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Insulin acts on the CNS to modulate behaviour and systemic metabolism. Disturbances in brain insulin action represent a possible link between metabolic and cognitive health. Current findings from human research suggest that boosting central insulin action in the brain modulates peripheral metabolism, enhancing whole-body insulin sensitivity and suppressing endogenous glucose production. Moreover, central insulin action curbs food intake by reducing the salience of highly palatable food cues and increasing cognitive control. Animal models show that the mesocorticolimbic circuitry is finely tuned in response to insulin, driven mainly by the dopamine system. These mechanisms are impaired in people with obesity, which might increase their risk of developing type 2 diabetes and associated diseases. Overall, current findings highlight the role of insulin action in the brain and its consequences on peripheral metabolism and cognition. Hence, improving central insulin action could represent a therapeutic option for people at an increased risk of developing metabolic and cognitive diseases., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The conscious perception of the hedonic sensory properties of caloric foods is commonly believed to guide our dietary choices. Current and traditional models implicate the consciously perceived hedonic qualities of food as driving overeating, whereas subliminal signals arising from the gut would curb our uncontrolled desire for calories. Here we review recent animal and human studies that support a markedly different model for food reward. These findings reveal in particular the existence of subcortical body-to-brain neural pathways linking gastrointestinal nutrient sensors to the brain's reward regions. Unexpectedly, consciously perceptible hedonic qualities appear to play a less relevant, and mostly transient, role in food reinforcement. In this model, gut-brain reward pathways bypass cranial taste and aroma sensory receptors and the cortical networks that give rise to flavor perception. They instead reinforce behaviors independently of the cognitive processes that support overt insights into the nature of our dietary decisions.

The compromise between lateral resolution and usable imaging depth range is a bottleneck for optical coherence tomography (OCT). Existing solutions for optical coherence microscopy (OCM) suffer from either large data size and long acquisition time or a nonideal point spread function. We present volumetric OCM of mouse brain ex vivo with a large depth coverage by leveraging computational adaptive optics (CAO) to significantly reduce the number of OCM volumes that need to be acquired with a Gaussian beam focused at different depths. We demonstrate volumetric reconstruction of ex-vivo mouse brain with lateral resolution of 2.2  μm, axial resolution of 4.7  μm, and depth range of ∼1.2  mm optical path length, using only 11 OCT data volumes acquired on a spectral-domain OCM system. Compared to focus scanning with step size equal to the Rayleigh length of the beam, this is a factor of 4 fewer datasets required for volumetric imaging. Coregistered two-photon microscopy confirmed that CAO-OCM reconstructions can visualize various tissue microstructures in the brain. Our results also highlight the limitations of CAO in highly scattering media, particularly when attempting to reconstruct far from the focal plane or when imaging deep within the sample.

Pleasant taste and nutritional value guide food selection behavior. Here, orosensory features of food may be secondary to its nutritional value in underlying reinforcement, but it is unclear how the brain encodes the reward value of food. Orosensory and peripheral physiological signals may act together on dopaminergic circuits to drive food intake. We combined fMRI and a novel [11C]raclopride PET method to assess systems-level activation and dopamine release in response to palatable food intake in humans. We identified immediate orosensory and delayed post-ingestive dopamine release. Both responses recruit segregated brain regions: specialized integrative pathways and higher cognitive centers. Furthermore, we identified brain areas where dopamine release reflected the subjective desire to eat. Immediate dopamine release in these wanting-related regions was inversely correlated with, and presumably inhibited, post-ingestive release in the dorsal striatum. Our results highlight the role of brain and periphery in interacting to reinforce food intake in humans., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Electronic cigarettes (e-cigarettes) are becoming increasingly popular. The popularity of fruit flavors among e-cigarette users suggests that sweet taste may contribute to e-cigarette appeal. We therefore tested whether sweet taste potentiates the reinforcing effects of nicotine. Using a conditioning paradigm adapted to study e-cigarettes, we tested whether exposure to flavored e-cigarettes containing nicotine plus sweet taste would be more reinforcing than unsweetened e-cigarettes. Sixteen light cigarette smokers smoked 4 distinctly colored e-cigarettes containing sweetened and unsweetened flavors with or without nicotine for 2 days each. Brain response was then assessed to the sight and smell of the 4 exposed e-cigarettes using fMRI. After exposure, sweet-paired flavors were wanted (p = .024) and tended to be liked (p = .053) more than nicotine-paired flavors. Moreover, sweet taste supra-additively increased liking for nicotine-paired flavors in individuals who did not show increased liking for nicotine alone (r = -.67, p = .005). Accordingly, cues predicting sweet compared to non-sweet flavors elicited a stronger response in the nucleus accumbens (NAcc, p SVC  = .050) and the magnitude of response to the sight (p SVC  = .022) and smell (p SVC  = .017) of the e-cigarettes correlated with changes in liking. By contrast, the sight and smell of cues predicting nicotine alone failed to elicit NAcc response. However, the sight and smell of e-cigarettes paired with sweet+nicotine (p SVC  = .035) produced supra-additive NAcc responses. Collectively, these findings demonstrate that sweet taste potentiates the reinforcing effects of nicotine in e-cigarettes resulting in heightened brain cue-reactivity., (Copyright © 2018. Published by Elsevier B.V.)

Post-ingestive signals conveying information about the nutritive properties of food are critical for regulating ingestive behavior. Here, using an auction task concomitant to fMRI scanning, we demonstrate that participants are willing to pay more for fat + carbohydrate compared with equally familiar, liked, and caloric fat or carbohydrate foods and that this potentiated reward is associated with response in areas critical for reward valuation, including the dorsal striatum and mediodorsal thalamus. We also show that individuals are better able to estimate the energy density of fat compared with carbohydrate and fat + carbohydrate foods, an effect associated with functional connectivity between visual (fusiform gyrus) and valuation (ventromedial prefrontal cortex) areas. These results provide the first demonstration that foods high in fat and carbohydrate are, calorie for calorie, valued more than foods containing only fat or carbohydrate and that this effect is associated with greater recruitment of central reward circuits., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Global brain connectivity (GBC) identifies regions of the brain, termed "hubs," which are densely connected and metabolically costly, and have a wide influence on brain function. Since obesity is associated with central and peripheral metabolic dysfunction we sought to determine if GBC is altered in obesity. Two independent fMRI data sets were subjected to GBC analyses. The first data set was acquired while participants (n = 15 healthy weight and 15 obese) tasted milkshake and the second with participants at rest (n = 33 healthy weight and 28 obese). In the resting state and during milkshake consumption GBC is consistently decreased in the ventromedial and ventrolateral prefrontal cortex, insula and caudate nucleus, and increased in brain regions belonging to the dorsal attention network including premotor areas, superior parietal lobule, and visual cortex. During milkshake consumption, but not at rest, additional decreases in GBC are observed in feeding-related circuitry including the insula, amygdala, anterior hippocampus, hypothalamus, midbrain, brainstem and somatomotor cortex. Additionally, GBC differences were not accounted for by age. These results demonstrate that obesity is associated with decreased GBC in prefrontal and feeding circuits and increased GBC in the dorsal attention network. We therefore conclude that global brain organization is altered in obesity to favor networks important for external orientation over those monitoring homeostatic state and guiding feeding decisions. Furthermore, since prefrontal decreases are also observed at rest in obese individuals future work should evaluate whether these changes are associated with neurocognitive impairments frequently observed in obesity and diabetes. Hum Brain Mapp 38:1403-1420, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Eating behavior is guided by a complex interaction between signals conveying information about energy stores, food availability, and palatability. How peripheral signals regulate brain circuits that guide feeding during sensation and consumption of a palatable food is poorly understood. We used fMRI to measure brain response to a palatable food (milkshake) when n=32 participants were fasted and fed with either a fixed-portion or ad libitum meal. We found that larger post-prandial reductions in ghrelin and increases in triglycerides were associated with greater attenuation of response to the milkshake in brain regions regulating reward and feeding including the midbrain, amygdala, pallidum, hippocampus, insula and medial orbitofrontal cortex. Satiation-induced brain responses to milkshake were not related to acute changes in circulating insulin, glucose, or free fatty acids. The impact of a meal on the response to milkshake in the midbrain and dorsolateral prefrontal cortex differed depending upon whether meal termination was fixed or volitional, irrespective of the amount of food consumed. We conclude that satiation-induced changes in brain response to a palatable food are strongly and specifically associated with changes in circulating ghrelin and triglycerides and by volitional meal termination., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: Obesity is associated with alterations in corticolimbic-striatal brain regions involved in food motivation and reward. Stress and the presence of food cues may each motivate eating and engage corticolimibic-striatal neurocircuitry. It is unknown how these factors interact to influence brain responses and whether these interactions are influenced by obesity, insulin levels, and insulin sensitivity. We hypothesized that obese individuals would show greater responses in corticolimbic-striatal neurocircuitry after exposure to stress and food cues and that brain activations would correlate with subjective food craving, insulin levels, and HOMA-IR., Research Design and Methods: Fasting insulin levels were assessed in obese and lean subjects who were exposed to individualized stress and favorite-food cues during functional MRI., Results: Obese, but not lean, individuals exhibited increased activation in striatal, insular, and hypothalamic regions during exposure to favorite-food and stress cues. In obese but not lean individuals, food craving, insulin, and HOMA-IR levels correlated positively with neural activity in corticolimbic-striatal brain regions during favorite-food and stress cues. The relationship between insulin resistance and food craving in obese individuals was mediated by activity in motivation-reward regions including the striatum, insula, and thalamus., Conclusions: These findings demonstrate that obese, but not lean, individuals exhibit increased corticolimbic-striatal activation in response to favorite-food and stress cues and that these brain responses mediate the relationship between HOMA-IR and food craving. Improving insulin sensitivity and in turn reducing corticolimbic-striatal reactivity to food cues and stress may diminish food craving and affect eating behavior in obesity.

In healthy individuals, food cues can trigger hunger and feeding behavior. Likewise, smoking cues can trigger craving and relapse in smokers. Brain imaging studies report that structures involved in appetitive behaviors and reward, notably the insula, striatum, amygdala and orbital frontal cortex, tend to be activated by both visual food and smoking cues. Here, by carrying out a meta-analysis of human neuro-imaging studies, we investigate the neural network activated by: 1) food versus neutral cues (14 studies, 142 foci) 2) smoking versus neutral cues (15 studies, 176 foci) 3) smoking versus neutral cues when correlated with craving scores (7 studies, 108 foci). PubMed was used to identify cue-reactivity imaging studies that compared brain response to visual food or smoking cues to neutral cues. Fourteen articles were identified for the food meta-analysis and fifteen articles were identified for the smoking meta-analysis. Six articles were identified for the smoking cue correlated with craving analysis. Meta-analyses were carried out using activation likelihood estimation. Food cues were associated with increased blood oxygen level dependent (BOLD) response in the left amygdala, bilateral insula, bilateral orbital frontal cortex, and striatum. Smoking cues were associated with increased BOLD signal in the same areas, with the exception of the insula. However, the smoking meta-analysis of brain maps correlating cue-reactivity with subjective craving did identify the insula, suggesting that insula activation is only found when craving levels are high. The brain areas identified here are involved in learning, memory and motivation, and their cue-induced activity is an index of the incentive salience of the cues. Using meta-analytic techniques to combine a series of studies, we found that food and smoking cues activate comparable brain networks. There is significant overlap in brain regions responding to conditioned cues associated with natural and drug rewards., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Combining genetic and neuroimaging techniques may elucidate the biological underpinnings of individual differences in neurophysiology and potential vulnerabilities to disease. The TaqIA A1 variant is associated with diminished dopamine D(2) receptor density, higher body mass, and food reinforcement. It also moderates the relationship between brain response to food and future weight gain. This suggests that the polymorphism is associated with a fundamental difference in the neurophysiology of food that may predispose toward overeating. An alternative possibility is that factors, such as impulsivity, eating style, reward drive, and perception, which may covary with the polymorphism, influence reward coding and eating behavior. To distinguish between these alternatives, we used functional magnetic resonance imaging to measure neural response to the ingestion of palatable and caloric milkshakes in healthy subjects with (A1+; n = 13) and without (A1-; n = 13) the TaqIA A1 allele. The groups were selected from a larger group to be matched for linked individual factors such as age, gender, education, body mass index, impulsivity, eating style, and perceptual responses to the milkshake. We demonstrate an interaction between genotype (A1+ vs A1-) and stimulus (milkshake vs a tasteless/odorless baseline) in the midbrain, thalamus, and orbital frontal cortex; whereas A1- shows increased responses to milkshake, A1+ shows decreased responses to milkshake relative to baseline. This interaction occurs despite similar ratings of milkshake pleasantness, intensity, and familiarity. We therefore conclude that there is a specific association between the TaqIA A1 polymorphism and brain response during ingestion of a palatable food.

One function of spatial attention is to enable goal-directed interactions with the environment through the allocation of neural resources to motivationally relevant parts of space. Studies have shown that responses are enhanced when spatial attention is predictively biased towards locations where significant events are expected to occur. Previous studies suggest that the ability to bias attention predictively is related to posterior cingulate cortex (PCC) activation [Small, D.M., et al., 2003. The posterior cingulate and medial prefrontal cortex mediate the anticipatory allocation of spatial attention. Neuroimage 18, 633-41]. Sleep deprivation (SD) impairs selective attention and reduces PCC activity [Thomas, M., et al., 2000. Neural basis of alertness and cognitive performance impairments during sleepiness. I. Effects of 24 h of sleep deprivation on waking human regional brain activity. J. Sleep Res. 9, 335-352]. Based on these findings, we hypothesized that SD would affect PCC function and alter the ability to predictively allocate spatial attention. Seven healthy, young adults underwent functional magnetic resonance imaging (fMRI) following normal rest and 34-36 h of SD while performing a task in which attention was shifted in response to peripheral targets preceded by spatially informative (valid), misleading (invalid), or uninformative (neutral) cues. When rested, but not when sleep-deprived, subjects responded more quickly to targets that followed valid cues than those after neutral or invalid cues. Brain activity during validly cued trials with a reaction time benefit was compared to activity in trials with no benefit. PCC activation was greater during trials with a reaction time benefit following normal rest. In contrast, following SD, reaction time benefits were associated with activation in the left intraparietal sulcus, a region associated with receptivity to stimuli at unexpected locations. These changes may render sleep-deprived individuals less able to anticipate the locations of upcoming events, and more susceptible to distraction by stimuli at irrelevant locations.

The purpose of this chapter is to provide a general overview of the central representation of gustatory information in the human brain. The anatomical pathways for the two primary animal models (rodent and nonhuman primate) are provided followed by the presumed human gustatory pathway. The section on the gustatory pathway describes what is known about how taste intensity, quality and affective value are represented in the human brain. The chapter concludes with a review of flavor processing.

To evaluate the effect of an abstract motivational incentive on top-down mechanisms of visual spatial attention, 10 subjects engaged in a target detection task and responded to targets preceded by spatially valid (predictive), invalid (misleading) or neutral central cues under three different incentive conditions: win money (WIN), lose money (LOSE), and neutral (neither gain nor lose). Activation in the posterior cingulate cortex was correlated with visual spatial expectancy, defined as the degree to which the valid cue benefited performance as evidenced by faster reaction times compared to non-directional cues. Winning and losing money enhanced this relationship via overlapping but independent limbic mechanisms. In addition, activity in the inferior parietal lobule was correlated with disengagement (the degree to which invalid cues diminished performance). This relationship was also enhanced by monetary incentives. Finally, incentive enhanced the relationship of activation in the visual cortex to visual spatial expectancy and disengagement for both types of incentive (WIN and LOSE). These results show that abstract incentives enhance neural processing within the attention network in a process- and valence-selective manner. They also show that different cognitive and motivational mechanisms may produce a common effect upon unimodal cortices in order to enhance processing to serve the current behavioral goal.

Odors perceived through the mouth (retronasally) as flavor are referred to the oral cavity, whereas odors perceived through the nose (orthonasally) are referred to the external world. We delivered vaporized odorants via the orthonasal and retronasal routes and measured brain response with fMRI. Comparison of retronasal versus orthonasal delivery produced preferential activity in the mouth area at the base of the central sulcus, possibly reflecting olfactory referral to the mouth, associated with retronasal olfaction. Routes of delivery produced differential activation in the insula/operculum, thalamus, hippocampus, amygdala, and caudolateral orbitofrontal cortex in orthonasal > retronasal and in the perigenual cingulate and medial orbitofrontal cortex in retronasal > orthonasal in response to chocolate, but not lavender, butanol, or farnesol, so that an interaction of route and odorant may be inferred. These findings demonstrate differential neural recruitment depending upon the route of odorant administration and suggest that its effect is influenced by whether an odorant represents a food.

Flavor perception arises from the central integration of peripherally distinct sensory inputs (taste, smell, texture, temperature, sight, and even sound of foods). The results from psychophysical and neuroimaging studies in humans are converging with electrophysiological findings in animals and a picture of the neural correlates of flavor processing is beginning to emerge. Here we used event-related fMRI to evaluate brain response during perception of flavors (i.e., taste/odor liquid mixtures not differing in temperature or texture) compared with the sum of the independent presentation of their constituents (taste and/or odor). All stimuli were presented in liquid form so that olfactory stimulation was by the retronasal route. Mode of olfactory delivery is important because neural suppression has been observed in chemosensory regions during congruent taste-odor pairs when the odors are delivered by the orthonasal route and require subjects to sniff. There were 2 flavors. One contained a familiar/congruent taste-odor pair (vanilla/sweet) and the other an unfamiliar/incongruent taste-odor pair (vanilla/salty). Three unimodal stimuli, including 2 tastes (sweet and salty) and one odor (vanilla), as well as a tasteless/odorless liquid (baseline) were presented. Superadditive responses during the perception of the congruent flavor compared with the sum of its constituents were observed in the anterior cingulate cortex (ACC), dorsal insula, anterior ventral insula extending into the caudal orbitofrontal cortex (OFC), frontal operculum, ventral lateral prefrontal cortex, and posterior parietal cortex. These regions were not present in a similar analysis of the incongruent flavor compared with the sum of its constituents. All of these regions except the ventrolateral prefrontal cortex were also isolated in a direct contrast of congruent - incongruent. Additionally, the anterior cingulate, posterior parietal cortex, frontal operculum, and ventral insula/caudal OFC were also more active in vanilla + salty minus incongruent, suggesting that delivery of an unfamiliar taste-odor combination may lead to suppressed neural responses. Taken together with previous findings in the literature, these results suggest that the insula, OFC, and ACC are key components of the network underlying flavor perception and that taste-smell integration within these and other regions is dependent on 1) mode of olfactory delivery and 2) previous experience with taste/smell combinations.

A network of brain regions has been implicated in food-reward processing. now provide evidence that this network is differentially modulated by anticipation versus receipt of a food reward and suggest an additional effect of valence of the stimulus.

We performed successive H(2)(15)O-PET scans on volunteers as they ate chocolate to beyond satiety. Thus, the sensory stimulus and act (eating) were held constant while the reward value of the chocolate and motivation of the subject to eat were manipulated by feeding. Non-specific effects of satiety (such as feelings of fullness and autonomic changes) were also present and probably contributed to the modulation of brain activity. After eating each piece of chocolate, subjects gave ratings of how pleasant/unpleasant the chocolate was and of how much they did or did not want another piece of chocolate. Regional cerebral blood flow was then regressed against subjects' ratings. Different groups of structures were recruited selectively depending on whether subjects were eating chocolate when they were highly motivated to eat and rated the chocolate as very pleasant [subcallosal region, caudomedial orbitofrontal cortex (OFC), insula/operculum, striatum and midbrain] or whether they ate chocolate despite being satiated (parahippocampal gyrus, caudolateral OFC and prefrontal regions). As predicted, modulation was observed in cortical chemosensory areas, including the insula and caudomedial and caudolateral OFC, suggesting that the reward value of food is represented here. Of particular interest, the medial and lateral caudal OFC showed opposite patterns of activity. This pattern of activity indicates that there may be a functional segregation of the neural representation of reward and punishment within this region. The only brain region that was active during both positive and negative compared with neutral conditions was the posterior cingulate cortex. Therefore, these results support the hypothesis that there are two separate motivational systems: one orchestrating approach and another avoidance behaviours.