Longitudinal changes in brain-derived neurotrophic factor (BDNF) but not cytokines contribute to hippocampal recovery in anorexia nervosa above increases in body mass index.

BACKGROUND: Physical sequelae of anorexia nervosa (AN) include a marked reduction in whole brain volume and subcortical structures such as the hippocampus. Previous research has indicated aberrant levels of inflammatory markers and growth factors in AN, which in other populations have been shown to influence hippocampal integrity. METHODS: Here we investigated the influence of concentrations of two pro-inflammatory cytokines (tumor necrosis factor-alpha [TNF-α] and interleukin-6 [IL-6]) and brain-derived neurotrophic factor (BDNF) on the whole hippocampal volume, as well as the volumes of three regions (the hippocampal body, head, and tail) and 18 subfields bilaterally. Investigations occurred both cross-sectionally between acutely underweight adolescent/young adult females with AN (acAN; n = 82) and people recovered from AN (recAN; n = 20), each independently pairwise age-matched with healthy controls (HC), and longitudinally in acAN after partial renourishment (n = 58). Hippocampal subfield volumes were quantified using FreeSurfer. Concentrations of molecular factors were analyzed in linear models with hippocampal (subfield) volumes as the dependent variable. RESULTS: Cross-sectionally, there was no evidence for an association between IL-6, TNF-α, or BDNF and between-group differences in hippocampal subfield volumes. Longitudinally, increasing concentrations of BDNF were positively associated with longitudinal increases in bilateral global hippocampal volumes after controlling for age, age2, estimated total intracranial volume, and increases in body mass index (BMI). CONCLUSIONS: These findings suggest that increases in BDNF may contribute to global hippocampal recovery over and above increases in BMI during renourishment. Investigations into treatments targeted toward increasing BDNF in AN may be warranted.

Effect of serum concentrations of IL-6 and TNF-α on brain structure in anorexia nervosa: a combined cross-sectional and longitudinal study.

Previous studies of brain structure in anorexia nervosa (AN) have reported reduced gray matter in underweight patients, which largely normalizes upon weight gain. One underlying biological mechanism may be glial cell alterations related to low-grade inflammation. Here, we investigated relationships between brain structure as measured by magnetic resonance imaging and serum concentrations of two pro-inflammatory cytokines (interleukin-6 and tumor necrosis factor alpha) cross-sectionally in 82 underweight adolescent and young adult female patients (mean age 16.8 years; 59 of whom were observed longitudinally after short-term weight restoration; mean duration 2.8 months), 20 individuals long-term weight-recovered from AN (mean age 22.7 years) and 105 healthy control (HC) participants (mean age 17.2 years). We measured cortical thickness, subcortical volumes and local gyrification index, a measure of cortical folding. In contrast to most previous studies of cytokine concentrations in AN, we found no cross-sectional group differences (interleukin-6: p = 0.193, tumor necrosis factor alpha: p = 0.057) or longitudinal changes following weight restoration (interleukin-6: p = 0.201, tumor necrosis factor alpha: p = 0.772). As expected, widespread gray matter reductions (cortical thickness, subcortical volumes, cortical folding) were observed in underweight patients with AN compared to HC. However, we found no evidence of associations between cytokine concentrations and structural brain measures in any participant group. Furthermore, longitudinal changes in cytokine concentrations were unrelated to changes in gray matter. In conclusion, we did not identify any association between (sub-)inflammatory processes and structural brain changes in AN. Future studies are needed to elucidate which other factors besides nutritional status may contribute to brain morphological alterations.

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.

Serum neurofilament light concentrations are associated with cortical thinning in anorexia nervosa.

BACKGROUND: Anorexia nervosa (AN) is characterized by severe emaciation and drastic reductions of brain mass, but the underlying mechanisms remain unclear. The present study investigated the putative association between the serum-based protein markers of brain damage neurofilament light (NF-L), tau protein, and glial fibrillary acidic protein (GFAP) and cortical thinning in acute AN. METHODS: Blood samples and magnetic resonance imaging scans were obtained from 52 predominantly adolescent, female patients with AN before and after partial weight restoration (increase in body mass index >14%). The effect of marker levels before weight gain and change in marker levels on cortical thickness (CT) was modeled at each vertex of the cortical surface using linear mixed-effect models. To test whether the observed effects were specific to AN, follow-up analyses exploring a potential general association of marker levels with CT were conducted in a female healthy control (HC) sample (n = 147). RESULTS: In AN, higher baseline levels of NF-L, an established marker of axonal damage, were associated with lower CT in several regions, with the most prominent clusters located in bilateral temporal lobes. Tau protein and GFAP were not associated with CT. In HC, no associations between damage marker levels and CT were detected. CONCLUSIONS: A speculative interpretation would be that cortical thinning in acute AN might be at least partially a result of axonal damage processes. Further studies should thus test the potential of serum NF-L to become a reliable, low-cost and minimally invasive marker of structural brain alterations in AN.

Liver and vitamin B12 parameters in patients with anorexia nervosa before and after short-term weight restoration.

Hepatic involvement in anorexia nervosa (AN) has been previously reported, but a link to elevated vitamin B12 concentrations, which can be a sign for liver damage, has not been thoroughly examined. We measured liver enzymes (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase) and vitamin B12 parameters (total B12, holotranscobalamin, methylmalonic acid) in the plasma of young female patients with acute AN (n=77) and after short-term weight restoration (n=58, median body mass increase=25%), in comparison to healthy control participants (n=63). For a comprehensive assessment of vitamin B12 status, the combined marker cB12 was calculated. In acute AN, activities of alanine aminotransferase and gamma-glutamyltransferase as well as holotranscobalamin concentrations were elevated, and alanine aminotransferase activities positively correlated with total B12, holotranscobalamin and cB12 in patients with elevated liver enzyme activities. After weight restoration, alanine aminotransferase activities and holotranscobalamin concentrations were elevated, and cB12 increased above the level of the healthy control group. The present study provides further evidence for a hepatic involvement in acute AN in concert with vitamin B12 parameters and points to refeeding-associated alterations of liver and vitamin B12 parameters. Future studies should include non-invasive methods to characterize hepatic involvement and evaluate vitamin B12 status as a potential marker of liver damage/irritation.

Neural and glial damage markers in women after long-term weight-recovery from anorexia nervosa.

PURPOSE: The acute state of anorexia nervosa (AN) is accompanied by increased peripheral concentrations of brain-derived damage markers indicative of ongoing neural and glial damage processes. Although these findings correspond with well-documented structural brain changes in the disorder, it remains unclear whether abnormal levels of brain-derived damage markers persist after long-term weight-recovery from AN. METHODS: To address this question, we used single-molecule array (Simoa) technology to measure serum levels of neurofilament light (NF-L), tau protein and glial fibrillary acidic protein (GFAP) in a group of 55 long-term weight-recovered women with a history of AN (recAN) and 55 age-matched healthy controls. Strict exclusion criteria allowed us to control for confounds present in previous studies including most importantly neurological conditions. RESULTS: We found not only no group differences but also statistical evidence for equal damage marker levels between groups using Bayesian hypothesis testing. CONCLUSION: These results provide evidence for the absence of neuronal and glial damage processes after long-term weight-recovery from AN. Together, our findings are indicative of complete normalization following long-term weight restoration provide hope that recovery from AN halts neuronal damage processes and support the need to test potential candidates for therapeutic interventions including pharmacological neuroprotection.

Associations between pituitary-thyroid hormones and depressive symptoms in individuals with anorexia nervosa before and after weight-recovery.

BACKGROUND: There is sound evidence that the hypothalamic-pituitary-thyroid axis plays a role in mood regulation. Alterations in this axis, particularly low triiodothyronine syndrome, are a common neuroendocrine adaptation to semi-starvation in patients with anorexia nervosa (AN), who also frequently suffer from co-existing depressive symptoms. We therefore aimed to investigate the associations between pituitary-thyroid function and psychopathology, in particular depressive symptoms, at different stages of AN using a combined cross-sectional and longitudinal study design. METHODS: Pituitary-thyroid status (FT3, free triiodothyronine; FT4, free thyroxine; conversion ratio FT3/FT4; TSH, thyroid-stimulating hormone) was assessed in 77 young acutely underweight females with AN (acAN) and in 55 long-term weight-recovered individuals with former AN (recAN) in a cross-sectional comparison to 122 healthy controls (HC). Further, pituitary-thyroid status of 48 acAN was reassessed after short-term weight-restoration. We performed correlation analyses of pituitary-thyroid parameters with self-reported measures of psychopathology. RESULTS: AcAN showed significantly lower FT3, FT4, FT3/FT4 ratio, and TSH levels compared to HC. Pituitary-thyroid alterations were partly reversed after short-term weight-restoration. RecAN still had lower FT3 concentrations than HC. Lower FT3 concentrations and FT3/FT4 ratios were associated with more severe depressive symptoms in acAN, occurring prominently in cases of manifest low triiodothyronine syndrome. Longitudinally increasing FT3/FT4 ratios (change scores) were inversely correlated with depressive and general psychiatric symptoms after short-term weight-restoration. CONCLUSIONS: Our results suggest a potential modulation of the severity of depressive symptoms by temporarily decreased FT3 concentrations and inhibited thyroid hormone conversion (FT3/FT4 ratios) in acutely underweight AN. Associations between conversion ratios FT3/FT4 and psychopathology seem to persist across short-term weight-restoration. The findings of our study might have relevant clinical implications, ranging from thyroid monitoring to experimental low-dose thyroid hormone supplementation in certain patients with AN showing severe psychiatric impairment and overt thyroid hormone alterations.

Harmonization of multi-scanner in vivo magnetic resonance spectroscopy: ENIGMA consortium task group considerations.

Magnetic resonance spectroscopy is a powerful, non-invasive, quantitative imaging technique that allows for the measurement of brain metabolites that has demonstrated utility in diagnosing and characterizing a broad range of neurological diseases. Its impact, however, has been limited due to small sample sizes and methodological variability in addition to intrinsic limitations of the method itself such as its sensitivity to motion. The lack of standardization from a data acquisition and data processing perspective makes it difficult to pool multiple studies and/or conduct multisite studies that are necessary for supporting clinically relevant findings. Based on the experience of the ENIGMA MRS work group and a review of the literature, this manuscript provides an overview of the current state of MRS data harmonization. Key factors that need to be taken into consideration when conducting both retrospective and prospective studies are described. These include (1) MRS acquisition issues such as pulse sequence, RF and B0 calibrations, echo time, and SNR; (2) data processing issues such as pre-processing steps, modeling, and quantitation; and (3) biological factors such as voxel location, age, sex, and pathology. Various approaches to MRS data harmonization are then described including meta-analysis, mega-analysis, linear modeling, ComBat and artificial intelligence approaches. The goal is to provide both novice and experienced readers with the necessary knowledge for conducting MRS data harmonization studies.

Hair-Based Assessment of Sex Steroid Hormones in Patients with Anorexia Nervosa.

Anorexia nervosa (AN) is a complex psychiatric disorder accompanied by a variety of endocrine effects. Altered levels of the sex steroid hormones progesterone and dehydroepiandrosterone (DHEA) have been shown to occur in patients with AN using short-term hormonal measurement methods based on blood, saliva, and urine samples. However, since sex steroid hormone levels fluctuate during the menstrual cycle, these measurement methods require a great deal of effort due to the need to collect multiple samples in order to correctly determine the basal level of sex hormones. In contrast, hair-based assessments provide a marker of accumulated longer-term hormone exposure using a single, non-invasive sample. The aim of this study was to investigate sex steroid hormone levels via hair-based assessments in acutely underweight AN in comparison with healthy, age-matched, female control participants. Additionally, we compared progesterone and DHEA hair levels longitudinally during inpatient treatment in AN. Collected hair samples were analyzed using liquid chromatography-mass spectrometry (LC-MS/MS) to determine a monthly hormone level of progesterone and DHEA. Our results indicate that DHEA hair hormone levels were similar across groups but progesterone was suppressed in underweight AN compared with healthy controls. In the longitudinal design, no significant change in hair hormone levels during partial weight restoration in patients with AN was observed. Our findings suggest that hair analysis can be used to detect suppressed progesterone levels in severe AN, and that progesterone does not increase during short-term weight restoration.

Adverse Effects of Refeeding on the Plasma Lipidome in Young Individuals With Anorexia Nervosa?

OBJECTIVE: Refeeding is the cornerstone of anorexia nervosa (AN) treatment, but little is known regarding the optimal pace and dietary composition or possible adverse effects of current clinical practices. Plasma lipids may be a moderating factor underlying unfavorable refeeding effects in AN, such as an abnormal central body fat distribution. The objective of this study was to analyze the plasma lipidome in the acutely underweight state of AN before and after refeeding. METHOD: Using high-throughput quantitative mass spectrometry-based shotgun lipidomics, we measured 13 lipid classes and 204 lipid species or subspecies in the plasma of young female patients with acute AN, before (n = 39) and after (n = 23) short-term weight restoration during an intensive inpatient refeeding program (median body mass index [BMI] increase = 26.4%), in comparison to those in healthy control participants (n = 37). RESULTS: Before inpatient treatment, patients with AN exhibited increased concentrations of cholesterol and several other lipid classes. After refeeding, multiple lipid classes including cholesterol and ceramides, as well as certain ceramide species previously associated with obesity or overfeeding, showed increased concentrations, and a pattern of shorter and more saturated triacylgycerides emerged. A machine learning model trained to predict BMI based on the lipidomic profiles revealed a sizable overprediction in patients with AN after weight restoration. CONCLUSION: The results point toward a profound lipid dysregulation with similarities to obesity and other features of the metabolic syndrome after short-term weight restoration. Thus, this study provides evidence for possible short-term adverse effects of current refeeding practices on the metabolic state and should inspire more research on nutritional interventions in AN.

Is Serum BDNF Altered in Acute, Short- and Long-Term Recovered Restrictive Type Anorexia Nervosa?

Brain-derived neurotrophic factor (BDNF), a neurotrophin involved in the regulation of food intake and body weight, has been implicated in the development and maintenance of Anorexia nervosa (AN). The majority of previous studies reported lower BDNF levels in acutely underweight AN patients (acAN) and increasing levels after weight rehabilitation. Here, we investigated serum BDNF concentrations in the largest known AN sample to date, both before and after weight restoration therapy. Serum BDNF was measured in 259 female volunteers: 77 in-patient acAN participants of the restrictive type (47 reassessed after short-term weight rehabilitation), 62 individuals long-term recovered from AN, and 120 healthy controls. We validated our findings in a post-hoc mega-analysis in which we reanalyzed combined data from the current sample and those from our previous study on BDNF in AN (combined sample: 389 participants). All analyses carefully accounted for known determinants of BDNF (age, sex, storage time of blood samples). We further assessed relationships with relevant clinical variables (body-mass-index, physical activity, symptoms). Contrary to our hypotheses, we found zero significant differences in either cross-sectional or longitudinal comparisons and no significant relationships with clinical variables. Together, our study suggests that BDNF may not be a reliable state- or trait-marker in AN after all.

Differential longitudinal changes of neuronal and glial damage markers in anorexia nervosa after partial weight restoration.

Atrophic brain changes in acute anorexia nervosa (AN) are often visible to the naked eye on computed tomography or magnetic resonance imaging scans, but it remains unclear what is driving these effects. In neurological diseases, neurofilament light (NF-L) and tau protein have been linked to axonal damage. Glial fibrillary acidic protein (GFAP) has been associated with astroglial injury. In an attempt to shed new light on factors potentially underlying past findings of structural brain alterations in AN, the current study investigated serum NF-L, tau protein, and GFAP levels longitudinally in AN patients undergoing weight restoration. Blood samples were obtained from 54 acutely underweight, predominantly adolescent female AN patients and 54 age-matched healthy control participants. AN patients were studied in the severely underweight state and again after short-term partial weight restoration. Group comparisons revealed higher levels of NF-L, tau protein, and GFAP in acutely underweight patients with AN compared to healthy control participants. Longitudinally, a decrease in NF-L and GFAP but not in tau protein levels was observed in AN patients upon short-term partial weight restoration. These results may be indicative of ongoing neuronal and astroglial injury during the underweight phase of AN. Normalization of NF-L and GFAP but not tau protein levels may indicate an only partial restoration of neuronal and astroglial integrity upon weight gain after initial AN-associated cell damage processes.

Hair endocannabinoid concentrations in individuals with acute and weight-recovered anorexia nervosa.

BACKGROUND: The endocannabinoid system has been suggested to modulate energy metabolism and stress response and could be an important factor in the pathophysiology of anorexia nervosa (AN). In the context of AN, excessive physical activity may influence endocannabinoid concentrations. The objective of this study was to investigate hair endocannabinoid concentrations at different stages of the disorder. Measurement in hair allows for a cumulative assessment of endocannabinoid concentrations independent of circadian rhythms. METHODS: In a combined cross-sectional and longitudinal design, we measured hair concentrations of the endocannabinoids anandamide and 2-arachidonoylglycerol and the endocannabinoid-related compounds palmitoylethanolamide, oleoylethanolamide, and stearoylethanolamide in female underweight patients with acute AN (n = 67, reassessment of n = 47 after short-term weight restoration with a body mass index increase of at least 14%), individuals long-term recovered from AN (n = 27), and healthy control participants (n = 84). RESULTS: Hair concentrations of anandamide and all endocannabinoid-related compounds were elevated in acute AN and decreased over the course of short-term weight restoration. Anandamide concentrations remained elevated in long-term recovered AN patients. In long-term recovered patients, physical activity correlated positively with the concentrations of all endocannabinoid-related compounds. CONCLUSION: The current study provides evidence for a significant alteration of the endocannabinoid system in acute AN, which may partly persist into long-term recovery. The endocannabinoid system may be a possible target for pharmaceutical interventions in AN, which should be explored in further preclinical and subsequently clinical randomized controlled trials.

Editorial: Refeeding in Anorexia Nervosa: Quo Vadis?

Refeeding is the cornerstone of treatment in anorexia nervosa (AN), a life-threatening eating disorder characterized by severe undernutrition. During refeeding, patients typically gain a large proportion of their body weight within a couple of weeks or months. The aims of this drastic nutritional intervention are mainly somatic stability and the improvement of the mental state of the patient, as a prerequisite for psychotherapy. There has been a recent trend away from the conventional low-calorie "start low, go slow" refeeding approach to higher calorie refeeding with a more rapid weight gain, shorter hospitalization time, and consequently, psychosocial and economic benefits. In favor of higher calorie refeeding, the rate of initial weight gain has been shown to predict weight recovery.1 Furthermore, recent neuroimaging studies suggest that the widespread reductions of gray matter volume and cortical thickness in acutely underweight AN patients abate rapidly after refeeding.2 Although the first studies provided evidence for the relative safety of higher calorie refeeding, particularly in the refeeding syndrome, a rare but possibly fatal complication,3,4 little is known about less acute side effects. However, relative to its significant clinical importance, the topic is understudied, and guidelines vary considerably across different countries. The clinical review at the focus of this editorial seeks to advance the medical literature by juxtaposing the details of refeeding protocols of 3 well-known specialized eating disorder centers.

DNA methylation of ghrelin and leptin receptors in underweight and recovered patients with anorexia nervosa.

Epigenetic mechanisms, which modulate gene expression, are becoming increasingly important in the research on anorexia nervosa (AN). Patients with AN have difficulties with the perception of hunger even though hormones like high ghrelin and low leptin signal the need for energy intake. Given the prominent role of the growth hormone secretagogue receptor (GHS-R1a) and the leptin receptor (LEPR) in appetite regulation, a dysregulation of the receptors' expression levels, possibly resulting from altered DNA promoter methylation, may contribute to the pathophysiology of AN. Such alterations could be secondary effects of undernutrition (state markers) or biological processes that may play an antecedent, possibly causal, role in the pathophysiology (trait markers). Therefore, the objective of this study was to examine DNA promoter methylation of the GHS-R1a and LEPR gene promoter regions and investigate whether methylation levels are associated with AN symptoms. We studied medication-free underweight patients with acute AN as well as weight-recovered patients and normal-weight, healthy female control subjects. While DNA methylation of the LEPR gene was similar across groups, GHS-R1a promoter methylation was increased in underweight AN compared to healthy controls - a finding which can be interpreted within the framework of the "ghrelin-resistance" hypothesis in AN. The results of the current study suggest for the first time a potential epigenetic mechanism underlying altered GHS-R1a sensitivity or altered ghrelin signaling in acutely underweight AN. If a ghrelin-centered model of AN can be verified, a next step could be the search for a dietary or psychopharmacological modulation at the ghrelin receptor, potentially via epigenetic mechanisms.

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.

Nutritional Status Affects Cortical Folding: Lessons Learned From Anorexia Nervosa.

BACKGROUND: Cortical folding is thought to remain relatively invariant after birth. Therefore, differences seen in psychiatric disorders have been proposed as early biomarkers or used as intermediate phenotypes in imaging genetics studies. Anorexia nervosa (AN) is associated with drastic and rapid structural brain alterations and thus may be an ideal model disorder to study environmental influences on cortical folding. METHODS: To date, the only two studies in AN applied different methods (local gyrification index and mean curvature) and found seemingly discordant results. We computed both vertexwise measures in a sizable sample of acutely underweight female AN patients (n = 87, mean age 16.5 years), long-term recovered patients (n = 58, mean age 22 years), and healthy control participants (n = 141, mean age 19.5 years). The majority of acutely ill patients were scanned longitudinally (n = 57) again after partial weight normalization (>14% body mass index increase). RESULTS: While gyrification was broadly reduced in acutely ill patients, normal values were restored in most brain regions after partial weight restoration (≈3 months), and after full recovery no significant differences were evident relative to control participants. Increased gyrification was largely predicted by weight restoration alone. Results for absolute mean curvature analyses complemented those obtained using the local gyrification index. CONCLUSIONS: Together, these findings indicate that nutritional status affects cortical folding and suggest that gyrification studies may need to better control for environmental factors. Moreover, they provide novel support for the likelihood that macroscopic changes in the cortical organization in AN are more reflective of nutritional state than premorbid trait markers or permanent scars.

Altered behavioral and amygdala habituation in high-functioning adults with autism spectrum disorder: an fMRI study.

Habituation to repeatedly presented stimuli is an important adaptive property of the nervous system. Autism spectrum disorder (ASD) has been associated with reduced neural habituation, for example in the amygdala, which may be related to social impairments. The main focus of this study was to investigate habituation effects on the level of behavioral responses as well as amygdala responses in adults with ASD during a working memory task flanked by task-irrelevant face stimuli. Twenty-two patients with high-functioning autism and 24 healthy controls (HC) were included in this functional magnetic resonance imaging (fMRI) study. We employed an established habituation index to investigate habituation effects. Suggestive of altered habituation, the habituation index showed a decrement of reaction time over the course of the experiment in the HC but not in the ASD group. Similarly, an expected pattern of habituation was evident in amygdala activation in HC but absent in ASD participants. These results provide evidence that habituation may be altered not only on a neural, but also on a behavioral level in ASD. While more research is needed to develop a better understanding of the underlying mechanisms, the current findings support the possibility that deficient habituation may be a biomarker of ASD.

Effects of perceptual body image distortion and early weight gain on long-term outcome of adolescent anorexia nervosa.

Anorexia nervosa (AN), a severe mental disorder with an onset during adolescence, has been found to be difficult to treat. Identifying variables that predict long-term outcome may help to develop better treatment strategies. Since body image distortion and weight gain are central elements of diagnosis and treatment of AN, the current study investigated perceptual body image distortion, defined as the accuracy of evaluating one's own perceived body size in relation to the actual body size, as well as total and early weight gain during inpatient treatment as predictors for long-term outcome in a sample of 76 female adolescent AN patients. Long-term outcome was defined by physical, psychological and psychosocial adjustment using the Morgan-Russell outcome assessment schedule as well as by the mere physical outcome consisting of menses and/or BMI approximately 3 years after treatment. Perceptual body image distortion and early weight gain predicted long-term outcome (explained variance 13.3 %), but not the physical outcome alone. This study provides first evidence for an association of perceptual body image distortion with long-term outcome of adolescent anorexia nervosa and underlines the importance of sufficient early weight gain.