Neurobiology of anorexia and bulimia nervosa
Introduction
Anorexia nervosa (AN) and bulimia nervosa (BN) are related disorders of unknown etiology that most commonly begin during adolescence in women (DSM-IV; Table 1). They are frequently chronic and often disabling conditions that are characterized by aberrant patterns of feeding behavior and weight regulation, and deviant attitudes and perceptions toward body weight and shape. In AN, an inexplicable fear of weight gain and unrelenting obsession with fatness, even in the face of increasing cachexia, accounts for a protracted course, extreme medical and psychological morbidity, and standardized mortality rates exceeding those of all other psychiatric disorders. BN usually emerges after a period of food restriction, which may or may not have been associated with weight loss. Binge eating is followed by either self-induced vomiting, or by some other means of compensation for the excess of food ingested. Although abnormally low body weight is an exclusion for the diagnosis of BN, some 25% to 30% of bulimics have a prior history of AN.
Because AN and BN present most often during adolescence in women, they are often theorized to be caused by cultural pressures for thinness [1] since dieting and the pursuit of thinness are common in industrialized countries. Still, AN and BN affect only an estimated 0.3% to 0.7% and 1.5% to 2.5%, respectively, of females in the general population [2]. This disparity between the high prevalence of pressures for thinness and the low prevalence of eating disorders (EDs), combined with clear evidence of AN occurring at least several centuries ago [3], the stereotypic presentation, substantial heritability, and developmentally specific age-of-onset distribution, underscores the possibility of contributing biological vulnerabilities.
Considering that transitions between syndromes occur in many, it has been argued that AN and BN share at least some risk and liability factors [4], [5]. In fact, AN and BN are cross transmitted in families. [6], [7] Moreover there is an increased prevalence of AN and BN as well as subthreshold forms of ED in relatives, consistent with the possibility of a continuum of transmitted liability in at risk families manifesting a broad spectrum of eating disorder phenotypes [7]. Twin studies can differentiate genetic from environmental effects by comparing concordance for a trait, or disorder, between identical (monozygotic; MZ) and fraternal (dizygotic; DZ) twins. Twin studies of AN and BN suggest there is approximately a 50 to 80% genetic contribution to liability [4], [8], [9], [10], [11] accounted for by additive genetic factors. These heritability estimates are similar to those found in schizophrenia and bipolar disorder, suggesting that AN and BN may be as genetically-influenced as disorders traditionally viewed as biological in nature.
Section snippets
Clinical symptoms and puzzling behaviors
The DSM-IV diagnostic criteria for AN and BN focus on eating behavior and body image distortions. Because of their unusual and prominent nature, these symptoms tend to capture much attention. The pathogenesis of the disturbed eating behaviors is poorly understood [5], [12]. Individuals with AN rarely have complete suppression of appetite, but rather exhibit an ego-syntonic resistance to feeding drives while simultaneously being preoccupied with food and eating rituals to the point of obsession.
Mood and impulse control
Individuals with AN and BN have elevated rates of lifetime diagnoses of anxiety and depressive disorders, and obsessive-compulsive disorder [6], [15], [16], [17]. In addition, individuals with AN and BN are both consistently characterized by perfectionism, obsessive–compulsiveness, neuroticism, negative emotionality, harm avoidance, low self-directedness, low cooperativeness, and traits associated with avoidant personality disorder (PD). Consistent differences that emerge between ED groups are
Neurocognition
Individuals with AN have an obsessive, perseverative, and rigid personality style and have difficulty shifting sets. While those with AN do well on goal directed behavior, they have difficulties incorporating feedback and modifying their behavior. For example, they often feel that they should be able to do things perfectly without making mistakes, and they have little appreciation for the fact that mistakes are a normal learning experience. Moreover, they often fail to accurately recognize and
State and trait
It has long been debated whether symptoms in individuals with AN and BN are cause or consequence of malnutrition. Confounding this understanding is the issue that most studies of symptoms have been done when individuals are ill with an ED. Recent studies have shown that the majority of people with AN and BN exhibit childhood perfectionism, obsessive–compulsive personality patterns, and anxiety that predate the onset of AN and BN [16], [23], [24]. Moreover, studies done on 3 continents (Table 2)
Gender, age, and puberty
AN and BN most commonly develop during adolescence or young adulthood [34] in proximity to puberty. Adolescence [35] is a time of profound biological, psychological and sociocultural change, and it demands a considerable degree of flexibility to successfully manage the transition into adulthood. Psychologically, change may challenge the rigidity of those at risk for AN and BN, and thus open a window of vulnerability [35]. Importantly, biological changes may significantly enhance the risk of
Neurobiology
There is growing acknowledgement that neurobiological vulnerabilities make a substantial contribution to the pathogenesis of AN and BN [3]. But we have little understanding of how such vulnerabilities result in disturbances of brain pathways or what systems are primarily involved. For example, are there disturbances of pathways related to the modulation of feeding behaviors, or mood, or temperament, or obsessionality, or impulse control? Are there primary disturbances of pathways that may
Neuropeptides
Central nervous system (CNS) neuropeptide dysregulation could contribute to abnormal function of gonadal hormones, cortisol, thyroid hormones and growth hormone in ED [40], [41]. Moreover, mechanisms for controlling food intake involve a complicated interplay [42] between peripheral systems (including gustatory stimulation, gastrointestinal peptide secretion, and vagal afferent nerve responses) and CNS neuropeptides and/or monoamines. Studies in animals show that neuropeptides, such as CRH,
Serotonin
Much technology has focused on characterizing monoamine function. In part, this is because many of the medications used to treat psychiatric disorders act on these systems. The monoamine systems, serotonin (5-HT), dopamine (DA), and norepinephrine (NE), are complex pathways with multiple receptors, transporters, enzymes, and intracellular cascades, etc. Consequently, our understanding of the pathophysiology of these systems in psychiatric disorders is limited. The cell bodies of monoamine
Diet and brain 5-HT neurotransmission
Tryptophan (TRP), an essential amino acid only available in the diet, is the precursor of 5-HT. Meal consumption, depending on the proportion of carbohydrate and protein, can enhance brain 5-HT release [70], [71]; thereby affecting appetite regulation. In brief, carbohydrate consumption causes an insulin-mediated fall in plasma levels of the large neutral amino acids (LNAA; tyrosine; phenylalanine; valine; leucine; isoleucine) which compete with TRP for uptake into the brain. This elevates the
Implications for medication
While BN individuals show a response to higher doses of fluoxetine [87], the efficacy of such medication has been questioned since relatively few individuals abstain from binge and purge behaviors, and relapse during treatment is common [88]. Despite the abundance of data implicating 5-HT dysregulation in AN, it remains controversial whether SSRIs are effective in restricting type AN (RAN) individuals [89], [90]. Our clinical experience [91] suggests that RAN respond better to fluoxetine than
Dopamine
Altered striatal DA function may contribute to symptoms in AN. Reduced CSF DA metabolites occur in malnourished individuals with AN [60] and persist after recovery [92]. Individuals with AN have altered frequency of functional polymorphisms of DA D2 receptor genes that might affect receptor transcription and translation efficiency [93]. The anteroventral striatum (AVS)and dorsal caudate are components of limbic and executive-associative pathways [94], [95], [96]. Thus striatal DA dysfunction
Brain imaging
The past decade has seen the introduction of tools, such as brain imaging, which hold the promise of being better able to characterize complex neurocircuits and their relationship to behavior in living humans. In fact, these tools have rapidly advanced knowledge to the point where we can begin to make educated guesses about the pathophysiology of AN and BN and start to model mechanisms that may be used to test hypotheses.
Brain imaging studies in AN and BN can be divided into several categories.
Brain structure
Neuroimaging studies with CT reported cerebral atrophy and enlarged ventricles in ill AN [98], [99], [100], [101], [102], [103], [104], [105], [106]. In BN similar but less pronounced structural brain abnormalities were reported [107] and may have been related to a chronic dietary restriction. Similarly, MRI studies in AN showed larger CSF volumes in association with deficits in both total grey matter (GM) and total white matter (WM) volumes [108] as well as enlarged ventricles [109], [110],
Body image distortion
A most puzzling symptom of AN is the severe and intense body image distortion in which emaciated individuals perceive themselves as fat. Theoretically, body image distortion might be related to the syndrome of neglect, [217] which may be coded in parietal, frontal, and cingulate regions that assign motivational relevance to sensory events. It is well known that lesions in the right parietal cortex may not only result in denial of illness or anosognosia, somatoparaphrenia, the numerous
Appetitive regulation
Individuals with AN and those who have had lifetime diagnoses of both AN and BN (AN-BN) tend to have negative mood states and dysphoric temperament. There is evidence that there is a dysphoria reducing character to dietary restraint [1], [12], [66] and binge-purge behaviors [119], [120], [121]. This would suggest some interaction between pathways regulating appetitive behaviors and emotions. In fact, functional magnetic resonance imaging (fMRI) studies support this hypothesis. When emaciated
Imaging studies of 5-HT and DA function
The development of selective tracers for the 5-HT system has made in vivo study of 5-HT receptor function possible using PET brain imaging. In turn, this offers the possibility of better understanding of 5-HT neurotransmitter activity and dynamic relationships to behavior.
5-HT1A receptor
Our group used PET imaging with the radioligand [11C]WAY100635 to assess the binding potential (BP) of the 5-HT1A receptor. The 5-HT1A autoreceptor is located presynaptically on 5-HT somatodendritic cell bodies in the raphe nucleus, where it functions to decrease 5-HT neurotransmission [130]. High densities of postsynaptic 5-HT1A exist in the hippocampus, septum, amygdala, and entorhinal and frontal cortex, where they serve to mediate the effects of released 5-HT. Although the molecular
5-HT2A receptor
Our group used PET imaging with the radioligand [18F]altanserin to assess BP of 5-HT2A receptors. (Fig. 2) Post-synaptic 5-HT2A receptors are in high densities in the cerebral cortex and other regions of rodents and humans [158], [159]. The 5-HT2A receptor is of interest in ED because it has been implicated in the modulation of feeding and mood, as well as SSRI response [116], [160], [161], [162], [163].
Ill AN subjects had normal [18F]altanserin BP values [137]. In comparison, REC RAN
Brain regions/pathways enervated by 5HT1A/2A receptors
In REC subjects, altered 5-HT1A and 5-HT2A receptor BP shows persistent alterations in frontal, subgenual cingulate and mesial temporal regions that are part of the ventral limbic system. The subcaudal cingulate regions play a role in emotion (‘affect component’) and have extensive connections with the amygdala, periaqueductal grey, frontal lobes, ventral striatum, etc. They are involved in conditioned emotional learning, vocalizations associated with expressing internal states and assigning
5-HT transporter (5-HTT)
Our group [172] used PET imaging with [11C]McN5652 to determine if alterations of 5-HTT persist after recovery from AN and BN. We compared 11 subjects recoveed (> 1 year normal weight, regular menstrual cycles, no bingeing or purging) from restricting type AN (REC RAN), 7 REC from bulimia-type AN (REC BAN), and 10 healthy CW. After correction for multiple comparisons, we found that the REC RAN had significantly increased [11C]McN5652 BP compared to REC BAN for the dorsal raphe and antero-ventral
DA D2/D3 receptor
A recent study from our group, [176] found that REC AN had increased binding of D2/D3 receptors in the anteroventral striatum (AVS), a region that contributes to optimal responses to reward stimuli [177], [178], [179]. In addition, there were positive correlations between DA D2/D3 binding in the dorsal caudate/dorsal putamen and anxiety measures in REC AN [176]. The AVS and dorsal caudate are components of limbic and executive-associative pathways [94], [95], [96]. Thus striatal DA dysfunction
5-HT, DA, and harm avoidance
The PET imaging studies in ill and REC AN and BN subjects described above have found significant correlations between harm avoidance and binding for the 5-HT1A, 5-HT2A, DA D2/D3 receptors in mesial temporal and other limbic regions. Bailer [116] found that REC AN-BN subjects showed a positive relationship between [18F]altanserin BP in the left subgenual cingulate and mesial temporal cortex and harm avoidance. For ill AN subjects, [18F]altanserin BP was positively related to harm avoidance in
Implications
Phillips [94] has described a ventral limbic system, which includes the amygdale, insula, ventral striatum, and ventral regions of the anterior cingulate gyrus and prefrontal cortex, which identifies the emotional significance of a stimulus and the production of an affective state in response to that stimulus. In addition, these regions are important for automatic regulation and mediation of autonomic responses to emotional stimuli and contexts accompanying the production of affective states.
Feeding behavior
Within the limbic system are brain regions that contribute to rewarding and sensory aspects of feeding behavior. That is, a primary taste cortex resides in the rostral insula and adjoining frontal operculum [189], [190], [191], [192]. Some studies argue that these regions provide a representation of food in the mouth that is independent of hunger, and thus is of reward value [193]. The responsiveness of taste neurons in secondary regions, such as the OFC, computes the hedonic value of food [193]
The insula and interoceptive awareness
Do individuals with AN have an insular disturbance specifically related to gustatory modulation, or a more generalized disturbance related to the integration of interoceptive stimuli? The insula is thought to play an important role in processing interoceptive information, which can be defined as the sense of the physiological condition of the entire body [209]. Aside from taste, interoceptive information includes sensations such as temperature, touch, muscular and visceral sensations, vasomotor
Conclusion
We hypothesize that a trait-related disturbance of 5-HT neuronal modulation predates the onset of AN and contributes to premorbid symptoms of anxiety and inhibition. This dysphoric temperament may involve an inherent dysregulation of emotional and reward pathways [216] which also mediate the hedonic aspects of feeding, thus making these individuals vulnerable to disturbed appetitive behaviors. This 5-HT disturbance contributes to a vulnerability for restricted eating and dysphoric mood states
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