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.

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.

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.

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.

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.

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.

Subcallosal cingulate deep brain stimulation for treatment-refractory anorexia nervosa: a phase 1 pilot trial.

BACKGROUND: Anorexia nervosa is characterised by a chronic course that is refractory to treatment in many patients and has one of the highest mortality rates of any psychiatric disorder. Deep brain stimulation (DBS) has been applied to circuit-based neuropsychiatric diseases, such as Parkinson's disease and major depression, with promising results. We aimed to assess the safety of DBS to modulate the activity of limbic circuits and to examine how this might affect the clinical features of anorexia nervosa. METHODS: We did a phase 1, prospective trial of subcallosal cingulate DBS in six patients with chronic, severe, and treatment-refractory anorexia nervosa. Eligible patients were aged 20-60 years, had been diagnosed with restricting or binge-purging anorexia nervosa, and showed evidence of chronicity or treatment resistance. Patients underwent medical optimisation preoperatively and had baseline body-mass index (BMI), psychometric, and neuroimaging investigations, followed by implantation of electrodes and pulse generators for continuous delivery of electrical stimulation. Patients were followed up for 9 months after DBS activation, and the primary outcome of adverse events associated with surgery or stimulation was monitored at every follow-up visit. Repeat psychometric assessments, BMI measurements, and neuroimaging investigations were also done at various intervals. This trial is registered with ClinicalTrials.gov, number NCT01476540. FINDINGS: DBS was associated with several adverse events, only one of which (seizure during programming, roughly 2 weeks after surgery) was serious. Other related adverse events were panic attack during surgery, nausea, air embolus, and pain. After 9 months, three of the six patients had achieved and maintained a BMI greater than their historical baselines. DBS was associated with improvements in mood, anxiety, affective regulation, and anorexia nervosa-related obsessions and compulsions in four patients and with improvements in quality of life in three patients after 6 months of stimulation. These clinical benefits were accompanied by changes in cerebral glucose metabolism (seen in a comparison of composite PET scans at baseline and 6 months) that were consistent with a reversal of the abnormalities seen in the anterior cingulate, insula, and parietal lobe in the disorder. INTERPRETATION: Subcallosal cingulate DBS seems to be generally safe in this sample of patients with chronic and treatment-refractory anorexia nervosa. FUNDING: Klarman Family Foundation Grants Program in Eating Disorders Research and Canadian Institutes of Health Research.

Trends in anorexia nervosa research: an analysis of the top 100 most cited works.

Analysis of highly cited papers provides unique insights into the status of research in a given field. We sought to identify the top 100 most highly cited papers in the field of anorexia nervosa (AN). A free, publically accessible software was used to conduct an online search of publications with accompanying citation data. Search terms were selected to focus on papers dealing predominantly with AN, and the results manually screened to exclude out-of-scope publications. Papers in bulimia nervosa, eating disorder not otherwise specified and binge-eating disorder, were not included. The top 100 most highly cited papers in the AN field were identified. Of these, 34 garnered greater than 400 citations, classifying them as 'citation classics'. These works were divided into five categories, those dealing with epidemiological trends, medical/psychiatric comorbidities, treatment, mechanisms of disease and measurement/classification. Publications examining the epidemiology and underlying mechanisms of AN account for the majority of the top 100 papers. Scales and measurement tools have had the greatest impact, garnering the greatest number of average citations per paper. Although reasonably diverse, the top 100 papers highlight areas still lagging behind, including the neuroscience of AN as well as research into novel treatment strategies.

Primary amenorrhea in anorexia nervosa: impact on characteristic masculine and feminine traits.

Animal studies indicate that gonadal hormones at puberty have an effect on the development of masculine and feminine traits. However, it is unknown whether similar processes occur in humans. We examined whether women with anorexia nervosa (AN), who often experience primary amenorrhea, exhibit attenuated feminization in their psychological characteristics in adulthood due to the decrease/absence of gonadal hormones at puberty. Women with AN were compared on a number of psychological characteristics using general linear models on the basis of the presence/absence of primary amenorrhea. Although women with primary amenorrhea exhibited lower anxiety scores than those without primary amenorrhea, in general, results did not provide evidence of attenuated feminization in women with AN with primary amenorrhea. Future research should utilize novel techniques and direct hormone measurement to explore the effects of pubertal gonadal hormones on masculine and feminine traits.

Neurosurgical treatment of anorexia nervosa: review of the literature from leucotomy to deep brain stimulation.

This paper reviews the literature on the surgical treatment of refractory anorexia nervosa (AN) and examines how this literature can inform current circuit models of the disease. The literature contains reports of 35 patients undergoing a neurosurgical procedure for the specific treatment of refractory AN, with the first reported operation, a lobotomy, in 1950. All patients were deemed treatment resistant according to contemporary standards, with the nature of the procedure changing with evolving surgical techniques and methods. All procedures targeted the limbic system and, in a majority of cases, were associated with reported symptomatic improvement. Neurosurgery in AN has been, and continues to be, reserved for patients with chronic and life-threatening illness, for whom conventional treatment has failed. Early procedures, which were viewed as life-saving measures, were crude by today's standards but targeted anatomic structures and pathways implicated in modern models of AN. The last decade has seen a concerted effort in elucidating the neurocircuitry underlying prominent etiologic and maintaining factors in AN, including mood, anxiety and dysfunctional reward processing. This has translated into the development of novel, focused therapeutic options for patients with treatment-refractory AN.

Retrospective maternal report of early eating behaviours in anorexia nervosa.

This exploratory study assessed whether maternal recall of childhood feeding and eating practices differed across anorexia nervosa (AN) subtypes. Participants were 325 women from the Genetics of Anorexia Nervosa study whose mothers completed a childhood feeding and eating questionnaire. Multinomial logistic regression analyses were used to predict AN subtype from measures related to childhood eating: (i) infant feeding (breastfed, feeding schedule, age of solid food introduction), (ii) childhood picky eating (picky eating before age 1 year and between ages one and five) and (iii) infant gastrointestinal problems (vomiting and colic). Results revealed no significant differences in retrospective maternal report of childhood feeding and eating practices among AN subtypes.

Understanding the association of impulsivity, obsessions, and compulsions with binge eating and purging behaviours in anorexia nervosa.

OBJECTIVE: To further refine our understanding of impulsivity, obsessions, and compulsions in anorexia nervosa (AN) by isolating which behaviours--binge eating, purging, or both--are associated with these features. METHODS: We conducted regression analyses with binge eating, purging, and the interaction of binge eating with purging as individual predictors of scores for impulsivity, obsessions, and compulsions in two samples of women with AN (n = 1373). RESULTS: Purging, but not binge eating, was associated with higher scores on impulsivity, obsessions, and compulsions. Purging was also associated with worst eating rituals and with worst eating preoccupations. CONCLUSION: Our results suggest that purging, compared with binge eating, may be a stronger correlate of impulsivity, obsessions, and compulsions in AN.

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.

Posttraumatic stress disorder in anorexia nervosa.

OBJECTIVES: Comorbidity among eating disorders, traumatic events, and posttraumatic stress disorder (PTSD) has been reported in several studies. The main objectives of this study were to describe the nature of traumatic events experienced and to explore the relationship between PTSD and anorexia nervosa (AN) in a sample of women. METHODS: Eight hundred twenty-four participants from the National Institutes of Health-funded Genetics of Anorexia Nervosa Collaborative Study were assessed for eating disorders, PTSD, and personality characteristics. RESULTS: From a final sample of 753 women with AN, 13.7% (n = 103) met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for PTSD. The sample mean age was 29.5 (standard deviation = 11.1) years. In pairwise comparisons across AN subtypes, the odds of having a PTSD diagnosis were significantly lower in individuals with restricting AN than individuals with purging AN without binge eating (odds ratio = 0.49, 95% confidence interval = 0.30-0.80). Most participants with PTSD reported the first traumatic event before the onset of AN (64.1%, n = 66). The most common traumatic events reported by those with a PTSD diagnosis were sexually related traumas during childhood (40.8%) and during adulthood (35.0%). CONCLUSIONS: AN and PTSD do co-occur, and traumatic events tend to occur before the onset of AN. Clinically, these results underscore the importance of assessing trauma history and PTSD in individuals with AN and raise the question of whether specific modifications or augmentations to standard treatment for AN should be considered in a subgroup to address PTSD-related psychopathology.

Life beyond the eating disorder: education, relationships, and reproduction.

OBJECTIVE: We investigated the sociodemographic characteristics in women with and without lifetime eating disorders. METHOD: Participants were from a multisite international study of eating disorders (N = 2,096). Education level, relationship status, and reproductive status were examined across eating disorder subtypes and compared with a healthy control group. RESULTS: Overall, women with eating disorders were less educated than controls, and duration of illness and age of onset were associated with educational attainment. Menstrual status was associated with both relationship and reproductive status, but eating disorder subtypes did not differ significantly from each other or from healthy controls on these dimensions. DISCUSSION: Differences in educational attainment, relationships, and reproduction do exist in individuals with eating disorders and are differentially associated with various eating disorder symptoms and characteristics. These data could assist in educating patients and family members about long-term consequences of eating disorders.

The significance of repetitive hair-pulling behaviors in eating disorders.

We studied the relation between intrusive and repetitive hair pulling, the defining feature of trichotillomania, and compulsive and impulsive features in 1,453 individuals with anorexia nervosa and bulimia nervosa. We conducted a series of regression models examining the relative influence of compulsive features associated with obsessive-compulsive disorder, compulsive features associated with eating disorders, trait features related to harm avoidance, perfectionism, and novelty seeking, and self harm. A final model with a reduced sample (n = 928) examined the additional contribution of impulsive attributes. One of 20 individuals endorsed hair pulling. Evidence of a positive association with endorsement of compulsive behavior of the obsessive-compulsive spectrum emerged. Hair pulling may be more consonant with ritualistic compulsions than impulsive urges in those with eating disorders.

Association of candidate genes with phenotypic traits relevant to anorexia nervosa.

This analysis is a follow-up to an earlier investigation of 182 genes selected as likely candidate genetic variations conferring susceptibility to anorexia nervosa (AN). As those initial case-control results revealed no statistically significant differences in single nucleotide polymorphisms, herein, we investigate alternative phenotypes associated with AN. In 1762 females, using regression analyses, we examined the following: (i) lowest illness-related attained body mass index; (ii) age at menarche; (iii) drive for thinness; (iv) body dissatisfaction; (v) trait anxiety; (vi) concern over mistakes; and (vii) the anticipatory worry and pessimism versus uninhibited optimism subscale of the harm avoidance scale. After controlling for multiple comparisons, no statistically significant results emerged. Although results must be viewed in the context of limitations of statistical power, the approach illustrates a means of potentially identifying genetic variants conferring susceptibility to AN because less complex phenotypes associated with AN are more proximal to the genotype and may be influenced by fewer genes.