Thinning of the retinal nerve fiber and choroidal layers in adolescents with anorexia nervosa: A controlled study.

PURPOSE: We aimed to evaluate retinal nerve fiber and choroidal layer alterations in adolescents with anorexia nervosa using spectral-domain optical coherence tomography. METHODS: Thirty patients with anorexia nervosa and 30 healthy adolescents aged 12-18 years were included in this study. Their age, sex, body mass index, anorexia nervosa type, disease duration, and spectral-domain optical coherence tomography data were recorded. RESULTS: Central macular thickness and retinal nerve fiber layer thickness in the temporal and inferior regions were significantly lesser in patients with anorexia than in healthy controls (p<0.05). Moreover, significant choroidal thinning around the foveal and subfoveal regions in patients with anorexia was observed (p<0.05). In addition, a statistically significant relation between the increase in disease duration and the thinning of the inferior retinal nerve fiber layer was detected (p<0.05). CONCLUSION: The retinal nerve fiber layer and choroidal layer thicknesses were lesser in patients with anorexia than in healthy controls. Screening for retinal indices might prevent the development of irreversible retinal pathologies in adolescents with anorexia nervosa. In addition, thinning of the retinal nerve fiber and choroidal layers could reflect structural or functional changes in the brain of adolescents with anorexia nervosa.

Intra-individual cortical networks in Anorexia Nervosa: Evidence from a longitudinal dataset.

OBJECTIVE: This work investigates cortical thickness (CT) and gyrification patterns in Anorexia Nervosa (AN) before and after short-term weight restoration using graph theory tools. METHODS: 38 female adolescents with AN underwent structural magnetic resonance imaging scans at baseline and after - on average - 3.5 months following short-term weight restoration while 53 age-matched healthy controls (HCs) were scanned once. Graph measures were compared between groups and longitudinally within the AN group. Associations with clinical measures such as age of onset, duration of illness, BMI standard deviation score (BMI-SDS), and longitudinal weight changes were tested via stepwise regression. RESULTS: Cortical thickness graphs of patients with acute AN displayed lower modularity and small-world index (SWI) than HCs. Modularity recovered after weight gain. Reduced global efficiency and SWI were observed in patients at baseline compared to HCs based on gyrification networks. Significant associations between local clustering of CT at admission and BMI-SDS, and clustering/global efficiency of gyrification and duration of illness emerged. CONCLUSIONS: Our results indicate a shift towards less organised CT networks in patients with acute AN. After weight recovery, the disarrangement seems to be partially reduced. However, longer-term follow-ups are needed to determine whether cortical organizational patterns fully return to normal.

Bone in Anorexia.

Anorexia nervosa is a feeding disorder involving intentional weight loss. Restricted dietary intake leads to disturbed bone metabolism due to various factors, notably endocrine, that affect bone microarchitecture and incur risk of fracture. Mild to moderate anorexia shows a paradoxical increase in bone marrow adipose tissue, whereas severe forms show gelatinous transformation known as serous atrophy of bone marrow (SABM). Imaging assessment of the mineralized and adipose components uses several techniques: dual-energy X-ray absorptiometry, computed tomography, chemical shift magnetic resonance imaging (MRI), and single-voxel MR spectroscopy. SABM induces MRI bone signal disturbances that can be hard to interpret and may hinder visualization of the fracture line.

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.

Can neuroimaging measures differentiate the disease course of anorexia nervosa? A systematic review.

Anorexia nervosa (AN) entails many uncertainties regarding the clinical outcome, due to large heterogeneity in the disease course. AN is associated with global decrease in brain volumes and altered brain functioning during acute illness. However, it is unclear whether structural and functional brain alterations can predict clinical outcome. We aimed to systematically review the predictive value of volumetric and functional brain outcome measures of structural and functional brain magnetic resonance imaging (MRI) on the disease course of AN. Four databases (Embase, Medline, Psycinfo, and Cochrane Central Register) were systematically searched. A total of 15 studies (structural MRI: n = 6, functional MRI: n = 9) were reviewed. In total 464 unique AN patients, and 328 controls were included. Follow-up time ranged between 1 and 43 months. Structural neuroimaging studies showed that lower brain volumes of the cerebellum, subcortical grey matter, and cortical white matter at admission predicted a worse clinical outcome. A smaller increase of the anterior cingulate cortex volume in the early phase of the disease predicted a worse clinical outcome. Lower overall gyrification, and a higher clustering coefficient predicted a worse clinical outcome. Functional MRI studies showed that frontal, parietal and temporal activity during task-based algorithms predicted follow-up body mass index, although results were bidirectional possibly due to the large heterogeneity in methodological approaches. Neuroimaging measures may predict the clinical outcome of AN. However, there is a lack of replication studies. Future studies are needed to validate the prognostic utility of neuroimaging measures in AN patients, and should harmonize demographic, clinical and neuroimaging features in order to enhance comparability.

Association between childhood maltreatment and cortical folding in women with eating disorders.

Childhood maltreatment (CM) is associated with distinct clinical and biological characteristics in people with eating disorders (EDs). The measurement of local gyrification index (lGI) may help to better characterize the impact of CM on cortical structure. Thus, the present study investigated the association of CM with lGI in women with EDs. Twenty-six women with anorexia nervosa (AN) and 24 with bulimia nervosa (BN) underwent a 3T MRI scan. All participants filled in the Childhood Trauma Questionnaire. All neuroimaging data were processed by FreeSurfer. LGI maps underwent a general linear model to evaluate differences between groups with or without CM. People with AN and BN were merged together. Based on the Childhood Trauma Questionnaire cutoff scores, 24 participants were identified as maltreated and 26 as non-maltreated. Maltreated people with EDs showed a significantly lower lGI in the left middle temporal gyrus compared with non-maltreated people, whereas no differences emerged in the right hemisphere between groups. The present study showed that in people with EDs, CM is associated with reduced cortical folding in the left middle temporal gyrus, an area that could be involved in ED psychopathology. This finding corroborates the hypothesis of a 'maltreated ecophenotype', which argues that CM may allow to biologically, other than clinically, distinguish individuals with the same psychiatric disorder.

Differential alterations of amygdala nuclei volumes in acutely ill patients with anorexia nervosa and their associations with leptin levels.

BACKGROUND: The amygdala is a subcortical limbic structure consisting of histologically and functionally distinct subregions. New automated structural magnetic resonance imaging (MRI) segmentation tools facilitate the in vivo study of individual amygdala nuclei in clinical populations such as patients with anorexia nervosa (AN) who show symptoms indicative of limbic dysregulation. This study is the first to investigate amygdala nuclei volumes in AN, their relationships with leptin, a key indicator of AN-related neuroendocrine alterations, and further clinical measures. METHODS: T1-weighted MRI scans were subsegmented and multi-stage quality controlled using FreeSurfer. Left/right hemispheric amygdala nuclei volumes were cross-sectionally compared between females with AN (n = 168, 12-29 years) and age-matched healthy females (n = 168) applying general linear models. Associations with plasma leptin, body mass index (BMI), illness duration, and psychiatric symptoms were analyzed via robust linear regression. RESULTS: Globally, most amygdala nuclei volumes in both hemispheres were reduced in AN v. healthy control participants. Importantly, four specific nuclei (accessory basal, cortical, medial nuclei, corticoamygdaloid transition in the rostral-medial amygdala) showed greater volumetric reduction even relative to reductions of whole amygdala and total subcortical gray matter volumes, whereas basal, lateral, and paralaminar nuclei were less reduced. All rostral-medially clustered nuclei were positively associated with leptin in AN independent of BMI. Amygdala nuclei volumes were not associated with illness duration or psychiatric symptom severity in AN. CONCLUSIONS: In AN, amygdala nuclei are altered to different degrees. Severe volume loss in rostral-medially clustered nuclei, collectively involved in olfactory/food-related reward processing, may represent a structural correlate of AN-related symptoms. Hypoleptinemia might be linked to rostral-medial amygdala alterations.

Large-Scale Exploration of Whole-Brain Structural Connectivity in Anorexia Nervosa: Alterations in the Connectivity of Frontal and Subcortical Networks.

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.

Pneumatosis Intestinalis and Anorexia Nervosa.

Background: Pneumatosis intestinalis (PI), the presence of gas within the intestinal wall, is a condition historically associated with many diagnoses and can be life-threatening. The purpose of this article is to understand PI better in the setting of malnutrition secondary to anorexia nervosa (AN), a condition not historically affiliated with PI. Patients and Methods: In this retrospective study, the clinical findings of seven patients with AN are reported. Results: The patients were all found to have PI involving the right colon, with only a single patient also found to have PI involving additional colonic areas. No patients had small intestine involvement, and most of the patients were also diagnosed with the binge-purge subtype of AN, were receiving tube feeds, and had tenderness on abdominal examination. All seven patients were managed non-operatively. Conclusions: The authors propose that there may be an association between AN and PI. Given the surgical risks associated with malnutrition, the decision to pursue surgery, in the absence of the discussed pathologic risk factors, should be made in a very thoughtful manner. Future studies are warranted to better understand this potential association between PI and AN.

Examining the relationship between autistic spectrum disorder characteristics and structural brain differences seen in anorexia nervosa.

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.

Initial evidence of abnormal brain plasticity in anorexia nervosa: an ultra-high field study.

Anorexia Nervosa has been associated with white matter abnormalities implicating subcortical abnormal myelination. Extending these findings to intracortical myelin has been challenging but ultra-high field neuroimaging offers new methodological opportunities. To test the integrity of intracortical myelin in AN we used 7 T neuroimaging to acquire T1-weighted images optimized for intracortical myelin from seven females with AN (age range: 18-33) and 11 healthy females (age range: 23-32). Intracortical T1 values (inverse index of myelin concentration) were extracted from 148 cortical regions at ten depth-levels across the cortical ribbon. Across all cortical regions, these levels were averaged to generate estimates of total intracortical myelin concentration and were clustered using principal component analyses into two clusters; the outer cluster comprised T1 values across depth-levels ranging from the CSF boundary to the middle of the cortical regions and the inner cluster comprised T1 values across depth-levels ranging from the middle of the cortical regions to the gray/white matter boundary. Individuals with AN exhibited higher T1 values (i.e., decreased intracortical myelin concentration) in all three metrics. It remains to be established if these abnormalities result from undernutrition or specific lipid nutritional imbalances, or are trait markers; and whether they may contribute to neurobiological deficits seen in AN.

White matter integrity is disrupted in adolescents with acute anorexia nervosa: A diffusion tensor imaging study.

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.

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.

Structural brain changes in severe and enduring anorexia nervosa: A multimodal magnetic resonance imaging study of gray matter volume, cortical thickness, and white matter integrity.

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.

Is the Activity-Based Anorexia Model a Reliable Method of Presenting Peripheral Clinical Features of Anorexia Nervosa?

Anorexia nervosa (AN) causes the highest number of deaths among all psychiatric disorders. Reduction in food intake and hyperactivity/increased anxiety observed in AN are also the core features of the activity-based anorexia animal model (ABA). Our aim was to assess how the acute ABA protocol mimics common AN complications, including gonadal and cardiovascular dysfunctions, depending on gender, age, and initial body weight, to form a comprehensive description of ABA as a reliable research tool. Wheel running, body weight, and food intake of adolescent female and male rats were monitored. Electrocardiography, heart rate variability, systolic blood pressure, and magnetic resonance imaging (MRI) measurements were performed. Immediately after euthanasia, tissue fragments and blood were collected for further analysis. Uterine weight was 2 times lower in ABA female rats, and ovarian tissue exhibited a reduced number of antral follicles and decreased expression of estrogen and progesterone receptors. Cardiovascular measurements revealed autonomic decompensation with prolongation of QRS complex and QT interval. The ABA model is a reliable research tool for presenting the breakdown of adaptation mechanisms observed in severe AN. Cardiac and hormonal features of ABA with underlying altered neuroendocrine pathways create a valid phenotype of a human disease.

Structural and functional brain alterations in anorexia nervosa:A multimodal meta-analysis of neuroimaging studies.

Anorexia nervosa (AN) is a complex psychiatric disorder with poorly understood etiology. Numerous voxel-based morphometry (VBM) and resting-state functional imaging studies have provided strong evidence of abnormal brain structure and intrinsic and functional activities in AN, but with inconsistent conclusions. Herein, a whole-brain meta-analysis was conducted on VBM (660 patients with AN, and 740 controls) and resting-state functional imaging (425 patients with AN, and 461 controls) studies that measured differences in the gray matter volume (GMV) and intrinsic functional activity between patients with AN and healthy controls (HCs). Overall, patients with AN displayed decreased GMV in the bilateral median cingulate cortex (extending to the bilateral anterior and posterior cingulate cortex), and left middle occipital gyrus (extending to the left inferior parietal lobe). In resting-state functional imaging studies, patients with AN displayed decreased resting-state functional activity in the bilateral anterior cingulate cortex and bilateral median cingulate cortex, and increased resting-state functional activity in the right parahippocampal gyrus. This multimodal meta-analysis identified reductions of gray matter and functional activity in the anterior and median cingulate in patients with AN, which contributes to further understanding of the pathophysiology of AN.

Peripheral Vascular Abnormalities in Anorexia Nervosa: A Psycho-Neuro-Immune-Metabolic Connection.

Immune, neuroendocrine, and autonomic nervous system dysregulation in anorexia nervosa lead to cardiovascular complications that can potentially result in increased morbidity and mortality. It is suggested that a complex non-invasive assessment of cardiovascular autonomic regulation-cardiac vagal control, sympathetic vascular activity, and cardiovascular reflex control-could represent a promising tool for early diagnosis, personalized therapy, and monitoring of therapeutic interventions in anorexia nervosa particularly at a vulnerable adolescent age. In this view, we recommend to consider in the diagnostic route, at least in the subset of patients with peripheral microvascular symptoms, a nailfold video-capillaroscopy as an easy not invasive tool for the early assessing of possible cardiovascular involvement.

Case report of anorexia nervosa showing periventricular gliosis at autopsy.

Anorexia nervosa (AN) is a serious eating disorder characterized by self-starvation and extreme weight loss. It has the highest mortality rate among all psychiatric disorders. Recent research indicates that malnutrition in AN patients induces various kinds of functional brain damage, but the pathophysiology of AN remains unclear. We report here the neuropathological findings of a 31-year-old Japanese woman. At age 24, she had a fear of gaining weight and reduced her dietary intake; she had extremely low body weight associated with overeating then self-induced vomiting. She was clinically diagnosed as having AN and was admitted to a psychiatric hospital with severe depression and suicidal thoughts. At age 31, she died despite intensive physical care and psychotherapy. Neuropathological examination revealed increased capillary blood vessels and slight fibrillary gliosis in the mammillary bodies, with similarities to Wernicke encephalopathy. The brainstem exhibited the characteristic features of central pontine myelinolysis, characterized by a sharply demarcated region of myelin pallor and relative sparing of axons. Senile changes, including neurofibrillary tangles/senile plaques, were not significant. Severe fibrillary gliosis was prominent around periventricular regions, including the caudate nucleus and nucleus accumbens, which are associated with cognition, emotion, and emotional behaviors via the dopaminergic pathways. These findings indicate that prolonged malnutrition in AN patients may induce brain damage, leading to dysfunction of the reward-related dopaminergic pathways. Furthermore, they represent the first pathological evidence that dysfunction of the cortico-limbic-striatal circuitry is involved in the pathophysiology of psychiatric symptoms in AN patients.

Metacognition in individuals recovered from anorexia nervosa: a voxel-based morphometry study.

Recent evidence shows that individuals with Anorexia Nervosa (AN) can be characterized by dysfunctional metacognition as well as reductions of gray matter volumes (GMV) in prefrontal brain regions involved in cognitive processes. However, whether these differences are reversible or stable markers has yet to be understood. Thus, we aimed at characterizing metacognition and brain morphometry in individuals recovered from AN (rec-AN). A combined psychometric-brain morphometry investigation on metacognitive functioning in rec-AN individuals was conducted. Fifteen healthy controls (HC) and fifteen rec-AN women underwent a psychometric assessment for metacognitive functioning and a high-resolution T1-weighted Magnetic Resonance Imaging measurement to assess global and regional brain volumes, using Voxel-Based Morphometry. The two groups did not differ for metacognitive functioning and GMV, while regional GMV reductions were observed in rec-AN compared to HC in the left Inferior Frontal Gyrus (IFG). While changes in metacognitive abilities may not represent a stable trait of AN, regional GMV reductions in brain regions devoted to specific cognitive functions, such as inhibitory/top-down control processes, can act as a neurobiological fingerprint for such condition. These findings can represent a promising hint for future investigations on the maintaining factors of AN.