Is Anorexia Nervosa a Neuropsychological Disease

Neuropsychology Review, Vol. 3, No. 2, 1992

Is Anorexia Nervosa a Neuropsychological Disease?

Claude M. J. Braun1 and Marie-Josee Chouinard1

Evidence for central nervous system, and more particularly cortical, etiology of anorexia nervosa is reviewed. Topics covered are neuropsychiatric comorbidity, inheritance patterns, the neurobiology of body-image disturbance and of the eating function, perinatal and alcoholic insult to the brain, neurochemical and neuroelectric disturbance, anatomic and metabolic brain imaging, and neuropsychological impairment. It is concluded that there is indeed an important neuropsychological etiological dimension to anorexia nervosa. The profile most frequently associated with anorexia nervosa is right posterior hypometabolism, followed by right anterior hypermetabolism, both associated with right-sided abnorm al electroencephalogram spiking. It is also proposed that bulimia consists of a "positive" neurological subtype and that restricting anorexia represents a "negative" neurological subtype. Priorities for further research into anorexia nervosa are specified to include twin adoption studies, brain electrical topography studies, postmortem histological studies, and experimentally inspired neuropsychological studies.

KEY WORDS: anorexia nervosa; eating disorders; CNS etiology; neuropsychology.

INTRODUCTION

It has become well established in recent years that anorexia nervosa presents itself in association with widely varying initial potentially causal conditions, including forms of severe psychiatric comorbidity, highly distinctive subtypes, and numerous indicators of associated brain dysfunction. These considerations have major implications for the attempt proposed

1Departement de psychologie, Universite du Quebec a Montreal, P. 0. Box 8888, Station "A," Montreal, PQ, Canada H3C 3P8.

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172 Braun and Chouinard

here to analyze the nature of putative central nervous system, and more specifically cortical, etiologies of the disease.

The body of the upcoming literature review will proceed from the most widely recognized ''biological" concomitants or dimensions of anorexia nervosa to the least published and least researched. The syndrome will be described first in terms of well-established behavioral subtypes, namely the bulimic and restrictor types. Psychiatric comorbidity will then be reviewed, followed by a focus on body-image distortion. The anatomy and neuropathology of the eating function will then be covered, and inheritance patterns as well as acquired insult to the brain will be reviewed. The bioclinical dimensions of the syndrome will be reviewed in detail in terms of neurochemistry, neuroendocrinology, electroencephalography, computer imaging, and finally neuropsychology. It will be argued in the discussion that all of these widely disparate sources of information about the syndrome lead to a coherent conclusion: anorexia nervosa is a biopsychosocial disorder comprising a neuropsychological, probably cortical, subtype (or even possibly dimension) involving the right hemisphere more than the left.

EATING BEHAVIOR SUBTYPES OF ANOREXIA NERVOSA

The two most frequently mentioned subtypes of the disease are the form without eating binges-the so-called "restrictive" type (approximately 60% ), as distinguished from the more recently described "bulimic" type (approximately 40%) involving eating binges on a background of self-starvation by means of laxative abuse and vomiting. The Diagnostic Statistical Manual (3rd edition, revised) (DSM-III-R) recognizes the distinctness of the two syndromes. "Bulimia nervosa" is viewed as bingeing accompanied by inappropriate weight loss practices and persistent overconcern with body shape and weight. Restricting "anorexia nervosa" is viewed as persistent weight loss at least 15% below ideal, loathing of fat, and amenorrhea of more than three months' duration. The "restrictor" type manifests less extraversion, stealing, self-mutilation, suicide, drug and alcohol abuse, sexual activity, and emotional lability, than the bulimic type (Garfinkel, 1981; Vandereyken and Pierloot, 1981 ). The restrictor type reports loss of appetite in 50% of cases (Halmi et al., 1977), though this lowers under more insistent questioning (Garfinkel, 1974). Bulimics suffer, of course, from uncontrollable episodes of excessive appetite. Their mothers are more frequently obese (Garfinkel, 1981 ; Herzog, 1982).

These two types of anorexia may present with entirely different central nervous system etiology. For example, one neurological account of the bulimic subtype, but not the restrictor subtype, proposes an epileptic source

Anorexia Nervosa 173

(Green and Rau, 1974) while loss of amygdaloid function, reminiscent of the Kli.iver-Bucy eating compulsion, has been considered as a potential etiology for bulimia (Pioog and Pirke, 1987, Gardner, 1983). A case of bulimia with several Kli.iver-Bucy symptoms and right-hemisphere electroencephalogram (EEG) abnormality is described by Anastasopoulos and Kokkini (1963). Several computed tomatography (CT) scan studies have now compared the restrictor to the bulimic subtypes of anorexia and found that restrictors have more severe brain atrophy (Lankenau et al. , 1985; Krieg, Lauer, and Pirke, 1987), suggesting that restrictors may represent a "negative" symptom complex, whereas bulimics may represent a "positive" symptom complex. This neurologically inspired way of looking at psychiatric disease has yielded fruitful distinctions in schizophrenia research, but has rarely, if ever, been applied to the problem of anorexia nervosa.

PSYCHIATRIC COMORBIDITY

Self-starving presents with diagnosed comorbidity of a primary depressive nature (Cantwell et al., 1977; Bambilla, 1986) and/or of an obsessive-compulsive nature (Solyon et al., 1982; Rothenberg, 1986, 1988). The argument for an obsessive-compulsive component to anorexia nervosa may appear tautological since anorexic behavior is in itself compulsive. However, two post hoc surveys of large numbers of male and female obsessive-compulsives found high incidence of anorexia (1 1 %, 13%) in the females (see Lemperiere and Rondepierre, 1990, for a review).

The high incidence of these two very different comorbidities and their familial incidence (suggesting hereditary factors) also invokes entirely different central nervous system etiologies. This does not mean, however, that a combination of these two psychopathologies might not increase risk for anorexia nervosa. A majority of early commentators state that bulimia is more related to depression than is the restrictive form of anorexia (Russell, 1979; Garfinkel et al. , 1980; Strober, 1980; but see Toner et al. , 1986, for a review of failures to replicate). The association between anorexia nervosa and affective disorder has been presented as an argument for neurological etiology in the following context: (1) many anorexic patients manifest "negative" neurobehavioral symptoms similar to those with primary affective disease; (2) affective disorder seems indirectly genetically linked to anorexia nervosa; (3) a substantial proportion of anorexics fail the dexamethasone suppression test (DST; Gerner and Gwirstman, 1981 ; Gwirstman and Gerner, 1981) as do, it is believed, genetically predisposed cases of depression. Interestingly, even normal-weight nondepressed bulimics fail the DST (Byrne et al., 1990); and (4) the pharmacological treat-


ment of choice for anorexics continues to be antidepressants (Johnson and Connors, 1987).

Mills (1985) recently drew the two forms of comorbidity together in a model of anorexia nervosa emphasizing hyperarousal due to neurochemical imbalance that explains, along a Yerkes-Dodson inverted-U curve, the initial high cognitive performance levels of anorexics, followed by sleep disturbances, depression, and decreasing cognitive performances, followed in the deepest phase by severe obsessive-compulsive impairment and frank neuropsychological deficit. In support of this "continuist" view, it has been demonstrated that there is a significant co-occurrence of unipolar depression and obsessive-compulsive disorder independently of anorexia nervosa (Nemiah, 1984). The high cooccurrence of primary depression (more often, the unipolar variant) and/or obsessive-compulsive disorder with self-starving (between 35 and 80% ), depending on the. reports, could be of utmost importance in our eventual understanding of cortical etiology of anorexia nervosa. Both unipolar depression and obsessive-compulsive disease present with neuropsychological deficits, EEG abnormalities, and brain metabolic abnormalities. On the other hand, the state of the cortex in these two diseases is very different. For example, whole brain metabolism, and most manifestedly caudate metabolism, are pathologically high in obsessive-compulsive disorder and are pathologically low in unipolar depression (Baxter et al., 1 985; Baxter et aL , 1987; Buchsbaum et aL , 1986). The electrophysiological data suggest more right than left hemisphere dysfunctional overactivation in depression (Myslobodsky and Horesch, 1978; Roemer et at. , 1978; Flor-Henry, 1979; Monakhov et al., 1979) and bilateral frontal dysfunctional overactivation in the obsessive-compulsive disorder (Flor-Henry, 1979; Ciesielski et al., 1981 ; Malloy, 1987). These differential effects are compatible with the neuropsychological findings (Flor-Henry, 1979; Flor-Henry et al., 1979; Goldstein et al., 1977; Kronfol et al., 1978; Taylor et aL , 1979; Wood et al. , 1982). More recently, results of some studies (neuropsychological testing, MRI, evoked potential) have suggested that brain dysfunction in obsessive-compulsive disorders are also more specifically Iateralized in right frontal cortex (Behar, et al., 1984; Christensen et al., 1992; Garber et al., 1989; Head et a/., 1989; Hollander et al., 1990; Insel et al., 1983).

A final important point is that a significant proportion of restricting and bulimic anorexics (around 44%) suffer from a primary depression prior to weight loss (Hudson et al. , 1983b; Piran et al., 1 985; Lee et al. , 1985; Walsh et al., 1985), suggesting along with other indicators (such as family incidence) that depression is not a trivial consequence of weight loss, but rather is part of the etiological matrix. It is not yet clear whether obsessive-compulsive comorbidity can be argued to be etiological.


DISTORTION OF BODY IMAGE IN ANOREXIA NERVOSA

In 1962, Bruch started what continues to be a hotly debated (Hsu, 1982) controversy over a potentially major etiological factor. Specifically, she proposed that body image disturbance is a major initial condition for the disease. She also believed anorexics have defective interpretation of visceral states. Because not all self-starvers seem to manifest this primary disturbance, however (Whitehouse et al. , 1988), the question of subtypes perforce arises again. For example, DSM-III-R criteria require presence of body schema distortion for a diagnosis of anorexia nervosa but not for bulimia. At any rate, the neurology of body image distortion (which to our knowledge has never been linked to anorexia nervosa) is based primarily on cases with irritative right parietal lesions suggesting another plausible reason for thinking about cortical etiology in anorexia nervosa. It is of further interest that a link has been reported between depressive symptomatology and body image distortion without anorexia nervosa (Gardner and Garfinkel, 1981).

Neurological disorders of body image or body schema take on very diverse forms such as the autotopagnosias, hemiasomatognosias, right-left orientation deficits relating to body parts, asymbolias for pain, autoscopias, and micro- and macrosomatognosias. All these syndromes have most frequently been associated with irritative parietal lobe foci caused by epilepsy or migraine-particularly within the right hemisphere (see Lhermitte, 1952, Freederiks, 1969, and Hecaen, 1972, for classical reviews) . The closest link with anorexia nervosa, which has never been put in print, is of course the latter. Automacrosomatognosia consists of a hallucination or delusion of one's body being more voluminous than it is in reality. This problem might be related to body image distortion in anorexia nervosa. The neurological literature on automacrosomatognosia is rather coherent in recognizing it as a pathology (1) that is associated with patients subject to brain paroxysms (epilepsy, migraine, etc.); (2) whose focus is within or contiguous with the parietal lobe; (3) whose focus may be located in either hemisphere, but is most often on the right side; and (4) whose focus may be subcortical but whose full actualization requires cortical involvement (see Cumming, 1988, for a brief review). Recent evidence and argumentation along these lines consists of a report by Signer and Benson (1990) of 3 cases of temporallimbic epilepsy with bulimia. The authors believe the irritative foci produced affective psychosis characterized principally by "dysmorphic or somatic delusion concerning body image," which in turn was a "necessary condition for appearance of other features of the anorexic syndrome." They believe "functional disturbance in the limbic regions may produce or exacerbate the full syndrome of anorexia nervosa."


This link between the neurology of automacrosomatognosia and anorexia nervosa is difficult to establish because (1) body image distortion is difficult to evaluate objectively, and (2) cases of automacrosomatognosia have been extremely rare and little is known about their underlying neuropathology and phenomenology. Nevertheless, it is obvious that future investigations designed to test the notion of cortical etiology must carefully evaluate body image distortion in anorexics.

SUBCORTICAL AND CORTICAL CONTRIBUTIONS TO THE EATING FUNCTION IN SUBHUMAN AND HUMAN SPECIES

Of all the brain systems invoked as putative pathological contributive cause of loss of appetite, the hypothalamus is the most frequently cited in the human eating disorder literature. However, this idea can be questioned on the following grounds: (1) The behavior pattern of anorexics is a highly complex, ultradeliberate, well-organized system. Such behavior systems simply cannot arise without cortical involvement. (2) The initial conditions of anorexia (especially bulimia) have to do not so much with loss of appetite or some other primary eating dysfunction, but with perverted attitudes, beliefs, and/or perceptions from which the eating disorder only secondarily develops. (3) Even if a primary eating disorder were an important initial condition of anorexia, there is no reason to ascribe the former, as is virtually always done, solely (as if necessarily) to the hypothalamus. Indeed, other subcortical and even cortical circuits have been implicated in the eating function.

In mammals, these are located from the brainstem up to the frontal lobes. Lesions including the hippocampus, amygdala, and pyriform cortex produce hyperphagia (Fuller et al., 1975) but the basal-lateral amygdala seems to be the key structure (Green et al., 1957; Borini and Rolls, 1984). Lesions of the nigratostriatal bundle produce an aphagia syndrome virtually identical to lateral-hypothalamic aphagia-even when only dopamine-specific neurons are destroyed (many of which course through the hypothalamus from the substantia nigra to the basal ganglia including the caudate nucleus [Ungerstedt, 1971; Fibiger et aL, 1973]). Lesions of the ventral noradrenergic bundle produce hyperphagia (Ahlskog and Hoebel, 1973) and trigeminal lemniscal lesions produce aphagia (Zeigler and Karten, 1975). Lesions of the frontal lobes-;>articularly the frontal poles-consistently produce hyperphagia (Ruch and Shenkin, 1943; Anand et al., 1958; Butter et al., 1970; WolfJurewicz, 1982). In experiments with monkeys, 25.8% of the neurons in the head of the caudate nucleus responded in conditioned tasks to the suggestion of food, whereas after unconditioned stimuli, only up to 9.6% of the neurons responded (Rolls et al., 1988). The head of the caudate receives most of its


afferants from the frontal cortex, but also some from the limbic system including, in particular, the amygdala (Dray, 1980; Kelley et al. , 1982). Herholz et al. (1987) recently argued that the known role of the head of the caudate in vigilance and initiation of action--including eating behavior--suggests that anorexic caudate hypermetabolism is related to the increased vigilance that they believe is typical of anorexics. Interestingly, these authors also observed significant caudate hypermetabolism in anorexics. In the same vein, it is noteworthy that obsessive-compulsives show atrophied caudate nuclei on cr scan, that Sydenham chorea patients who suffer from striatal degeneration are at risk (20%) for the obsessive-compulsive syndrome, and that 20% of obsessive-compulsives manifest choreiform tics (Rapoport, 1989). Finally, 75% of patients with Huntington's disease, involving marked degeneration of the caudate nuclei, become severely emaciated (Sawopoulos et a/., 1990). These authors argue that the emaciation is not due to choreic movements, and that these patients frequently manifest bulimic behavior as such rather than simple overeating. Whittier (1973) obtained similar findings, and also believes the bulimia cannot be explained by chorea since bulimia is observed in obese cases with little chorea.

These data have led Grossman (1972, 1975) to argue that hypothalamic regulation of appetite and eating behavior is secondary in importance to other more distributed circuits that terminate in the frontal lobes. Even if the hypothalamus were a key element in the eating behavior disorder of anorexia nervosa, the now well-established direct connections between the former and the orbital cortex (Fuster, 1980) suggest that the hypothalamus is not solely involved. In 1945, Hofstatter, Smolik and Busch observed that some patients who had undergone frontal lobotomies for treatment of intractable psychoses and behavioral disturbances developed hyperphagia. Erb et a!. (1989) reported extreme hinging and purging in a patient with frontal periventricular white matter infarction. Hecaen (1964) also reported bulimia in a patient with frontal lobe tumor. Crisp and Kalucy (1973) reported that frontal Ieucotomy of 2 cases of anorexia and 1 case of bulimia resulted in increased food intake. Sargant (1951), Sifneos (1952), and Mitchell et al. (1976) reported similar (bulimic) cases. Kirschbaum (1951) reported a patient with a midline frontal tumor who was hyperphagic, and Drake (1987) reported hyperphagia following frontal infarctions. Bulimia and/or obesity have been less frequently reported following temporal lobectomy (Sawa et a!., 1954; Alajouanine et al., 1957; Grossman, 1972). A series of tumor patients (glioma) were reviewed for weight loss (Griffith and Hochberg, 1988). It was found that right-sided gliomatic tumors were twice as likely to produce weight loss than left and nearly all were anterior. In short, bilateral cortical tissue loss, particularly frontal and temporal, tends to produce hyperphagia, and seems therefore an unlikely etiology for re-


stricting anorexia or even under or normal-weight bulimia. Unilateral irritative focus and/or tissue loss in the right anterior cortex seems sufficient, however, for inducing restricting anorexia nervosa.

Though loss of appetite is not a necessary condition in anorexia nervosa, it is frequently (50%) present. Restricting anorexics report low appetite, low palatability of meals, and high satiety after meals in experimentally controlled conditions, even after successful treatment of emaciation (Halmi et al., 1989). Bulimics, on the other hand, manifest the opposite characteristics. It therefore appears that central nutritional "drive" systems might occasionally play an etiologic role in certain anorexic conditions. The failure of eating disorder researchers so far to think through a full neurological account of anorexia nervosa leads them nearly invariably to consider the very numerous vegetative dysfunctions associated with anorexia nervosa as secondary to starvation, to be subcortically located, and then to (incorrectly) dismiss neurological etiology altogether as completely implausible. Much of these judgments are due to the fact that many parameters of subcortical (hypothalamic) dysfunction tend to normalize after return to normal weight. Rather than proving total absence of neural etiology, however, this leaves open the possibility of several neurogenic etiologies, one of which could be a primary cortical etiology followed by secondary starvation stress upon subcortical control systems. It is interesting to note that a few indices of disturbed hypothalamic dysfunction, in anorexics, seem to persist beyond renourishment. For example, the sucrose test of satiety, a variant of the Cabanac procedure, is abnormal beyond renourishment (Garfinkel, 1981).

INHERITANCE OF ANOREXIA NERVOSA

There is at present no specific model of the nature of hereditary transmission of anorexia nervosa. Twin studies of anorexia nervosa consisted of case reports until the group studies of Schepank (1981) and Holland and colleagues (1984). A meta-analysis of the ensemble of published cases (Nowlin, 1983) concluded with a 35-55% concordance for monozygotic (MZ) twins and 11% for dizygotic (DZ) twins. Holland and colleagues have recently reported an analysis of 25 MZ and 20 DZ twin pairs, one member of which was admitted, consecutively, to an eating disorder clinic (1988). They found 56% concordance in MZ twins and 5% concordance in DZ twins. They concluded that 80% of anorexia nervosa variance is genetic. They proposed that (a) the genetic mechanism is multiple, because of the marked discrepancy between MZ and DZ twins, and (b) the phenotype consists of a "hypothalamic sensitivity to environmental stress,"


because of the well-known influence of social factors, as well as other considerations.

Studies of family incidence of anorexia nervosa (Theanders, 1970; Morgan and Russell, 1975; Kalucy et al., 1975; Cantwell et aL, 1977; Dally and Gomez, 1977; Garfinkel et a!., 1980; Gershon et al., 1983; Hudson et al., 1984a, b; Strober et al. , 1985) indicate up to a sixfold risk for first degree relatives.

Candidate biological coetiology of anorexia presently includes, at the forefront, primary depression for which first degree relatives are at high risk (Cantwell et al., 1977; Gershon et al., 1984; Logue et al., 1989; Hudson et al., 1983a, 1983b; Winokur et al., 1980) and for which anorexics are also at very high risk (Cantwell et al., 1977; Rivinus et al., 1984a,b; Winokur et al., 1980; Hendren, 1983; Hudson et al., 1984a,b). The depression associated with both the restricting and bulimic variants of anorexia may not be a necessary effect, or a necessary cause, of starvation since depression persists or arises de novo in 20-50% of patients after the eating disorder has resolved (Cantwell et al., 1977; Hsu, 1980; Morgan and Russell, 1975) . There is evidence, however, that depression may not be abnormally frequent in families of norm al-weight bulimics (Stern et al., 1984).

It is increasingly being argued that depression and anorexia nervosa have different, though concomitant, genetic etiologies because of the following: (1) Though anorexics have high rates of primary depression, relatives of primary depressives do not seem to have elevated rates of anorexia nervosa (Strober and Katz, 1988. (2) Co-occurrence of depression in relatives of anorexics seems more highly significant for anorexics with primary depression than without (Biederman et al., 1985). (3) the phenomenology of depression with or without anorexia differs on several counts. For example, depressives complain of loss of appetite, not anorexics; depressives complain of loss of libido, not anorexics; depression is not as markedly sex biased as anorexia; whereas anorexia is related to social class, depression is not (Vandereycken, 1987). (4) The cohort of 25 anorexic MZ probands recently studied by Holland and colleagues (1988) contained no depressives, and their twins manifested high concordance for anorexia but no depression. It does not seem, however, that depression was carefully investigated in that study.

As for family incidence of alcoholism, early reports placed it at 2% in mothers and from 13 to 17% in fathers of anorexics (Halmi and Lony, 1973; Cantwell et al., 1077; Eckert et a!., 1979; Rivinus et al., 1984). In a survey of families of 30 restricting anorexics and 30 bulimics, Herzog (1982) found alcoholism in 33% of parents of bulimics and 20% of parents of restrictors. Remarkably, fathers of bulimic anorexics seem at threefold risk (29%) over restricting anorexics (9%; Strober et al., 1982). This finding in conjunction with frequent obesity of mothers of bulimics, suggests familial risk for impulse disturbance in bulimia.


These data have important implications for a neurological account of the etiology of anorexia nervosa. Indeed, to the extent that a specific set of genes is involved in the etiology of anorexia nervosa, and that a subcode is involved in hereditary depression and perhaps another in impulse disturbance, then obviously, a complex central nervous system etiology of anorexia nervosa must be considered all the more plausible.

ACQUIRED INSULT TO THE BRAIN IN ANOREXIA NERVOSA

Perinatal Complications

Incidence of perinatal complications is significantly high (between 15 and 25%) in anorexics (Halmi et al, 1977). Artmann and colleagues (1985) concluded from the qualitative analysis of CT scans of 59 anorexics that the incidence of "irreversible perinatally incurred" lesions was 60%. This was probably a biased group however. In another CT scan study of 21 anorexics, Lankenau and colleagues (1985) tabulated cases with CNS insult from medical records, rather than from the CT scans, and found that 38% of their cases had suffered some form of CNS insult other than anorexia. A small portion of the "perinatal insult" variance could be imputable to maternal alcoholism since a statistically significant prevalence of this disorder has been associated with anorexia nervosa (Molgraad et al. , 1989), and since maternal alcoholism is a known fetal brain stressor.

Alcohol Abuse

In their collaborative hospital study of 105 female anorexics, Eckert and colleagues (1979) found 6.7% of well-documented alcoholism. This is a high frequency considering the youth and sex of this sample. The rate in the general population of same age and sex is well below 1% (Woodruff et al., 1974). Alcoholism was more heavily associated with the bulimic than the restrictor type of anorexia, and concurred with depression. Alcohol abuse results, of course, in reversible brain atrophy as measured by CT scan (Carlen et al. , 1978) .

NEUROCHEMICAL DISTURBANCE I N ANOREXIA NERVOSA

Despite the fact that chemical approaches to psychiatric disorders have represented by far the most powerful means of advancing neurological


theory of behavior disorders because of the simplicity of dispensation of effective pharmacotherapy and immense research efforts thus vested, no all-encompassing breakthrough has occurred as of yet as far as anorexia nervosa is concerned.

Significant effects of various drugs on food intake have been demonstrated experimentally in animals (see Krahn et al., 1987, and Morley and Blundell, 1988, for reviews). Given that approximately 50% of restricting anorexics report abnormally low appetite (Halmi et a/., 1989) it would seem logical that pharmacological intervention should have attempted to induce appetite in these particular cases. However, appetite per se, independent of weight gain, has generally been ignored in studies of the effects of pharmacological agents. Furthermore, drugs selected to reduce appetite in bulimics have been found generally only mildly effective in reducing hinging, and decreasing weight, respectively. (See Tables I and II.)

As shown in Tables III and IV, concentrations of these and other relevant substances in emaciated anorexics' brains, suggest, by and large, that "central control (particularly of the hypothalamic-pituitary-adrenal axis) of feeding is responding appropriately (which means, 'excessively') to starvation" and stress (Tarnai et al., 1986). This notion is further buttressed by the fact that most if not all the neuropharmacological and neuroendocrine anomalies apparently revert to near normal upon renourishment and removal of stressful living conditions.

Pharmacotherapy geared at manipulating food intake by directly influencing the above substances has not been very satisfying. The most successful pharmacological intervention for anorexia nervosa (restrictors and bulimics) has been the use of antidepressants (Hudson et al., 1984a,b; Herzog, 1984), most specifically those which influence the serotonergic system such as MAOI, agonists and antagonists of serotonin (ex: phenelzine, clomipramine, fluoxetine) (Goldbloom, 1987; Herzog and Brotman, 1987; Kennedy and Walsh, 1987; Morley and Blundell, 1988). In fact, results of recent studies suggest that eating disorders are associated with dysfunctions of the serotonergic system (Arato et al., 1991; Jimerson et al. , 1990a; Jimerson et al., 1990b; Kaye et a!., 1984). However, serotonin dysfunction is not exclusively associated with eating disorders. We also find it in depression (FlorHenry, 1985; Henniger et al., 1984; Jimerson et a/., 1990b) and in the obsessive-compulsive disorder (Hollander et al., 1992a; Hollander et al., 1992b; Goodman and McDougle, 1990; Kim and Dysken, 1988), two psychopathologies frequently present in anorexia and bulimia nervosa.

Interestingly, researchers have recently demonstrated with post-mortem histochemical studies, neurochemical studies, and pharmaco-EEG studies that serotonergic mechanisms are more lateralized in the right hemisphere of the brain (Arato et al., 1991; Flor-Henry, 1985; Frecska et


Table I. Neurodynamic Agents Favoring Weight Gain in Subhuman Mammals and/or Normal Humansa

Other General class Subclass Specific agent characteristics

Biogenic amines Serotonin antagonists Cyproheptadineb Antidepressant Amitryptalineb Antidepressant Clomipramineb Antidepressant Parachlorophenylanine 5-7 Dihydroxytryptamine

Norepinephrine Desmethylimipramineb Antidepressant agonists

Low-dose dopamine Levodopab

agonists Dopamine antagonists Butyrophenone Neuroleptic

Clorpromazineh Neuroleptic Pimozideb Neuroleptic Sulpirideh Neuroleptic

Peptides Neuropeptides Neuropeptide Y Neuropeptide YY

GABA GABA agonists Diazepam Anxiolytic Muscimol Anxiolytic Benzodiazepine Anxiolytic

Opioids Opioid agonists B-Endorphin X-Neoendorphin Enkephalin Dynorphin Butorphanol

Hormones Peripheral action Motilin Mineral salts Lithium Lithium carbonate b Neuroleptic

aThis table is principally based on the reviews of Krahn et al. (1987) and Morley and Blundell (1988) regarding the animal and experimental literature, and the reviews of Fava eta/. (1989), Kaplan and Woodside (1987), and Tolstoi (1989) regarding pharmacotherapeutics.

bclinical studies have been carried out on restricting anorexics using the agent.

al., 1990; Mandell and Knapp, 1979). Therefore, these results support the hypothesis of dysfunctions of the right hemisphere in eating disorders, depression, and obsessive-compulsive disorders.

CNS SENSITMTY TO HORMONES AND ANOREXIA NERVOSA

Young (1975) proposed that CNS hypersensitivity to estrogen is the primary etiology of anorexia nervosa. The argument ran as follows: CNS estrogen hypersensitivity can explain characteristics of anorexics including amenorrhea, low appetite, restlessness, insomnia, defective thermoregulatory response to cold, nausea, diminished vigilance, failure to suppress dex-

Anorexia Nervosa

Table II. Neurodynamic Agents Favoring Weight Loss in Subhuman Mammals and/or Normal Humansa,b

General class

Peptides

Hormones

Purines

Biogenic amines

Stimulants

Opioid antagonists

Subclass

Peripheral action

Peptidic

Serotonin agonists

Amphetamine agonist

Morphine antagonist

Specific agent

Glucagon Somatostatin Cholecystokinin Bombesin Gastrin releasing peptide Neurotensin Corticotropin releasing factor Naltrexonec Thyrotropin releasing hormone Prostaglandin Adrenocorticotropin (ACTH)c Calcitonin Adenosine Caffeine Xanthine D-Fenfluraminec Tryptophane Fluoxetinec Phenylethylamine Methylamphetaminec Naloxonec

Other characteristics

Antidepressant

0This table is principally based on the reviews of Krahn et al. (1987) and Morley and Blundell ( 1 988) regarding the animal and experimental literature, and the reviews of Fava e t al. (1989), Kaplan and Woodside (1987) and Tolstoi (1989) regarding pharmacotherapeutics.

hcontrolled clinical studies have tested the efficacy of drugs selected to attenuate the binge compulsion in normal or overweight bulimics. These include diphenylhydantoin, phenytoin, imipramine, lithium carbonate, desipramine, amitriptaline, mianserin, and phenelzine (see Hsu, 1990).

cclinical studies have been carried out on bulimics using this agent.

183

amethasone, anxiety, and moodiness. Evidence for this comes from brain infusions of estrogen in rats, studies of menstrual cycles in women, and clinical manipulation of brain estrogen with clomiphene. The author proposes that anorexics have abnormal hypothalamic maturation, and therefore "grow into" a pathological response to pubertal estrogen infusion. This disorder makes them more susceptible to stress, which in turn can then trigger a full anorexia nervosa syndrome. Finally, the author presents a similar set of arguments and evidence to the effect that the KJeine-Levin syndrome represents a testosterone analog, with an opposite clinical picture suggestive of bulimia. Young failed to mention the interesting fact that the KJeine-Levin syndrome includes frequent presence of EEG abnormalities (Wilkus and Chiles, 1975). This fascinating proposal has unfortunately been


Table III. Neuropharmacology and Neuroendocrinology of Acutely Underweight Restricting Unmedicated Anorexics0

Concentration Normalization Body fluid Substance or activity with

sampled or activity assayed reported renourishment

csF' GABA Normal NA CSF Opioid activity Up Yes CSF Neuropeptide Y Up Yes CSF B-endorphin Down Yes CSF HVA (dopamine metabolite) Down Yes CSF SHIAA (serotonin metabolite) Down Yes CSF MHPG (norepinephrine metabolite) Down Yes CSF B-lipotropin Down Yes CSF ACTH Down Yes CSF Pro-opiomelanocortin Down Yes CSF Corticotropin releasing factor Up Yes CSF Cortisol Up NR CSF Oxytocin Down Yes CSF Galanin immunoreactivity Normal NA CSF Adrenocorticotropic hormone Down Yes CSF �-Lipotropin Down Yes CSF Norepinephrine Normal/down Yes CSF "Somatostatin-like immunoreactivity" Down NR CSF "Bombesin-Iike immunoreactivity" Normal NR CSF "Cholecystokinin-like immunoreactivity" Normal NR Plasma Growth hormone Up NR Plasma Cortisol Up Yes Plasma Vasopressin reactivity Erratic ? Plasma Luteinizing hormone Down NR Urine Cortisol Up Yes

0See review by Fava et al. (1989). See also Berrettini et al. (1988), Demitrack et al. (1990), Gerner and colleagues (1981, 1982, 1983, 1984), Gold et a[. (1986), Kaye and colleagues (1982, 1984, 1985, 1987, 1988, 1989, 1990), and Maeda et al. (1987) for results not reviewed by Fava et al. (1989). NR: not reported; NA: non-applicable.

bcerebral spinal fluid.

virtually completely ignored in the eating disorder literature. It is noteworthy that beyond Young's account of his "CNS-hormone" theory of anorexia, clomiphene used to instill menses in anorexics has failed to reinstill menses or to alleviate starving behavior.

ELECTROENCEPHALOGRAPHY, EPILEPSY, AND PHENYTOIN TREATMENT IN ANOREXIA NERVOSA

It has been proposed that the bulimic subtype of anorexia nervosa in association with neurological soft signs (unbridled anger attacks, headache,

Anorexia Nervosa

Table IV. Neuropharmacology and Neuroendocrinology of Unmedicated Bulimics (Under- or Normal Weight)a

Body fluid Substance Concentration sampled or activity assayed or activity reported

CSF Oxytocin Normal CSF Neuropeptide YY Up CSF Galanin immunoreactivity Normal CSF SHIAA (serotonin metabolite) Down Plasma B-endorphin Down Plasma Norepinephrine Down Plasma Postprandial cholecystokinin Down Plasma Platelet MAO activity Normal Plasma Serotonin uptake Normal Plasma Serotonin release Normal

0See review by Fava et al. (1989). See also Berrettini et al. (1988). Demitrack et al. ( 1990), Hallman et al. ( 1 990), and Kaye et a/. ( 1 990} for additional empirical results.

185

vertigo, nausea, paresthesia, disorders of arousal) and epileptiform EEG on the one hand, and auras prior to, convulsions during, and passing out after bulimic binges, represents a special and large subtype of anorexics with neurological etiology (Green and Rau, 1974; Rau and Green, 1978). Low to high incidence of epileptic attacks or epileptic EEG ranging from 10 to 90% have since been reported by numerous investigators. An antiepileptic drug, phenytoin, has consequently been administered to several groups of bulimics by independent research groups, reporting weakly positive to very positive results. Initial enthusiasm for the notion of an epileptic etiology for subgroups of anorexics was attacked in a recent exhaustive critical review by Pope and colleagues (1989). On the basis of a post hoc analysis of 41 bulimics as well as other research reports, these authors concluded that the EEG anomaly is no more frequent in bulimics than in nonbulimic anorexics, or in age-matched depressives (or psychiatric patients in general, for that matter). They also argued that the "small" beneficial effect of phenytoin on bulimics is probably due to its antidepressant action more than its anticonvulsant action. Pope and colleagues have come close to dismissing any "paroxysmal" etiology in bulimia, but they have overstated their case. A 30-40% incidence of abnormal EEG in depressives and other psychiatric groups as observed by Pope and colleagues and many others could also be interpreted as paroxysmal etiology for these diseases. Rau and Green (1984) have also made the following important points: (1) the most predictive BEG sign for beneficial effects of phenytoin in bulimia is the 14 + 6 positive spike pattern, a sign picked up only during drowsy or sleep states ignored by other researchers; (2) there is a 40-50% false-negative


probability of obtaining EEG signs in known grand mal epilepsy-indicating that EEG cannot be expected to identify more than 50% of the targeted group (bulimics). Though epileptiform EEG disturbances are indeed frequent in psychiatric populations, a large-scale review of 3225 EEG files in a psychiatric center refutes the notion that anorexics and other psychiatric categories are at equal risk for epileptiform EEG (Bridgers, 1987). This study found that only 2.6% of patients referred for EEG, without a prior impression of epilepsy, showed epileptiform EEG. Of these, anorexia was by far the most proportionately frequent presenting impression, relative to mania, depression, schizophrenia, and other psychoses. Remarkably, in a CT scan study of anorexics, Kohlmeyer and colleagues (1983) serendipitously mentioned that nearly every one of their 23 cases had EEG abnormalities, most of which receded with renourishment and reversal of brain atrophy viewed on CT scans. It is unfortunate that a full report of these important EEG findings is not available. A case of pubertal anorexia with normalization of bitemporal abnormal slowing upon renourishment is reported by Sein et al. (1981). Not all anorexics with EEG abnormalities recover normal EEG after weight gain however. Several of the cases reported by Lundberg and Walinder (1967) continued to have abnormal EEGs after renourishment. The authors interpreted several of their cases as having their EEG abnormalities prior to their anorexic symptoms. Systematic studies of EEG in anorexia report incidences of abnormality between 34 and 59% (Crisp et al., 1968; Neil et al., 1980). At any rate, whatever the significance of these findings may be, they do not justify dismissal of the notion of paroxysmal etiology for at least a minority (perhaps a distinct subtype) of bulimics. Evidence of reversibility of EEG disturbance may mean that anorexics have low thresholds (which could be constitutional or even genetic) or that starving produces such anomalies even in normal brains.

Co-occurrence of EEG signs in twins and/or first degree relatives has never been systematically investigated. Goor and Groningen (1954) did find that 4 anorexic patients with abnormal EEGs had families with high incidence of EEG abnormalities (11 of 15 relatives), suggesting that "paroxysmal" variants of eating disorders may be hereditary. Foster and colleagues found high concurrence of sleep-EEG abnormalities and anorexia nervosa in one pedigree (Foster and Kupfer, 1976; Foster et al., 1976). Case 4 reported by Lundberg and Walinder (1967) had anorexia and epilepsy, and her twin (zygosity unspecified) was concordant for both. A confirmed monozygote twin was also concordant for epileptic 6/sec spike-wave EEG (Crisp et al., 1968).


Case reports of classical epilepsy characterized by spike-wave patterns have noted associated bulimia (Lundberg and Walinder, 1967; Remick et al., 1980; Shimada and Itagawa, 1973; Signer and Benson, 1990). Though all of the authors conclude that bulimia in these cases is neurogenic, not all believe the pathological system is cortical (Shimada and Kitagawa, 1973). Those who do believe in a cortical etiology propose the temporolimbic circuit as a prime candidate (Lundberg and Walinder, 1967; Remick et al., 1980; Signer and Benson, 1990).

Rau and colleagues (1979) believe the most frequent EEG abnormalities in bulimia are suggestive of subcortical foci rather than cortical ones. Specifically, the thalamus and hypothalamus are considered to be the most plausible source(s). Other authors who have ventured interpretations of CNS foci for anorexic EEG abnormality, based on group data, also suggest subcortical loci, either the hypothalamus (Gibbs and Gibbs, 1964) or the brain stem (Hughes et a/., 1965; Shimoda and Kitagawa, 1973). However, rare cases of lateralized EEG disturbance suggest that a cortical, or at least telencephalic disease focus, could contribute to anorexia nervosa. A first meta-analysis of the published anorexia-BEG literature carried out for the present report (see Table V) revealed 19 cases of right focus and only 2 cases of left focus. Unfortunately, though EEG asymmetry has been reported to be infrequent in restricting as well as bulimic anorexics (Crisp et al. , 1968; Rau and Green, 1984; Artmann et aL, 1985), EEG asymmetry has never been carefully looked at, any more than locus of pathological leads. Furthermore, though migraine headache is known to be frequent in bulimia, no attention has been paid to the side of the head at which those attacks might most frequently occur. The trends visible in Table V suggest that when electrical disturbance is lateralized it is primarily right sided in both restricting and bulimic anorexia, that the area involved is primarily temporo-occipital, and that these effects apply mostly to adult anorexics. In the 2 cases showing a left focus, the problem consisted of EEG "slowing," whereas in the large majority of right-sided foci, the abnormality consisted of abnormal "spiking ." Lateralized EEG effects suggest cortical involvement though perhaps only in a minority of cases. This effect is compatible with the available neuropsychological and positron emission tomography (PET) scan data on restricting anorexics and bulimics presented in further sections.

As for phenytoin therapy for bulimia, though it is possible, as Pope and colleagues argue, that its antibulimic action may be thymoleptic rather than anticonvulsive, it would appear worthwhile to more seriously test the anticonvulsive idea with other anticonvulsants that have fewer or different

Table V. EEG Lateralization in Anorexia Ner vosaa

Year First data Patient's Patient's Patient's Patient's Patient's Pathological Pathological

author published sex diagnosis weight age name side site EEG form

Rau 1975 Female Bulimia Underweight 25 Nan Right Temporo-occipital 14 + 6 ctenoids Rau 1975 Male Bulimia Overweight 23 Paul Right Temporo-occipital 14 + 6 ctenoids Green 1974 Female Bulimia Underweight 23 T.N. Right Temporo-occipital High-voltage negative spike Green 1 974 Female Bulimia Normal 29 J. S. Right Temporo-occipital 14 + 6 ctenoids Green 1974 Female Bulimia Overweight 16 R. L. Right Occipital 14 + 6 ctenoids Green 1 974 Female Bulimia Underweight 1 8 No. 2 Right Temporo-occipital 14 + 6 ctenoids Green 1974 Female Bulimia Underweight 24 No. 3 Right Temporo-occipital 14 + 6 ctenoids Green 1974 Female Bulimia Underweight 1 9 No. 4 Right Temporal Positive spikes Green 1974 Male Bulimia Normal 36 No. 6 Right Unspecified 14 + 6 ctenoids Moore 1982 Female Bulimia Normal 21 Mrs. A Right Temporo-occipital 14 + 6 ctenoids Weiss 1976 Female Bulimia Underweight 25 - Right Temporo-occipital "Abnormal" Wermuth 1977 Female Bulimia Normal 3 7 No. 8 Left Temporal " Slowing" Crisp 1968 Female Anorexia Underweight ? No. 20 Right Unspecified " Low and fast" abnormality Lundberg 1 965 Female Anorexia Underweight 25 No. 1 Right Temporo-occipital "Episodic epileptiform" Lundberg 1965 Female Anorexia Underweight 23 No. 4 Right Unspecified "Episodically abnormal" Davis 1974 Female Bulimia ? ? - Right Frontal 6/sec spikes, slow waves Mitchell 1983 Female Bulimia Normal ? - Right Posterior quadrant "excessive slow waves" Tachibana 1989 Female Anorexia Underweight 13 No. 1 Right Occipital Spikes/slow EEG

Signer 1 990 Female Bulimia Underweight 36 A Right Fronto-temporal Spike-wave Signer 1990 Female Bulimia Underweight 25 B Left Fronto-temporal 3-4-Hz slow waves Shimoda 1973 Female Anorexia Underweight 19 No. 2 Right Antero-temporal 6-Hz spike-wave

a All reports of lateralized EEG abnormalities found in the literature are tabulated here.


effects on mood before altogether dismissing a potentially useful treatment for an easily identifiable subset of bulimic patients.

SOMNOGRAPHY AND ANOREXIA NERVOSA

There has recently been intense interest in EEG during sleep in anorexia because, as has been hinted in preceding pages, these data have bearing on the depressive comorbidity issue, the inheritance issue, the epilepsy issue, as well as the various attempts being made to subtype anorexia nervosa. Recent studies have reported largely negative results. Young anorexics with or without bulimia, and even with or without depression, have sleep EEGs that do not significantly differ from normal control groups (Byrne et a/., 1990; Lauer and colleagues, 1988, 1989, 1990; Levy et al., 1988; Walsh et al., 1985). It should be noted, however, that adolescent depressives typically do not show the disturbed sleep-EEG architecture of adult depressive (Byrne et al., 1990). Furthermore, family pedigrees have not been taken into consideration in the recent somnography studies. Consequently, it remains possible that high and low genetic risk and depressive and nondepressive subtyping of adult anorexics could be achieved by means of somnography.

BRAIN SCANNING AND ANOREXIA NERVOSA

At least 22 CT scan studies of anorexia have now been published, several of which have investigated large groups of patients. All of these studies have reported very significant occurrence (up to 91%) of sulcal widening and/or lateral and third ventricle enlargement. Only 2 studies revealed, in addition to the above, cerebellar atrophy, either because other investigators did not look for it or because they failed to report negative findings. At any rate, in one particular investigation, 49% of anorexics manifested cerebellar atrophy (Artmann et al., 1985). These findings indicate the frequent presence of both cortical and subcortical atrophy, respectively (see Table VI).

Studies comprising follow-up scans after renourishment found mildly significant, or more often nonsignificant, reversal of brain atrophy and correlation of atrophy with rapidity of weight loss, suggesting that some of the brain atrophy is secondary to starvation. However, in no case did all brain scans return to perfect normality after renourishment. Most authors described their positive findings as pseudo-atrophy with slow recovery because of the fact that there is evidence of some degree of reversal in most cases. Furthermore, normal weight bulimics showed atrophy that was similar to, though milder than, starved restrictors (Hoffman et al., 1989; Krieg et al.,

..... IC Q

Table VI. Synopsis of CT Scan Findings in Anorexia Nervosa0

Weight First Date Diagnosis Presence of Presence of Presence of Reversal of Clinical variable( s)

author's article of patients sulcal (cortical) lateral venticle third ventricle atrophy correlates correlated surname published evaluated atrophy atrophy atrophy observed of atrophy with atrophy

Enzmann 1977 Anorexia Yes No NR NR No NR Heinz 1977 Anorexia NR Yes Yes Yes NR NR Nussbaum 1 980 Anorexia Yes Yes NR Yes NR Yes Luton 1981 Anorexia Yes Yes NR Yes Yes NR Zeumer 1 982 Anorexia Yes Yes NR Yes NR NR Kohlmeyer 1 983 Anorexia Yes Yes Yes Yes NR NR Emrich 1 984 Anorexia Yes No NR NR NR NR Sein 1 984 Anorexia Yes Yes NR Yes NR NR Lankenau 1 985 Anorexia/bulimia Yes Yes Yes NR No Yes Art mann 1985 Anorexia Yes Yes No Yes No NR Kreig 1986 Anorexia Yes Yes No Yes No Yes Datlof 1986 Anorexia Yes Yes Yes NR NR Yes Krieg 1987 Bulimia Yes Yes NR NR No No Krieg 1987 Anorexia/bulimia Yes Yes NR Yes Yes Yes Ploog 1 987 Anorexia/bulimia Yes NR NR Yes N R N R Krieg 1988 Anorexia Yes Yes NR Yes No Yes Dolan 1988 Anorexia Yes Yes NR Yes No No Krieg 1989 Anorexia Yes Yes NR NR NR NR Krieg 1989 Bulimia Yes Yes NR NR Yes No Krieg 1989 Anorexia Yes Yes NR NR Yes Yes

= ;!

Hoffman�> 1989 Bulimia Yes No NR NR Yes No = =

Palazidou 1990 Anorexia Yes No NR NR Yes NR = =

0NR: not reported; Yes: observed; No: not observed. Q..

(j bMRI scan. ::r

Q = = = .., Q..


1987; Krieg, Lauer, and Pirke, 1989; Ploog and Pirke, 1987) suggesting to these authors that electrolyte imbalances due to vomiting and/or laxative abuse also cause brain atrophy. Brain atrophy was generally unrelated to clinical variables such as age, weight, presence of depression, serum protein levels, or duration of illness. However, atrophy has, on occasion, been reported to correlate with hinging frequency in bulimics as well as low plasma triiodothyronine, and in restrictors, with high plasma cortisol level and percent of weight loss. A substantial minority of originally brain-atrophied cases showed no change whatsoever at the time of the second scan, even after several months of normal weight. Artmann and colleagues concluded that the main characteristic feature of ventricular enlargement is a "flattening" and outward widening of the lateral borders of the frontal horns. This conclusion is compatible with the qualitative description of an anorexic CT scan provided by Heinz et al. (1977), and of the group data of Datlof et al. (1986).

Cerebral ventricular size is genetically determined (Reveley et al., 1984). The findings of persistent cerebral atrophy in a few cases, long after renourishment, and of CT signs of perinatal damage (Artmann et al., 1985) suggest that macroscopic brain damage may be an etiological factor, but perhaps only in a minority of cases.

METABOLIC BRAIN IMAGING AND ANOREXIA NERVOSA

Only a few research groups have recently started investigations in view of mapping brain metabolism in anorexics. The sample sizes are small (N = 5-12). Only four brief reports have been published. It is unclear whether two reports by the same group (Emrich et al. , 1984; Herholz et al., 1987) included some of the same patients. One study of anorexics found caudate hypermetabolism (Herholz et al., 1987) while another found nonsignificantly lowered metabolism (Emrich et al. , 1984) and another found a normal level (Krieg, Lauer, Leinsinger et aL , 1989). One study of underweight bulimics found frank caudate hypometabolism (Rooney et al., 1988) while another study of normal-weight bulimics did not (Wu et al. , 1990). One study of anorexics found temporal cortex hypermetabolism (Herholz et al., 1987) while the two others found normal to high levels. One study of anorexics (Emrich et al., 1984) found nonsignificantly elevated metabolism of the frontal cortex, but the two other studies of anorexics found no such trend. None of the studies found abnormal hypothalamic rates. Both studies of bulimics found what seems a significant right hemisphere (mostly posterior) hypometabolism. This trend was not observed in the other studies of nonbulimic anorexics. The general tendency was for the large majority of brain areas to be in the normal metabolic range with no indication of hy-


pometabolism---despite the presence of brain atrophy in a number of patients. One PET scan study found that brain metabolism returned to normal upon renourishment (Herholz et al. , 1987), while a single photon emission tomography scan study observed no deviation from normal prior to or during renourishment (Krieg, Lauer, Leinsinger et aL, 1989).

The now-confirmed finding of right hemisphere hypometabolism in bulimia is particularly important. It is consistent with most of the data from other sources suggesting cortical dysfunction and it seems remarkably salient. Consider, for example, that no right-left asymmetries have been found in PET scan studies of a now well-recognized right hemisphere disorder, namely depression (Baxter et al. , 1985; Buchsbaum et al. , 1984).

THE NEUROPSYCHOLOGY OF ANOREXIA NERVOSA

Restricting Anorexics

Neuropsychological testing comprises the advantage of favoring identification of subtle cortical dysfunction below anatomically or physiologically detectable threshold. Deficit patterns may be suggestive of dysfunction of relatively specific brain systems. On the whole, the most frequently reported and the least reversible neuropsychological deficits of restricting anorexics are in the domain of visuospatial, and to a lesser extent, somatospatial perception (Fox, 1981; Maxwell et al. , 1984; Rovet et al. , 1988; Witt et al. , 1985). In a study of 20 restricting anorexics and 15 bulimics, Touyz et al. (1986) found slightly above average IQ and academic performance in both groups. The Trail Making Test appeared normally performed by both groups. However, the Benton Visual Retention Test seemed slightly below norm in the restricting anorexics (10.53% were frankly impaired). Impairment of memory functions and information processing speed seems to occur frequently as a function of emaciation but these functions recover after renourishment (Rovet et al. , 1988). Verbal functions, especially overlearned school-oriented performances, are never disturbed in restricting anorexics or bulimics (Fox, 1981; Hamsher et al. , 1981; Tucker et al. , 1981; Maxwell et al. , 1984; Witt et al. , 1985; Strupp et al. , 1986; Rovet et al. , 1988; Rooney et al. , 1988). Rovet and colleagues (1988) recently observed abnormal lateralization on experimental cognitive tasks and on neuropsyc h o l o gi ca l tes t s , p ar t icu lar ly in t h e v i suospat ia l m o d al i ty . Neuropsychological profiles (low scores on the Benton Visual Retention Test, on Performance-IQ, on nonverbal tachistoscopic tasks) have been interpreted as evidence of predominantly posterior right hemisphere dysfunction (Fox, 1981; Maxwell et al. , 1984; Rovet et al. , 1988). Though Raven's


Progressive Matrices test has never been shown to be differentially sensitive to localized brain dysfunction, it does include a heavy visuospatial component. Smart et al. (1976) found that restricting anorexics were slightly above average on this test. It must be noted also that frontal (executive) functions have not been exhaustively investigated as of yet in restricting anorexics though resistance to interference on traditional Stroop tasks has recently been reported to be normal (Ben-Tovim et al. , 1989; Channon et al., 1988). The effect of acute or even stabilized starvation on performance on cognitive tests is, of course, a matter of very legitimate concern. This issue has only been addressed weakly in the neuropsychological studies of restricting anorexics. Three studies found similar results for small subgroups of underweight and renourished restrictors (Maxwell et al. , 1984; Rovet et al. , 1988; Strupp et al., 1986). Witt and colleagues (1985) found no relationship between neuropsychological test performance and percent weight loss in their restrictors--all of whom were underweight. Fox (1981 ) and Touyz et al. (1986) made no attempt to estimate the effect of starvation per se in their underweight restricting subjects. Hamsher et al. (1981 ) found that several deficits persisted after renourishment.

Finally, a very recent report that is by far the most methodologically outstanding of neuropsychological investigations is worthy of detailed review. Pendelton-Janes and her colleagues (1991) assessed 30 underweight restricting anorexics, 20 weight-restored restricting anorexics, 38 normalweight bulimics, and 39 well-matched normal controls using 29 neuropsychologial measures. They found that weight-restored restricting anorexics were impaired only on a factor that they named "focussing/execution," comprising Digit Symbol, Trail Making and Letter Cancellation tests. Their performances on factors named "vigilance," "verbal ," "memory," and "visuospatial" were spared. The underweight restricting anorexics were impaired on all factors except "vigilance," a factor comprising Continuous Performance Test measures.

Bulimics

In neuropsychological investigations of bulimics, McKay and colleagues (1986) found a significant impairment on the right frontal scale of the Luria Nebraska Neuropsychological Battery (LNNB). A recent study by Beatty et al. (1990) also obtained results compatible with a right frontal disorder. They compared 32 bulimics to 14 depressives and 42 normal control subjects. They administered (1) the Symbol Digit Modalities Test, (2) a word fluency test using letters and (3) another using animal, fruit, and body-part categories, (4) a design fluency test, (5) a Brown-Peterson type


verbal memory task, (6) and a task resembling the Rey Auditory Verbal Learning task. The bulimics and depressives were impaired only the last task. However, the bulimics manifested 3-4 times more rule-breaking behavior than the other two groups on only one task, namely design fluency (p < 0.05). The authors did not interpret this neuropsychologically, and simply attributed it to "impulse disturbance." However, patients with right frontal lobectomy manifest such rule-breaking behavior even more significantly than design inertia (Jones-Gotman and Milner, 1977). Besides, since one would postulate dysfunctional right frontal overactivation in bulimia, sluggish design fluency should perhaps not be expected to occur as much as "positive" indicators of dysfunction in this lobe. This is not wholely incompatible with the finding of Rooney and colleagues (1988) of normal performance of bulimics on the Wisconsin Card Sorting Test (preservative error score) and Stroop test, which draw most upon left frontal lobes. However, deficits found in the latter study also suggest a right (posterior) disorder since impairments were observed only on the Benton Visual Retention Test, the Serial Digits Test, and a Continuous Performance Test of vigilance (p < 0.035, one tailed).

In the study carried out by Pendleton-Jones and colleagues ( 1991), the group of normal-weight bulimics was unimpaired on all five of the factors outlined in the preceding section.

Attention and Vigilance Deficits in Anorexia and Bulimia

Finally, Strupp and colleagues (1986) designed their investigation to determine whether automatic cognitive processing is more impaired than the effortful sort in anorexia nervosa. This was indeed the case, and was interpreted as a cognitive style of anorexics consisting of a tendency to massively mobilize attention in a narrow focused intentional "compulsive" range leaving impaired "incidental, automatic, unconscious, unfocussed" processing. This interpretation of a specific form of "automatic" attention deficit recently received independent support from a study published by Laessle et a!. (1989). Groups of anorexics with (N = 17) or without (N =

22) bulimia were impaired on a degraded-stimulus continuous-performance vigilance task lasting 8 minutes. The task was a go-no-go reaction time task. Both "hit" and "miss" errors were significantly higher in the clinical than control groups, and significantly increased over time in the clinical groups, suggesting a true vigilance impairment. Though half the subjects had cerebral atrophy, this was not correlated with vigilance performance. Rooney and colleagues (1988) also found an impairment of vigilance in bulimics, as mentioned previously. It is also highly relevant to this hypothe-


sis to consider the extent to which, in various neuropsychologial investigations, the most effort-demanding "attentional" tasks were preserved--or even "superior" in anorexics. In the study by Rovet and colleagues the anorexics were well above norm on a verbal fluency task. The Stroop task has always been found to indicate preserved function. Fox (1981) found that her anorexic subjects performed significantly better than controls on the Digit Symbol subtest of the Weschler Adult Intelligence Scale.

In the study carried out by Pendleton-Jones and colleagues (1991), large groups of underweight and weight-restored restricting anorexics and normal-weight bulimics were all spared on measures of "vigilance" probably most akin to "automatic" attention. Furthermore both groups of restricting anorexics were impaired on the "focussing/execution" factor, a dimension probably most akin to the "effortfu1 attention" construct of Strupp and colleagues (1986). In short, the best neuropsychologial study carried out to date provides evidence against both the "right hemisphere impairment" and the "automatic cognitive processing impairment" hypotheses, but strongly supports the idea of neuropsychological impairment, independent of weight loss, in restricting anorexia, on tasks involving focused attention.

The neuropsychologial literature is still in its incipient stage. It is suggestive, but it is in no way definitive. Few of these studies included sufficient numbers of subjects. Control groups were nonexistent, or consisted of psychiatric patients, or were not matched for critical variables such as age, education, body weight, and especially socioeconomic status of parents, except for the study of Pendleton-Jones and colleagues (1991). Most studies could not support parametric statistical analysis. None of the studies used a complete established neuropsychological test battery such as the LNNB or the Halstead-Reitan Neuropsychological Battery except the study by McKay and colleagues (1986). None of the studies used a selection of tests that are most closely associated with hemilobe function, even though interpretations were advanced in these terms, including the study by Pendleton-Jones and colleagues (1991). Comorbidity and other neurologically relevant variables were not evaluated in sufficient detail in any of the studies. There was no systematic attempt to study the effect of renourishment prospectively.

DISCUSSION

Most of the brain-oriented data relevant to the syndrome of anorexia nervosa are compatible with, or strongly suggest (e.g., the EEG data), right hemispheric disturbance, which plays an etiological role in the syndrome.


The preceding review has focused only on brain-oriented aspects of the disorder and has purposely ignored issues of putative psychosocial etiology. To determine the relative strength of the brain-disorder etiology it will be worthwhile to briefly confront it with the major facts supporting arguments of psychosocial etiology.

Can the Etiology of Anorexia Nervosa Be Plausibly Posited to Consist Solely of Biological Variables or Solely of Psychosocial Variables?

Anorexia occurs disproportionately frequently in higher socioeconomic classes (Crisp et al., 1976; Herzog, 1982) and up to 10 times more frequently in certain professions such as ballet dancing (Garfinkel, 1981). Nine of ten anorexics are female (Farmer et al. , 1986). Anorexia nervosa seems to occur more frequently in industrialized consumer societies. While the feminine ideal is increasingly thin, the average weight of women is on the increase (Gardner et a/. , 1980). At the same time the incidence of anorexia nervosa has increased dramatically over the years (Szmukler, 1985) . Stressful life events, such as chronic illness or death of a parent or parental divorce, are linked to the onset of anorexia nervosa (Herzog, 1982; Schwabe et a!., 1981). Parents of bulimics are frequently (37%) obese (Herzog, 1982). Deliberate motives of self-starvation (fear of maturity, sometimes specifically of sexual maturity) have been clearly documented (Halmi et al., 1977). Psychotherapy has on several occasions been shown more efficient in promoting weight gain than antidepressive chemotherapy (Mitchell et al., 1990). Anorexics typically manifest high to very high academic achievement, which is higher than would be expected from their slightly above average (108-113) IQs, thus qualifying, according to Touyz et al. (1986), for the label of "overachievers." All of these facts suggest at least partial psychosocial etiology. However, this does not preclude the plausibility of biopathological etiology as well as social. Rather, it suggests that anorexia nervosa is a stress-related disorder. On the other hand, there is no evidence that neuropathological etiology is the sole cause of anorexia nervosa. Rather, most of the CNS abnormalities observed in restricting anorexia nervosa can easily be explained as an effect of starvation rather than a cause.

On the other hand, even the most conservative tally of findings of incidence of biologic disorder antedating self-starvation in anorexia nervosa leads to the conclusion that anorexia nervosa can have a neurological etiology. A high proportion of patients with Huntington's disease (HD) develop bulimia and become emaciated. Temporal-lobe epileptics seem to also be at risk for anorexia nervosa (far from as much as HD patients


however). Tumor, perhaps particularly the irritative, infiltrating, fast-expanding type, frequently leads to anorexia nervosa. It must be underscored, however, that many of the neurogenic cases of so-called bulimia may or may not show vomiting or laxative abuse, since this has not been carefully investigated. Neurogenic restricting anorexia may also consist more of loss of appetite than loathing of body fat. There are significant proportions of anorexics who, prior to self-starvation, have suffered from perinatal trauma or other types of CNS insult, have inherited or have vicariously acquired neuropsychiatric diseases (depression, obsessive-compulsive disorders, alcoholism, other impulse disorders), and have acquired or sometimes inherited abnormal electroencephalographic profiles and abnormal brain anatomy as seen on CT scans. Anorexia nervosa also appears strongly genetically transmissible in solo, i.e., without associated psychiatric disorders.

To summarize, data pertinent to etiology of anorexia nervosa suggest that the direct or immediate cause of the anorexic starvation compulsion or of bulimia is primarily psychosocial, and that inherited and acquired CNS pathology frequently (if not always) predisposes certain young women, subjected to stress, to become entrapped in a vicious circle of "addiction" to thinness, which in turn results in moderate-to-severe additional damage to the CNS, which in turn further aggravates the behavioral profile. In addition, a substantial number of cases with a pure neurogenic etiology certainly exist, but these may be atypical of the DSM-III-R syndromes of adolescence.

Is There a Coherent Set of Evidence for a Specific Contribution of Cortical Pathology in the Etiology of Anorexia Nervosa?

The Right Hemisphere Hypothesis

There are several lines of evidence that support the hypothesis of predominantly posterior right cortical pathological involvement in anorexia nervosa. In decreasing order of importance, these are the following: (1) Lateralization of EEG abnormalities, though rare, seems to virtually always dominate at right posterior leads. (2) Metabolic disorders are more frequently right hemispheric. (3) Body image distortion and depression are posterior right-hemisphere disorders, which are heavily associated with anorexia nervosa. (4) Idiopathic neurogenic anorexia results more frequently from right hemisphere lesions or foci. (5) Neuropsychological tests reveal visual and tactile spatial deficits that have been interpreted as posterior right hemisphere dysfunction. (6) Obsessive-compulsive disorders and stud-


ies on lateralization of serotonergic mechanisms also support the right hemisphere hypothesis although these may less specifically involve posterior cortex.

Some of the EEG abnormalities and the neuropsychological deficits mentioned just previously can be expected to have preceded weight loss and seem to manifest little or no recovery upon renourishment even though most may have resulted from weight loss and seem to recede with weight gain. Perhaps, then, the most plausible explanation of right hemisphere etiology would be the following: depressive right posterior cortical underactivation and further irritative (electrical, tumoral, chemical, vascular) disturbance of right-sided posterior cortex both independently contribute to distorted body image, which in turn further predisposes to extreme selfstarvation or brutal dieting practices in both the restricting and bulimic variants of anorexia. The proper test of this hypothesis would consist of applying brain electrical activity mapping (BEAM) or other types of topographical EEG spectral analysis to large series of consecutive cases of anorexia nervosa with and without body image distortion. A neuropsychological test battery with validated scales of hemi-lobe function, such as the LNNB, should also be administered. Such a study remains to be carried out. In the interim, researchers who have large banks of EEG recordings should reanalyze their data to determine whether right-sided pathological foci are indeed more frequent.

Frontal Lobe Involvement

The frontal lobes play an important role in appetite. However, not all anorexics have low appetite, though many certainly do. Loss of appetite would more l ikely be caused by frontal hypermetabolism than hypometabolism. Obsessive-compulsive disorder also presents with frontal hypermetabolism but not much impairment on "frontal" neuropsychological tests. In restricting anorexics the CT scan data reveal that frontal periventricular tissue is particularly atrophied. Metabolic scan studies are too preliminary to be conclusive, but there is evidence of mild frontal, perhaps more particularly cingulate, hypermetabolism. Both the CT and metabolic disturbances seem at least partially reversible, however. One neuropsychological study led its authors to the conclusion that bulimics have a right frontal dysfunction. Expansive lesions producing anorexia, which can also be irritative, are much more frequently located in the right than left anterior hemisphere.

Perhaps the most plausible explanation of frontal-lobe etiology in anorexia nervosa, then, is to consider dysfunctional hyperfrontality of two


independent type&-<>ne of which may cause Joss of appetite, the other of which may cause the compulsive ritualism surrounding food. A proper test of the "frontal" hypothesis would consist of BEAM, magnetic resonance imaging (MRI), neuropsychological, and metabolic evaluation of a large consecutive series of restricting and bulimic anorexics before and after renourishment.

Intriguingly, Kinsbourne and Bemporad (1984) had intuited both the posterior right-hemisphere and frontal dysfunction hypotheses by postulating the existence of anorexia nervosa of right frontal hypermetabolic and right posterior hypometabolic cortical dysfunction. This reasonable prediction has still not been adequately tested to this day, though evidence is slowly accruing in its favor.

Should a Distinction Be Made Between "Positive" and "Negative" Variants of Anorexia Nervosa?

Hughlings Jackson contributed the profound distinction between "negative" and "positive" syndromes in neurology-attributing the former to loss of brain tissue and the latter to irritation of brain tissue. The distinction has been explored in the neurological approaches to schizophrenia. It has been suggested that positive schizophrenics with numerous florid expressive symptoms (hallucinations, delusions, and/or emotional upheavals) have less severely atrophied brains and better performance on neuropsychological tests than negative schizophrenics who have psychomotor retardation, affective flattening, social withdrawal, and paucity of speech (Andreasen et al. , 1986; but see Raz, 1988, for a counterview). There is now good evidence that of starved anorexics it is the restrictors (negatives) rather than the starved bulimics (positives) who manifest most severe brain atrophy. Though restrictors also manifest EEG abnormalities, bulimics may manifest higher rates of paroxysmal disorder, dyscontrol, and impulsive life styles and "positive" clinical signs--including, of course, binging. To test the hypothesis of clearly demarcated negative and positive subtypes of anorexia nervosa, it will be necessary to carry out investigations comparing large series of consecutively admitted, and repeatedly evaluated, starved and recovered restrictors and bulimics on EEG measurements, CT, or MRI scans and neuropsychological tests, and well-planned analysis of behavior patterns. An interesting additional line of investigation should consist of large-scale surveys of the side of the head at which migraine attacks occur. The ensemble of neurological evidence reviewed in this paper predicts a predominance of right-sided foci.


What Else Remains To Be Done in a Neurological Research Perspective?

It is important to keep in mind that metabolic concomitants of anorexia nervosa, say for example, those associated with depression vs. obsessive-compulsive disorder, may cancel out on certain measurements, leaving researchers with falsely inconclusive results. This is only one reason why it will be important in any metabolic, or even otherwise neurological or neuropsychological, investigation of anorexia nervosa to very carefully evaluate departure from ideal weight, depression, obsessive-compulsive disorder, behavioral agitation, presence of hinging, laxative abuse, vomiting, alcoholism, EEG abnormalities, cerebral atrophy, and body-image distortion, in each patient, and to determine the extent of relationship between these variables.

A top priority should consist of an adoption study of homozygotic twins. Until this is done, discussion about putative hereditary predisposition for anorexia nervosa will remain problematic. This is even more the case for anorexia nervosa than it was in the past for another disease with complex hereditary etiology, namely schizophrenia. Indeed, there is little doubt that a disturbed family can trigger anorexia more easily than it can schizophrenia. A follow-up to twin adoption studies should consist of biomolecular research into the chromosomal locus of the disease-producing gene(s). A second priority should consist of postmortem brain histology performed on recovered anorexics. Martin (1955, 1958) carried out postmortem neurohistological study of 4 cases but none of these would classify as anorexic by DSM-III or DSM-III-R criteria. All his cases died of involuntary inability to retain food and probably suffered from some special neurological affliction. A third priority should consist of neuropsychological evaluation of restricting and bulimic anorexics.

PRIORITIES FOR NEUROPSYCHOLOGICAL RESEARCH INTO ANOREXIA NERVOSA

The psychometric profile of anorexia nervosa is a puzzle the complexity of which should not be underestimated. Neuropsychological deficits will be found on a background of high academic (and therefore cognitive) achievement and upper class family background. Lobular hypotheses (the right frontal overactivation/dysfunction hypothesis for bulimia, the right posterior underactivation/dysfunction hypothesis for restricting anorexia) will have to be further supported by means of wide ranging batteries of tests such as the Luria-Nebraska Neuropsychological Battery or large arrays of well-selected (lobe-specific) tests. As for any study attempting to evaluate


brain function in anorexia, all the critical relevant issues will have to be addressed (percent weight loss, subtyping, comorbidity, EEG, CT scan, etc.). Large groups of probands and control groups will have to be matched for age, education, departure from ideal body weight, and very importantly, socioeducational level of the parents.

One particular issue that has emerged from neuropsychological testing and that deserves more careful investigation is the proposal by Strupp and colleagues that effortful attention is spared and that automatic attention is impaired. This promising idea has not yet been tested with optimal methodology. Support for the hypothesis is presently based on tasks that differ in numerous respect such as stimulus, task, and response modalities. A proper task could consist, for example, of Posner's movement of attention paradigm (Posner et al. , 1984). It has been shown that when an abstract, centrally emplaced, probabilistic cue is used, effortful mobilization of attention into the cued hemispace occurs. When a salient and concrete laterally emplaced probabilistic cue is used, automatic mobilization of attention occurs (Jonides, 1981). These two conditions of a same paradigm would allow investigators to isolate the "automatic vs. effortful attention" construct from general reaction time (which is affected by starvation) from stimulus modality, task modality, and response modality.

Perhaps the most interesting line of neuropsychological investigation would be to combine hemispheric deficit hypotheses with fine-grained hypotheses about cognitive operations. For example, it would be reasonable to predict that the postulated deficit of automatic mobilization of attention in the Posner paradigm might be more manifest in the left hemifield. However, since most of the neuropsychological studies suggest a right hemisphere visuospatial deficit , tachistoscopic or computer-d ispensed visuospatial tasks could be expected to also reveal left hemifield deficits, especially in restricting anorexia. The right frontal deficit proposed for bulimia could also be further explored with experimental laboratory-type tasks. For example, a computerized task of subtle motor hemineglect could be devised. A simple way to operationalize this construct is simply to look at hand effects on tachistoscopic tasks such as the Posner task or other paradigms.

CONCLUSION

This review has attempted to show that brain-behavior relations are a key aspect of the anorexia nervosa syndrome. Complex dimensions of brain-behavior relations seem to contribute to various etiologies and out-


comes of the disease. An important role for neuropsychological research has been outlined.

Clearly, anorexia nervosa, in addition to being a psychosocial disturbance, is also a neuropsychological disorder. Clinical neuropsychology should be involved in the field of health care for anorexia nervosa at the level of (a) initial assessment, (b) ongoing management during treatment, and (c) evaluation of treatment outcome.

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Is Anorexia Nervosa a Neuropsychological Disease