Altered interoceptive activation before, during, and after aversive breathing load in women remitted from anorexia nervosa.

BACKGROUND: The neural mechanisms of anorexia nervosa (AN), a severe and chronic psychiatric illness, are still poorly understood. Altered body state processing, or interoception, has been documented in AN, and disturbances in aversive interoception may contribute to distorted body perception, extreme dietary restriction, and anxiety. As prior data implicate a potential mismatch between interoceptive expectation and experience in AN, we examined whether AN is associated with altered brain activation before, during, and after an unpleasant interoceptive state change. METHODS: Adult women remitted from AN (RAN; n = 17) and healthy control women (CW; n = 25) underwent functional magnetic resonance imaging during an inspiratory breathing load paradigm. RESULTS: During stimulus anticipation, the RAN group, relative to CW, showed reduced activation in right mid-insula. In contrast, during the aversive breathing load, the RAN group showed increased activation compared with CW in striatum and cingulate and prefrontal cortices (PFC). The RAN group also showed increased activation in PFC, bilateral insula, striatum, and amygdala after stimulus offset. Time course analyses indicated that RAN responses in interoceptive processing regions during breathing load increased more steeply than those of CW. Exploratory analyses revealed that hyperactivation after breathing load was associated with markers of past AN severity. CONCLUSIONS: Anticipatory deactivation with a subsequent exaggerated brain response during and after an aversive body state may contribute to difficulty predicting and adapting to internal state fluctuation. Because eating changes our interoceptive state, restriction may be one method of avoiding aversive, unpredictable internal change in AN.

Increased brain response to appetitive tastes in the insula and amygdala in obese compared with healthy weight children when sated.

OBJECTIVE: There is evidence of altered neural taste response in female adolescents who are obese (OB), and in adolescents who are at risk for obesity. To further understand risk factors for the development of overeating and obesity, we investigated response to tastes of sucrose and water in 23 OB and healthy weight (HW) children. METHODS AND DESIGN: Thirteen HW and 10 OB 8-12-year-old children underwent functional magnetic resonance imaging while tasting sucrose and water. Additionally, children completed an eating in the absence of hunger paradigm and a sucrose-liking task. RESULTS: A region of interest analysis revealed an elevated BOLD response to taste (sucrose and water) within the bilateral insula and amygdala in OB children relative to HW children. Whole-brain analyses revealed a group by condition interaction within the paracingulate, medial frontal, middle frontal gyri and right amygdala: post hoc analyses suggested an increased response to sucrose for OB relative to HW children, whereas HW children responded more strongly to water relative to sucrose. In addition, OB children, relative to HW, tended to recruit the right putamen as well as medial and lateral frontal and temporal regions bilaterally. CONCLUSION: This study showed increased reactivity in the amygdala and insula in the OB compared with HW children, but no functional differentiation in the striatum, despite differences in the striatum previously seen in older samples. These findings support the concept of the association between increased neural processing of food reward in the development of obesity, and raise the possibility that emotional and interoceptive sensitivity could be an early vulnerability in obesity.

Genetic neuropathology of obsessive psychiatric syndromes.

Anorexia nervosa (AN), bulimia nervosa (BN) and obsessive-compulsive disorder (OCD) are complex psychiatric disorders with shared obsessive features, thought to arise from the interaction of multiple genes of small effect with environmental factors. Potential candidate genes for AN, BN and OCD have been identified through clinical association and neuroimaging studies; however, recent genome-wide association studies of eating disorders (ED) so far have failed to report significant findings. In addition, few, if any, studies have interrogated postmortem brain tissue for evidence of expression quantitative trait loci (eQTLs) associated with candidate genes, which has particular promise as an approach to elucidating molecular mechanisms of association. We therefore selected single-nucleotide polymorphisms (SNPs) based on candidate gene studies for AN, BN and OCD from the literature, and examined the association of these SNPs with gene expression across the lifespan in prefrontal cortex of a nonpsychiatric control cohort (N=268). Several risk-predisposing SNPs were significantly associated with gene expression among control subjects. We then measured gene expression in the prefrontal cortex of cases previously diagnosed with obsessive psychiatric disorders, for example, ED (N=15) and OCD/obsessive-compulsive personality disorder or tics (OCD/OCPD/Tic; N=16), and nonpsychiatric controls (N=102) and identified 6 and 286 genes that were differentially expressed between ED compared with controls and OCD cases compared with controls, respectively (false discovery rate (FDR) <5%). However, none of the clinical risk SNPs were among the eQTLs and none were significantly associated with gene expression within the broad obsessive cohort, suggesting larger sample sizes or other brain regions may be required to identify candidate molecular mechanisms of clinical association in postmortem brain data sets.

Neurocognitive correlates of obesity and obesity-related behaviors in children and adolescents.

Childhood obesity rates have risen dramatically over the past few decades. Although obesity has been linked to poorer neurocognitive functioning in adults, much less is known about this relationship in children and adolescents. Therefore, we conducted a systematic review to examine the relationship between obesity and obesity-related behaviors with neurocognitive functioning in youth. We reviewed articles from 1976 to 2013 using PsycInfo, PubMed, Medline and Google Scholar. Search terms included cognitive function, neurocognitive function/performance, executive function, impulsivity, self-regulation, effortful control, cognitive control, inhibition, delayed gratification, memory, attention, language, motor, visuo-spatial, academic achievement, obesity, overweight, body mass index, waist-hip ratio, adiposity and body fat. Articles were excluded if participants had health problems known to affect cognitive functioning, the study used imaging as the only outcome measure, they were non-peer-reviewed dissertations, theses, review papers, commentaries, or they were non-English articles. Sixty-seven studies met inclusion criteria for this review. Overall, we found data that support a negative relationship between obesity and various aspects of neurocognitive functioning, such as executive functioning, attention, visuo-spatial performance, and motor skill. The existing literature is mixed on the effects among obesity, general cognitive functioning, language, learning, memory, and academic achievement. Executive dysfunction is associated with obesity-related behaviors, such as increased intake, disinhibited eating, and less physical activity. Physical activity is positively linked with motor skill. More longitudinal research is needed to determine the directionality of such relationships, to point towards crucial intervention time periods in the development of children, and to inform effective treatment programs.

Is season of birth related to disordered eating and personality in women with eating disorders?

We assessed the relation between season of birth and eating disorder symptoms and personality characteristics in a sample of 880 women with eating disorders and 580 controls from two Price Foundation Studies. Eating disorder symptoms were assessed using the Structured Interview of Anorexic and Bulimic Disorders and the Structured Clinical Interview for DSM-IV. Personality traits were assessed using the Temperament and Character Inventory and the Frost Multidimensional Perfectionism Scale. Date of birth was obtained from a sociodemographic questionnaire. No significant differences were observed 1) in season of birth across eating disorder subtypes and controls; nor 2) for any clinical or personality variables and season of birth. We found no evidence of season of birth variation in eating disorders symptoms or personality traits. Contributing to previous conflicting findings, the present results do not support a season of birth hypothesis for eating disorders.

Anorexia nervosa trios: behavioral profiles of individuals with anorexia nervosa and their parents.

BACKGROUND: Anorexia nervosa (AN) is associated with behavioral traits that predate the onset of AN and persist after recovery. We identified patterns of behavioral traits in AN trios (proband plus two biological parents). METHOD: A total of 433 complete trios were collected in the Price Foundation Genetic Study of AN using standardized instruments for eating disorder (ED) symptoms, anxiety, perfectionism, and temperament. We used latent profile analysis and ANOVA to identify and validate patterns of behavioral traits. RESULTS: We distinguished three classes with medium to large effect sizes by mothers' and probands' drive for thinness, body dissatisfaction, perfectionism, neuroticism, trait anxiety, and harm avoidance. Fathers did not differ significantly across classes. Classes were distinguished by degree of symptomatology rather than qualitative differences. Class 1 (approximately 33%) comprised low symptom probands and mothers with scores in the healthy range. Class 2 ( approximately 43%) included probands with marked elevations in drive for thinness, body dissatisfaction, neuroticism, trait anxiety, and harm avoidance and mothers with mild anxious/perfectionistic traits. Class 3 (approximately 24%) included probands and mothers with elevations on ED and anxious/perfectionistic traits. Mother-daughter symptom severity was related in classes 1 and 3 only. Trio profiles did not differ significantly by proband clinical status or subtype. CONCLUSIONS: A key finding is the importance of mother and daughter traits in the identification of temperament and personality patterns in families affected by AN. Mother-daughter pairs with severe ED and anxious/perfectionistic traits may represent a more homogeneous and familial variant of AN that could be of value in genetic studies.

Role of endocannabinoids and their analogues in obesity and eating disorders.

Fatty acids ethanolamides (FAEs) are a family of lipid mediators. A member of this family, anandamide, is an endogenous ligand for cannabinoid receptors targeted by the marijuana constituent Delta-9-tetrahydrocannabinol. Anandamide is now established as a brain endocannabinoid messenger and multiple roles for other FAEs have also been proposed. One emerging function of these lipid mediators is the regulation of feeding behavior and body weight. Anandamide causes overeating in rats because of its ability to activate cannabinoid receptors. This action is of therapeutic relevance: cannabinoid agonists are currently used to alleviate anorexia and nausea in AIDS patients, whereas the cannabinoid receptor CB1 antagonist rimonabant was recently found to be effective in the treatment of obesity. In contrast to anandamide, its monounsatured analogue, oleoylethanolamide (OEA), decreases food intake and body weight gain through a cannabinoid receptor-independent mechanism. In the rat proximal small intestine, endogenous OEA levels decrease during fasting and increase upon refeeding. These periprandial fluctuations may represent a previously undescribed signal that modulates between-meal satiety. Pharmacological studies have shown, indeed, that, as a drug, OEA produces profound anorexiant effects in rats and mice, due to selective prolongation of feeding latency and post-meal interval. The effects observed after chronic administration of OEA to different animal models of obesity, clearly indicate that inhibition of eating is not the only mechanism by which OEA can control energy metabolism. In fact, stimulation of lipolysis is responsible for the reduced fat mass and decrease of body weight gain observed in these models. Although OEA may bind to multiple receptors, several lines of evidence indicate that peripheral PPAR-alpha mediates the effects of this compound. The pathophysiological significance of OEA in the regulation of eating and body weight is further evidenced by preliminary clinical results, showing altered levels of this molecule in the cerebrospinal fluid and plasma of subjects recovered from eating disorders. These results complete previous observation on anandamide content, which resulted altered in plasma of women affected by anorexia nervosa or binge-eating disorder.

Serotonin transporter missense mutation associated with a complex neuropsychiatric phenotype.

Two common serotonin transporter (SERT) untranslated region gene variants have been intensively studied, but remain inconclusively linked to depression and other neuropsychiatric disorders. We now report an uncommon coding region SERT mutation, Ile425Val, in two unrelated families with OCD and other serotonin-related disorders. Six of the seven family members with this mutation had OCD (n=5) or obsessive-compulsive personality disorder (n=1) and some also met diagnostic criteria for multiple other disorders (Asperger's syndrome, social phobia, anorexia nervosa, tic disorder and alcohol and other substance abuse/dependence). The four most clinically affected individuals--the two probands and their two slbs--had the I425V SERT gene gain-of-function mutation and were also homozygous for 5'-UTR SERT gene variant with greater transcriptional efficacy.

Candidate gene analysis of the Price Foundation anorexia nervosa affected relative pair dataset.

The eating disorders are severe psychiatric illnesses with significant morbidity and mortality that exhibit statistically significant familial risk and heritability, providing support for a molecular genetic approach toward defining etiological factors. An emerging candidate gene literature has concentrated on serotinergic and dopaminergic candidates. With the financial support of the Price Foundation, a group of investigators initiated an international multi-center collaboration (Price Foundation Collaborative Group) in 1995 to study the genetics of anorexia and bulimia nervosa by collecting and analyzing phenotypes and genotypes of individuals and their relatives affected with eating disorders. The first sample of families collected by this collaborative group, known as the Price Foundation Anorexia Nervosa Affected Relative Pair (AN-ARP) dataset, was ascertained on an proband affected with Anorexia Nervosa (AN), with relative pairs affected with the eating disorders AN, Bulimia Nervosa or Eating Disorders Not Otherwise Specified [1]. Biognosis U.S., Inc. was founded to identify and characterize candidate susceptibility genes for anorexia and bulimia nervosa phenotypes in the Price Foundation eating disorder datasets. During 2000-2001, Biognosis U.S., Inc. developed and implemented a research program with a focus on the analysis of candidate genes nominated by neurochemical characteristics of eating disorder patients [2], serotonergic and dopaminergic candidate gene polymorphisms [3], neuroendocrine regulation of appetite [4], and by a positional hypothesis from a linkage analysis of the AN-ARP dataset [5]. This report reviews the anorexia nervosa candidate gene literature through 2001, the candidate gene research program implemented at Biognosis U.S., Inc. and selected candidate gene findings in the AN-ARP dataset derived from that research program.

Candidate genes for anorexia nervosa in the 1p33-36 linkage region: serotonin 1D and delta opioid receptor loci exhibit significant association to anorexia nervosa.

Serotonergic and opioidergic neurotransmitter system alterations have been observed in people with eating disorders; the genes for the serotonin 1D receptor (HTR1D) and the opioid delta receptor (OPRD1) are found on chr1p36.3-34.3, a region identified by our group in a linkage analysis of anorexia nervosa (AN). These candidate genes were evaluated for sequence variation and for linkage and association of this sequence variation to AN in family and case : control data sets. Resequencing of the HTR1D locus and a portion of the OPRD1 locus identified novel SNPs and confirmed existing SNPs. Genotype assay development and genotyping of nine SNPs (four at HTR1D and five at OPRD1) was performed on 191 unrelated individuals fulfilling DSM-IV criteria (w/o amenorrhea criterion) for AN, 442 relatives of AN probands and 98 psychiatrically screened controls. Linkage analysis of these candidate gene SNPs with 33 microsatellite markers in families including relative pairs concordantly affected with restricting AN (N=37) substantially increased the evidence for linkage of this region to restricting AN to an NPL score of 3.91. Statistically significant genotypic, allelic, and haplotypic association to AN in the case : control design was observed at HTR1D and OPRD1 with effect sizes for individual SNPs of 2.63 (95% CI=1.21-5.75) for HTR1D and 1.61 (95% CI=1.11-2.44) for OPRD1. Using genotype data on parents and AN probands, three SNPs at HTR1D were found to exhibit significant transmission disequilibrium (P&<0.05). The combined statistical genetic evidence suggests that HTR1D and OPRD1 or linked genes may be involved in the etiology of AN.

Eating-related concerns, mood, and personality traits in recovered bulimia nervosa subjects: a replication study.

OBJECTIVE: Limited data suggest that eating-related concerns and behaviors, disturbances in mood, and altered temperament persist following recovery from bulimia nervosa (BN). METHOD: In order to replicate and extend such findings, 11 women who were long-term recovered from BN (>1 year with no binging, purging, or restricting behaviors, normal weight, and regular menstrual cycles) were compared with 15 healthy volunteer women on the Eating Disorders Invertory-2 (EDI-2), the Beck Depression Inventory, the State Trait Anxiety Inventory, and the Multidimensional Personality Questionnaire (MPQ). RESULTS: Compared with the control women, the recovered BN women showed elevated levels of the EDI-2 subscales of Drive for Thinness, Body Dissatisfaction, Ineffectiveness, Perfectionism, and Social Insecurity, greater depression and anxiety, elevated levels of the MPQ Stress Reaction dimension and the higher-order factor of Negative Emotionality, and lower levels of the MPQ Well Being and Closeness dimensions. DISCUSSION: Core eating and weight-related concerns, dysphoric affect, social discomfort, and personality traits indicative of perfectionism persist following long-term recovery from BN.

Evidence for a susceptibility gene for anorexia nervosa on chromosome 1.

Eating disorders, such as anorexia nervosa (AN), have a significant genetic component. In the current study, a genomewide linkage analysis of 192 families with at least one affected relative pair with AN and related eating disorders, including bulimia nervosa, was performed, resulting in only modest evidence for linkage, with the highest nonparametric linkage (NPL) score, 1.80, at marker D4S2367 on chromosome 4. Since the reduction of sample heterogeneity would increase power to detect linkage, we performed linkage analysis in a subset (n=37) of families in which at least two affected relatives had diagnoses of restricting AN, a clinically defined subtype of AN characterized by severe limitation of food intake without the presence of binge-eating or purging behavior. When we limited the linkage analysis to this clinically more homogeneous subgroup, the highest multipoint NPL score observed was 3.03, at marker D1S3721 on chromosome 1p. The genotyping of additional markers in this region led to a peak multipoint NPL score of 3.45, thereby providing suggestive evidence for the presence of an AN-susceptibility locus on chromosome 1p.

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.

Altered response to meta-chlorophenylpiperazine in anorexia nervosa: support for a persistent alteration of serotonin activity after short-term weight restoration.

OBJECTIVE: Patients with anorexia nervosa (AN) have disturbances of appetite and behaviors, such as dysphoria, inhibition, and obsessions, that could be related to altered serotonin activity. To investigate such relationships, we administered meta-chlorophenylpiperazine (m-CPP), a relatively serotonin-specific drug. METHODS: To avoid the confounding effects of malnutrition or weight loss, we studied 12 patients with restricting-type AN between 5 and 17 days after a return to a normal weight and while on a stable dietary intake. We compared them to 12 healthy control women (CW). m-CPP was administered double blind and placebo controlled. RESULTS: Although weight restored, AN women had lower body weight and increased ratings for depression and obsessionality compared with CW. After m-CPP, AN women had an elevation in mood and a reduction in body image distortion when compared with placebo. After m-CPP, groups had similar cortisol, adrenocorticotropin (ACTH), and growth hormone responses whereas AN women had an uncertain reduction in prolactin response. DISCUSSION: These data support other studies that suggest that altered serotonin activity persists after weight restoration in AN patients. The finding that m-CPP temporarily improved mood and reduced body image distortions supports the hypothesis that altered serotonin activity may contribute to the pathophysiology of AN.

Physical and sexual abuse histories in patients with eating disorders: a comparison of Japanese and American patients.

Physical and sexual abuse among patients with eating disorders has been a focus of attention in Western countries, however, there is no study comparing the incidence of these factors in Western and Asian countries. Japanese subjects consisted of 38 patients with anorexia nervosa restricting type (AN-R), 46 patients with anorexia nervosa binge eating/purging type (AN-BP), 76 patients with bulimia nervosa purging type (BN) and 99 controls. Subjects from the USA consisted of 29 AN-R, 34 AN-BP and 16 BN. The Physical and Sexual Abuse Questionnaire was administered to all subjects. Minor sexual abuse such as confronting exhibitionism or being fondled by a stranger tended to be more prevalent among Japanese subjects, while victimization by rape or incest was more prevalent among USA subjects. Conversely, physical abuse history was similarly distributed across each diagnostic subgroup in both countries. Events related to physical abuse, such as an abusive family background, may contribute whether eating disorder patients are restricting or bulimic and regardless of culture.

Cognitive therapy, nutritional therapy and their combination in the treatment of bulimia nervosa.

BACKGROUND: This study compared the effectiveness of cognitive therapy (CT), nutritional therapy (NT), the combination of cognitive and nutritional therapy (CNT), against a control condition of support group (SG) in the treatment of bulimia nervosa. METHODS: One hundred female out-patients who fulfilled DSM-III-R criteria for bulimia nervosa were randomized to the four treatment groups. NT and CT were designed to cover different areas with minimal overlap, and CNT provided all of the features of both of these treatments. The control condition was conducted in a group self-help format. Each of the treatments lasted 14 weeks. RESULTS: All three active treatments as well as SG produced significant decreases in binge/vomit episodes. Intent-to-treat analysis found CNT and CT to be significantly more effective than SG in retaining subjects in treatment and completion of study, as well as in producing greater improvements in dysfunctional attitudes and self-control. CNT was superior to SG in achieving abstinence from bulimic behaviour. NT was superior to SG only in increase of self-control. Logistic regression found that the cognitive component, whether given alone or in conjunction with NT, and higher pre-treatment self-control scores were significant predictors for both completion of study and abstinence. CONCLUSION: CT (either alone, or in combination with nutritional therapy) remains the treatment of choice for bulimia nervosa. A treatment escalation approach should be tested for the treatment of bulimia with the more intensive and less widely available CT (with or without nutritional counselling) offered after patients have failed the less intensive and more widely available support group treatment.

The evolving genetic foundations of eating disorders.

Data described earlier are clear in establishing a role for genes in the development of eating abnormalities. Estimates from the most rigorous studies suggest that more than 50% of the variance in eating disorders and disordered eating behaviors can be accounted for by genetic effects. These high estimates indicate a need for studies identifying the specific genes contributing to this large proportion of variance. Twin and family studies suggest that several heritable characteristics that are commonly comorbid with AN and BN may share genetic transmission with these disorders, including anxiety disorders or traits, body weight, and possibly major depression. Moreover, some developmental research suggests that the genes involved in ovarian hormones or the genes that these steroids affect also may be genetically linked to eating abnormalities. Molecular genetic research of these disorders is in its infant stages. However, promising areas for future research have already been identified (e.g., 5-HT2A receptor gene, UCP-2/UCP-3 gene, and estrogen receptor beta gene), and several large-scale linkage and association studies are underway. These studies likely will provide invaluable information regarding the appropriate phenotypes to be included in genetic studies and the genes with the most influence on the development of these disorders.

Altered serotonin 2A receptor activity in women who have recovered from bulimia nervosa.

OBJECTIVE: The authors' goal was to confirm that brain serotonin (5-HT) alterations are present in patients who have recovered from bulimia nervosa. Positron emission tomography imaging with [(18)F]altanserin was used to characterize binding of the 5-HT(2A) receptor, which might contribute to altered feeding, mood, or impulse control. METHOD: Nine women who had recovered from bulimia nervosa (they had no episodes of binge eating or purging, were at normal weight, and had regular menstrual cycles for more than 1 year) were compared with 12 female volunteers who had never had bulimia. RESULTS: The healthy volunteers, but not the women who had recovered from bulimia nervosa, had an age-related decline in 5-HT(2A) binding. Women who had recovered from bulimia nervosa had a reduction of medial orbital frontal cortex 5-HT(2A) binding. CONCLUSIONS: The lack of age-related changes in 5-HT activity is further evidence of 5-HT alterations in subjects who have recovered from bulimia nervosa. In addition, vulnerabilities for eating disorders, impulse dyscontrol, and mood disturbances may involve 5-HT and frontal lobe activity.

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.