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Introduction

Eating disorders are deWned as those disorders in which there is excessive concern with the control of body weight and shape, accompanied by grossly inadequate, irregular, or chaotic food intake. It is widely accepted that eating disorders occur in young adults and adolescents, but their occurrence in younger children has received little attention. Recently, a number of reports have described series of young patients, ages 8 years and above, with eating disorders (Fosson et al., 1987; Higgs et al., 1989; Gowers et al., 1991; Bryant-Waugh and Lask, 1995). The range of these disorders in children include selective eating, food avoidance emotional disorder, functional dysphagia, and pervasive refusal syndrome (discussed later in this chapter), as well as the more common conditions of anorexia nervosa and bulimia nervosa. In the medical literature, there have been an increasing number of studies published involving functional brain imaging in adults with eating disorders, and some of these studies have also included older adolescent subjects. There have been relatively few reports of functional imaging studies in children with eating disorders.

In this chapter, we will Wrst provide background information, including theories of etiology concerning earlyonset anorexia nervosa and bulimia nervosa. We will then review some of the structural and functional neuroimaging studies of eating disorders in the adult population. Finally, we will describe in detail the recent neuroimaging studies in children with anorexia nervosa.

Anorexia nervosa

Diagnostic considerations

DSM-IV criteria for anorexia (American Psychiatric Association, 1994) include (i) refusal to maintain body

weight at or above a minimally normal weight for age and height (e.g., weight loss leading to the maintenance of body weight less than 85% of expected or failure to make weight gain during a growth period); (ii) an intense fear of gaining weight or becoming fat, even though underweight; (iii) a disturbance in the way in which body weight and shape is experienced, undue inXuence of body weight or shape on self-evaluation, or denial of the seriousness of current low body weight; and (iv) the absence of at least three consecutive menstrual cycles. Subtypes include a ªrestricting typeº without regular binge eating or purging behavior, and a ªbinge-eating/purging typeº.

These criteria, intended primarily for use with older patients, fail to address the identiWcation of anorexia nervosa in children adequately. For example, criterion (iv) specifying the absence of menstrual cycles applies only to postmenarcheal females and is clearly inapplicable to children, most of whom are premenarcheal. Equally unhelpful is the statement that weight should be maintained at less than 85% of that expected, for expected weight can only be calculated on the basis of height and age; yet growth may also be impaired because of poor nutrition.

For these reasons, the Eating Disorders Team at Great Ormond Street Hospital for Sick Children in London, UK developed more practical diagnostic criteria for earlyonset anorexia nervosa (Lask and Bryant-Waugh, 1986). The Great Ormond Street diagnostic criteria for earlyonset anorexia nervosa (Lask and Bryant-Waugh, 1999) include (i) determined weight loss (e.g., food avoidance, self-induced vomiting, excessive exercising, abuse of laxatives), (ii) abnormal cognition regarding weight and/or shape, and (iii) morbid preoccupation with weight and/or shape.

Since children should be growing, static weight may be regarded as equivalent to weight loss in adults. Weight loss is a real cause for concern in children, since they have lower total body fat deposits and, therefore, less fat to lose. One

measurement for weight loss uses the Tanner±Whitehouse Standards (Tanner et al., 1966) where 100% represents the desired weight for a child's sex, age, and height, and 80% or less is classiWed as wasting.

As with later-onset anorexia, in early-onset anorexia, weight is controlled through food avoidance, self-induced vomiting, and excessive exercise; less commonly it can occur through laxative abuse. Children most often attribute food avoidance to a fear of becoming obese. Other reasons for food refusal are feelings of nausea or fullness, abdominal pain, appetite loss and diYculty swallowing (Fosson et al., 1987). In their study of early-onset anorexia nervosa, Fosson et al. (1987) reported that at least 40% of the 48 children included were known to be vomiting at presentation. Excessive exercising is not uncommon in children. Daily workouts may be a feature, with exercise sometimes carried out in secret in the privacy of a bedroom or bathroom. Perhaps because children have little access to laxatives, their abuse is not common in early-onset anorexia.

Cognition regarding weight and/or shape focuses around a distortion of body image, although it must be acknowledged that body image is diYcult to assess reliably. Many children with anorexia nervosa will report that they consider themselves fat even when severely underweight, not unlike the image suggested by clinical observations in adult patients with the same condition. Closely related to their fear of fatness, children with anorexia nervosa tend to be preoccupied with their own body weight and are often experts at calorie counting.

Physical aspects

The majority of physical changes in anorexia nervosa are predominantly related to the eVects of starvation and dehydration. These include slow pulse rate, low blood pressure, and poor circulation leading to cold hands and feet. Often there is excess Wne hair, known as lanugo, especially on the back. Teeth may be pitted, eroded, and decayed from their exposure to gastric acid during vomiting.

Although there is little information speciWcally relating to children, a wide range of biochemical and endocrine changes have been described in anorexia nervosa. These include low hemoglobin and white cell count, low levels of potassium and chloride, raised liver enzymes such as alanine transaminase and alkaline phosphatase, and low levels of plasma zinc and serum iron. Endocrine changes, which are likely secondary to starvation, include increased cortisol, growth hormone, and cholecystokinin, and decreased luteinizing hormone, follicle-stimulating

hormone, estrogen, triiodothyronine, and thyroid-stimu- lating hormone.

Comorbidity

Herzog et al. (1992) reported that major depressive disorder was the most prevalent comorbid disorder, occurring in 37% of patients with anorexia nervosa. Obsessional behaviors in anorexia nervosa are also common and are usually focused around food, eating, and exercise. Kaye et al. (1992) showed that patients with anorexia nervosa had elevated scores on the Yale±Brown Obsessive±Compulsive Scale even after compulsive eating behaviors and obsessive concerns about weight were excluded. This clinical characteristic is important to consider in the interpretation of brain imaging data.

Bulimia nervosa

Diagnostic considerations

DSM-IV criteria (American Psychiatric Association, 1994) include (i) recurrent episodes of binge eating (e.g., eating large amounts of food in 2h and a sense of lack of control during the episodes), (ii) regular use of methods of weight control (e.g., vomiting, laxatives, diuretics, fasting/strict diet, vigorous exercise), (iii) a minimum of two binges per week for 3 months, (iv) self-evaluation being unduly inXuenced by body shape and weight, and (v) these disturbances are not limited to episodes of anorexia nervosa. Subtypes include a ªpurging typeº, with regular selfinduced vomiting or misuse of laxatives, diuretics, or enemas and a ªnonpurging typeº with other inappropriate compensatory behaviors (e.g., fasting or excess exercise) but without use of the methods used by the purging type.

Until recently, very few cases of bulimia nervosa with onset below the age of 14 years were reported (Schmidt et al., 1992). During the 1990s, there has been a gradual increase in referrals of such children to the eating disorders clinic at the Great Ormond Street Hospital, but reported cases of bulimia remain relatively rare in children under 12 years. The clinical features do not seem to diVer from those found in adult patients with bulimia nervosa. The physical manifestations of bulimia nervosa are initially less dramatic than those of anorexia nervosa because weight is usually maintained within normal range. However, selfinduced vomiting can lead to complications such as Xuid and electrolyte disturbance and gastrointestinal bleeding. Other physical complications include dental erosions, enlargement of the salivary glands, and muscle weakness.

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Comorbidity

Studies in adult patients with bulimia nervosa have shown that depressive and anxiety symptoms are prevalent (Laessle et al., 1987). Drug and alcohol abuse are also common, as are disorders of impulse control such as selfmutilation (Treasure, 1997). This comorbidity holds implications for the subtyping of patients in order to achieve homogeneous study samples.

Other eating disorders in children

A number of other eating disorders have been identiWed in children (additional information on these can be obtained from Lask and Bryant-Waugh (1999)).

Food avoidance emotional disorder

First introduced by Higgs et al. (1989), food avoidance emotional disorder describes a group of underweight children who present with inadequate food intake and emotional disturbance and who do not meet the criteria for anorexia nervosa. An operational deWnition used by us has evolved from Higgs and colleagues' original description together with our own clinical experience. Included are (i) food avoidance not accounted for by a primary aVective disorder, (ii) weight loss, (iii) mood disturbance not meeting criteria for primary aVective disorder, (iv) lack of abnormal cognition regarding weight or shape, (v) lack of morbid preoccupation regarding weight or shape, (vi) no morbid preoccupation regarding weight or shape, and (vii) no organic, brain disease or psychosis.

Selective eating

Selective eaters are a group of children who present with very restricted eating habits in terms of the range of foods they will accept. Their characteristics include (i) having eaten a narrow range of foods for at least 2 years, (ii) an unwillingness to try new foods, (iii) a lack of abnormal cognition regarding weight or shape, (iv) a lack of fear of choking or vomiting, and (v) weight loss that may be low, normal, or high.

Pervasive refusal syndrome

The term pervasive refusal syndrome was Wrst used by Lask et al. (1991) to describe children with (i) a profound refusal to eat, drink, walk, talk or engage in self-care; and (ii) a determined resistance to the eVorts of others to help.

Initially these children present with features fairly typical of anorexia nervosa, but their food avoidance is gradually followed by a more generalized avoidance with marked fear responses.

Functional dysphagia

Children with functional dysphagia generally present with complaints of diYculty or pain on swallowing. Features include (i) food avoidance; (ii) a fear of swallowing, choking, or vomiting; (iii) no abnormal cognition regarding weight or shape; (iv) no morbid preoccupation regarding weight or shape; and (v) no organic brain disease or psychosis.

For additional information on the above eating disorders in children, the reader is referred to Lask and BryantWaugh (1999).

Epidemiology of eating disorders

For a number of reasons, the incidence and prevalence of childhood-onset anorexia are unknown. There have been no epidemiologic studies that have focused speciWcally on this age group, and the use of strict diagnostic criteria in epidemiologic studies may lead to a substantial underestimate of the true incidence of these disorders (BryantWaugh and Lask, 1995). However, studies in adolescent populations estimate the prevalence to be in the order of 0.1±0.2% (Bentovim and Morton, 1990; Whitaker et al., 1990), and it is likely to be even lower in children. Although debatable, an increase in the referral rate of child cases of anorexia nervosa has been reported (Bryant-Waugh and Lask, 1995). With regard to gender distribution, only 5±10% of cases of anorexia nervosa in adolescents and young adults occur in males (Barry and Lippmann, 1990). However, studies have reported that between 19 and 30% of children with anorexia nervosa have been boys (Hawley, 1985; Jacobs and Isaacs, 1986; Fosson et al., 1987; Higgs et al., 1989). At present, there is little epidemiologic information on the other disorders in children.

Etiology of eating disorders

Although the etiology of anorexia nervosa is unknown, a number of interacting factors, including biological, psychologic, familial, and sociocultural factors, appear to contribute to its development. Contributing biological factors include genetics, neurotransmitter levels, and

endocrine dysfunction, as well as mechanisms of appetite regulation and malnutrition. Biological variables that inXuence eating behavior include various CNS structures, central and peripheral neurotransmitters, neuropeptides, and neurohormones.

Brain structures implicated in the regulation of eating

A number of CNS structures have been implicated in the regulation of eating behavior. Discoveries in the early 1950s supported for a time a ªdual-center theoryº of the control of eating (Anand and Brobeck, 1951). According to this theory, the hypothalamus contained the primary control centers for hunger and satiety. Experiments showed that bilateral lesions of the ventromedial hypothalamus caused rats to become obese. This area was, therefore, called the satiety center. It had also been shown that bilateral destruction of the lateral hypothalamus caused rats to stop eating; consequently this area was called the feeding center. It was proposed that the ventromedial hypothalamus normally acted as a brake on feeding by inhibiting the lateral hypothalamus. Informations from the rest of the brain and from other factors (e.g., hormones) that inXuence eating were presumed to act through these hypothalamic control centers.

Several subsequent observations challenged this dual center hypothesis. Studies showed that following bilateral damage to the ventromedial hypothalamus, rats began to increase food consumption. After a few weeks, body weight stabilized at an obese level and food intake was not much above normal. Similarly, with bilateral destruction of the lateral hypothalamus, the resulting aphagia was not permanent, and a few rats began to eat spontaneously after about a week (Teitelbaum and Stellar, 1954). The ability of animals with these lesions to regulate their weights around higher or lower than normal points casts doubt on the simple dual center theory.

Clinical evidence in humans has shown that hypothalamic lesions, both neoplastic (Lewin et al., 1972; Heron and Johnston, 1976; Goldrey, 1978) and degenerative (White and Hain, 1959), have been associated with undereating and emaciation. De Vile et al. (1995) described two boys who initially presented with features of anorexia nervosa but were found to have tumors aVecting the hypothalamus. Other clinical examples of organic brain disease in humans have highlighted other parts of the brain that may have a role in feeding. Overeating has been described in patients with lesions of the amygdala (Terzian and Ore, 1955) and of the orbitofrontal cortex (Erb et al., 1989).

Neuroendocrine aspects

Russell (1985) postulated the existence of a primary hypothalamic disorder manifested by endocrine disturbances involving the hypothalamus and pituitary gland as a basis for eating disorders. This hypothesis was based on the endocrine changes seen in anorexia nervosa (see above). However, the endocrine changes are similar to those found in starvation from other causes and tend to normalize after the patient's weight returns to normal (Casper, 1984). So far, therefore, the hope of Wnding an endocrinologic cause for anorexia nervosa has not materialized.

Neurotransmitter system

The mechanisms whereby the above brain structures regulate food intake involve neurotransmitters of both central and peripheral origin that stimulate and inhibit eating behavior. At least three neurotransmitters have been implicated in eating disorders: serotonin, noradrenaline (norepinephrine), and dopamine. Serotonergic agents cause a reduction in food intake in animals and humans. Injection of serotonergic agents directly into the medial hypothalamus in animals is followed by the suppression of food intake. In contrast, injection of noradrenaline into the medial hypothalamus causes an increase in food intake. Dopamine appears to act via the lateral hypothalamus to produce a decrease in feeding. Dopamine blockers such as chlorpromazine and haloperidol have the opposite eVect (Hsu, 1990). Dopamine has also been implicated in reward and reinforcement processes (Wise and Rompre, 1989) that could constitute a core symptom in eating disorders.

It has also been suggested that anorexia nervosa could be viewed as a state of dependence on starvation, similar to alcohol dependence (Szmukler and Tam, 1984), and that during starvation there would be increased central opioid activity. In fact, elevated opioid activity has been found in the cerebrospinal Xuid of patients with anorexia nervosa (Kaye et al., 1982; Jonas and Gold, 1986), but as yet the hypothesis remains untested.

Genetics

It is important to consider genetic contributions when discussing the biological factors related to the possible pathogenesis of eating disorders. Strober et al. (1990) have shown that the frequency of anorexia nervosa in female relatives of patients with anorexia nervosa is about eight times higher than that in the general population. Holland et al. (1988), in a study of 45 twin pairs, showed a concordance rate for anorexia nervosa in dizygotic twins of 5%

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compared with 56% for monozygotes. In identical twin pairs discordant for anorexia nervosa, the aVected twin had higher levels of stress related to signiWcant life events prior to onset.

Molecular genetic studies have attempted to identify genes contributing to eating disorders. Although unreplicated (Hinney et al., 1997; Campbell et al., 1998), an associ-

ation between a polymorphism of the serotonin 5-HT2A receptor gene and anorexia nervosa has recently been

reported (Collier et al., 1997; Sorbi et al., 1998). A lack of association between polymorphisms and anorexia has been found for serotonin transporter (Hinney et al., 1997) and the dopamine D3 receptor gene (Bruins-Slot et al., 1998).

Neuropsychology

A number of studies in adults and adolescents with anorexia nervosa provide evidence of cognitive impairment in anorexia nervosa. Although an early study by Dally (1969) showed that patients with anorexia nervosa had above average IQs, recent studies have reported mean IQ scores to be within an average range (Szmukler et al., 1992; Gillberg et al., 1996; Kingston et al., 1996). None of these studies looked at a younger prepubertal population. However, Christie et al. (1998) recently reported a pilot study looking at IQ, memory, and attainments in a group of 12 girls with anorexia nervosa (age range, 10.6±16.5 years). They found that three cognitive factors that contribute to IQ score (verbal comprehension, perceptual organization, and freedom from distractibility) were within the average range. In contrast, the girls showed a relative increase in a fourth factor: processing speed. The implication of this Wnding is not yet known and further research is needed.

There have been conXicting reports of attentional dysfunction in adult and adolescent patients with anorexia nervosa. Szmukler et al. (1992) found that patients at low weight were impaired on tests of attention, perceptualmotor functions, visuospatial construction, and problemsolving. Weight gain resulted in signiWcant improvements in performance. Pendleton-Jones et al. (1991) found deWcits in underweight anorexic women on tests assessing the focusing and execution aspects of attention (in verbal, memory, and visuospatial domains). Witt et al. (1985), however, found that patients with anorexia nervosa performed as well as normal healthy controls on measures of attention but not on an associative learning task. Visuospatial processing has also been found to be impaired (Szmukler et al., 1992; Maxwell et al., 1984; Kingston et al., 1996). A follow-up study by Kingston et al. (1996) found that attention, but not visuospatial ability, improved signiWcantly with weight gain, suggesting that

attention deWcits are state related while visuospatial deWcits are trait-related Wndings in anorexia nervosa.

Overall, neuropsychologic proWles are still poorly characterized in the adult and adolescent populations. There is also inadequate documentation of the impact of low body weight associated with the psychopathology of anorexia nervosa on the development of intellectual functioning, school performance, and cognitive processing in children whose brains are still developing.

The theories and hypotheses regarding the neurobiology of eating disorders are still at a relatively early stage. This may account for the few hypothesis-driven functional imaging studies in this Weld. The next section reviews Wrst structural studies and then moves on to functional imaging studies.

Structural neuroimaging studies

A number of computed tomography (CT) and magnetic resonance imaging (MRI) studies in female adult and adolescent patients with anorexia nervosa have shown structural abnormalities in the brain. Although some studies have shown changes in subcortical areas of the brain, such as a reduction in size of the thalamus and midbrain (Husain et al., 1992) and a decreased size in the pituitary (Doriaswamy et al., 1991), the most consistent Wnding has been sulcal widening and/or ventricular enlargement (Artmann et al., 1985; Krieg et al., 1988). These changes were to a large extent reversible after weight gain and, therefore, appeared to be secondary to the eVects of starvation. However, in the majority of studies, the brain did not entirely return to complete normality following weight gain (Krieg et al., 1988). Furthermore, cross-sectional CT studies of normal-weight bulimic patients have revealed morphologic brain changes similar to those in anorexia nervosa (i.e., ventricular dilatation and sulcal widening; Krieg et al., 1987).

A recent MRI study involving 12 female patients with anorexia nervosa (age range 11.7±37.6 years; mean age 18.9 years) showed that there were signiWcant reductions in both total gray matter and total white matter volumes compared with controls (Lambe et al., 1997). A longitudinal study by the same team showed that the gray matter volume changes persisted in patients who recovered their weight, suggesting that anorexia nervosa had a reversible and an irreversible component in relation to structural brain changes with weight recovery (Katzman et al., 1997).

Some researchers have examined the relationship between brain alterations and cognitive impairment in a series of patients with anorexia nervosa (Laessle et al.,

1989; Palazidou et al., 1990; Kingston et al., 1996). Palazidou et al. (1990) reported a negative correlation between sulcal width and scores on a symbol-digit coding task. A study by Kingston et al. (1996) reported cognitive deWcits in a large group of patients with anorexia nervosa (mean age 22.1 years) both before and after treatment. DeWcits on memory tasks and on cognitive Xexibility and response inhibition tasks persisted despite substantial weight recovery, but relationships between morphologic brain changes and cognitive impairments were weak.

In summary, the majority of Wndings using structural imaging techniques appear to be secondary to the eVects of starvation and contribute little to the understanding of the pathogenesis of eating disorders.

Functional neuroimaging studies

Caveats and methodologic limitations

Several methodologic problems present special challenges for functional neuroimaging studies of patients with eating disorders. The timing of the scan needs to be considered in the experimental designs, as changes in brain function may vary around mealtimes. Abnormally high plasma levels of ketone bodies have been observed in patients with anorexia nervosa (Pirke et al., 1985). Such high ketone bodies levels may inXuence cerebral glucose metabolic rates (CMRGlu) measured by positron emission tomography (PET) and [18F]-Xuorodeoxyglucose (FDG) (Krieg et al., 1991). Hawkins and Biebuyck (1979) have reported that uptake of ketone bodies is higher in the cerebral cortex than in the basal ganglia. Therefore, if there were a global change in brain metabolism in anorexia nervosa, such as an increased, preferential utilization of ketone compounds in the cerebral cortex, this could actually lead to the appearance of an increased CMRGlu in the basal ganglia (Herholz et al., 1987). Consequently, at the time of FDGPET studies, patients should ideally be in a stable metabolic state, assessed by the absence of ketone bodies in urine and by normal plasma glucose levels. However, the chronic eVect of ketoacidosis on the brain following chronic starvation cannot be totally excluded. Herholz (1996) has suggested that malnutrition may aVect the uptake of tracers in the brain through changes in tissue amino acids, leading to an artifactual diVerence in brain function between controls and starved patients.

Other problems with functional imaging studies in patients with eating disorders include the selection of a suitable control group. Some adult studies have used healthy volunteers as a control group, though this is clearly

diYcult in child studies. Other informative comparison groups could include patients with low weight for reasons other than anorexia nervosa; however, it is likely that the numbers would be small, especially in childhood studies. In addition, such low-weight comparison groups might introduce confounding eVects of the other etiologies for low weight.

Few functional imaging studies in adults with eating disorders have been published to date and only a single study of children. Not only are the number of studies relatively few, but the patient sample sizes involved in the studies are small. Other limitations include the use of mixed age groups, suboptimal control groups, inadequate details concerning patient characteristics (e.g., chronicity of illness, nutritional state, therapy involved prior to or at the time of the study, handedness). Study designs vary; there is little or no consistency in the states in which patients are at the time of study (e.g., resting condition, eyes closed, eyes open, during task performance). Finally, there is a shortage of longitudinal studies. Well-controlled studies with larger sample sizes are needed to provide a better understanding of eating disorders.

Some of the main Wndings in this patient group are now described (Table 17.1).

PET studies of anorexia nervosa in adults and adolescents

The PET studies described below have measured regional CMRGlu (rCMRGlu). The Wrst published study using PET in anorexia nervosa was carried out in Germany by Herholz et al. (1987). In this study, Wve females with anorexia nervosa (aged 17±21 years) were scanned when their weight ranged from 66% to 74% of their ideal body weight and then rescanned after a period of behavior therapy and an average weight gain of 16% of their ideal body weight. Because of legal constraints in Germany on the exposure of young women of reproductive age to PET procedures, the researchers were unable to use a healthy female control group. Young healthy males (n5 15; mean age 23±35 years) were, therefore, used for comparison. The results showed that the patients with active anorexia nervosa had signiWcant higher absolute CMRGlu in the caudate and temporal cortex prior to weight gain compared with postweight gain. The hypermetabolism in the caudate nucleus was also signiWcantly higher in patients with active anorexia compared with the control group. Global CMRGlu tended to be higher in patients prior to weight gain, relative to postweight gain, and also higher compared with healthy males. The authors suggested that global hypermetabolism, with accentuation in the caudate nucleus,