A cross-sectional and follow-up voxel-based morphometric MRI study in adolescent anorexia nervosa.

The objective was to examine whether cerebral volumes are reduced, and in what regions, in adolescents with anorexia nervosa and to study changes after nutritional recovery. Twelve anorexia nervosa (DSM-IV) patients aged 11-17 consecutively admitted to an Eating Disorders Unit were assessed by means of psychopathological scales, neuropsychological battery and voxel-based morphometric (VBM) magnetic resonance imaging at admission and after 7 months' follow-up. Nine control subjects of similar age, gender and estimated intelligence level were also studied. The two groups showed differences in gray matter (F=22.2; p<0.001) and cerebrospinal fluid (CSF) (F=21.2; p<0.001) but not in white matter volumes. In anorexic patients, gray matter volume correlated negatively with the copy time from the Rey Complex Figure Test. In the regional VBM study several temporal and parietal gray matter regions were reduced. During follow-up there was a greater global increase in gray matter (F=10.7; p=0.004) and decrease in CSF (F=22.1; p=0.001) in anorexic patients. The increase in gray matter correlated with a decrease in cortisol (Spearman correlation=-0.73; p=0.017). At follow-up there were no differences in global gray matter (F=2.1; p=0.165), white matter (F=0.02, p=0.965) or CSF (F=1.8; p=0.113) volumes between both groups. There were still some smaller areas, in the right temporal and both supplementary motor area, showing differences between them in the regional VBM study. In conclusion, in adolescent anorexic patients gray matter is more affected than white matter and mainly involves the posterior regions of the brain. Overall gray matter alterations are reversible after nutritional recovery.

Brain tissue volume segmentation in patients with anorexia nervosa before and after weight normalization.

OBJECTIVE: To examine whether gray and white matter volumes are preferentially reduced and cerebral spinal fluid (CSF) increased with starvation in patients with anorexia nervosa compared with healthy controls and to determine what changes occur with weight normalization. METHOD: Whole intracranial volumes of patients and controls were segmented into gray matter, white matter, and CSF volumes and results compared. A subgroup of patients were rescanned after weight normalization. RESULTS: Total white matter and several regional white matter volumes were significantly reduced and total and regional CSF volumes were significantly increased in patients versus controls whereas gray matter was not significantly reduced. Total and regional CSF volumes were significantly decreased in patients upon weight normalization whereas white and gray matter volumes increased. DISCUSSION: These changes in brain tissue may be related to a variety of pathophysiologic mechanisms. We hypothesize that insulin-like growth factor-1 may be involved.

Reduced gastrin releasing peptide in cerebrospinal fluid after recovery from bulimia nervosa.

People with anorexia (AN) and bulimia nervosa (BN) have altered patterns of eating. It is possible that alterations of the neuropeptide gastrin releasing peptide (GRP), a bombesin (BBS) -like peptide with potent central anorexigenic activity, could contribute to disturbed eating behavior. To avoid the confounding effects of pathologic eating behavior, we measured cerebrospinal fluid (CSF) GRP concentrations in women who were long-term recovered (>1 year, normal weight, and regular menstrual cycles, no binging or purging) from AN (REC AN, N=12) or BN (REC BN, N=21) compared to healthy control women (NC, N=15). CSF GRP was significantly lower (chi(2)=9.41(3), p<0.01) in REC BN (9.6+/-3.1 pg/ml) compared to NC (13.4+/-5.5 pg/ml) and REC AN (11.6+/-2.9 pg/ml). Persistent GRP abnormalities after recovery from BN raise the possibility that this alteration might be trait-related and contribute to episodic hyperphagia in BN.

Could reduced cerebrospinal fluid (csf) galanin contribute to restricted eating in anorexia nervosa?

Galanin (GAL) and gamma amino butyric acid (GABA) are orexigenic neuropeptides that could contribute to the pathogenesis of anorexia nervosa (AN). To avoid the confounding effects of the ill state, we studied women who were recovered (> 1 year, normal weight, and regular menstrual cycles, no binging or purging) from AN (REC AN) and matched healthy control women (NC). CSF GAL was reduced in REC AN (64.4 +/- 8.6 pg/ml) compared to NC (72.0 +/- 11.6 pg/ml; p <.05), GABA was similar between groups. In the brain, GAL stimulates appetite and fat consumption. These data raise the question of whether alterations in brain GAL activity plays a role in clinical symptoms in AN, such as food restriction and fat avoidance.

Altered dopamine activity after recovery from restricting-type anorexia nervosa.

When ill, women with eating disorders have disturbances of mood and behavior and alterations of catecholamine activity. It is not known whether these alterations are cause or consequence of pathological eating behaviors. To avoid confounding effects of pathologic eating behavior, we studied women who were recovered (> 1 year, normal weight, regular menstrual cycles, no restricting eating pattern, no bingeing or purging) from anorexia nervosa (AN) and bulimia nervosa (BN) compared to healthy control women. Recovered AN women had significantly lower height-adjusted weight than did recovered BN women. CSF HVA (pmol/ml +/- SD), a major metabolite of dopamine, was significantly lower (p < .02) in six restricting-type AN women (131 +/- 49) compared to 19 BN women (216 +/- 73) and at a trend (p < .08) less than 13 bulimic-type AN women (209 +/- 53, p < .06) and 18 control women (202 +/- 57, p < .08). These four groups had similar values for CSF MHPG, a norepinephrine metabolite. Dopamine neuronal function has been associated with motor activity, reward, and novelty seeking. These behaviors are altered in restricting-type AN compared to other eating disorder subtypes. A trait-related disturbance of dopamine metabolism may contribute to a vulnerability to develop this sub-type of eating disorder.

Cerebrospinal fluid leptin in anorexia nervosa: correlation with nutritional status and potential role in resistance to weight gain.

Studies in rodents have shown that leptin acts in the central nervous system to modulate food intake and energy metabolism. To evaluate the possible role of leptin in the weight loss of anorexia nervosa, this study compared cerebrospinal fluid (CSF) and plasma leptin concentrations in anorexic patients and controls. Subjects included 11 female patients with anorexia nervosa studied at low weight and after treatment, and 15 healthy female controls. Concentrations of leptin in blood and CSF were measured by RIA. Patients with anorexia nervosa, compared to controls, had decreased concentrations of leptin in CSF (98 +/- 26 vs. 160 +/- 58 pg/mL; P < 0.0005) and plasma (1.75 +/- 0.46 vs. 7.01 +/- 3.92 ng/mL; P < 0.005). The CSF to plasma leptin ratio, however, was higher for patients (0.060 +/- 0.023) than for controls (0.025 +/- 0.007; P < 0.0001). At posttreatment testing, although patients had not yet reached normal body weight, CSF and plasma leptin concentrations had increased to normal levels. These results demonstrate the dynamic changes in plasma and CSF leptin during positive energy balance in anorexia nervosa. The results further suggest that normalization of CSF leptin levels before full weight restoration during treatment of anorexic patients could contribute to resistance to weight gain and/or incomplete weight recovery.

Cerebral gray matter and white matter volume deficits in adolescent girls with anorexia nervosa.

OBJECTIVES: This study was undertaken to determine whether the increased cerebrospinal fluid (CSF) volumes found in anorexia nervosa (AN) are the result of differences in gray matter or white matter volumes or both. METHODS: Thirteen adolescent girls with AN who were receiving inpatient care at a tertiary-care university children's hospital and eight healthy female control subjects were studied by using magnetic resonance imaging. Images were processed by means of software developed to classify all pixels as either CSF, gray matter, or white matter. Pixels of each class were then summed across all sections. RESULTS: The AN group had larger total CSF volumes in association with deficits in both total gray matter and total white matter volumes. Lowest reported body mass index was inversely correlated with total CSF volume and positively correlated with total gray matter volume. Urinary free cortisol levels were positively correlated with total CSF volume and inversely correlated with central gray matter volume. CONCLUSIONS: These findings add support to the view that the brain abnormalities found in AN are in large part the result of the effects of the illness. The extent to which these differences in gray matter and white matter volumes are reversible with recovery remains to be established.

Cerebrospinal fluid levels of kynurenine pathway metabolites in patients with eating disorders: relation to clinical and biochemical variable.

In brain, most L-tryptophan is metabolized to indoleamines, whereas in systemic tissues L-tryptophan is catabolized to kynurenine pathway metabolites. Among these latter compounds are: quinolinic acid, an N-methyl-D-aspartate receptor agonist; kynurenic acid, an antagonist of excitatory amino acid receptors that also reduces quinolinic acid-mediated neurotoxicity; and L-kynurenine, a possible convulsant. Because the metabolism of L-tryptophan through the kynurenine pathway is dependent upon adequate nutrition, we sought to determine whether the impaired nutrition characteristic of eating-disordered patients might be associated with specific disturbances in this metabolic pathway. Cerebrospinal fluid levels of L-tryptophan, quinolinic acid, kynurenic acid, L-kynurenine, and 5-hydroxyindoleacetic acid were measured in medication-free female patients meeting DSM-III-R criteria for either anorexia nervosa (n = 10) or normal-weight bulimia nervosa (n = 22), studied at varying stages of nutritional recovery. Eight healthy, normal-weight females served as a comparison group. Cerebrospinal fluid levels of kynurenic acid were significantly reduced in underweight anorectics, compared to normal females, but returned to normal values with restoration of normal body weight. Although cerebrospinal fluid quinolinic acid levels were not different from controls, the ratio of quinolinic acid to kynurenic acid was significantly increased during the underweight phase of anorexia nervosa. Furthermore, in the eating-disordered patients, kynurenic acid levels in cerebrospinal fluid correlated positively with percent-of-population average body weight.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebrospinal fluid TRH immunoreactivity in anorexia nervosa.

Central nervous system (CNS) thyrotropin-releasing hormone (TRH) activity is of interest in patients with anorexia nervosa. First, anorexics have peripheral thyroid abnormalities that appear to be related to weight and nutritional status. Second, CNS TRH activity may effect many other physiologic systems that are known to be disturbed in patients with anorexia nervosa. We found that anorexic patients, when both underweight and studied after attaining goal weight, had significantly reduced CSF TRH concentrations in comparison to controls. These data suggest that weight gain or increased caloric intake, in contrast to its large effect on peripheral thyroid function, has relatively little effect on CNS TRH activity. The reason for reduced CSF TRH in goal weight anorexics is not known but could be trait related, a persistent defect slow to normalize after weight gain, or related to these patients still being at a weight lower than controls. Finally, in terms of CSF TRH concentrations, this study suggests that anorexia nervosa has a different pathophysiology than major depressive disorder.

Relation of dissociative phenomena to levels of cerebrospinal fluid monoamine metabolites and beta-endorphin in patients with eating disorders: a pilot study.

Dissociation is made manifest by a failure to integrate thoughts, feelings, memories, and actions into a unified sense of consciousness. Although dissociation is presumed to be a special state of consciousness manifested by state-dependent memory and physiology, the psychobiology of dissociation is poorly understood. In this study, we examined cerebrospinal fluid levels of the major monoamine metabolites and beta-endorphin in patients with eating disorders (11 with anorexia nervosa, 16 with bulimia nervosa), while they were acutely ill. Dissociative capacity was measured using the Dissociative Experiences Scale (DES). We provide evidence that neurochemical changes in dopaminergic, serotonergic, and opioid systems may be associated with the clinical expression of dissociation in patients with eating disorders during the acute phase of their illness. These preliminary results are compatible with previous studies of neurochemical disturbances in the eating disorders and suggest that future work in dissociation should specifically include examination of these neurobiologic systems.

Altered serotonin activity in anorexia nervosa after long-term weight restoration. Does elevated cerebrospinal fluid 5-hydroxyindoleacetic acid level correlate with rigid and obsessive behavior?

To avoid the confounding influences of malnutrition or weight loss, we studied patients with anorexia nervosa at normal weight and stable dietary intake. Compared with 15 controls, 17 long-term weight-restored anorectic subjects had elevated concentrations of cerebrospinal fluid 5-hydroxyindoleacetic acid, the major serotonin metabolite, whereas levels of cerebrospinal fluid homovanillic acid, the major dopamine metabolite, were normal. Elevated levels of cerebrospinal fluid 5-hydroxyindoleacetic acid may indicate increased serotonin activity. Such activity could contribute to pathological feeding behavior. Most importantly, this study raises the question as to whether increased cerebrospinal fluid 5-hydroxyindoleacetic acid levels are associated with overly inhibited, anxious, or obsessive traits.

Measurement of CSF dynorphin A 1-8 immunoreactivity in anorexia nervosa and normal-weight bulimia.

Twenty-one patients with anorexia nervosa and 35 normal-weight patients with bulimia underwent a series of CSF studies involving measurement of CSF dynorphin A 1-8 immunoreactivity during hospitalization in an eating-disorder treatment and research program. The control group consisted of 17 healthy volunteers. There were no statistically significant differences in CSF dynorphin A 1-8 measurements among groups or within a group at various stages of treatment. These results regarding dynorphin A 1-8 immunoreactivity are discussed in light of other evidence for altered opiate function in some eating-disorder patients.

CSF oxytocin in anorexia nervosa and bulimia nervosa: clinical and pathophysiologic considerations.

Oxytocin is a hypothalamic neuropeptide with both centrally and peripherally directed pathways. Data from experimental animals indicate that oxytocin impairs consolidation of aversively conditioned behaviors and is released after feeding or experimental gastric distension. The authors report that the mean CSF oxytocin level of five underweight women with restricting anorexia, but not 12 underweight bulimic anorexic women or 35 normal-weight women with bulimia nervosa, was significantly lower than the level of 11 control subjects. Restricting anorexic patients' low CSF oxytocin levels may reflect their persistently low food intake, and this behavior may exacerbate their tendency for perseverative preoccupation with adverse consequences of food intake.

Altered cerebrospinal fluid neuropeptide Y and peptide YY immunoreactivity in anorexia and bulimia nervosa.

The related central nervous system peptides neuropeptide Y and peptide YY have been found to be among the most potent endogenous stimulants of feeding behavior. We measured these neuropeptides in cerebrospinal fluid to determine whether they contributed to the pathophysiologic characteristics of anorexia and bulimia nervosa. Cerebrospinal fluid neuropeptide Y concentrations were significantly elevated in underweight anorectic patients and in many of the anorectic patients studied at intervals after weight restoration. These levels normalized in long-term weight-restored anorectic patients who had a return of normal menstrual cycles. Increased neuropeptide Y activity may contribute to several characteristic disturbances in anorexia, including menstrual dysregulation. Cerebrospinal fluid peptide YY concentrations were significantly elevated in normal-weight bulimic patients abstinent from pathological eating behavior for a month compared with themselves when actively bingeing and vomiting or compared with healthy volunteers. Increased peptide YY activity may contribute to a drive to overfeed in normal-weight bulimic patients.

Central and peripheral ACTH and cortisol levels in anorexia nervosa and bulimia.

To explore the relationship of central and peripheral adrenocorticotropic hormone (ACTH, or corticotropin) levels to hypothalamo-pituitary-adrenal axis dysfunction in patients with eating disorders, levels of cerebrospinal fluid (CSF) and plasma ACTH, cortisol, and 24-hour urinary free cortisol were measured in 16 patients with anorexia nervosa (60% +/- 1.1% of ideal body weight), 14 patients with bulimia (93.2% +/- 4.6% of ideal body weight), and 11 healthy age-matched women volunteers. The CSF, plasma, and urinary free cortisol levels were elevated in underweight anorexic patients and showed declines following weight recovery. Cortisol-binding globulin levels were similar in anorexics and controls. In contrast, underweight anorexics showed low CSF ACTH levels that returned to normal following weight recovery, and their plasma ACTH levels were normal. On hospital admission, bulimic patients demonstrated normal ACTH and cortisol levels. After their abstinence from binge-purge episodes, the CSF ACTH levels decreased significantly. Positive relationships were found among CSF, plasma, and urinary cortisol levels, and inverse relationships were seen between cortisol measures and CSF ACTH levels in patients with eating disorders. Secretion of ACTH into the CSF may respond to feedback by cortisol or, alternatively, may be suppressed by the hypersecretion of corticotropin-releasing hormone, leading to the depletion of the pro-opiomelanocortin molecule.

Neurotensin-like immunoreactivity in cerebrospinal fluid of patients with schizophrenia, depression, anorexia nervosa-bulimia, and premenstrual syndrome.

Neurotensin (NT) concentrations in cerebrospinal fluid (CSF) were measured by a sensitive and specific radioimmunoassay in psychiatric patients and age- and sex-matched normal controls. No increase in CSF NT concentrations was observed after antipsychotic drug treatment. CSF NT concentrations were significantly lower in one group of schizophrenic subjects. NT concentrations were unaltered in patients with depression, anorexia/bulimia, or premenstrual syndrome, and no rostral-caudal gradient for NT in CSF was evident. NT concentrations were not related to age or sex, and probenecid treatment did not alter CSF NT concentrations. Finally CSF NT concentrations were unaltered in paranoid schizophrenic subjects. These findings confirm and extend previous studies of CSF NT that showed certain patients with schizophrenia, nonparanoid type, have reduced CSF concentrations of this tridecapeptide.

Cerebrospinal fluid peptide YY immunoreactivity in eating disorders.

Peptide YY (PYY), a recently discovered peptide, is a potent stimulant of eating behavior in rats. We developed a radioimmunoassay for PYY and measured cerebrospinal fluid (CSF) levels in subjects with anorexia nervosa, bulimia and matched normal controls. Bulimics who had abstained from bingeing for 30 days showed a dramatic increase in CSF PYY levels compared to normal values (p less than 0.001) or their own values when actively bingeing (p less than 0.01, paired t test). No differences were seen for anorexia nervosa. These results suggest that bulimic behavior may correct a central nervous system abnormality in PYY.