Diminished Adaptation, Satisfaction, and Neural Responses to Advantageous Social Signals in Anorexia Nervosa and Bulimia Nervosa.

BACKGROUND: Development and recurrence of 2 eating disorders (EDs), anorexia nervosa and bulimia nervosa, are frequently associated with environmental stressors. Neurobehavioral responses to social learning signals were evaluated in both EDs. METHODS: Women with anorexia nervosa (n = 25), women with bulimia nervosa (n = 30), or healthy comparison women (n = 38) played a neuroeconomic game in which the norm shifted, generating social learning signals (norm prediction errors [NPEs]) during a functional magnetic resonance imaging scan. A Bayesian logistic regression model examined how the probability of offer acceptance depended on cohort, block, and NPEs. Rejection rates, emotion ratings, and neural responses to NPEs were compared across groups. RESULTS: Relative to the comparison group, both ED cohorts showed less adaptation (p = .028, ηp2 = 0.060), and advantageous signals (positive NPEs) led to higher rejection rates (p = .014, ηp2 = 0.077) and less positive emotion ratings (p = .004, ηp2 = 0.111). Advantageous signals increased neural activations in the orbitofrontal cortex for the comparison group but not for women with anorexia nervosa (p = .018, d = 0.655) or bulimia nervosa (p = .043, d = 0.527). More severe ED symptoms were associated with decreased activation of dorsomedial prefrontal cortex for advantageous signals. CONCLUSIONS: Diminished neural processing of advantageous social signals and impaired norm adaptation were observed in both anorexia nervosa and bulimia nervosa, while no differences were found for disadvantageous social signals. Development of neurocognitive interventions to increase responsivity to advantageous social signals could augment current treatments, potentially leading to improved clinical outcomes for EDs.

Structural brain differences in recovering and weight-recovered adult outpatient women with anorexia nervosa.

BACKGROUND: Anorexia nervosa is a complex psychiatric illness that includes severe low body weight with cognitive distortions and altered eating behaviors. Brain structures, including cortical thicknesses in many regions, are reduced in underweight patients who are acutely ill with anorexia nervosa. However, few studies have examined adult outpatients in the process of recovering from anorexia nervosa. Evaluating neurobiological problems at different physiological stages of anorexia nervosa may facilitate our understanding of the recovery process. METHODS: Magnetic resonance imaging (MRI) images from 37 partially weight-restored women with anorexia nervosa (pwAN), 32 women with a history of anorexia nervosa maintaining weight restoration (wrAN), and 41 healthy control women were analyzed using FreeSurfer. Group differences in brain structure, including cortical thickness, areas, and volumes, were compared using a series of factorial f-tests, including age as a covariate, and correcting for multiple comparisons with the False Discovery Rate method. RESULTS: The pwAN and wrAN cohorts differed from each other in body mass index, eating disorder symptoms, and social problem solving orientations, but not depression or self-esteem. Relative to the HC cohort, eight cortical thicknesses were thinner for the pwAN cohort; these regions were predominately right-sided and in the cingulate and frontal lobe. One of these regions, the right pars orbitalis, was also thinner for the wrAN cohort. One region, the right parahippocampal gyrus, was thicker in the pwAN cohort. One volume, the right cerebellar white matter, was reduced in the pwAN cohort. There were no differences in global white matter, gray matter, or subcortical volumes across the cohorts. CONCLUSIONS: Many regional structural differences were observed in the pwAN cohort with minimal differences in the wrAN cohort. These data support a treatment focus on achieving and sustaining full weight restoration to mitigate possible neurobiological sequela of AN. In addition, the regions showing cortical thinning are similar to structural changes reported elsewhere for suicide attempts, anxiety disorders, and autistic spectrum disorder. Understanding how brain structure and function are related to clinical symptoms expressed during the course of recovering from AN is needed.

Anorexia nervosa is a life-threatening mental illness defined in part by an inability to maintain a body weight in the normal range. Malnutrition and low weight are factors typically present in the anorexia nervosa and can affect brain structure. We conducted a detailed analysis of brain structure using Freesurfer, focusing on regional cortical thicknesses, areas, and volumes, in adult outpatient women with anorexia nervosa. The study included both a partially weight-restored cohort with anorexia nervosa, a cohort sustaining a healthy body weight with history of anorexia nervosa, and a healthy comparison cohort. Reduced cortical thicknesses were observed in eight regions, primarily in the frontal lobe and cingulate for the cohort recently with anorexia nervosa but only one frontal region in the weight-maintained cohort. These data emphasize the importance of sustained weight-restoration for adult women with anorexia nervosa. Further, the impacted neural regions have been associated with impulsivity, attention, self-regulation, and social interactions in other clinical cohorts, suggesting that these neuropsychological processes may warrant study in patients recovering from anorexia nervosa. Future work should consider whether these factors have clinical relevance in the outpatient treatment of adults with anorexia nervosa.

Treatment Utilization and Medical Problems in a Community Sample of Adult Women With Anorexia Nervosa.

Anorexia nervosa (AN) has a prolonged course of illness, making both defining recovery and determining optimal outpatient treatments difficult. Here, we report the types of treatments utilized in a naturalistic sample of adult women with AN in Texas. Participants were recruited from earlier studies of women with AN (n = 28) and in weight recovery following AN (n = 18). Participants provided information about both their illness and treatments during their most severe period as well as during the 2-6 years following original assessments. Based upon their baseline and follow-up clinical status participants were classified as remaining ill (AN-CC, n = 17), newly in recovery (AN-CR, n = 11), and sustained weight-recovery (AN-WR, n = 18). Utilization of health care institutions and providers were compared across groups. There were no differences in groups related to symptoms or treatments utilized during the severe-period. During the follow-up period, intensive outpatient programs were utilized significantly more by the AN-CC group than the other groups, and dietitians were seen significantly less by the AN-WR group. Medical complications related to the ED were significantly more common in the AN-CC group. All groups maintained similar levels of contact with outpatient psychiatrists, therapists, and primary care physicians. Current treatments remain ineffective for a subset of AN participants. Future prospective studies assessing medical health and comorbidities in AN may provide additional insights into disease severity and predictors of clinical outcome.

Neuropsychological and Cognitive Correlates of Recovery in Anorexia Nervosa.

OBJECTIVE: To identify clinical or cognitive measures either predictive of illness trajectory or altered with sustained weight recovery in adult women with anorexia nervosa. METHODS: Participants were recruited from prior studies of women with anorexia nervosa (AN-C) and in weight-recovery following anorexia nervosa (AN-WR). Participants completed a neuropsychological battery at baseline and clinical assessments at both baseline and follow-up. Groups based on clinical outcome (continued eating disorder, AN-CC; newly in recovery, AN-CR; sustained weight-recovery, AN-WR) were compared by using one-way ANOVAs with Bonferroni-corrected post hoc comparisons. RESULTS: Women with continued eating disorder had poorer neuropsychological function and self-competence at baseline than AN-CR. AN-CR showed changes in depression and externalizing bias, a measure of self-related attributions. AN-WR differed from both AN-CC and AN-CR at baseline in externalizing bias, but only from AN-CC at outcome. DISCUSSION: Neuropsychological function when recently ill may be a prognostic factor, while externalizing bias may provide a clinical target for recovery. Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association.

Influence of treatments on prognosis for vulvar lichen sclerosus: facts and controversies.

Lichen sclerosus (LS) is an inflammatory dermatosis with a predilection for the anogential skin. Vulvar LS can be a debilitating disease, causing pruritus and pain, and it carries the potential for atrophy, scarring, and significant functional impairment. Recently, many advances have been made regarding the etiology and natural history of the disease process; however, much debate still exists regarding the most advantageous medical and surgical management of this disorder. In an effort to provide a comprehensive review on current vulvar LS literature, the following three controversies will be discussed: (1) optimal disease treatment, (2) theories behind LS's oncogenicity and treatments for minimizing malignancy, and (3) the value of surgical treatment for LS. Ultra-potent topical corticosteroids (TCSs) are the first-line treatment for vulvar LS, while topical calcineurin inhibitors (TCIs) remain second-line agents for patients for whom TCS treatment resulted in incomplete resolution of symptoms or adverse events. Due to the relapsing nature of the disease, long-term maintenance therapy is often required. In addition, recent advances have contributed to the understanding of the association between LS and squamous cell carcinoma (SCC). While the exact mechanism responsible for LS-associated SCC is not known, immune dysregulation and inflammation may play an important role; therefore, successful treatment of LS should be directed towards alleviation of symptoms and reversal of the underlying histopathologic changes. Patients with LS-associated malignancy, as well as patients who need correction of functionally restrictive, scarring processes, can successfully undergo surgical intervention with tissue conservation.

Fibroblast growth factor receptor-3 (FGFR-3) regulates expression of paneth cell lineage-specific genes in intestinal epithelial cells through both TCF4/beta-catenin-dependent and -independent signaling pathways.

Fibroblast growth factor receptor-3 (FGFR-3) expression in the developing intestine is restricted to the undifferentiated epithelial cells within the lower portion of the crypt. We previously showed that mice lacking functional FGFR-3 have a significant decrease in the number of Paneth cells in the small intestine. Here, we used Caco2 cells to investigate whether FGFR-3 signaling can directly modulate expression of Paneth cell differentiation markers through its effects on TCF4/ß-catenin or through other signaling pathways downstream of this receptor. Caco2 cells treated with FGFR-3 ligands or expressing FGFR-3(K650E), a constitutively active mutant, resulted in a significantly increased expression of genes characteristic of mature Paneth cells, including human α-defensins 5 and 6 (HD5 and HD6) and Paneth cell lysozyme, whereas enterocytic differentiation markers were reduced. Activation of FGFR-3 signaling sustained high levels of ß-catenin mRNA expression, leading to increased TCF4/ß-catenin-regulated transcriptional activity in Caco2 cells. Sustained activity of the TCF4/ß-catenin pathway was required for the induction of Paneth cell markers. Activation of the MAPK pathway by FGFR-3 is also required for the induction of Paneth cell markers in addition to and independent of the effect of FGFR-3 on TCF4/ß-catenin activity. These studies suggest that coordinate activation of multiple independent signaling pathways downstream of FGFR-3 is involved in regulation of Paneth cell differentiation.

Fibroblast growth factor receptor-3 regulates Paneth cell lineage allocation and accrual of epithelial stem cells during murine intestinal development.

Fibroblast growth factor receptor 3 (FGFR-3) is expressed in the lower crypt epithelium, where stem cells of the intestine reside. The role of FGFR-3 signaling in regulating features of intestinal morphogenesis was examined in FGFR-3-null (FGFR-3(-/-)) mice. FGFR-3(-/-) mice had only about half the number of intestinal crypts and a marked decrease in the number of functional clonogenic stem cells, as assessed by an in vivo microcolony-forming assay, compared with wild-type littermates. A marked deficit in allocation of progenitor cells to Paneth cell differentiation was noted, although all the principal epithelial lineages were represented in FGFR-3(-/-) mice. The total cellular content and nuclear localization of beta-catenin protein were reduced in FGFR-3(-/-) mice, as was expression of cyclin D1 and matrix metalloproteinase-7, major downstream targets of beta-catenin/T cell factor-4 (Tcf-4) signaling. Activation of FGFR-3 in Caco-2 cells, an intestinal epithelial cell line, abrogated the fall in beta-catenin/Tcf-4 signaling activity that is normally observed in these cells as cultures become progressively more confluent. These findings are consistent with the hypothesis that, during intestinal development, FGFR-3 signaling regulates crypt epithelial stem cell expansion and crypt morphogenesis, as well as Paneth cell lineage specification, through beta-catenin/Tcf-4-dependent and -independent pathways.