Handbook of Eating Disorders - part 3 pps

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(1994) Positional cloning of the mouse obese gene and its human homologue [published erratum appears in Nature, 1995, Mar 30; 374 (6521), 479] [see comments]. Nature, 372 (6505), 425–432. CHAPTER 5 Basic Neuroscience and Scanning Martina de Zwaan Department of General Psychiatry, W ¨ ahringer G ¨ urtel, Wien, Austria SUMMARY Structural neuroimaging techniques: r There is sufficient evidence of a relationship between eating disorders and altered brain structures. r Morphological brain alterations are most likely a consequence of endocrine and metabolic reactions to starvation, regardless of whether starvation leads to an underweight state (‘pseudoatrophy’). r However, there are individual cases in whom the brain alterations continue to exist. r Improvement in MRI technique will shed more light on the regional distribution of structural brain abnormalities. Functional neuroimaging techniques: r The functional abnormalities may be partly secondary to weight loss but may also reflect underlying primary brain dysfunction. r Cognitive activation and symptom provocation paradigms might elucidate typical brain activation patterns in eating disorder patients. r Re-assessment should be performed upon recovery to determine if the structural and functional abnormalities are strictly secondary to the abnormal eating behavior or related to underlying traits. r The enormously rapid development of new technology in structural and functional neuroimaging techniques will allow more precise observation of the brain. Serotonin activity: r Disturbances of brain serotonin activity have been described in patients with anorexia nervosa and bulimia nervosa. r Whether abnormalities are a consequence or a potential antecedent of pathological eating behavior remains a major question. Handbook of Eating Disorders. Edited by J. Treasure, U. Schmidt and E. van Furth. C  2003 John Wiley & Sons, Ltd. 90 MARTINA DE ZWAAN r There are distinct differences in serotonin activity between recovered and ill patients with anorexia or bulimia nervosa (challenge tests, CSF 5-HIAA). r It cannot be ruled out that subjects at risk of an eating disorder might have trait abnormalities in the regulation of brain serotonin function that might make them vulnerable to abnormal eating behavior (as a way to ‘treat’ abnormal serotonin activity) or to dieting- induced decreases in plasma tryptophan. r In addition, a disturbance of serotonin activity may also explain associated psychopatho- logical features (e.g. obsessionality, depression) that are common to both anorexia and bulimia nervosa. Other neurochemicals: r Altered regulation in several neurotransmitter systems (e.g. dopamine) may contribute to the disorder. NEUROIMAGING The correlations between eating disorders and brain abnormalities are best assessed using neuroimaging techniques, both structural and functional. Structural techniques assess brain anatomy and include computerised tomography (CT) and magnetic resonance imaging (MRI). Functional techniques assess brain physiology and chemistry and include positron emission tomography (PET), single photon emission tomography (SPECT), magnetic resonance spectroscopy (MRS) and functional magnetic resonance imaging (fMRI). Structural Imaging CT and MRI Krieg et al. (1986, 1987) reported that 82% of patients with anorexia and 46% of patients with bulimia show one or more morphological brain alteration. The most consistent finding in the brains of patients with anorexia nervosa has been an enlargement of the external CSF spaces (sulcal widening) and, less frequently, internal CSF spaces (ventricular enlargement); both have been shown to be largely reversible after weight gain (‘pseudoatrophy’) (e.g. Golden et al., 1996; Swayze et al., 1996). See Table 5.1. The findings for patients with bulimia nervosa are less consistent, with some studies showing no morphological changes (Lakenau et al., 1985) while others show sulcal widening and ventricular enlargement (Krieg et al., 1987). Other findings using MRI have included a mild atrophy of the thalamus and midbrain area in patients with anorexia nervosa (Husain et al., 1992) and a decrease in pituitary size in patients with both anorexia nervosa and bulimia nervosa (Doraiswamy et al., 1990). Katzman et al. (1996) reported an MRI study showing that adolescent patients with anorexia nervosa had significant reductions in both total gray matter and total white matter volumes when compared to healthy controls. The authors observed that these abnormalities were present in adolescents with relatively short duration of illness. BASIC NEUROSCIENCE AND SCANNING 91 Table 5.1 Results of CT and MRI studies in patients with eating disorders r Enlargement of external CSF spaces (enlargement of cortical sulci, narrowing of the gyri) r Enlargement of internal CSF spaces (ventricular enlargement) r Decreased total gray matter volume r Decreased total white matter volume r Mild atrophy of the thalamus and midbrain area r Reduced pituitary size Since a considerable number of normal-weight bulimic patients display the same kind of sulcal widening as anorexic patients, malnutrition cannot be the only explanation for these structural brain abnormalities. However, bulimic patients show low T 3 and elevated β-HBA values as a consequence of intermittent starvation. Hypercortisolemia may contribute di- rectly to the brain abnormalities. Hypercortisolism is a common finding in eating disorders and similar structural brain changes can be found in patients with Cushing syndrome and those taking corticosteroids (Table 5.2). As mentioned previously, the abnormalities are usually reversible with weight restoration; however, there are individual cases in whom the brain alterations continue to exist unaltered over a period of one year after the body weight has returned to normal. Change that persists might be due to residual damage of the brain (‘scar’) or persistent abnormal metabolism. The results of neuropathologic examinations of patients who died of anorexia nervosa revealed ventricular enlargement, but also neuronal loss and gliosis in the cerebral cortex. However, persistence of changes might also be a consequence of comorbid disorders such as alcoholism. Even though there is no good evidence for a primary structural deficit, this possibility for explaining a persistent brain alteration can not be completely excluded. Technological advances in MRI should shed more light on the regional distribution of tissue shrinkage. From a clinical standpoint, CT and MRI are useful for identifying structural lesions involving the hypothalamus which have been reported in emaciated patients (‘diencephalic Table 5.2 Significant clinical correlates with CT and MRI findings Positive correlations between r serum/urinary cortisol and total/cortical CSF volumes r lowest BMI and total gray matter volumes r serum creatinine and total/cortical gray matter volumes r total protein and central gray matter volume Negative correlations between r urinary free cortisol and central gray matter volumes r body weight and external CSF volumes r lowest BMI and total/external CSF volumes r T 3 (as a sign of starvation) and CSF volumes No correlations r estradiol, LH, FSH, prolactin r duration of illness r age 92 MARTINA DE ZWAAN wasting’), but such cases are extremely rare. Both CT and MRI should be used clinically in patients who have atypical symptoms of eating disorders such as food aversions without body image disturbances (Swayze, 1997). Functional Imaging These techniques allow the identification of possible brain dysfunction even where there are no structural changes. Currently, SPECT, PET, MRS and fMRI have only research applications for patients with eating disorders. PET and SPECT require the introduction of manufactured radioactive compounds. The major advantage of SPECT over PET is the longer half-lives of SPECT’s isotopes, which do not require an on-site cyclotron. A major disadvantage is that SPECT has poorer image resolution than PET. Positron Emission Tomography Most PET studies of eating disorders have evaluated glucose metabolism (metabolic rate, blood flow) with the use of 18-fluorodeoxyglucose (FDG). At rest with eyes closed, patients with anorexia nervosa usually present an absolute global and regional hypometabolism of glucose. However, this can also be found in low-weight patients with depression and is most likely a consequence of starvation since it disappears after weight gain. Most recently regional cerebral blood flow (rCBF) was investigated using PET in 9 women in long-term recovery from BN (Frank et al., 2000). There were no differences between bulimics and controls, suggesting that alterations in rCBF during the ill state of bulimia nervosa may be a state-related phenomenon. Both, anorexic and normal-weight bulimic patients have been shown to have relative parietal hypometabolism which persisted after weight gain in some anorexic patients (Delvenne et al., 1995, 1997a, 1997b, 1999). The authors hypothesise that this might be a characteristic of eating disorders, a primary cerebral dysfunction, which may be related to distortions of body image. However, it might also be a particular sensitivity of this cortical region to nutritional factors. In their most recent study Delvenne et al. (1999) found that patients with anorexia nervosa showed an increased relative glucose metabolism in the inferior frontal cortex and in the basal ganglia compared to controls, confirming the finding by Herholz et al. (1987). This might be due to a more pronounced reduction in cortical than in basal ganglia glucose metabolism and may be related to increased vigilance or anxiety in patients compared to controls. Two studies of glucose metabolism in bulimia applied PET scans together with cognitive activation tasks which stimulate particular regions of brain activity (Wu et al., 1990; Andreason et al., 1992). Bulimics showed an abnormal hemispheric lateralization (left greater than right hemispheric asymmetry as opposed to healthy controls in whom right is greater than left) in the parietotemporal region and parts of the frontal lobes, which ap- peared to be independent of the mood state (similar findings were reported for depression and OCD). It is an open question whether the loss of normal right activation in some areas has a role in the aetiology of this disorder. Another option is symptom provocation studies, which have already been performed in patients with anxiety disorders. In healthy subjects the confrontation with desirable food BASIC NEUROSCIENCE AND SCANNING 93 stimuli was associated with decreases in left temporo-insular cortical blood flow (Gordon et al., 2000). Further studies are needed to elucidate brain activity patterns in patients with eating disorders using the same provocation paradigms. Specific ligands for serotonin and dopamine sites can be utilised to clarify the involvement of these neurotransmitter systems in eating disorders. Data of PET with altanserin, a serotonergic ligand that binds to 5-HT 2a receptors, in 9 women who had recovered from bulimia nervosa versus 12 normal controls, have shown reduced 5-HT 2a binding in the medial orbital frontal cortex, an area involved in regulating emotional and impulse control (Kaye et al., 2001). A study in 16 women recovered from anorexia nervosa versus 23 controls demon- strated significantly reduced altanserin binding in mesial temporal and cingulate cortical regions (Frank et al., 2002). These studies suggest that altered 5-HT neuronal system activity may persist after recovery from BN or AN. Single Photon Emission Tomography SPECT is a functional imaging technique that is mainly used for studies of regional cerebral blood flow (rCBF). SPECT studies in adults with eating disorders have been inconclusive. Krieg et al. (1989) reported no change in regional blood flow in patients with anorexia nervosa before and after eating or when compared with a control group. Nozoe et al. (1993) reported an increase in rCBF in response to food intake in the left inferior frontal cortex in patients with anorexia nervosa. Gordon et al. (1997) showed unilateral temporal lobe hypoperfusion in 13 out of 15 children and adolescent patients with anorexia nervosa. The authors speculate as to whether this is a primary finding since temporal lobe hypoperfusion persisted in three patients who had regained normal weight. Furthermore, changes in the brain secondary to starvation would be expected to produce global and symmetrical changes. SPECT can also be used to study neurotransmitter systems. In addition to those compounds used for measuring blood flow, iodine labeled ligands for the muscarinic, dopamin- ergic, and serotonergic receptors can be used. [ 123 ]Beta-CIT SPECT studies are used to investigate the availability of brain serotonin transporters (SERT) and dopamine transporters (DAT). Tauscher et al. (2000) performed scans in 10 medication-free, bulimic patients and 10 age-matched controls. They found a 17% reduced SERT availability in hypothalamus and thalamus and a similar reduction in striatal DAT availability. In addition, there was a negative correlation between illness duration and SERT availability. As with other alterations it remains unclear whether reduced SERT availability might be an etiologic defect, adaptive mechanism or an unrelated epiphenomenon of another etiologic lesion. Functional Magnetic Resonance Imaging fMRI studies offer an important opportunity to look at cognitive processing. Ellison et al. (1998) studied cerebral blood oxygenation changes with fMRI in six adult patients with anorexia nervosa and six healthy controls. Images were obtained while the participants viewed a 5-minute videotape that showed pictures of labelled high and low calorie drinks. 94 MARTINA DE ZWAAN The group with anorexia nervosa showed more extreme and powerful signal changes in response to the contrasting stimuli, especially in the left insula, anterior cingulate gyrus and left amygdala–hippocampal region. Anxiety was also rated and found to be much higher in the anorexic group when viewing the high calorie drinks. The authors suggest that the left amygdala–hippocampal region may mediate conditioned fear of high calorie foods and that the insula and anterior cingulate may be involved in autonomic arousal and attentional processes. Magnetic Resonance Spectroscopy With MRS a wide range of metabolic processes can be studied. Roser et al. (1999) found that patients with anorexia nervosa showed a decrease in myo-inositol (by 15%) and lipid compounds (by 50%) within the frontal white matter. Interestingly, myo-inositol is a metabolite which is found in reduced levels also in patients treated with corticosteroids. The concen- tration was further reduced with decreasing BMI. Again, the metabolic changes seem to be a consequence of nutritional deficiency and hormonal changes typical in patients with anorexia nervosa. The authors could not find evidence for neuronal degeneration or damage. NEUROTRANSMITTER SYSTEMS Central Nervous System Serotonin Activity Brain serotonin (5-HT) systems (Table 5.3) play a role in the modulation of appetite, depression, anxiety, impulse control, obsessionality, and neuroendocrine function. Central serotonin pathways, particularly involving the paraventricular nucleus of the hypothalamus, Table 5.3 Research methods of assessing serotonin function Pharmacological challenge strategy Administration of an agent (e.g. mCPP, fenfluramine, L-tryptophan) with serotonin-specific properties and the subsequent assessment of changes in behavior or hormonal release (e.g. prolactin). Measure of hypothalamic–pituitary neuroendocrine responsiveness Acute tryptophan depletion Methodology that induces a rapid and substantial lowering of plasma tryptophan levels and markedly reduces brain 5-HT synthesis in humans followed by the examination of behavioral responses (mood, urge to eat, food consumption) Platelet measures of serotonin function Peripheral measures of 5-HT activity as an indirect means of assessing central 5-HT function: 3 H-imipramine binding, platelet uptake of serotonin, serotonin-amplified platelet aggregation, serotonin-induced platelet calcium mobilization, 3 H-LSD binding, platelet MAO activity Precursor and metabolite studies Tryptophan levels and plasma TRP/LNAA ratio, CSF concentrations of 5-HIAA, the major metabolite of serotonin Treatment trials with serotonergic agents Serotonin antagonists (cyproheptadine), serotonin agonists (SSRIs) [...]... bulimia nervosa International Journal of Eating Disorders, 21, 31 3 32 0 Delvenne, V., Goldman, S., Simon, Y., De Maertalaer, V & Lotstra, F (1999) Brain glucose metabolism in eating disorders as assessed by positron emission tomography International Journal of Eating Disorders, 25, 29 37 Delvenne, V., Lotstra, F., Goldman, S., Biver, F., De Maertalaer, V., Appelboom-Fondu, J., Schoutens, A., Bidaut, L.M.,... the AAI, found that the majority of their eatingdisordered patients ( 13/ 14) were Unresolved (U) with respect to abuse or loss Many of these patients, however, had Axis II diagnoses in addition to the eating disorder, and so the finding is less specific The relatively low incidence of U in Candelori’s study (1 /36 ) is surprising, given that approximately 16 30 % of eatingdisordered patients have suffered... Bulletin, 102, 35 7 38 9 Parker, G., Tupling, H & Brown, L.B (1979) A parental bonding instrument British Journal of Medical Psychology, 52, 1–10 Salzman, J.P (1997) Ambivalent attachment in female adolescents: Association with affective instability and eating disorders International Journal of Eating Disorders, 21, 251–259 Schmidt, U.H., Tiller, J.M & Treasure, J (19 93) Setting the scene for eating disorders: ... Psychiatry, 176, 132 – 137 Stein, A (1995) Eating disorders and childrearing In K.D Brownell & C.G Fairburn (Eds), Eating Disorders and Obesity: A Comprehensive Handbook (pp 188–190) New York: Guilford Press Stein, A., Murray, L., Cooper, P & Fairburn, C (1996) Infant growth in the context of maternal eating disorders and maternal depression: A comparative study Psychological Medicine, 26 (3) , 569–574 Tanner,... Biological Psychiatry, 49, 32 6 33 2 Ward, A., Brown, N., Lightman, S., Campbell, I.C & Treasure, J (1998) Neuroendocrine, appetitive and behavioural responses to d-fenfluramine in women recovered from anorexia nervosa British Journal of Psychiatry, 172, 35 1 35 8 Weizman, R., Carmi, M., Tyano, S., Apter, A & Rehavi, M (1986) High affinity 3 H-imipramine binding and serotonin uptake to platelets of adolescent females... important influence than the direct effect of bottle feeding on infant growth Children’s perceptions of their parents’ health in turn impact on their feelings of security and their view of their own health and resilience The development of an external locus of control or a feeling of personal ineffectiveness may be particularly potent as risk factors for eating disorders Parental Attachment Status There... in the former Also the mothers with eating disorders were more concerned about their daughter’s weight from the age of 2 onwards At 5 years, the children of mothers with eating disorders had greater negative affect than controls Although most studies have shown that children of eatingdisordered mothers tend to be thinner than controls (Stein et al., 1996), a group of mothers in this study overfed their... attachment style and the development of eating disorders, followed by a review of non-attachment developmental influences ATTACHMENT AND EATING DISORDERS Historical Perspective Hilde Bruch, writing in the 1970s, linked emergent attachment ideas to her clinical observations In her seminal work, Eating Disorders: Anorexia Nervosa, Obesity and the Person Within (1974), she offers an unusual insight into Mary... the time of rating Findings specifically relating to a diagnosis of eating disorder (compared to other Axis I diagnoses) were a positive association with idealisation of attachment figures on the State of Mind score, and low Reflective Self-Functioning The authors comment that idealisation of parents echoes the clinical observation that patients with eating disorders are perfectionists whose eating disorder... prolongation of the binge–purge cycle (Kaye et al., 1988b) suggesting a self-medicating model of restoration of 5-HT activity With regard to platelet measures, high platelet 5-HT uptake, which may reflect increased 5-HT uptake at central nervous system synapses (Goldbloom et al., 1990) and decreased platelet 3 H-imipramine binding have been reported (Marazziti et al 1988) Others found evidence of an increased . 124 (8), 132 7S– 133 3S. Reidelberger, R.D. (1992) Abdominal vagal mediation of the satiety effects of exogenous and en- dogenous cholecystokinin in rats. Am. J. Physiol., 2 63 (6), R 135 4–R 135 8. Robbins,. measures of 5-HT activity as an indirect means of assessing central 5-HT function: 3 H-imipramine binding, platelet uptake of serotonin, serotonin-amplified platelet aggregation, serotonin-induced. International Journal of Eating Disorders, 21, 31 3 32 0. Delvenne, V.,Goldman, S., Simon, Y., De Maertalaer, V.& Lotstra, F. (1999) Brainglucose metabolism in eating disorders as assessed