Fatty Acids and Their Lipogenic Enzymes in Anorexia Nervosa Clinical Subtypes.

Disordered eating behavior differs between the restricting subtype (AN-R) and the binging and purging subtype (AN-BP) of anorexia nervosa (AN). Yet, little is known about how these differences impact fatty acid (FA) dysregulation in AN. To address this question, we analyzed 26 FAs and 7 FA lipogenic enzymes (4 desaturases and 3 elongases) in 96 women: 25 AN-R, 25 AN-BP, and 46 healthy control women. Our goal was to assess subtype-specific patterns. Lauric acid was significantly higher in AN-BP than in AN-R at the fasting timepoint (p = 0.038) and displayed significantly different postprandial changes 2 h after eating. AN-R displayed significantly higher levels of n-3 alpha-linolenic acid, stearidonic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid, and n-6 linoleic acid and gamma-linolenic acid compared to controls. AN-BP showed elevated EPA and saturated lauric acid compared to controls. Higher EPA was associated with elevated anxiety in AN-R (p = 0.035) but was linked to lower anxiety in AN-BP (p = 0.043). These findings suggest distinct disordered eating behaviors in AN subtypes contribute to lipid dysregulation and eating disorder comorbidities. A personalized dietary intervention may improve lipid dysregulation and enhance treatment effectiveness for AN.

Soluble Epoxide Hydrolase Is Associated with Postprandial Anxiety Decrease in Healthy Adult Women.

The metabolism of bioactive oxylipins by soluble epoxide hydrolase (sEH) plays an important role in inflammation, and sEH may be a risk modifier in various human diseases and disorders. The relationships that sEH has with the risk factors of these diseases remain elusive. Herein, sEH protein expression and activity in white blood cells were characterized before and after a high-fat meal in healthy women (HW) and women with anorexia nervosa (AN). sEH expression and sEH activity were significantly correlated and increased in both groups two hours after consumption of the study meal. Fasting sEH expression and activity were positively associated with body mass index (BMI) in both groups, while an inverse association with age was found in AN only (p value < 0.05). sEH was not associated with anxiety or depression in either group at the fasting timepoint. While the anxiety score decreased after eating in both groups, a higher fasting sEH was associated with a lower postprandial anxiety decrease in HW (p value < 0.05). sEH characterization using direct measurements verified the relationship between the protein expression and in vivo activity of this important oxylipin modulator, while a well-controlled food challenge study design using HW and a clinical control group of women with disordered eating elucidated sEH's role in the health of adult women.

Habenular Involvement in Response to Subcallosal Cingulate Deep Brain Stimulation for Depression.

The habenula (Hb) is a small, evolutionarily conserved epithalamic structure implicated in functions such as reward and mood regulation. Prior imaging work suggests that Hb's structural and functional properties may relate to treatment response in depression and other mood disorders. We used multimodal MRI techniques to investigate the potential involvement of Hb in response to subcallosal cingulate area deep brain stimulation (SCC-DBS) for treatment-resistant mood disorders. Using an automated segmentation technique, we compared Hb volume at baseline and at a subsequent post-operative timepoint (4.4 ± 3.0 years after surgery) in a cohort of 32 patients who received SCC-DBS. Clinical response to treatment (≥50% decrease in HAMD-17 from baseline to 12 months post-operation) was significantly associated with longitudinal Hb volume change: responders tended to have increased Hb volume over time, while non-responders showed decreased Hb volume (t = 2.4, p = 0.021). We additionally used functional MRI (fMRI) in a subcohort of SCC-DBS patients (n = 12) to investigate immediate within-patient changes in Hb functional connectivity associated with SCC-DBS stimulation. Active DBS was significantly associated with increased Hb connectivity to several prefrontal and corticolimbic regions (TFCE-adjusted p Bonferroni < 0.0001), many of which have been previously implicated in the neurocircuitry of depression. Taken together, our results suggest that Hb may play an important role in the antidepressant effect of SCC-DBS.

Structuro-functional surrogates of response to subcallosal cingulate deep brain stimulation for depression.

Subcallosal cingulate deep brain stimulation produces long-term clinical improvement in approximately half of patients with severe treatment-resistant depression. We hypothesized that both structural and functional brain attributes may be important in determining responsiveness to this therapy. In a treatment-resistant depression subcallosal cingulate deep brain stimulation cohort, we retrospectively examined baseline and longitudinal differences in MRI-derived brain volume (n = 65) and 18F-fluorodeoxyglucose-PET glucose metabolism (n = 21) between responders and non-responders. Support vector machines were subsequently trained to classify patients' response status based on extracted baseline imaging features. A machine learning model incorporating preoperative frontopolar, precentral/frontal opercular and orbitofrontal local volume values classified binary response status (12 months) with 83% accuracy [leave-one-out cross-validation (LOOCV): 80% accuracy] and explained 32% of the variance in continuous clinical improvement. It was also predictive in an out-of-sample subcallosal cingulate deep brain stimulation cohort (n = 21) with differing primary indications (bipolar disorder/anorexia nervosa; 76% accuracy). Adding preoperative glucose metabolism information from rostral anterior cingulate cortex and temporal pole improved model performance, enabling it to predict response status in the treatment-resistant depression cohort with 86% accuracy (LOOCV: 81% accuracy) and explain 67% of clinical variance. Response-related patterns of metabolic and structural post-deep brain stimulation change were also observed, especially in anterior cingulate cortex and neighbouring white matter. Areas where responders differed from non-responders-both at baseline and longitudinally-largely overlapped with depression-implicated white matter tracts, namely uncinate fasciculus, cingulum bundle and forceps minor/rostrum of corpus callosum. The extent of patient-specific engagement of these same tracts (according to electrode location and stimulation parameters) also served as an independent predictor of treatment-resistant depression response status (72% accuracy; LOOCV: 70% accuracy) and augmented performance of the volume-based (88% accuracy; LOOCV: 82% accuracy) and combined volume/metabolism-based support vector machines (100% accuracy; LOOCV: 94% accuracy). Taken together, these results indicate that responders and non-responders to subcallosal cingulate deep brain stimulation exhibit differences in brain volume and metabolism, both pre- and post-surgery. Moreover, baseline imaging features predict response to treatment (particularly when combined with information about local tract engagement) and could inform future patient selection and other clinical decisions.

3T MRI of rapid brain activity changes driven by subcallosal cingulate deep brain stimulation.

Deep brain stimulation targeting the subcallosal cingulate area, a hub with multiple axonal projections, has shown therapeutic potential for treatment-resistant mood disorders. While subcallosal cingulate deep brain stimulation drives long-term metabolic changes in corticolimbic circuits, the brain areas that are directly modulated by electrical stimulation of this region are not known. We used 3.0 T functional MRI to map the topography of acute brain changes produced by stimulation in an initial cohort of 12 patients with fully implanted deep brain stimulation devices targeting the subcallosal cingulate area. Four additional subcallosal cingulate deep brain stimulation patients were also scanned and employed as a validation cohort. Participants underwent resting state scans (n = 78 acquisitions overall) during (i) inactive deep brain stimulation; (ii) clinically optimal active deep brain stimulation; and (iii) suboptimal active deep brain stimulation. All scans were acquired within a single MRI session, each separated by a 5-min washout period. Analysis of the amplitude of low-frequency fluctuations in each sequence indicated that clinically optimal deep brain stimulation reduced spontaneous brain activity in several areas, including the bilateral dorsal anterior cingulate cortex, the bilateral posterior cingulate cortex, the bilateral precuneus and the left inferior parietal lobule (PBonferroni < 0.0001). Stimulation-induced dorsal anterior cingulate cortex signal reduction correlated with immediate within-session mood fluctuations, was greater at optimal versus suboptimal settings and was related to local cingulum bundle engagement. Moreover, linear modelling showed that immediate changes in dorsal anterior cingulate cortex, posterior cingulate cortex and precuneus activity could predict individual long-term antidepressant improvement. A model derived from the primary cohort that incorporated amplitude of low-frequency fluctuations changes in these three areas (along with preoperative symptom severity) explained 55% of the variance in clinical improvement in that cohort. The same model also explained 93% of the variance in the out-of-sample validation cohort. Additionally, all three brain areas exhibited significant changes in functional connectivity between active and inactive deep brain stimulation states (PBonferroni < 0.01). These results provide insight into the network-level mechanisms of subcallosal cingulate deep brain stimulation and point towards potential acute biomarkers of clinical response that could help to optimize and personalize this therapy.

A pilot trial of repetitive transcranial magnetic stimulation of the dorsomedial prefrontal cortex in anorexia nervosa: resting fMRI correlates of response.

BACKGROUND: Patients with anorexia nervosa (AN) face severe and chronic illness with high mortality rates, despite our best currently available conventional treatments. Repetitive transcranial magnetic stimulation (rTMS) has shown increasing efficacy in treatment-refractory cases across a variety of psychiatric disorders comorbid with AN, including major depression, Obsessive Compulsive Disorder (OCD), and Post traumatic Stress Disorder (PTSD). However, to date few studies have examined the effects of a course of rTMS on AN pathology itself. METHODS: Nineteen patients with AN underwent a 20-30 session open-label course of dorsomedial prefrontal rTMS for comorbid Major Depressive Disorder (MDD) ± PTSD. Resting-state functional MRI was acquired at baseline in 16/19 patients. RESULTS: Following treatment, significant improvements were seen in core AN pathology on the EDE global scale, and to a lesser extent on the shape and weight concerns subscales. Significant improvements in comorbid anxiety, and to a lesser extent depression, also ensued. The greatest improvements were seen in patients with lower baseline functional connectivity from the dorsomedial prefrontal cortex (DMPFC) target to regions in the right frontal pole and left angular gyrus. CONCLUSIONS: Despite the limited size of this preliminary, open-label study, the results suggest that rTMS is safe in AN, and may be useful in addressing some core domains of AN pathology. Other targets may also be worth studying in this population, in future sham-controlled trials with larger sample sizes. TRIAL REGISTRATION: Trial registration ClinicalTrials.gov NCT04409704 . Registered May 282,020. Retrospectively registered.

Anorexia nervosa is a serious illness that is difficult to treat. New treatments are urgently needed. This paper describes a preliminary study of a potential new treatment for Anorexia Nervosa, transcranial magnetic stimulation. In this treatment a magnetic field is generated and applied from outside the skull to affect specific areas of the brain thought to be involved in Anorexia nervosa. The results of this preliminary trial, conducted with 19 subjects over 6 weeks, showed some improvements in the way people with Anorexia nervosa think about weight, shape and their eating. The benefits were associated with areas of the brain involved in decision making and in regulating emotions. These changes did not appear to be related to improvements in other conditions, such as depression.

Probabilistic Mapping of Deep Brain Stimulation: Insights from 15 Years of Therapy.

Deep brain stimulation (DBS) depends on precise delivery of electrical current to target tissues. However, the specific brain structures responsible for best outcome are still debated. We applied probabilistic stimulation mapping to a retrospective, multidisorder DBS dataset assembled over 15 years at our institution (ntotal = 482 patients; nParkinson disease = 303; ndystonia = 64; ntremor = 39; ntreatment-resistant depression/anorexia nervosa = 76) to identify the neuroanatomical substrates of optimal clinical response. Using high-resolution structural magnetic resonance imaging and activation volume modeling, probabilistic stimulation maps (PSMs) that delineated areas of above-mean and below-mean response for each patient cohort were generated and defined in terms of their relationships with surrounding anatomical structures. Our results show that overlap between PSMs and individual patients' activation volumes can serve as a guide to predict clinical outcomes, but that this is not the sole determinant of response. In the future, individualized models that incorporate advancements in mapping techniques with patient-specific clinical variables will likely contribute to the optimization of DBS target selection and improved outcomes for patients. ANN NEUROL 2021;89:426-443.

Characterizing Treatment-Resistant Anorexia Nervosa.

Background: The issue of treatment resistance in eating disorder care is controversial. Prior research has identified multiple failed treatment attempts as a common criterion for severe and enduring anorexia nervosa, but little is known about patients who have multiple failed treatment attempts. This study was designed to compare the clinical and demographic characteristics of eating disorder patients with multiple, incomplete inpatient admissions to those with good outcomes. Understanding if these patient populations differ at initial admissions has implications for the prediction and characterization of inpatient eating disorder treatment resistance. Methods: This study analyzed existing data from a specialist inpatient eating disorder program at a large Canadian teaching hospital collected between 2000 and 2016. Treatment resistance was defined as two or more incomplete admissions and no complete admissions in the study period. Data were available on 37 patients who met this criteria, and 38 patients who had completed their first admission and remained well (defined as a BMI > 18.5 with no binging or purging behavior) 1 year after discharge. Variables of interest included age, weight, diagnoses, duration of illness, eating disorder psychopathology, eating disorder behavioral frequencies and depressive symptoms at the time of index inpatient admissions. Statistical analyses consisted of Mann-Whitney U tests, Chi-square tests, and a logistic regression. Results: In our main bivariate analyses, patients with multiple incomplete admissions were characterized by more severe eating disorder psychopathology and depressive symptoms at admission as well as an increased prevalence of the binge purge subtype of anorexia nervosa. In our exploratory multivariate analyses controlling for diagnostic subtype and depressive symptoms, severity of eating disorder psychopathology did not remain significant. No statistically significant difference in body mass index (BMI) or frequencies of eating disorder behaviors were found. A trend toward a longer duration of illness did not meet statistical significance. Conclusions: This study found that patients considered resistant to inpatient eating disorder treatment differ from those with good outcomes at initial admission. These results suggest that while treatment-resistant anorexia nervosa may be related to severe and enduring anorexia nervosa, it may also be a different concept that warrants additional research.

Therapist adherence to family-based treatment for adolescents with anorexia nervosa: A multi-site exploratory study.

OBJECTIVE: This exploratory study is the first to examine family-based treatment (FBT) adherence and association to treatment outcome in the context of a large-scale, multi-centre study for the treatment of adolescents with anorexia nervosa. METHOD: One hundred and ninety recorded FBT sessions from 68 adolescents with anorexia nervosa and their families were recruited across multiple sites (N = 6). Each site provided 1-4 tapes per family over four treatment time points, and each was independently rated for therapist adherence. RESULTS: There were differences in adherence scores within and between sites. ANOVA produced a main effect for site, F(5, 46) = 8.6, p < .001, and phase, F(3, 42) = 12.7, p < .001, with adherence decreasing in later phases. Adherence was not associated to end of treatment percent ideal body weight after controlling for baseline percent ideal body weight (r = .088, p = .48). CONCLUSIONS: Results suggest that FBT can be delivered with adherence in phase one of treatment. Adherence was not associated with treatment outcome as determined using percent ideal body weight.

Associations between dimensions of anorexia nervosa and obsessive-compulsive disorder: An examination of personality and psychological factors in patients with anorexia nervosa.

OBJECTIVE: Anorexia nervosa (AN) and obsessive-compulsive disorder (OCD) are highly comorbid. However, the factors that account for this comorbidity are poorly understood. We examined the core dimensions of AN and OCD and psychological and personality factors shared by both disorders. METHOD: In path analyses (N = 732 women with either current AN or recovered from AN), we examined which factors were uniquely and independently associated with the core dimensions of AN and OCD. We also examined recovery from AN as a moderator. RESULTS: When individuals with AN reported greater concern over mistakes, they endorsed more severity in both AN and OCD core dimensions. These unique associations existed above and beyond all other transdiagnostic personality and psychological factors and regardless of AN recovery status. CONCLUSIONS: Concern over mistakes partially accounts for severity in the core dimensions of both AN and OCD. Concern over mistakes may represent an important target in the aetiology of AN and OCD.

The Anorexia Nervosa Genetics Initiative (ANGI): Overview and methods.

BACKGROUND: Genetic factors contribute to anorexia nervosa (AN); and the first genome-wide significant locus has been identified. We describe methods and procedures for the Anorexia Nervosa Genetics Initiative (ANGI), an international collaboration designed to rapidly recruit 13,000 individuals with AN and ancestrally matched controls. We present sample characteristics and the utility of an online eating disorder diagnostic questionnaire suitable for large-scale genetic and population research. METHODS: ANGI recruited from the United States (US), Australia/New Zealand (ANZ), Sweden (SE), and Denmark (DK). Recruitment was via national registers (SE, DK); treatment centers (US, ANZ, SE, DK); and social and traditional media (US, ANZ, SE). All cases had a lifetime AN diagnosis based on DSM-IV or ICD-10 criteria (excluding amenorrhea). Recruited controls had no lifetime history of disordered eating behaviors. To assess the positive and negative predictive validity of the online eating disorder questionnaire (ED100K-v1), 109 women also completed the Structured Clinical Interview for DSM-IV (SCID), Module H. RESULTS: Blood samples and clinical information were collected from 13,363 individuals with lifetime AN and from controls. Online diagnostic phenotyping was effective and efficient; the validity of the questionnaire was acceptable. CONCLUSIONS: Our multi-pronged recruitment approach was highly effective for rapid recruitment and can be used as a model for efforts by other groups. High online presence of individuals with AN rendered the Internet/social media a remarkably effective recruitment tool in some countries. ANGI has substantially augmented Psychiatric Genomics Consortium AN sample collection. ANGI is a registered clinical trial: clinicaltrials.govNCT01916538; https://clinicaltrials.gov/ct2/show/NCT01916538?cond=Anorexia+Nervosa&draw=1&rank=3.

Dorsomedial prefrontal cortex repetitive transcranial magnetic stimulation treatment of posttraumatic stress disorder in eating disorders: An open-label case series.

Posttraumatic stress disorder (PTSD) is a common comorbid condition in anorexia nervosa (AN) and bulimia nervosa (BN), and may be associated with reduced response to treatment. We report on a case series employing repetitive transcranial magnetic stimulation (rTMS) with a novel target, the dorsomedial prefrontal cortex (DMPFC). Fourteen subjects with eating disorders and comorbid PTSD received 20-30 neuronavigated DMPFC-rTMS treatments on an open-label basis. PTSD symptoms were assessed pretreatment and posttreatment with the PTSD checklist-Civilian (PCL-C) and the Difficulties in Emotional Regulation Scale (DERS). PCL-C scores were reduced by 51.99% ± 27.24% overall, from a mean of 54.29 ± 19.34 pretreatment to 24.86 ± 17.43 posttreatment (p < .001). Of the 14, 8 showed an improvement of >50%. DERS scores improved by 36.02% ± 24.24% overall, from 140.00 ± 22.09 at pretreatment to 89.29 ± 38.31 at posttreatment (p < .001). OF the 14 subjects, 5 achieved >50% improvement. These data may suggest that DMPFC-rTMS could be helpful in the treatment of PTSD in some ED patients.

Deep brain stimulation of the subcallosal cingulate for treatment-refractory anorexia nervosa: 1 year follow-up of an open-label trial.

BACKGROUND: Anorexia nervosa is a life-threatening illness. Brain circuits believed to drive anorexia nervosa symptoms can be accessed with surgical techniques such as deep brain stimulation (DBS). Initial results suggest that DBS of the subcallosal cingulate is safe and associated with improvements in mood and anxiety. Here, we investigated the safety, clinical, and neuroimaging outcomes of DBS of the subcallosal cingulate in a group of patients during 12 months of active stimulation. METHODS: We did this prospective open-label trial at the Department of Surgery of the University of Toronto (Toronto, ON, Canada). Patients were eligible to participate if they were aged 20-60 years and had a diagnosis of anorexia nervosa (restricting or binge-purging subtype) and a demonstrated history of chronicity or treatment resistance. Following a period of medical stabilisation, patients underwent surgery for DBS and received open-label continuous stimulation for the entire 1 year study duration. The primary outcome was safety and acceptability of the procedure. The secondary outcomes were body-mass index (BMI), mood, anxiety, affective regulation, and anorexia nervosa-specific behaviours at 12 months after surgery, as well as changes in neural circuitry (measured with PET imaging of cerebral glucose metabolism at baseline and at 6 and 12 months after surgery). This trial was registered with ClinicalTrials.gov, number NCT01476540. FINDINGS: 16 patients with treatment-refractory anorexia nervosa were enrolled between September, 2011, and January, 2014, and underwent DBS of the subcallosal cingulate between November, 2011, and April, 2014. Patients had a mean age of 34 years (SD 8) and average illness duration of 18 years (SD 6). Two patients requested that their devices be removed or deactivated during the study, although their reasons for doing so were poorly defined. The most common adverse event was pain related to surgical incision or positioning that required oral analgesics for longer than 3-4 days after surgery (five [31%] of 16 patients). Seven (44%) of 16 patients had serious adverse events, most of which were related to the underlying illness, including electrolyte disturbances. Average BMI at surgery was 13·83 (SD 1·49) and 14 (88%) of the 16 patients had comorbid mood disorders, anxiety disorders, or both. Mean BMI after 12 months of stimulation was 17·34 (SD 3·40; p=0·0009 vs baseline). DBS was associated with significant improvements in measures of depression (mean Hamilton Depression Rating Scale scores 19·40 [SD 6·76] at baseline vs 8·79 [7·64] at 12 months; p=0·00015), anxiety (mean Beck Anxiety Inventory score 38·00 [15·55] vs 27·14 [18·39]; p=0·035), and affective regulation (mean Dysfunction in Emotional Regulation Scale score 131·80 [22·04] vs 104·36 [31·27]; p=0·019). We detected significant changes in cerebral glucose metabolism in key anorexia nervosa-related structures at both 6 months and 12 months of ongoing brain stimulation. INTERPRETATION: In patients with chronic treatment-refractory anorexia nervosa, DBS is well tolerated and is associated with significant and sustained improvements in affective symptoms, BMI, and changes in neural circuitry at 12 months after surgery. FUNDING: Klarman Family Foundation Grants Program in Eating Disorders Research and Canadian Institutes of Health Research.

Contemporary views on the genetics of anorexia nervosa.

Anorexia nervosa (AN) is a serious mental illness characterized by severe dietary restriction that leads to high rates of morbidity, chronicity, and mortality. Unfortunately, effective treatment is lacking and few options are available. High rates of familial aggregation and significant heritability suggested that the complex etiology of AN is affected by both genetic and environmental factors. In this paper, we review studies that reported common and rare genetic variation that influence susceptibility of AN through candidate gene studies, genome-wide association studies, and sequencing-based studies. We also discuss gene expression, methylation, imaging genetics, and pharmacogenetics to demonstrate that these studies have collectively advanced our knowledge of how genetic variation contributes to AN susceptibility and clinical course. Lastly, we highlight the importance of gene by environment interactions (G×E) and share our enthusiasm for the use of nutritional genomic approaches to elucidate the interaction among nutrients, metabolic intermediates, and genetic variation in AN. A deeper understanding of how nutrition alters genome stability, how genetic variation influences uptake and metabolism of nutrients, and how response to food components affects disordered eating, will lead to personalized dietary interventions and effective nutraceutical and pharmacological treatments for AN.

Subcallosal Cingulate Connectivity in Anorexia Nervosa Patients Differs From Healthy Controls: A Multi-tensor Tractography Study.

BACKGROUND: Anorexia nervosa is characterized by extreme low body weight and alterations in affective processing. The subcallosal cingulate regulates affect through wide-spread white matter connections and is implicated in the pathophysiology of anorexia nervosa. OBJECTIVES: We examined whether those with treatment refractory anorexia nervosa undergoing deep brain stimulation (DBS) of the subcallosal white matter (SCC) show: (1) altered anatomical SCC connectivity compared to healthy controls, (2) white matter microstructural changes, and (3) microstructural changes associated with clinically-measured affect. METHODS: Diffusion magnetic resonance imaging (dMRI) and deterministic multi-tensor tractography were used to compare anatomical connectivity and microstructure in SCC-associated white matter tracts. Eight women with treatment-refractory anorexia nervosa were compared to 8 age- and sex-matched healthy controls. Anorexia nervosa patients also completed affect-related clinical assessments presurgically and 12 months post-surgery. RESULTS: (1) Higher (e.g., left parieto-occipital cortices) and lower (e.g., thalamus) connectivity in those with anorexia nervosa compared to controls. (2) Decreases in fractional anisotropy, and alterations in axial and radial diffusivities, in the left fornix crus, anterior limb of the internal capsule (ALIC), right anterior cingulum and left inferior fronto-occipital fasciculus. (3) Correlations between dMRI metrics and clinical assessments, such as low pre-surgical left fornix and right ALIC fractional anisotropy being related to post-DBS improvements in quality-of-life and depressive symptoms, respectively. CONCLUSIONS: We identified widely-distributed differences in SCC connectivity in anorexia nervosa patients consistent with heterogenous clinical disruptions, although these results should be considered with caution given the low number of subjects. Future studies should further explore the use of affect-related connectivity and behavioral assessments to assist with DBS target selection and treatment outcome.

Neurocircuitry of limbic dysfunction in anorexia nervosa.

Anorexia Nervosa (AN) is a serious psychiatric condition marked by firmly entrenched and maladaptive behaviors and beliefs about body, weight and food, as well as high rates of psychiatric comorbidity. The neural roots of AN are now beginning to emerge, and appear to be related to dysfunctional, primarily limbic, circuits driving pathological thoughts and behaviors. As a result, the significant physical symptoms of AN are increasingly being understood at least partially as a result of abnormal or dysregulated emotional processing. This paper reviews the nature of limbic dysfunction in AN, and how structural and functional imaging has implicated distinct emotional and perceptual neural circuits driving AN symptoms. We propose that top-down and bottom-up influences converge on key limbic modulatory structures, such as the subcallosal cingulate and insula, whose normal functioning is critical to affective regulation and emotional homeostasis. Dysfunctional activity in these structures, as is seen in AN, may lead to emotional processing deficits and psychiatric symptoms, which then drive maladaptive behaviors. Modulating limbic dysregulation may therefore be a potential treatment strategy in some AN patients.

The role of leptin, melanocortin, and neurotrophin system genes on body weight in anorexia nervosa and bulimia nervosa.

OBJECTIVE: Although low weight is a key factor contributing to the high mortality in anorexia nervosa (AN), it is unclear how AN patients sustain low weight compared with bulimia nervosa (BN) patients with similar psychopathology. Studies of genes involved in appetite and weight regulation in eating disorders have yielded variable findings, in part due to small sample size and clinical heterogeneity. This study: (1) assessed the role of leptin, melanocortin, and neurotrophin genetic variants in conferring risk for AN and BN; and (2) explored the involvement of these genes in body mass index (BMI) variations within AN and BN. METHOD: Our sample consisted of 745 individuals with AN without a history of BN, 245 individuals with BN without a history of AN, and 321 controls. We genotyped 20 markers with known or putative function among genes selected from leptin, melanocortin, and neurotrophin systems. RESULTS: There were no significant differences in allele frequencies among individuals with AN, BN, and controls. AGRP rs13338499 polymorphism was associated with lowest illness-related BMI in those with AN (p = 0.0013), and NTRK2 rs1042571 was associated with highest BMI in those with BN (p = 0.0018). DISCUSSION: To our knowledge, this is the first study to address the issue of clinical heterogeneity in eating disorder genetic research and to explore the role of known or putatively functional markers in genes regulating appetite and weight in individuals with AN and BN. If replicated, our results may serve as an important first step toward gaining a better understanding of weight regulation in eating disorders.