Researchers at University of California San Diego School of Medicine have discovered differences in brain circuitry that contribute to starvation and weight loss in people with anorexia nervosa (AN).
The findings, published in the March 12, 2020 online issue of The American Journal of Psychiatry, shed new light on the neurobiology of starvation and emaciation — primary characteristics of AN.
“It has long been puzzling how people with anorexia are able to starve themselves and become emaciated, when most people struggle to lose just a few pounds,” said Walter Kaye, MD, Distinguished Professor of Psychiatry and executive director of the Eating Disorder Research and Treatment Program at UC San Diego Health.
“Because we lack effective treatments that normalize eating in AN, this illness is often chronic and has the highest death rate of any behavioral disorder.”
The National Eating Disorders Association estimates that at any given point in time between 0.3 and 0.4 percent of young women and 0.1 percent of young men suffer from AN.
A 2007 study found that 0.9 percent of women and 0.3 percent of men reported anorexia during their lives. Young people between the ages of 15 and 24 with AN are estimated to be at 10 times greater risk of dying compared to same-aged peers.
In their latest study, Kaye and colleagues compared brain responses of two groups of female participants who received tastes of sugar water and plain water after either fasting or after a standardized meal.
One group of women had been diagnosed with AN, but were in remission (RAN); the other group did not have AN. Neural responses were observed and measured by functional magnetic resonance imaging.
Hunger in people and animals makes food more rewarding because hunger activates brain circuits that motivate eating.
The major finding in this study, said Kaye, was that hunger failed to activate this food reward circuit in people with AN, which raises the possibility that the trait underlies restrictive eating and severe weight loss in persons with a history of AN.
Specifically, data showed that the brain’s ventral caudal putamen produced varied responses to hunger within the two study groups.
RAN participants and the control group both displayed similar responses to food stimulation when sated, but in the RAN group, response to hunger was abnormal. In addition, the RAN group showed reduced neural activation to taste stimulation in the brain’s anterior insula and reduced connectivity between the right anterior and mid-dorsal insula and ventral caudal putamen.
“These findings highlight the specific brain circuitry that may play a key role in unhealthy eating in anorexia,” said Kaye.
“In part, this circuitry involves connected regions that are important for recognizing the feeling of hunger, motivating us to want to eat when we are deprived of food, and helping to initiate actual eating or to decide to avoid it.
This same circuitry has been implicated in appetite changes associated with major depression. The distortion of signals in the brain in both depression and anorexia impact the awareness of hunger, the motivation to eat and food avoidance.”
Kaye added that the study is the first to show its dysfunction in anorexia after tasting food, specifically after a period of fasting.
Disturbances of this circuitry may help explain symptoms that often occur in anorexia. Most people report that hunger increases the reward and pleasure of food, and thus drives the motivation to eat.
Individuals with AN, however, tend to have a disconnect in this process, Kaye said, noting that individuals with the disorder tend to be obsessed with food, yet do not eat.
Study results support the idea that the brain in anorexia is able to recognize hunger signals, but individuals with the disorder may lack an intuitive drive to consume food because they are not able to convert this hunger signal into the motivation to eat.
In addition, many persons with AN describe increased anxiety when they eat, even when they are famished. Researchers found that those with a history of AN associated higher anxiety with a reduced food reward signal in a part of the brain involved in initiating eating behavior. The finding indicates anxiety may contribute to starvation because it impairs the ability to start eating.
The researchers said the findings suggest a powerful biology contributes to restricted eating behavior in AN, and that the findings provide new answers to how those with anorexia are able to become severely underweight.
“These data open the door to potential new ways of treating this disorder,” said co-author Christina E. Wierenga, PhD, associate professor and clinical neuropsychologist in the Department of Psychiatry at UC San Diego School of Medicine.
“For example, developing behavioral strategies for enhancing initiation to eat or compensating for altered motivational drives may be helpful. In addition, the brain circuitry implicated in these findings have also been highlighted in other studies and support a fresh look at medications acting on the dopamine system.”
Co-authors include: Amanda Bischoff-Grethe, Laura Berner, Alice V. Ely, Ursula F. Bailer, and Martin P. Paulus, all at UC San Diego; and Julie L. Fudge, University of Rochester Medical Center.
A Psychoneuroimmunological Model of Eating Disorders
Intrasexual competition for thinness and the adaptive metaproblem that arises from the abundance of sensorily rewarding and calorically dense foods (King, 2013; Rozin and Todd, 2015) seem to provide a plausible ultimate explanation for the pursuit of thinness in women living in developed societies.
However, these hypotheses do not explain why only a fraction of women and homosexual men develop eating disorders. In addition, the hypotheses do not explain why some people develop such a strong obsession to lose weight that they starve themselves to death, while others binge eat and become overweight.
The hypotheses also fail to explain the existence of non-fat-phobic AN (see section “Autoimmunity and Eating Disorders”).
Scientific progress depends on a good fit between theory and empirical evidence (Mathot and Frankenhuis, 2018). This fit is currently lacking between theory from evolutionary psychiatry and clinical evidence on eating disorders. We therefore posit the existence of proximate mechanisms that explain between-individual and within-individual variation in eating disorders, further improving the fit between theory and empirical findings.
We propose a new model that explains the findings that
(1) intensified intrasexual competition leads to eating disorders in only a small proportion of women;
(2) this subset of women is likely to develop different eating disorders that entail the opposite phenotypic outcomes of extreme thinness and obesity; and
(3) patient diagnoses may shift between eating disorders over time.
Eating Disorders and Obsessive Compulsive Disorder
According to diagnostic criteria, obsession with physical exercise, appearance and food are common in eating disorders (American Psychiatric Association, 2013). These obsessions lead to emotional discomfort and to the development of series of behaviors like checking weight, exercising, purging or fasting.
In addition to these classical symptoms of eating disorders, many other obsessive-compulsive traits, like doubting, checking and the need for symmetry and exactness are much more common in BN and AN patients than in psychiatric control groups (Cassidy et al., 1999).
Some patients with eating disorders have visual or tactile checking rituals, such as touching body parts repetitively or viewing one’s body shape in the mirror (Legenbauer et al., 2014). Thus, the behaviors of eating disorder patients have many similarities with OCD behaviors (Bastiani et al., 1996; Garcia-Soriano et al., 2014).
In a Swedish multigenerational family and twin study that included 19,814 participants with a diagnosis of OCD and 8,462 with AN (6.4% males), it was found that women with OCD had a 16-fold diagnosis of AN, whereas males with OCD had a 37-fold increased risk (Cederlof et al., 2015). AN and BN are also associated with personality traits linked to OCD, such as perfectionism and neuroticism (Cassidy et al., 1999; Anderluh et al., 2003; Halmi et al., 2005; Altman and Shankman, 2009).
In addition, AN is more common in unaffected relatives of individuals with OCD, compared to the relatives of matched controls, suggesting shared genetic risk factors (Kaye et al., 1993). Accordingly, a GWAS meta-analysis found a genetic correlation between AN and OCD phenotypes (Anttila et al., 2018).
A recent positron emission tomography (PET) study found neuroinflammation in OCD patients; in particular, they have elevated microglia activity in their brains (Attwells et al., 2017). The distress associated with preventing compulsive behaviors is strongly correlated with neuroinflammation in the orbitofrontal cortex (Attwells et al., 2017).
It is likely that neuroinflammation causes a cascade of biochemical events culminating in a dysregulation of neurohormones, neuropeptides and neurotransmitters which causes OCD symptoms. However, prior research (Attwells et al., 2017) has not been able to explain why OCD patients have neuroinflammation.
Although the obsessions in OCD cause significant stress for patients, stress itself seems to play an important role also in the onset of OCD (Toro et al., 1992; Behl et al., 2010; Adams et al., 2018). Stress triggers OCD symptoms and increases their frequency and severity (Findley et al., 2003).
Experimental studies in non-human animals have shown that stress increases neuroinflammation and elevates microglia activity (reviewed in Calcia et al., 2016). Thus, chronic stress might be a source of the neuroinflammation that occurs in the OCD phenotype. Since stress and the activation of the HPA axis have such an important role in OCD (Sousa-Lima et al., 2019), one could expect a similar association with stress and eating disorder symptoms.
Eating Disorders and Stress
Individuals with BN and AN are trying to lose weight to meet “the beauty ideal” and to persist in intrasexual competition for thinness (cf. Abed, 1998). AN and BN patients respond to competition by high stress hormone levels which become chronic over time (see Soukup et al., 1990; Rojo et al., 2006).
Stress can be caused by peer and societal pressures to have the “perfect body type” (Castellini et al., 2017), while feelings of shame and guilt about one’s self image can cause individuals to continue in a vicious cycle of stress.
Some patients with AN have identified retrospectively that negative comments about their body weight have been the triggering event for AN (Dignon et al., 2006). Especially in sports where low body weight is a competitive factor, requirements for thinness may trigger an eating disorder (Joy et al., 2016; Arthur-Cameselle et al., 2017). The same is true in the fashion world, dance and ballet (Marquez, 2008). The requirement to lose weight in sport and fashion may cause body dissatisfaction and social stress (cf. Castellini et al., 2017).
Retrospective research on patients with AN and BN has identified six other triggering events for eating disorders:
(1) school transitions,
(2) death of a family member, (3) relationship changes,
(4) home and job transitions,
(5) illness/hospitalization and
(6) abuse, sexual assault or incest (Berge et al., 2012).
Common to all of these triggering events is that they are known to increase stress. DSM-5 therefore states that AN onset is often associated with stressful life events (American Psychiatric Association, 2013).
Chronic stress is known to upregulate the immune system (reviewed in Stanton et al., 2018; Rohleder, 2019).
Studies in humans and other animals have shown that social stressors are particularly potent triggers of the production of proinflammatory cytokines that may promote low-grade peripheral inflammation and neuroinflammation. Social rejection in humans is associated with increased levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) (Slavich et al., 2010). Accordingly, a meta-analysis that included 23 studies found that AN patients have significantly increased levels of TNF-α and IL-6, suggesting that AN patients have an upregulated immune system (Dalton et al., 2018).
However, studies have not been able to exclude the possibility that increased IL-6 occurs because of weight loss. Since IL-6 stimulates lipolysis (Wedell-Neergaard et al., 2019), it is not clear whether increased levels of IL-6 are caused by malnutrition or inflammation, or both. Nevertheless, Dalton et al. (2018) found that patients with AN also have elevated levels of IL-15. IL-15 is associated with neuroinflammation (Pan et al., 2013), suggesting a link between AN and neuroinflammation.
As with AN patients (Solmi et al., 2015; Dalton et al., 2018), individuals with OCD also have increased levels of TNF-α and IL-6 (Konuk et al., 2007). Since AN and BN patients are often diagnosed with OCD (and since losing weight becomes a strong obsession for them), we hypothesize that neuroinflammation triggered by chronic stress underlies AN and BN – as it does with OCD (cf. Attwells et al., 2017).
Indirect evidence for this hypothesis comes from observations that 74% of patients with AN and BN suffer from migraine (Brewerton and George, 1993; Brewerton et al., 1993; D’Andrea et al., 2009), which is a neuroinflammatory disease (Malhotra, 2016). Since starvation is known to increase stress hormone levels (Naisbitt and Davies, 2017), it appears that self-induced starvation may strengthen the stress-induced obsession to lose weight in AN patients. This feedback loop can create a vicious cycle which can be difficult to stop and which can escalate up to life-threatening levels.
Interestingly, the stress hormone cortisol that is upregulated in AN patients (see Soukup et al., 1990; Rojo et al., 2006) is one of the hormones that increases gluconeogenesis in humans. Gluconeogenesis is the process of synthesizing glucose in the body from protein or fat, to be used as energy by the body (Khani and Tayek, 2001). By increasing stress hormone levels, gluconeogenesis can increase neuroinflammation during dieting and starvation in AN patients.
Experimental studies in humans and other animals have shown that proinflammatory cytokines reduce appetite and may cause sickness-induced anorexia (Dantzer, 2009). The mesolimbic reward system, which processes appetitive motivation and hedonic value of food, does not work as effectively in AN patients as in healthy controls or those with other eating disorders (Ceccarini et al., 2016). Thus, eating may not constitute an equally hedonic experience for AN patients as it does for unaffected individuals (cf. Stanton et al., 2018). This hedonic decline may partly contribute to the efficiency of AN patients’ dieting, while most healthy dieters fail in their efforts (see Mann et al., 2007).
Binge Eating and Stress
As with BN and AN, we hypothesize that in many cases, also BED is triggered by intrasexual competition for thinness. Indirect evidence for this hypothesis is given by findings showing that BED patients have low self-esteem, general body dissatisfaction (Pearl et al., 2014) and elevated psychological distress (Castellini et al., 2017; Mustelin et al., 2017).
They are prone to overestimate their weight and to see their body shape in a negative light (Pearl et al., 2014). Despite weight loss intentions, BED patients end up binge eating and gaining more weight, often leading to obesity. Castellini et al. (2017) reported that binge eating was associated with dysfunctional body image esteem and greater sexual distress in a non-clinical population of women, further supporting our hypothesis that BED is triggered by intrasexual competition for thinness.
This hypothesis could be challenged by showing that BED symptoms are an effect of BED rather than its cause. However, a study that compared normal-weight BED individuals and obese BED individuals found that the normal-weight ones had a stronger urge to lose weight than the obese ones (Goldschmidt et al., 2011).
There were no between-group differences in overvaluation of shape or weight, suggesting that these symptoms are not caused by comorbid obesity (Goldschmidt et al., 2011).
While many people lose their appetite when feeling heavily stressed, even a mild psychological stressor or a negative affective episode may trigger binge eating in BED or BN patients (Masheb et al., 2011).
Usually stress activates the sympathetic nervous system and the body’s fight-or-flight response. Under these circumstances, corticotropin-releasing factor (CRF) suppresses appetite by affecting the digestive system and decreasing the sense of hunger.
This is why individuals with BED do not experience binge cravings and binge eating during the acute stress, but in the privacy of their homes and when alone long after the acute stressor has subsided (Masheb et al., 2011). Binge eating can be seen as a way to “escape” from a negative aversive emotional state (Burton and Abbott, 2019).
BED and BN patients have an express wish to lose weight, and therefore it is important to understand why it is so difficult for them to resist binge eating. The reason might lie in their dieting practice. In calorie-restricted rats, psychological stress has been shown to trigger binge eating episodes if subjects have an opportunity to eat food items that are heavy in sugar and fat (Hagan et al., 2002, 2003).
Likewise, footshock stress with calorie restriction leads rats to consume twice the normal amount of food (Boggiano et al., 2005). Food-restricted rats that are experimentally stressed develop inflammation in discrete brain regions which directly or indirectly regulate food intake; these rats also develop binge-like eating behaviors (Alboni et al., 2017).
Correspondingly in human subjects, psychological stress may trigger binge eating in healthy dieters if highly palatable food is available (Oliver and Wardle, 1999; see also Castellini et al., 2017; Klatzkin et al., 2018).
An evaluation of the psychophysiological state of patients provides further insight into BED. BED patients have higher stress responsivity than controls (Klatzkin et al., 2018). BED patients may turn to binge eating more easily than controls precisely because of their elevated stress responsivity (cf. Klatzkin et al., 2018).
One reason for their high stress responsivity may be inflammation caused by visceral fat tissue (Shields et al., 2017; Krams et al., 2018; Rohleder, 2019). Although psychosocial stressors are present in the lives of most people, self-regulatory abilities buffer individuals against negative health outcomes that are frequently caused by stress (Evans and Fuller-Rowell, 2013; Shields et al., 2017).
Accumulating evidence suggests, however, that inflammation may cause widespread biobehavioral alterations that promote self-regulatory failure (Shields et al., 2017). BED patients have 88% higher sensitive CRP values than controls matched for body weight, suggesting that BED patients have severe inflammation in their body (Succurro et al., 2015).
The peripheral inflammation may therefore reduce self-regulatory capacity (Shields et al., 2017) in BED patients and further increase their stress responsivity. This is because proinflammatory cytokines produced by immune cells or adipocytes are known to stimulate the HPA axis (Yau and Potenza, 2013).
This mechanistic link may cause a vicious cycle, leading to obesity (cf. Shields et al., 2017; Milaneschi et al., 2018) and, as we suggest, to BED. Peripheral inflammation is a potential causal mechanism that explains why mood disorders are so common among BED patients: inflammation, for instance, increases the likelihood that an adaptive mood change turns to maladaptive clinical depression (cf. Luoto et al., 2018; Rantala et al., 2018). Genetic factors may further increase the comorbidity between these disorders (as reviewed in section “Risk Factors for Eating Disorders”).
The Neurochemistry of Anorexia Nervosa and Bulimia Nervosa
Serotonin (5-hydroxytryptophan) is known to influence impulse control, obsessionality, mood and appetite (Bailer and Kaye, 2011; Dalley and Roiser, 2012; Garcia-Garcia et al., 2017). Treatments that upregulate serotonergic activity tend to reduce food consumption, while treatments that downregulate serotonergic activity increase food consumption and promote weight gain (reviewed in Bailer and Kaye, 2011; see also Alonso-Pedrero et al., 2019). Studies on AN patients have reported serotonergic system dysfunction (reviewed in Bailer and Kaye, 2011; Riva, 2016). Interestingly, IL-15 is upregulated in AN patients (Dalton et al., 2018), and studies on mice have shown that IL-15 upregulates the serotonergic system (Wu et al., 2011; Pan et al., 2013).
In the acute phase of AN (when individuals are underweight), patients have significantly lower levels of serotonin metabolites in their cerebrospinal fluid than healthy controls (Kaye et al., 1984, 1988). They also have blunted prolactin response to drugs with serotonin activity and reduced 3H-imipramine binding, further suggesting reduced serotonergic activity (Bailer and Kaye, 2011).
Since serotonin is synthesized from an amino acid called tryptophan, an essential amino acid that must be obtained from food, the most plausible explanation for low serotonin metabolism in AN patients during the acute phase of the illness is that it results from starvation/dieting (Kaye et al., 2009; Haleem, 2012). In contrast, individuals who have recovered from AN have elevated serotonin levels (Kaye et al., 1991). An experimental study found that a reduction of dietary tryptophan reduced anxiety and elevated mood in women with AN, but had no effect on control women (Kaye et al., 2003).
AN patients are known to have high levels of anxiety, obsessionality and harm avoidance both premorbidly and after recovery. They may also have higher levels of serotonin premorbidly, resulting in a dysphoric state (Bailer and Kaye, 2011). Kaye et al. (2009) suggested that dieting/starvation makes AN patients feel better by decreasing serotonergic activity in the brain.
These individuals may also get positive feedback from their peers about their thinner appearance, which further motivates them to continue starvation. As a result of tryptophan depletion caused by starvation, the brain responds by increasing the number of serotonin receptors to utilize the remaining serotonin more efficiently (Kaye et al., 2009).
This leads to a vicious homeostatic cycle (Figure 1), because in order to feel better, AN patients need to reduce tryptophan even more, leading to reduced food consumption (Kaye et al., 2009). If the patient starts to eat food that has tryptophan in it, serotonin levels arise sharply which causes extreme anxiety and emotional chaos (Kaye et al., 2009).
This makes the recovery of AN patients so difficult (Kaye et al., 2009). The drop of serotonin levels during the acute phase of the illness due to shortage of tryptophan (Riva, 2016) may explain the serious body image disturbances that are typical in AN. Although the exact neurophysiological mechanism that causes such disturbances is not known, the mechanism is probably similar to the low self-esteem often seen in depression (cf. Orth and Robins, 2013).
Kaye et al. (2009) hypothesized that individuals with AN have an intrinsic defect in their serotonergic system and that gonadal steroid changes during menarche or stress-related issues on adolescent individuation might further alter activity of the serotonergic system. However, this explanation is not able to account for increased AN prevalence in modern societies nor for the occurrence of eating disorders in men. To link proximate mechanisms with ultimate causes, it is important to consider the timing of the onset of AN in menarche and early adulthood as potentially caused by intensified intrasexual competition for thinness around this central period in reproductive development.
Intrasexual competition may cause chronic stress for individuals who are highly competitive (cf. Vaillancourt, 2013). Importantly, chronic stress is known to increase serotonin levels in brains both in humans (reviewed in Hale et al., 2012) and in other animals (e.g., Adell et al., 1988; Keeney et al., 2006; Vindas et al., 2016). Experimental studies in rats have shown that fasting reduces serotonin levels in brains (Haleem and Haider, 1996). The same mechanism can also occur in stressed people with an upregulated serotonergic system when they start dieting to alleviate the dysphoric state. In the aggregate, these findings explain one part of the mechanistic link between chronic stress and disordered eating (Figure 1).
There is also evidence on dysfunction in the serotonergic system in bulimia nervosa (reviewed in Sjögren, 2017), but in a different way than in AN. The serotonin levels of BN patients drop more than in healthy controls even during short periods of fasting (e.g., during sleep), leading to mood irritability and binge eating episodes (Steiger et al., 2001). These abnormalities in the functioning of the serotonergic system persist after recovery, suggesting that they might have existed already before the onset of BN (Kaye et al., 2001).
In contrast to AN patients, tryptophan depletion in BN patients lowers mood and causes an urge to binge eat (reviewed in Sjögren, 2017). A neuroimaging study found increased 5-HT1A binding in BN patients compared to healthy controls (Galusca et al., 2014). Activation of the serotonin receptor 5-HT2CR reduced binge eating of palatable food in a rat model (Martin et al., 1998; Fletcher et al., 2010; Higgins et al., 2013; Price et al., 2018). Likewise, SSRI medication reduced the urge to binge eat (reviewed in Tortorella et al., 2014). These findings support the hypothesis that BN patients have reduced serotonin production in the central nervous system.