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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., (© 2023. Springer Nature Limited.)

Background: Anorexia nervosa (AN) is characterized by disturbances in cognition and behavior surrounding eating and weight. The severity of AN combined with the absence of localized brain abnormalities suggests distributed, systemic underpinnings that may be identified using diffusion-weighted magnetic resonance imaging and tractography to reconstruct white matter pathways., Methods: Diffusion-weighted magnetic resonance imaging data acquired from female patients with AN (n= 147) and female healthy control (HC) participants (n = 119), ages 12 to 40 years, were combined across 5 studies. Probabilistic tractography was completed, and full-cortex connectomes describing streamline counts between 84 brain regions were generated and harmonized. Graph theory methods were used to describe alterations in network organization in AN. The network-based statistic tested between-group differences in brain subnetwork connectivity. The metrics strength and efficiency indexed the connectivity of brain regions (network nodes) and were compared between groups using multiple linear regression., Results: Individuals with AN, relative to HC peers, had reduced connectivity in a network comprising subcortical regions and greater connectivity between frontal cortical regions (p < .05, familywise error corrected). Node-based analyses indicated reduced connectivity of the left hippocampus in patients relative to HC peers (p < .05, permutation corrected). Severity of illness, assessed by body mass index, was associated with subcortical connectivity (p < .05, uncorrected)., Conclusions: Analyses identified reduced structural connectivity of subcortical networks and regions, and stronger cortical network connectivity, among individuals with AN relative to HC peers. These findings are consistent with alterations in feeding, emotion, and executive control circuits in AN, and may direct hypothesis-driven research into mechanisms of persistent restrictive eating behavior., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Cortical differences have been reported in Anorexia Nervosa (AN) compared with healthy controls (HC); however, it is unclear if Autism Spectrum Disorder (ASD) characteristics are related to these cortical differences. The aim of this study was to examine if structural measures were correlated to ASD traits in AN. In total 184 female participants participated in the study; 57 acutely underweight AN participants (AAN), 59 weight-restored participants (WR) and 68 HC. Participants underwent structural magnetic resonance imaging as well as completing the Autism Diagnostic Observation schedule, second edition to examine ASD characteristics. Group differences in curvature, gyrification, surface area, thickness, global grey matter and white matter were measured. Correlation and regression analysis were conducted to examine the relationship between cortical measures and ASD characteristics. Two decreased gyrification clusters in the right post central and supramarginal gyrus and decreased global grey matter were observed in the AAN group compared to HC and WR. No correlations between ASD traits and structural measures existed. Our results suggest structural differences seen in individuals with AN do not appear to be related to ASD characteristics., (© 2022 The Authors. European Eating Disorders Review published by Eating Disorders Association and John Wiley & Sons Ltd.)

Anorexia nervosa (AN) is a highly debilitating mental illness with multifactorial etiology. It oftentimes begins in adolescence, therefore understanding the pathophysiology in this period is important. Few studies investigated the possible impact of the acute state of illness on white matter (WM) tissue properties in the developing adolescent brain. The present study expands our understanding of the implications of AN and starvation on WM integrity. 67 acutely ill adolescent patients suffering from AN restricting type were compared with 32 healthy controls using diffusion tensor imaging assessing fractional anisotropy (FA) and mean diffusivity (MD). We found widespread alterations in the vast majority of the WM regions with significantly decreased FA and increased MD in the AN group. In this highly selective sample in the acute stage of AN, the alterations are likely to be the consequence of starvation. Still, we cannot rule out that some of the affected regions might play a key role in AN-specific psychopathology., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Whole-brain T1-weighted imaging and diffusion tensor imaging was performed in 35 adult women with anorexia nervosa (AN) and 35 healthy controls. We conducted voxel-based group comparisons for gray matter volume (GMV), cortical thickness (CT), and fractional anisotropy (FA) values, using age and total intracranial volume as nuisance covariates. We then conducted the same group comparisons for these three measures, but this time also controlled for the following global pathological measures: total GMV, mean CT across the whole brain, and mean FA across the entire white matter skeleton. Compared with the healthy controls, AN patients had lower GMV and CT in widespread cortical regions, and smaller FA values in widespread white matter regions. After controlling for global parameters, almost all of the differences between the two groups disappeared, except for higher CT in the medial orbital gyrus and parietal operculum in the AN group. Structural brain changes in AN are likely to be composed of both global and region-specific changes. The former changes are likely to have a dominant impact, while the latter changes might in part explain the disease-specific pathophysiology of AN., (Copyright © 2021. Published by Elsevier B.V.)

Introduction: Disruptions in homeostatic and hedonic food motivation are proposed to underlie anorexia nervosa (AN) and atypical AN, restrictive eating disorders which commonly onset in puberty. Ghrelin, a neuroprotective hormone that drives hedonic eating is increased in AN and is expressed in the hippocampus. White matter (WM) undergoes significant change during puberty in regions involved in food motivation, particularly WM tracts connected with the hippocampus. The association between ghrelin and WM region of interest (ROI) with hippocampal connections in restrictive eating disorders, particularly in adolescence during key neurodevelopmental growth, is unknown., Methods: We evaluated fasting plasma ghrelin and WM microstructure (measured by free-water corrected fractional anisotropy (FA-t)) in WM ROIs with hippocampal connections - the fornix and the hippocampal portion of the cingulum - in 56 adolescent females (age range: 11.9 - 22.1 y; mean: 19.0 y) with low-weight eating disorders including AN and atypical AN (N = 36) and healthy controls (N = 20)., Results: FA-t in the fornix or hippocampal portion of the fornix did not differ between groups. Ghrelin was higher in AN/atypical AN vs. HC and was positively correlated with puberty stage in the AN/atypical AN group, but not the HC group. The correlation between ghrelin and FA-t in the fornix was significantly different in females with AN/atypical AN compared to controls. In AN/atypical AN, pubertal stage moderated the relation between fasting plasma ghrelin and FA-t in the fornix: higher fasting ghrelin was associated with lower FA-t in the fornix in late-post-puberty, but was not associated with FA-t in the early to mid stages of puberty., Conclusions: In post-pubertal females with low-weight AN/atypical AN, higher levels of ghrelin are associated with lower FA-t in the fornix. This relationship is not evident in the early to mid stages of puberty in AN/atypical AN or in HC, and may reflect a lack of possible neuroprotective effects of ghrelin in late-post puberty only. Understanding the effects of ghrelin on WM microstructure longitudinally and following recovery from AN/Atypical AN and how this differs across pubertal stages will be an important next step. These findings could ultimately inform treatment staging and aid in diagnosis and detection of AN/atypical AN., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Gray matter (GM) 'pseudoatrophy' is well-documented in patients with anorexia nervosa (AN), but changes in white matter (WM) are less well understood. Here we investigated the dynamics of microstructural WM brain changes in AN patients during short-term weight restoration in a combined longitudinal and cross-sectional study design., Methods: Diffusion-weighted images were acquired in young AN patients before (acAN-Tp1, n = 56) and after (acAN-Tp2, n = 44) short-term weight restoration as well as in age-matched healthy controls (HC, n = 60). Images were processed using Tract-Based-Spatial-Statistics to compare fractional anisotropy (FA) across groups and timepoints., Results: In the cross-sectional comparison, FA was significantly reduced in the callosal body in acAN-Tp1 compared with HC, while no differences were found between acAN-Tp2 and HC. In the longitudinal arm, FA increased with weight gain in acAN-Tp2 relative to acAN-Tp1 in large parts of the callosal body and the fornix, while it decreased in the right corticospinal tract., Conclusions: Our findings reveal that dynamic, bidirectional changes in WM microstructure in young underweight patients with AN can be reversed with brief weight restoration therapy. These results parallel those previously observed in GM and suggest that alterations in WM in non-chronic AN are also state-dependent and rapidly reversible with successful intervention.

Anorexia nervosa (AN) is a severe psychiatric disorder with a complex and poorly understood etiology. Recent studies have sought to investigate differences in white matter microstructure in AN, with significant results in several brain regions. A systematic literature search of Embase, PubMed and Psychinfo databases was conducted in order to identify Diffusion Tensor Imaging (DTI) studies of patients with AN and controls. We performed a meta-analysis of studies that met our inclusion criteria (N = 13) using effect size-signed differential mapping (AES-SDM) to detect differences in Fractional Anisotropy (FA) in patients with AN (N = 227) compared to healthy controls (N = 243). The quantitative meta-analysis of DTI studies identified decreased FA in the posterior areas of the corpus callosum, the left superior longitudinal fasciculus II, and the left precentral gyrus, as well as increased FA in the right cortico-spinal projections, and lingual gyrus in AN vs. controls. Studies of WM architecture are still limited in AN; further studies with longitudinal design are needed to better understand the complexity of abnormalities, and their persistence., (Copyright © 2019. Published by Elsevier Ltd.)

Objective: Reduced grey (GM) and white matter (WM) volumes and increased cerebrospinal fluid (CSF) have been frequently reported in anorexia nervosa (AN), but studies focusing on cortical thickness (CT) are scarce and findings inconsistent. We conducted the first study in AN that analyzed both parameters in the same study to gain novel and comprehensive insight., Method: Voxel-based morphometry (VBM) analysis was performed on T1-weighted magnetic resonance images from 34 predominantly adult women with acute AN, 24 REC participants, and 41 healthy controls (HC). Global brain segment volumes (GM, WM, and CSF), regional GM volume, and cortical thickness measures were obtained from the same study sample. We further focused on recovery by including a REC group., Results: The GM and WM volumes were decreased, and correspondingly, the CSF volume increased in the AN in comparison to the HC and REC groups. No significant volume differences between the REC and HC groups could be observed. AN patients showed reduced regional GM volumes in the right hippocampus and the left middle and right inferior frontal gyrus. Cortical thinning occurred in the AN group, which was particularly robust in fronto-parietal areas. The REC and HC groups failed to show any regional GM or cortical thickness differences., Discussion: AN is accompanied by severe loss of brain volume and cortical thickness as assessed by complementary investigation tools. However, these changes seem to be largely reversible, which should be encouraging for therapists and patients. The underlying neurobiological mechanisms remain unclear and should be assessed in further studies., (© 2018 Wiley Periodicals, Inc.)

Objectives: Studies point to white matter (WM) microstructure alterations in both adolescent and adult patients with anorexia nervosa (AN). These include reduced fractional anisotropy in several WM fiber tracts, suggesting reduced WM integrity. The extent to which these alterations are reversible with recovery from AN is unclear. There is a paucity of research investigating the presence of WM microstructure alterations in recovered AN patients, and results are inconsistent. This study aimed to investigate the presence of WM microstructure alterations in women long-term recovered from AN., Method: Twenty-one adult women who were recovered from AN for at least 1 year were compared to 21 adult comparison women. Participants were recruited via user-organizations for eating disorders, local advertisements, and online forums. Diffusion tensor imaging was used to compare WM microstructure between groups. Correlations between WM microstructure and clinical characteristics were also explored., Results: There were no statistically significant between-group differences in WM microstructure. These null findings remained when employing liberal alpha level thresholds. Furthermore, there were no statistically significant correlations between WM microstructure and clinical characteristics., Discussion: Our findings showed normal WM microstructure in long-term recovered patients, indicating the alterations observed during the acute phase are reversible. Given the paucity of research and inconsistent findings, future studies are warranted to determine the presence of WM microstructure alterations following recovery from AN., (© 2017 Wiley Periodicals, Inc.)

Few studies have examined white matter (WM) integrity in long-lasting Anorexia Nervosa (AN) patients using Diffusion Tensor Imaging (DTI). In this paper, we investigated WM integrity at the earliest stages of AN (i.e. less than 6 months duration). Fourteen treatment-naive female adolescents with AN restrictive type (AN-r) in its earliest stages and 15 age-matched healthy females received brain MRI. Fractional Anisotropy (FA), Axial Diffusivity (AD), Radial diffusivity (RD), and Mean Diffusivity (MD) maps were computed from DTI data using Tract-Based Spatial Statistics analysis. AN-r patients showed FA decreases compared to controls (p FWE < 0.05) mainly in left anterior and superior corona radiata and left superior longitudinal fasciculus. AN-r patients also showed decreased AD in superior longitudinal fasciculus bilaterally and left superior and anterior corona radiata, (p FWE < 0.05). No significant differences were found in RD and MD values between the two groups. FA and AD integrity appears to be specifically affected at the earliest stages of AN. Alterations in the microstructural properties of the above mentioned tracts, also involved in cognitive control and visual perception and processing, may be early mechanisms of vulnerability/resilience of WM in AN and sustain the key symptoms of AN, such as impaired cognitive flexibility and body image distortion., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Background: Anorexia nervosa (AN) often begins in adolescence, however, the understanding of the underlying pathophysiology at this developmentally important age is scarce, impeding early interventions. We used diffusion tensor imaging (DTI) to investigate microstructural white matter (WM) brain changes including an experimental longitudinal follow-up., Methods: We acquired whole brain diffusion-weighted brain scans of 22 adolescent female hospitalized patients with AN at admission and nine patients longitudinally at discharge after weight rehabilitation. Patients (10-18 years) were compared to 21 typically developing controls (TD). Tract-based spatial statistics (TBSS) were applied to compare fractional anisotropy (FA) across groups and time points. Associations between average FA values of the global WM skeleton and weight as well as illness duration parameters were analyzed by multiple linear regression., Results: We observed increased FA in bilateral frontal, parietal and temporal areas in AN patients at admission compared to TD. Higher FA of the global WM skeleton at admission was associated with faster weight loss prior to admission. Exploratory longitudinal analysis showed this FA increase to be partially normalized after weight rehabilitation., Conclusions: Our findings reveal a markedly different pattern of WM microstructural changes in adolescent AN compared to most previous results in adult AN. This could signify a different susceptibility and reaction to semi-starvation in the still developing brain of adolescents or a time-dependent pathomechanism differing with extend of chronicity. Higher FA at admission in adolescents with AN could point to WM fibers being packed together more closely.

Anorexia nervosa is a severe psychiatric disorder associated with reduced drive to eat. Altered taste-reward circuit white matter fiber organization in anorexia nervosa after recovery could indicate a biological marker that alters the normal motivation to eat. Women recovered from restricting-type anorexia (Recovered AN, n = 24, age = 30.3 ± 8.1 years) and healthy controls (n = 24, age = 27.4 ± 6.3 years) underwent diffusion weighted imaging of the brain. Probabilistic tractography analyses calculated brain white matter connectivity (streamlines) as an estimate of fiber connections in taste-reward-related white matter tracts, and microstructural integrity (fractional anisotropy, FA) was assessed using tract-based spatial statistics. Recovered AN showed significantly (range P<0.05-0.001, Bonferroni corrected) greater white matter connectivity between bilateral insula regions and ventral striatum, left insula and middle orbitofrontal cortex (OFC), and right insula projecting to gyrus rectus and medial OFC. Duration of illness predicted connectivity of tracts projecting from the insula to ventral striatum and OFC. Microstructural integrity was lower in Recovered AN in most insula white matter tracts, as was whole-brain FA in parts of the anterior corona radiata, external capsule, and cerebellum (P<0.05, family-wise error-corrected). This study indicates higher structural white matter connectivity, an estimate of fibers connections, in anorexia after recovery in tracts that connect taste-reward processing regions. Greater connectivity together with less-fiber integrity could indicate altered neural activity between those regions, which could interfere with normal food-reward circuit function. Correlations between connectivity and illness duration suggest that connectivity could be a marker for illness severity. Whether greater connectivity can predict prognosis of the disorder requires further study.

Anorexia nervosa (AN) is a serious eating disorder that typically emerges during adolescence and occurs most frequently in females. To date, very few studies have investigated the possible impact of AN on white matter tissue properties during adolescence, when white matter is still developing. The present study evaluated white matter tissue properties in adolescent girls with AN using diffusion MRI with tractography and T1 relaxometry to measure R1 (1/T1), an index of myelin content. Fifteen adolescent girls with AN (mean age = 16.6 years ± 1.4) were compared to fifteen age-matched girls with normal weight and eating behaviors (mean age = 17.1 years ± 1.3). We identified and segmented 9 bilateral cerebral tracts (18) and 8 callosal fiber tracts in each participant's brain (26 total). Tract profiles were generated by computing measures for fractional anisotropy (FA) and R1 along the trajectory of each tract. Compared to controls, FA in the AN group was significantly decreased in 4 of 26 white matter tracts and significantly increased in 2 of 26 white matter tracts. R1 was significantly decreased in the AN group compared to controls in 11 of 26 white matter tracts. Reduced FA in combination with reduced R1 suggests that the observed white matter differences in AN are likely due to reductions in myelin content. For the majority of tracts, group differences in FA and R1 did not occur within the same tract. The present findings have important implications for understanding the neurobiological factors underlying white matter changes associated with AN and invite further investigations examining associations between white matter properties and specific physiological, cognitive, social, or emotional functions affected in AN.

Background: Acute anorexia nervosa (AN) is associated with marked brain volume loss potentially leading to neuropsychological deficits. However, the mechanisms leading to this brain volume loss and its influencing factors are poorly understood and the clinical relevance of these brain alterations for the outcome of these AN-patients is yet unknown., Methods: Brain volumes of 56 female adolescent AN inpatients and 50 healthy controls (HCs) were measured using MRI scans. Multiple linear regression analyses were used to determine the impact of body weight at admission, prior weight loss, age of onset and illness duration on volume loss at admission and to analyse the association of brain volume reduction with body weight at a 1-year follow-up (N = 25)., Results: Cortical and subcortical grey matter (GM) and cortical white matter (WM) but not cerebellar GM or WM were associated with low weight at admission. Amount of weight loss, age of onset and illness duration did not independently correlate with any volume changes. Prediction of age-adjusted standardized body mass index (BMI-SDS) at 1-year follow-up could be significantly improved from 34% of variance explained by age and BMI-SDS at admission to 47.5-53% after adding cortical WM, cerebellar GM or WM at time of admission., Conclusion: Whereas cortical GM changes appear to be an unspecific reflection of current body weight ("state marker"), cortical WM and cerebellar volume losses seem to indicate a longer-term risk (trait or "scar" of the illness), which appear to be important for the prediction of weight rehabilitation and long-term outcome., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: The etiology of anorexia nervosa is still unknown. Multiple and distributed brain regions have been implicated in its pathophysiology, implying a dysfunction of connected neural circuits. Despite these findings, the role of white matter in anorexia nervosa has been rarely assessed. In this study, we used diffusion tensor imaging (DTI) to characterize alterations of white matter microstructure in a clinically homogeneous sample of patients with anorexia nervosa., Methods: Women with anorexia nervosa (restricting subtype) and healthy controls underwent brain DTI. We used tract-based spatial statistics to compare fractional anisotropy (FA) and mean diffusivity (MD) maps between the groups. Furthermore, axial (AD) and radial diffusivity (RD) measures were extracted from regions showing group differences in either FA or MD., Results: We enrolled 19 women with anorexia nervosa and 19 healthy controls in our study. Patients with anorexia nervosa showed significant FA decreases in the parietal part of the left superior longitudinal fasciculus (SLF; p(FWE) < 0.05), with increased MD and RD but no differences in AD. Patients with anorexia nervosa also showed significantly increased MD in the fornix (p(FWE) < 0.05), accompanied by decreased FA and increased RD and AD., Limitations: Limitations include our modest sample size and cross-sectional design., Conclusion: Our findings support the presence of white matter pathology in patients with anorexia nervosa. Alterations in the SLF and fornix might be relevant to key symptoms of anorexia nervosa, such as body image distortion or impairments in body-energy-balance and reward processes. The differences found in both areas replicate those found in previous DTI studies and support a role for white matter pathology of specific neural circuits in individuals with anorexia nervosa.