Dynamic functional connectivity in anorexia nervosa: alterations in states of low connectivity and state transitions.

BACKGROUND: The onset of anorexia nervosa (AN) frequently occurs during adolescence and is associated with preoccupation with body weight and shape and extreme underweight. Altered resting state functional connectivity in the brain has been described in individuals with AN, but only from a static perspective. The current study investigated the temporal dynamics of functional connectivity in adolescents with AN and how it relates to clinical features. METHOD: 99 female patients acutely ill with AN and 99 pairwise age-matched female healthy control (HC) participants were included in the study. Using resting-state functional MRI data and an established sliding-window analytic approach, we identified dynamic resting-state functional connectivity states and extracted dynamic indices such as dwell time (the duration spent in a state), fraction time (the proportion of the total time occupied by a state), and number of transitions (number of switches) from one state to another, to test for group differences. RESULTS: Individuals with AN had relatively reduced fraction time in a mildly connected state with pronounced connectivity within the default mode network (DMN) and an overall reduced number of transitions between states. CONCLUSIONS: These findings revealed by a dynamic, but not static analytic approach might hint towards a more "rigid" connectivity, a phenomenon commonly observed in internalizing mental disorders, and in AN possibly related to a reduction in energetic costs as a result of nutritional deprivation.

Triangulating brain alterations in anorexia nervosa: a multimodal investigation of magnetic resonance spectroscopy, morphometry and blood-based biomarkers.

The acute state of anorexia nervosa (AN) is associated with widespread reductions in cortical gray matter (GM) thickness and white matter (WM) volume, suspected changes in myelin content and elevated levels of the neuronal damage marker neurofilament light (NF-L), but the underlying mechanisms remain largely unclear. To gain a deeper understanding of brain changes in AN, we applied a multimodal approach combining advanced neuroimaging methods with analysis of blood-derived biomarkers. In addition to standard measures of cortical GM thickness and WM volume, we analyzed tissue-specific profiles of brain metabolites using multivoxel proton magnetic resonance spectroscopy, T1 relaxation time as a proxy of myelin content leveraging advanced quantitative MRI methods and serum NF-L concentrations in a sample of 30 female, predominately adolescent patients with AN and 30 age-matched female healthy control participants. In patients with AN, we found a reduction in GM cortical thickness and GM total N-acetyl aspartate. The latter predicted higher NF-L levels, which were elevated in AN. Furthermore, GM total choline was elevated. In WM, there were no group differences in either imaging markers, choline levels or N-acetyl aspartate levels. The current study provides evidence for neuronal damage processes as well as for increased membrane lipid catabolism and turnover in GM in acute AN but no evidence for WM pathology. Our results illustrate the potential of multimodal research including tissue-specific proton magnetic resonance spectroscopy analyses to shed light on brain changes in psychiatric and neurological conditions, which may ultimately lead to better treatments.

Predicting long-term outcome in anorexia nervosa: a machine learning analysis of brain structure at different stages of weight recovery.

BACKGROUND: Anorexia nervosa (AN) is characterized by sizable, widespread gray matter (GM) reductions in the acutely underweight state. However, evidence for persistent alterations after weight-restoration has been surprisingly scarce despite high relapse rates, frequent transitions to other psychiatric disorders, and generally unfavorable outcome. While most studies investigated brain regions separately (univariate analysis), psychiatric disorders can be conceptualized as brain network disorders characterized by multivariate alterations with only subtle local effects. We tested for persistent multivariate structural brain alterations in weight-restored individuals with a history of AN, investigated their putative biological substrate and relation with 1-year treatment outcome. METHODS: We trained machine learning models on regional GM measures to classify healthy controls (HC) (N = 289) from individuals at three stages of AN: underweight patients starting intensive treatment (N = 165, used as baseline), patients after partial weight-restoration (N = 115), and former patients after stable and full weight-restoration (N = 89). Alterations after weight-restoration were related to treatment outcome and characterized both anatomically and functionally. RESULTS: Patients could be classified from HC when underweight (ROC-AUC = 0.90) but also after partial weight-restoration (ROC-AUC = 0.64). Alterations after partial weight-restoration were more pronounced in patients with worse outcome and were not detected in long-term weight-recovered individuals, i.e. those with favorable outcome. These alterations were more pronounced in regions with greater functional connectivity, not merely explained by body mass index, and even increases in cortical thickness were observed (insula, lateral orbitofrontal, temporal pole). CONCLUSIONS: Analyzing persistent multivariate brain structural alterations after weight-restoration might help to develop personalized interventions after discharge from inpatient treatment.

Mouse-cursor trajectories reveal reduced contextual influence on decision conflict during delay discounting in anorexia nervosa.

OBJECTIVE: The capacity of individuals with anorexia nervosa (AN) to forgo immediate food rewards in their long-term pursuit of thinness is thought to reflect elevated self-control and/or abnormal reward sensitivity. Prior research attempted to capture an increased tendency to delay gratification in AN using delay-discounting tasks that assess how rapidly the subjective value of rewards decreases as a function of time until receipt. However, significant effects were mostly subtle or absent. Here, we tested whether the process leading to such decisions might be altered in AN. METHOD: We recorded mouse-cursor movement trajectories leading to the final choice in a computerized delay-discounting task (238 trials) in 55 acutely underweight females with AN and pairwise age-matched female healthy controls (HC). We tested for group differences in deviations from a direct choice path, a measure of conflict strength in decision making, and whether group moderated the effect of several predictors of conflict strength (e.g., choice difficulty, consistency). We also explored reaction times and changes in trajectory directions (X-flips). RESULTS: No group differences in delay-discounting parameters or movement trajectories were detected. However, the effect of the aforementioned predictors on deviations (and to a lesser extent reaction times) was reduced in AN. DISCUSSION: These findings suggest that while delay discounting and conflict strength in decision making are generally unaltered in AN, conflict strength was more stable across different decisions in the disorder. This might enable individuals with AN to pursue (maladaptive) long-term body-weight goals, because particularly conflicting choices may not be experienced as such. PUBLIC SIGNIFICANCE: The deviations from a direct path of mouse-cursor movements during a computerized delay-discounting task varied less in people with anorexia nervosa. Assuming such deviations measure decision conflict, we speculate that this increased stability might help people with anorexia nervosa achieve their long-term weight goals, as for them the struggle with the decision to eat high-calorie meals when hungry will be milder, so they would be more likely to skip them.

The effects of acute tryptophan depletion on instrumental reward learning in anorexia nervosa - an fMRI study.

BACKGROUND: The serotonin (5-HT) hypothesis of anorexia nervosa (AN) posits that individuals predisposed toward or recovered from AN (recAN) have a central nervous hyperserotonergic state and therefore restrict food intake as a means to reduce 5-HT availability (via diminished tryptophan-derived precursor supply) and alleviate associated negative mood states. Importantly, the 5-HT system has also been generally implicated in reward processing, which has also been shown to be altered in AN. METHODS: In this double-blind crossover study, 22 individuals recAN and 25 healthy control participants (HC) underwent functional magnetic resonance imaging (fMRI) while performing an established instrumental reward learning paradigm during acute tryptophan depletion (ATD; a dietary intervention that lowers central nervous 5-HT availability) as well as a sham depletion. RESULTS: On a behavioral level, the main effects of reward and ATD were evident, but no group differences were found. fMRI analyses revealed a group × ATD × reward level interaction in the ventral anterior insula during reward anticipation as well as in the medial orbitofrontal cortex during reward consumption. DISCUSSION: The precise pattern of results is suggestive of a 'normalization' of reward-related neural responses during ATD in recAN compared to HC. Our results lend further evidence to the 5-HT hypothesis of AN. Decreasing central nervous 5-HT synthesis and availability during ATD and possibly also by dieting may be a means to normalize 5-HT availability and associated brain processes.

No effects of acute tryptophan depletion on anxiety or mood in weight-recovered female patients with anorexia nervosa.

BACKGROUND: Previous studies have suggested that individuals recovered from anorexia nervosa (AN) are characterized by increased serotonergic (5-HT) activity that might be related to elevated levels of anxiety. Assuming these traits to be also present in individuals at risk for AN, it was further hypothesized that restricting food intake might be a means to temporarily alleviate dysphoric affective states by reducing central nervous availability of tryptophan (TRP), the sole precursor of 5-HT. One study that supported this hypothesis found anxiolytic effects in individuals with a history of AN during an experimentally induced short-term depletion of TRP supply to the brain. METHODS: In this placebo-controlled, double-blind cross-over study, 22 patients weight-recovered from AN (recAN) and 25 healthy control participants (HC) completed questionnaires assessing anxiety and momentary mood during acute tryptophan depletion (ATD), a dietary intervention that lowers central 5-HT synthesis. RESULTS: The ATD procedure effectively reduced the ratio of TRP to competing for large neutral amino acids in the peripheral blood, indicating decreased TRP supply to the brain. Effects of ATD on anxiety and mood did not differ between recAN and HC. Bayesian null hypothesis testing confirmed these initial results. DISCUSSION: Our results do not support the hypothesis that short-term depletion of TRP and its impact on the brain 5-HT reduces anxiety or improves mood in AN. As the evidence for the role of 5-HT dysfunction on affective processes in patients with AN is limited, further studies are needed to assess its relevance in the pathophysiology of AN.

Common Genetic Variation and Age of Onset of Anorexia Nervosa.

Background: Genetics and biology may influence the age of onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to age of onset of AN and to investigate the genetic associations between age of onset of AN and age at menarche. Methods: A secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed, which included 9335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age of onset, early-onset AN (<13 years), and typical-onset AN, and genetic correlation, genetic risk score, and Mendelian randomization analyses. Results: Two loci were genome-wide significant in the typical-onset AN GWAS. Heritability estimates (single nucleotide polymorphism-h 2) were 0.01-0.04 for age of onset, 0.16-0.25 for early-onset AN, and 0.17-0.25 for typical-onset AN. Early- and typical-onset AN showed distinct genetic correlation patterns with putative risk factors for AN. Specifically, early-onset AN was significantly genetically correlated with younger age at menarche, and typical-onset AN was significantly negatively genetically correlated with anthropometric traits. Genetic risk scores for age of onset and early-onset AN estimated from independent GWASs significantly predicted age of onset. Mendelian randomization analysis suggested a causal link between younger age at menarche and early-onset AN. Conclusions: Our results provide evidence consistent with a common variant genetic basis for age of onset and implicate biological pathways regulating menarche and reproduction.

Acute tryptophan depletion balances altered resting-state functional connectivity of the salience network in female patients recovered from anorexia nervosa.

BACKGROUND: It has been suggested that individuals predisposed to or recovered from anorexia nervosa experience a hyperserotonergic state associated with anxiety that might be mitigated by restricted food intake, because diminished levels of the tryptophan precursor lower the central availability of serotonin (5-HT). At the neural level, the salience network is a system of functionally connected brain regions; it has been closely associated with 5-HT functioning and mental disorders (including anorexia nervosa). The aim of the present study was to investigate the effect on the salience network of a temporary dietary manipulation of 5-HT synthesis in patients with anorexia nervosa. METHODS: In this double-blind crossover study, we obtained data on resting-state functional connectivity from 22 weight-recovered female patients with a history of anorexia nervosa, and 22 age-matched female healthy controls. The study procedure included acute tryptophan depletion (a dietary intervention that lowers the central 5-HT synthesis rate) and a sham condition. RESULTS: We identified an interaction of group and experimental condition in resting-state functional connectivity between the salience network and the orbitofrontal cortex extending to the frontal pole (F 1,42 = 12.52; p FWE = 0.026). Further analysis revealed increased resting-state functional connectivity during acute tryptophan depletion in patients recovered from anorexia nervosa, resembling that of healthy controls during the sham condition (T 42 = -0.66; p = 0.51). LIMITATIONS: The effect of acute tryptophan depletion on the central availability of 5-HT can be judged only indirectly using plasma ratios of tryptophan to large neutral amino acids. Moreover, the definition of anorexia nervosa recovery varies widely across studies, limiting comparability. CONCLUSION: Taken together, our findings support the notion of 5-HT dysregulation in anorexia nervosa and indicate that reduced 5-HT synthesis and availability during acute tryptophan depletion (and possibly with food restriction) may balance hyperserotonergic functioning and the associated resting-state functional connectivity of the salience network.

Increased Habit Frequency in the Daily Lives of Patients with Acute Anorexia Nervosa.

Strict eating routines and frequent rigid behavior patterns are commonly observed in patients with anorexia nervosa (AN). A recent theory proposes that while these behaviors may have been reinforced initially, they later become habitual. To date, however, research has been overly focused on eating-disorder (ED)-related habits. Over the course of seven days, we applied an ecological momentary assessment (EMA) to investigate the habit frequency and strength of ED-specific (food intake) and ED-unspecific (hygiene) habits in the daily lives of a sample of n = 57 AN and n = 57 healthy controls (HC). The results of the hierarchical models revealed that habits were significantly more likely in patients compared with HC for both categories, independently. Furthermore, a lower body mass index (BMI) was associated with increased habit frequency in AN. Our study strengthens the habit theory of AN by showing the relevance of habits beyond ED-specific behavioral domains. This also supports the development of innovative therapeutic interventions targeting habitual behavior in EDs.

Aberrant neural representation of food stimuli in women with acute anorexia nervosa predicts treatment outcome and is improved in weight restored individuals.

Anorexia nervosa (AN) has been associated with altered reward processing. We recently reported greater neural response in secondary visual areas when processing visual food stimuli in acutely underweight AN patients (acAN). In order to examine whether the observed alterations are indicative of acute undernutrition or a potential trait marker of AN, we set out to assess neural responses in acAN and in individuals weight-recovered from AN (recAN). FMRI data were collected from a total of 126 female volunteers, 35 acAN, 33 recAN, and 58 age-matched healthy controls (HC) while they viewed streams of food, social and neutral stimuli. A standard general linear model (GLM) was used to interrogate neural responses to the different stimuli in recAN vs. age-matched HC. Moreover, within-subject multivoxel pattern analyses (MVPA) in the two matched samples (acAN/HC and recAN/HC) were used to estimate neural representation of food vs. neutral, and social vs. neutral stimuli. A multiple regression analysis was conducted to test associations between the accuracy of the neural representation and treatment outcome. The GLM revealed no group differences between recAN and HC. The MVPAs showed greater classification accuracy of food stimuli in the posterior fusiform gyrus in acAN but not recAN. Classification accuracy was associated with better treatment outcome. Our findings suggest that the neural representation of food stimuli is altered in secondary visual areas in acAN and normalizes with weight recovery. Possibly this altered representation reflects attentional engagement motivating food intake, which may promote the recovery process.

Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies.

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [rg ], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (rg = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (rg = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (rg = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (rgs = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.

Study protocol of comprehensive risk evaluation for anorexia nervosa in twins (CREAT): a study of discordant monozygotic twins with anorexia nervosa.

BACKGROUND: Anorexia nervosa (AN) is a severe disorder, for which genetic evidence suggests psychiatric as well as metabolic origins. AN has high somatic and psychiatric comorbidities, broad impact on quality of life, and elevated mortality. Risk factor studies of AN have focused on differences between acutely ill and recovered individuals. Such comparisons often yield ambiguous conclusions, as alterations could reflect different effects depending on the comparison. Whereas differences found in acutely ill patients could reflect state effects that are due to acute starvation or acute disease-specific factors, they could also reflect underlying traits. Observations in recovered individuals could reflect either an underlying trait or a "scar" due to lasting effects of sustained undernutrition and illness. The co-twin control design (i.e., monozygotic [MZ] twins who are discordant for AN and MZ concordant control twin pairs) affords at least partial disambiguation of these effects. METHODS: Comprehensive Risk Evaluation for Anorexia nervosa in Twins (CREAT) will be the largest and most comprehensive investigation of twins who are discordant for AN to date. CREAT utilizes a co-twin control design that includes endocrinological, neurocognitive, neuroimaging, genomic, and multi-omic approaches coupled with an experimental component that explores the impact of an overnight fast on most measured parameters. DISCUSSION: The multimodal longitudinal twin assessment of the CREAT study will help to disambiguate state, trait, and "scar" effects, and thereby enable a deeper understanding of the contribution of genetics, epigenetics, cognitive functions, brain structure and function, metabolism, endocrinology, microbiology, and immunology to the etiology and maintenance of AN.

Metabolic state and value-based decision-making in acute and recovered female patients with anorexia nervosa

Background: Patients with anorexia nervosa forgo eating despite emaciation and severe health consequences. Such dysfunctional decision-making might be explained by an excessive level of self-control, alterations in homeostatic and hedonic regulation, or an interplay between these processes. We aimed to understand value-based decision-making in anorexia nervosa and its association with the gut hormone ghrelin. Besides its homeostatic function, ghrelin has been implicated in the hedonic regulation of appetite and reward via the modulation of phasic dopamine signalling. Methods: In a cross-sectional design, we studied acutely underweight (n = 94) and recovered (n = 37) patients with anorexia nervosa of the restrictive subtype, as well as healthy control participants (n = 119). We assessed plasma concentrations of desacyl ghrelin and parameters of delay discounting, probability discounting for gains and losses, and loss aversion. Results: Recovered patients displayed higher risk aversion for gains, but we observed no group differences for the remaining decision-making parameters. Desacyl ghrelin was higher in acutely underweight and recovered participants with anorexia nervosa relative to healthy controls. Moreover, we found a significant group × desacyl ghrelin interaction in delay discounting, indicating that in contrast to healthy controls, acutely underweight patients with anorexia nervosa who had high desacyl ghrelin concentrations preferably chose the delayed reward option. Limitations: We probed decision-making using monetary rewards, but patients with anorexia nervosa may react differently to disorder-relevant stimuli. Furthermore, in contrast to acyl ghrelin, the functions of desacyl ghrelin are unclear. Therefore, the interpretation of the results is preliminary. Conclusion: The propensity for risk aversion as found in recovered patients with anorexia nervosa could help them successfully complete therapy, or it could reflect sequelae of the disorder. Conversely, ghrelin findings might be related to a mechanism contributing to disease maintenance; that is, in acutely underweight anorexia nervosa, a hungry state may facilitate the ability to forgo an immediate reward to achieve a (dysfunctional) long-term goal.

Peptide YY3-36 concentration in acute- and long-term recovered anorexia nervosa.

PURPOSE: The gut-brain axis could be a possible key factor in the pathophysiology of anorexia nervosa. The neuropeptide peptide YY3-36, secreted by endocrine L cells of the gastrointestinal tract, is a known regulator of appetite and food intake. The objective of this study was to investigate peptide YY3-36 plasma concentrations at different stages of anorexia nervosa in a combined cross-sectional and longitudinal design to differentiate between effects of acute undernutrition and more enduring characteristics. METHODS: We measured fasting plasma peptide YY3-36 concentrations in young patients with acute anorexia nervosa (n = 47) and long-term recovered patients (n = 35) cross-sectionally in comparison to healthy control participants (n = 58), and longitudinally over the course of inpatient treatment. Physical activity was controlled as it may modulate peptide YY secretion. RESULTS: There was no group difference in peptide YY3-36 concentration among young acutely underweight anorexia nervosa patients, long-term recovered anorexia nervosa patients, and healthy control participants. Longitudinally, there was no change in peptide YY3-36 concentration after short-term weight rehabilitation. For acute anorexia nervosa patients at admission to treatment, there was a negative correlation between peptide YY3-36 concentration and body mass index. CONCLUSIONS: The current study provides additional evidence for a normal basal PYY3-36 concentration in AN. Future studies should study multiple appetite-regulating peptides and their complex interplay and also use research designs including a food challenge.

Altered global brain network topology as a trait marker in patients with anorexia nervosa.

BACKGROUND: Resting state functional magnetic resonance imaging studies have identified functional connectivity patterns associated with acute undernutrition in anorexia nervosa (AN), but few have investigated recovered patients. Thus, a trait connectivity profile characteristic of the disorder remains elusive. Using state-of-the-art graph-theoretic methods in acute AN, the authors previously found abnormal global brain network architecture, possibly driven by local network alterations. To disentangle trait from starvation effects, the present study examines network organization in recovered patients. METHODS: Graph-theoretic metrics were used to assess resting-state network properties in a large sample of female patients recovered from AN (recAN, n = 55) compared with pairwise age-matched healthy controls (HC, n = 55). RESULTS: Indicative of an altered global network structure, recAN showed increased assortativity and reduced global clustering as well as small-worldness compared with HC, while no group differences at an intermediate or local network level were evident. However, using support-vector classifier on local metrics, recAN and HC could be separated with an accuracy of 70.4%. CONCLUSIONS: This pattern of results suggests that long-term recovered patients have an aberrant global brain network configuration, similar to acutely underweight patients. While the finding of increased assortativity may represent a trait marker of AN, the remaining findings could be seen as a scar following prolonged undernutrition.

Peripheral serotonin transporter DNA methylation is linked to increased salience network connectivity in females with anorexia nervosa

Background: Epigenetic variation in the serotonin transporter gene (SLC6A4) has been shown to modulate the functioning of brain circuitry associated with the salience network and may heighten the risk for mental illness. This study is, to our knowledge, the first to test this epigenome­brain­behaviour pathway in patients with anorexia nervosa. Methods: We obtained resting-state functional connectivity (rsFC) data and blood samples from 55 acutely underweight female patients with anorexia nervosa and 55 age-matched female healthy controls. We decomposed imaging data using independent component analysis. We used bisulfite pyrosequencing to analyze blood DNA methylation within the promoter region of SLC6A4. We then explored salience network rsFC patterns in the group × methylation interaction. Results: We identified a positive relationship between SLC6A4 methylation levels and rsFC between the dorsolateral prefrontal cortex and the salience network in patients with anorexia nervosa compared to healthy controls. Increased rsFC in the salience network mediated the link between SLC6A4 methylation and eating disorder symptoms in patients with anorexia nervosa. We confirmed findings of rsFC alterations for CpG-specific methylation at a locus with evidence of methylation correspondence between brain and blood tissue. Limitations: This study was cross-sectional in nature, the sample size was modest for the method and methylation levels were measured peripherally, so findings cannot be fully generalized to brain tissue. Conclusion: This study sheds light on the neurobiological process of how epigenetic variation in the SLC6A4 gene may relate to rsFC in the salience network that is linked to psychopathology in anorexia nervosa.

A naturalistic investigation of cognitive-affective dysfunction in anorexia nervosa: The role of inefficiency.

OBJECTIVE: Research has shown that rumination and negative affect are elevated in patients with anorexia nervosa (AN), but the underlying origins remain unclear. Drawing from the theoretical framework of the Goal Progress Theory of rumination, we propose that heightened feelings of "inefficiency" (i.e., low self-efficacy) in AN might play an important role in these dysfunctional cognitive-affective processes. METHOD: Thirty-two weight-recovered participants with a history of AN and 32 healthy control participants filled out questionnaires regarding rumination and affect six times a day over a period of 2 weeks via ecological momentary assessment in real-life. RESULTS: Analyses via hierarchical as well as conceptual process modeling suggest that while inefficiency is generally associated with more rumination and negative affect, additional amplifying mechanisms between these variables exist specifically in recovered participants with a history of AN. DISCUSSION: Inefficiency as a core aspect of AN appears to trigger dysfunctional cognitive-affective processes which may contribute to vulnerability for AN.

Peripheral serotonin transporter DNA methylation is linked to increased salience network connectivity in females with anorexia nervosa

Background: Epigenetic variation in the serotonin transporter gene (SLC6A4) has been shown to modulate the functioning of brain circuitry associated with the salience network and may heighten the risk for mental illness. This study is, to our knowledge, the first to test this epigenome­brain­behaviour pathway in patients with anorexia nervosa. Methods: We obtained resting-state functional connectivity (rsFC) data and blood samples from 55 acutely underweight female patients with anorexia nervosa and 55 age-matched female healthy controls. We decomposed imaging data using independent component analysis. We used bisulfite pyrosequencing to analyze blood DNA methylation within the promoter region of SLC6A4. We then explored salience network rsFC patterns in the group × methylation interaction. Results: We identified a positive relationship between SLC6A4 methylation levels and rsFC between the dorsolateral prefrontal cortex and the salience network in patients with anorexia nervosa compared to healthy controls. Increased rsFC in the salience network mediated the link between SLC6A4 methylation and eating disorder symptoms in patients with anorexia nervosa. We confirmed findings of rsFC alterations for CpG-specific methylation at a locus with evidence of methylation correspondence between brain and blood tissue. Limitations: This study was cross-sectional in nature, the sample size was modest for the method and methylation levels were measured peripherally, so findings cannot be fully generalized to brain tissue. Conclusion: This study sheds light on the neurobiological process of how epigenetic variation in the SLC6A4 gene may relate to rsFC in the salience network that is linked to psychopathology in anorexia nervosa.

Goal-directed vs. habitual instrumental behavior during reward processing in anorexia nervosa: an fMRI study.

Previous studies have proposed that altered reward processing and elevated cognitive control underlie the etiology of anorexia nervosa (AN). A newly debated notion suggests altered habit learning and an overreliance on habits may contribute to the persistence of AN. In weight-recovered AN patients, we previously found neuroimaging-based evidence for unaltered reward processing, but elevated cognitive control. In order to differentiate between state versus trait factors, we here contrast the aforementioned hypotheses in a sample of acutely underweight AN (acAN) patients. 37 acAN patients and 37 closely matched healthy controls (HC) underwent a functional MRI while performing an established instrumental motivation task. We found no group differences with respect to neural responses during the anticipation or receipt of reward. However, the behavioral response data showed a bimodal distribution, indicative for a goal-directed (gAN) and a habit-driven (hAN) patient subgroup. Additional analyses revealed decreased mOFC activation during reward anticipation in hAN, which would be in line with a habit-driven response. These findings provide a new perspective on the debate regarding the notion of increased goal-directed versus habitual behavior in AN. If replicable, the observed dissociation between gAN and hAN might help to tailor therapeutic approaches to individual patient characteristics.