Food stress and reward

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The limbic system is a complex set of structures that includes the hypothalamus, the hippocampus, the amygdala, and several nearby areas. It seems to be primarily responsible for emotional life and the formation of memories. As described earlier, the hypothalamus is mainly responsible for homeostasis and thereby regulates heart rate, blood pressure, breathing, and gastrointestinal motility and also regulates behavior and arousal in response to hunger, thirst, and emotional circumstances (eg, pain, pleasure, sex, fear, or hostility).

Repeated stress especially affects the hippocampus, which participates in verbal memory and is particularly important for the memory of context, that is, the time and place of events that have a strong emotional bias [23]. Moreover, glucocorticoids are involved in remembering the context in which an emotionally laden event took place. The hippocampus also regulates the stress response and acts to inhibit the response of the HPA axis to stress.

The hypothalamus, especially the arcuate nucleus, is relatively accessible to circulating factors and receives inputs from other areas of the brain, including the tractus solitarius and the area postrema [79]. The hypothalamus receives signals that relate to total energy stores in fat and to immediate changes in energy availability, including insulin, leptin, and nutrients within the gut. Afferent signals from the gut to the brain are carried in vagal and splanchnic nerve pathways. The gut also releases several hormones that have incretin- (GLP-1, GIP), hunger- (Ghrelin), and satiety-stimulating (PYY, GLP-1, OXM) actions [79]. In addition, major afferent input originates from the adipose tissue. The adipocyte is now recognized as a bona fide endocrine cell. Adipocyte hormones such as adiponectin, resistin, and visfatin influence appetite, glucose homeostasis and insulin sensitivity, and vascular function, among other functions [80].

The hypothalamus integrates these peripheral and central signals and exerts homeostatic control over food intake, levels of physical activity, basal energy expenditure, and endocrine systems.

There is no doubt that food intake in humans is influenced by emotional factors, social cues, and learned behavior. Functional neuroimaging techniques have provided the first insight in the response of the brain to nutritional stimuli. Differences regarding both the need to eat and the pleasure of eating between obese and lean individuals have been noted [81].

In obese individuals the decrease in hypothalamic activity following a meal is significantly reduced compared with lean individuals. Importantly, the neural substrates of the sensory perception of food overlap extensively with the brain representation of reward. Dopamine is the neurotransmitter that plays a central role in mediating the anticipation of reward. Abnormalities in dopaminergic transmission can be evidenced in obese individuals [82]. A decreased D2 receptor function in this same reward area of the brain has been shown, varying inversely with body mass index.

Various other data suggest that the link between chronic psychologic distress and adverse behavior such as overeating may be centrally mediated [83,84]. Normally, glucocorticoids help end acute stress responses by exerting negative feedback on the HPA axis. In contrast, it has been shown in a rat model that glucocorticoids occupy central glucocorticoid receptors during chronic stress, with resultant activation of the chronic stress response network, including continued glucocorticoid production [85]. This combination of chronic stress and high glucocorticoid levels seems to stimulate a preferential desire to ingest sweet and fatty foods, presumably by affecting dopaminergic transmission in areas of the brain associated with motivation and reward [86]. Similar to observations in obese individuals, diminished do-pamine D2-binding potential within midbrain systems under conditions of chronic stress has been shown by positron-emission tomography scanning in the Cynomolgus monkey [87]. It has been demonstrated that in humans this area is involved specifically in food motivation [88].

Recent evidence also links brain areas associated with reward with those that sense physical pain. It is common notion that chronic pain can cause depression, and depression can increase pain. Most patients who have depression also present with mainly physical symptoms [89]. Studies using functional MRI have shown that social rejection lights up brain areas that are also key regions in the response to physical pain. The area of the anterior cingulate cortex that is activated by visceral pain also is activated in cases of social rejection [90]. The importance of these brain areas is underscored by the observation that the right ventral prefrontal cortex that mitigates emotional distress caused by pain is activated when placebo administration relieves pain [91].

These stress-induced changes (ie, allostatic load) are not without consequences. MRI has shown that stress-related disorders such as recurrent depressive illness or posttraumatic stress disorder are associated with atrophy of the hippocampus [92,93]. Impairment of the hippocampus decreases the reliability and accuracy of contextual memories. This decrement may exacerbate stress by preventing access to the information needed to decide that a situation is not an emotional or physical threat. Also, the suppression of routine sensory input from the body that normally occurs might, under these circumstances, be felt as discomfort or pain. There is evidence that an-tidepressants can reverse these changes [94].

Integrative approach to treatment

From the previous discussion, it has become clear that some parts of the pathophysiologic basis for the association between depression, cardiovascular diseases, and the metabolic syndrome are gradually becoming clearer, but these associations are complex and should be modeled over the lifetime. Because exposure to various disease risks (ie, physical, psychosocial stress, and behavioral stressors) in humans changes over time, and risks cluster together in variable fashion, it is evident that a simple cause-and-effect approach does not fit the individual patient. One must define the chain of risk (as discussed later) with its mediating and modifying factors that have played and still play a role. For this reason an integrated approach with close attention to the history and actual needs and expectations of the individual patient in both the biologic and psychosocial domains is necessary.

It is not necessary to identify with certainty or to address every component cause or risk to prevent or avoid further deterioration of a disease. To understand this notion, one needs to address the issue of causation once more. When one defines a cause of a disease as an event, condition, or characteristic that preceded the disease and without which the disease either would not have occurred at all or would not have occurred until some later time, it follows that no specific event, condition, or characteristic is sufficient by itself to produce disease [95]. A sufficient cause can be defined as a set of minimal conditions and events that over time inevitably produce disease. A minimal cause implies that all of the conditions or events are necessary for disease occurrence. For a disease to occur, a multitude of component causes are needed that act over time in a chain of risk that in turn involves mediating and modifying factors. The importance of this notion is that most identified causes are neither necessary nor sufficient to produce disease. Vice-versa, a cause need not be either necessary or sufficient for its removal to result in disease prevention in some individuals. Because each individual has a unique chain of risks over time, it should come as no surprise that until now it has been difficult to prove that treatment for depression benefits the cardiovascular outcome after myocardial infarction [96].

This lack of proof, however, does not preclude the possibility that some subjects do benefit in this respect. Although the therapeutic advice in this context should be based on the overall outcome of such intervention studies,




Change from BREAK HABITS —• sedentary to active lifestyle





Change from BREAK HABITS —• sedentary to active lifestyle


Fig. 2. Hierarchy of interventions relative to their complexity. (From Rozanski A. Integrating psychologic approaches into the behavioral management of cardiac patents. Psychosom Med 2005;67(Suppl 1):S68; with permission.)

it is important to pay proper attention to all three biopsychosocial domains, and thus the individual situation of a patient, and to act as one deems necessary for the general health of the patient. This approach is, at the same time, the most difficult, because inducing patients to make behavioral changes is much more difficult than prescribing some medication (Fig. 2) [97]. Such an approach, however, will best address the patients' physical, emotional, and social well being and, importantly, create a trusting patient-doctor relationship. It is evident that current medical services, which by definition act upon simple cause-and-effect disease models, do not suffice to provide this kind of patient-tailored therapy.


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