRD4 on brain food responsiveness in adolescence, with modulation of distributed regions relevant to cognitive control and motivation observable in female adolescents.

Brain Responses to High-Calorie Visual Food Cues in Individuals with Normal-Weight or Obesity: An Activation Likelihood Estimation Meta-Analysis

Overconsumption of high-calorie or unhealthy foods commonly leads to weight gain. Understanding people’s neural responses to high-calorie food cues might help to develop better interventions for preventing or reducing overeating and weight gain. In this review, we conducted a coordinate-based meta-analysis of functional magnetic resonance imaging studies of viewing high-calorie food cues in both normal-weight people and people with obesity. Electronic databases were searched for relevant articles, retrieving 59 eligible studies containing 2410 unique participants. The results of an activation likelihood estimation indicate large clusters in a range of structures, including the orbitofrontal cortex (OFC), amygdala, insula/frontal operculum, culmen, as well as the middle occipital gyrus, lingual gyrus, and fusiform gyrus. Conjunction analysis suggested that both normal-weight people and people with obesity activated OFC, supporting that the two groups share common neural substrates of reward processing when viewing high-calorie food cues. The contrast analyses did not show significant activations when comparing obesity with normal-weight. Together, these results provide new important evidence for the neural mechanism underlying high-calorie food cues processing, and new insights into common and distinct brain activations of viewing high-calorie food cues between people with obesity and normal-weight people.

Effects of food availability cycles on phase and period of activity/rest rhythm in Drosophila melanogaster

Foraging and feeding are indispensable for survival and their timing depends not only on the metabolic state of the animal but also on the availability of food resources in their environment. Since both these aspects are subject to change over time, these behaviours exhibit rhythmicity in occurrence. As the locomotor activity of an organism is related to its disposition to acquire food, and peak feeding in fruit flies has been shown to occur at a particular time of the day, we asked if cyclic food availability can entrain their rhythmic activity. By subjecting flies to cyclic food availability i.e., feeding/starvation (FS) cycles, we provided food cues contrasting to the preferred activity times and observed if this imposed cycling in food availability could entrain the activity/rest rhythm. We found that phase control, which is a property integral to entrainment, was not achieved despite increasing starvation duration of FS cycles (FS12:12, FS10:14 and FS8:16). We also found that flies subjected to T21 and T26 FS cycles were unable to match period of the activity rhythm to short or long T-cycles. Taken together these results show that external food availability cycles do not entrain the activity/rest rhythm of fruit flies. However, we find that starvation induced hyperactivity causes masking which results in phase changes. Additionally, T-cycle experiments resulted in minor period changes during FS treatment. These findings highlight that food cyclicity by itself may not be a potent zeitgeber but may act in unison with other abiotic factors like light and temperature to help flies time their activity appropriately.

Non-invasive vagus nerve stimulation normalizes food liking and improves liking ratings in depression

Introduction: The vagus nerve plays a prominent role in the regulation of food reward and energy metabolism. However, previous studies using vagus nerve stimulation yielded conflicting results regarding changes in food reward in healthy participants and participants with major depressive disorder (MDD), for which vagal nerve stimulation is an effective treatment. Methods: We investigated the acute effects of right transcutaneous auricular vagus nerve stimulation (taVNS) on ratings of liking and wanting of food and non-food items in 63 participants, including 31 patients with MDD. To test for taVNS-induced changes and interactions with between-subject variables group (MDD vs. healthy controls) and questionnaire scores as well as within-subject variables, we performed linear mixed-effects analysis. In addition, we assessed whether individual taVNS-induced changes in food reward ratings were dependent on average ratings.Results: taVNS increased liking of food cues in participants with MDD (p= 0.023), but not in healthy participants (p= 0.657). Specifically, taVNS induced larger improvements in liking ratings with increasing scores of anhedonia (p= 0.029). Notably, across all participants, taVNS reduced the variance of food liking compared to sham, suggesting that taVNS normalizes extreme liking ratings towards moderate levels (p = 0.039).Discussion: Our results show that taVNS acutely ameliorates hedonic responses in MDD suggesting that it could provide an effective treatment of anhedonia. Since anhedonia is difficult to treat with conventional therapies, taVNS may provide a powerful adjuvant to rapidly improve motivational deficiencies.

Imbalanced sensitivities to primary and secondary rewards in internet gaming disorder

Background Internet gaming disorder (IGD) is a type of behavioral addiction characterized by poorly controlled and interfering patterns of game playing. Studies have suggested that the IGD is usually accompanied by increased desire or craving for gaming, suggesting that secondary rewards related to gaming may become more salient than those for primary rewards like food. However, this hypothesis has not been formally tested and potential neural mechanisms remain unclear. Methods This is a functional magnetic resonance imaging (fMRI) study. Twenty-one IGD subjects and 23 matched individuals with recreational game use (RGU) were scanned when exposed to gaming (secondary rewards), food (primary rewards) and neutral cues. Group-by-cue-type interaction analyses and subsequent within-group analyses for fMRI data were performed and seed-based functional connectivity (FC) analyses explored further potential neural features. Results IGD subjects’ subjective craving responses to gaming cues were higher than to food cues, while the opposite was observed in RGU subjects. Group-by-cue interaction effects implicated the precuneus and precuneus-caudate FC. Simple effect analysis showed that for IGD subjects, gaming-related cues elicited higher FC in precuneus-caudate relationships than did food-related cues. In the RGU subjects, the opposite was observed. Significant correlations were found between brain features and craving scores. Conclusions These results support the hypothesis regarding imbalances in sensitivities to different types of reward in IGD, and suggest neural mechanisms by which craving for gaming may make secondary rewards more salient than primary ones, thus promoting participation in addictive patterns of gaming.

Altered prefrontal signaling during inhibitory control in a salient drug context in human cocaine addiction

Drug addiction is characterized by impaired Response Inhibition and Salience Attribution (iRISA), where the salience of drug cues is postulated to overpower that of other reinforcers with a concomitant decrease in self-control. However, the neural underpinnings of the interaction between the salience of drug cues and inhibitory control in drug addiction remain unclear. We developed a novel stop-signal fMRI task where the stop-signal reaction time (SSRT—a classical inhibitory control measure) was tested under different salience conditions (modulated by drug, food, threat or neutral words) in individuals with cocaine use disorder (CUD; n=26) vs. demographically matched healthy control participants (HC; n=26). Despite similarities in drug cue-related SSRT and valence and arousal word ratings between groups, the dorsolateral prefrontal cortex (dlPFC) activity was diminished during the successful inhibition of drug versus food cues in CUD, and was correlated with lower frequency of recent use, lower craving, and longer abstinence (Z > 3.1, p < .05 corrected). Results suggest reduced involvement of cognitive control regions (e.g., dlPFC) during inhibitory control under a drug context, relative to an alternative reinforcer, in CUD. Supporting the iRISA model, these results elucidate the direct impact of drug-related cue-reactivity on the neural signature of inhibitory control in drug addiction.Significance statementExcessive salience attribution to drugs and related cues at the expense of nondrug reinforcers and cues and inhibitory control impairments are hallmark symptoms of drug addiction. Although these neuropsychological functions have been investigated independently, brain representations of their interaction are less clear. We illustrate that, despite matched behavioral performance and valence and arousal ratings, the dorsolateral prefrontal cortex—a key node of the cognitive control network also associated with craving—exhibits decreased signaling when successfully inhibiting responses to drug compared to nondrug (food) cues (words) in cocaine-addicted individuals. Modulating salience while taxing self-control permits the study of their combined impact, an ecologically valid examination of the addiction experience. Better understanding inhibitory control under drug cue-reactivity may refine targeted neuromodulatory interventions.

Emotional reactivity to binge food and erotic cues in women with bulimia nervosa symptoms

Background Studies on food cue reactivity have documented that altered responses to high-calorie food are associated with bulimic symptomatology, however, alterations in sexual motivations and behaviors are also associated clinical features in this population, which justify their inclusion as a research target. Here, we study responses to erotic cues—alongside food, neutral and aversive cues—to gain an understanding of specificity to food versus a generalized sensitivity to primary reinforcers. Methods We recorded peripheral psychophysiological indices –the startle reflex, zygomaticus, and corrugator responses—and self-reported emotional responses (valence, arousal, and dominance) in 75 women completing the Bulimia Test-Revised (BULIT-R). Multiple regression analysis tested whether BULIT-R symptoms were predicted by self-reported and psychophysiological responses to food versus neutral and erotic versus neutral images. Results The results showed that individuals with higher bulimic symptoms were characterized by potentiated eye blink startle response during binge food (vs. neutral images) and more positive valence ratings during erotic (vs. neutral) cues. Conclusions The results highlight the negative emotional reactivity of individuals with elevated bulimic symptoms toward food cues, which could be related to the risk of progression to full bulimia nervosa and thereby addressed in prevention efforts. Results also point to the potential role of reactivity to erotic content, at least on a subjective level. Theoretical models of eating disorders should widen their conceptual scope to consider reactivity to a broader spectrum of primary reinforcers, which would have implications for cue exposure-based treatments. Plain English summary We examined appetitive and aversive cue responses in college women to investigate how bulimic symptoms relate to primary reinforcers such as food and erotic images. We recorded peripheral psychophysiological indices (the startle reflex, zygomaticus, and corrugator responses) and self-reported emotional responses (valence, arousal, and dominance) in 75 college women that were presented with the Spanish version of the Bulimia Test-Revised. The results showed that bulimic symptoms increase both psychophysiological defensiveness toward food cues and subjective pleasure toward erotic cues. The findings suggest a generalized sensitivity to primary reinforcers in the presence of bulimic symptoms, and emphasize the relevance of adopting a wider framework in research and treatment on bulimia nervosa.