Systematic reduction of gray matter volume in anorexia nervosa, but relative enlargement with clinical symptoms in the prefrontal and posterior insular cortices: a multicenter neuroimaging study.

Although brain morphological abnormalities have been reported in anorexia nervosa (AN), the reliability and reproducibility of previous studies were limited due to insufficient sample sizes, which prevented exploratory analysis of the whole brain as opposed to regions of interest (ROIs). Objective was to identify brain morphological abnormalities in AN and the association with severity of AN by brain structural magnetic resonance imaging (MRI) in a multicenter study, and to conduct exploratory analysis of the whole brain. Here, we conducted a cross-sectional multicenter study using T1-weighted imaging (T1WI) data collected between May 2014 and February 2019 in Japan. We analyzed MRI data from 103 female AN patients (58 anorexia nervosa restricting type [ANR] and 45 anorexia nervosa binge-purging type [ANBP]) and 102 age-matched female healthy controls (HC). MRI data from five centers were preprocessed using the latest harmonization method to correct for intercenter differences. Gray matter volume (GMV) was calculated from T1WI data of all participants. Of the 205 participants, we obtained severity of eating disorder symptom scores from 179 participants, including 87 in the AN group (51 ANR, 36 ANBP) and 92 HC using the Eating Disorder Examination Questionnaire (EDE-Q) 6.0. GMV reduction were observed in the AN brain, including the bilateral cerebellum, middle and posterior cingulate gyrus, supplementary motor cortex, precentral gyrus medial segment, and thalamus. In addition, the orbitofrontal cortex (OFC), ventromedial prefrontal cortex (vmPFC), rostral anterior cingulate cortex (ACC), and posterior insula volumes showed positive correlations with severity of symptoms. This multicenter study was conducted with a large sample size to identify brain morphological abnormalities in AN. The findings provide a better understanding of the pathogenesis of AN and have potential for the development of brain imaging biomarkers of AN. Trial Registration: UMIN000017456. https://center6.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000019303 .

Comprehensive elucidation of resting-state functional connectivity in anorexia nervosa by a multicenter cross-sectional study.

BACKGROUND: Previous research on the changes in resting-state functional connectivity (rsFC) in anorexia nervosa (AN) has been limited by an insufficient sample size, which reduced the reliability of the results and made it difficult to set the whole brain as regions of interest (ROIs). METHODS: We analyzed functional magnetic resonance imaging data from 114 female AN patients and 135 healthy controls (HC) and obtained self-reported psychological scales, including eating disorder examination questionnaire 6.0. One hundred sixty-four cortical, subcortical, cerebellar, and network parcellation regions were considered as ROIs. We calculated the ROI-to-ROI rsFCs and performed group comparisons. RESULTS: Compared to HC, AN patients showed 12 stronger rsFCs mainly in regions containing dorsolateral prefrontal cortex (DLPFC), and 33 weaker rsFCs primarily in regions containing cerebellum, within temporal lobe, between posterior fusiform cortex and lateral part of visual network, and between anterior cingulate cortex (ACC) and thalamus (p < 0.01, false discovery rate [FDR] correction). Comparisons between AN subtypes showed that there were stronger rsFCs between right lingual gyrus and right supracalcarine cortex and between left temporal occipital fusiform cortex and medial part of visual network in the restricting type compared to the binge/purging type (p < 0.01, FDR correction). CONCLUSION: Stronger rsFCs in regions containing mainly DLPFC, and weaker rsFCs in regions containing primarily cerebellum, within temporal lobe, between posterior fusiform cortex and lateral part of visual network, and between ACC and thalamus, may represent categorical diagnostic markers discriminating AN patients from HC.

Effects of integrated hospital treatment on the default mode, salience, and frontal-parietal networks in anorexia nervosa: A longitudinal resting-state functional magnetic resonance imaging study.

The psychopathology of patients with anorexia nervosa has been hypothesized to involve inappropriate self-referential processing, disturbed interoceptive awareness, and excessive cognitive control, including distorted self-concern, disregard of their own starvation state, and extreme weight-control behavior. We hypothesized that the resting-state brain networks, including the default mode, salience and frontal-parietal networks, might be altered in such patients, and that treatment might normalize neural functional connectivity, with improvement of inappropriate self-cognition. We measured resting-state functional magnetic resonance images from 18 patients with anorexia nervosa and 18 healthy subjects before and after integrated hospital treatment (nourishment and psychological therapy). The default mode, salience, and frontal-parietal networks were examined using independent component analysis. Body mass index and psychometric measurements significantly improved after treatment. Before treatment, default mode network functional connectivity in the retrosplenial cortex and salience network functional connectivity in the ventral anterior insula and rostral anterior cingulate cortex were decreased in anorexia nervosa patients compared with those in controls. Interpersonal distrust was negatively correlated with salience network functional connectivity in the rostral anterior cingulate cortex. Default mode network functional connectivity in the posterior insula and frontal-parietal network functional connectivity in the angular gyrus were increased in anorexia nervosa patients compared with those in controls. Comparison between pre- and post-treatment images from patients with anorexia nervosa exhibited significant increases in default mode network functional connectivity in the hippocampus and retrosplenial cortex, and salience network functional connectivity in the dorsal anterior insula following treatment. Frontal-parietal network functional connectivity in the angular cortex showed no significant changes. The findings revealed that treatment altered the functional connectivity in several parts of default mode and salience networks in patients with anorexia nervosa. These alterations of neural function might be associated with improvement of self-referential processing and coping with sensations of discomfort following treatment for anorexia nervosa.

Psychological characteristics associated with the brain volume of patients with fibromyalgia.

Fibromyalgia (FM) is a disease characterized by chronic widespread pain concomitant with psychiatric symptoms such as anxiety and depression. It has been reported that FM patients engage in pain catastrophizing. In this study, we investigated characteristics of the brain volume of female FM patients and the association between psychological indices and brain volume. Thirty-nine female FM patients and 25 female healthy controls (HCs) were recruited for the study, and five FM patients were excluded due to white matter lesions. The following analyses were performed: (1) T1-weighted MRI were acquired for 34 FM patients (age 41.6 ± 7.4) and 25 HCs (age 39.5 ± 7.4). SPM12 was used to compare their gray and white matter volumes. (2) Data from anxiety and depression questionnaires (State-Trait Anxiety Inventory and Hospital Anxiety and Depression Scale), the Pain Catastrophizing Scale (subscales rumination, helplessness, magnification), and MRI were acquired for 34 FM patients (age 41.6 ± 7.4). Correlation analysis was done of the psychological indices and brain volume. We found that (1) The white matter volume of the temporal pole was larger in the FM patient group than in the HC group. (2) Correlation analysis of the psychological indices and gray matter volume showed a negative correlation between trait anxiety and the amygdala. For the white matter volume, positive correlations were found between depression and the brainstem and between magnification and the postcentral gyrus. Changes in the brain volume of female FM patients may be related to anxiety, depression, and pain catastrophizing.

Alexithymia characteristics are associated with salience network activity in healthy participants: an arterial spin labeling study.

BACKGROUND: Alexithymia, a personality trait characterized by difficulties in identifying and expressing their emotions despite having a range of emotional experiences, can impact individuals' stress coping mechanisms. While many studies have investigated brain functions associated with specific tasks in relation to emotion processing, research focusing on resting-state brain functions has been limited. Thus, the aim of this study was to investigate the relationship between alexithymia and brain function by analyzing arterial spin labeling (ASL) data obtained during the resting state. METHODS: A brain structural and functional imaging study was conducted on 42 healthy adult men and women using ASL and the 20-item Toronto Alexithymia Scale (TAS-20) questionnaire survey. Cerebral blood flow and functional connectivity values were calculated for regions of interest in the default mode network, saliency network, and central executive network from the ASL data. Correlation analysis was performed with TAS20 scores, and partial correlation analysis was conducted to control for anxiety and depression. RESULTS: The functional connectivity analysis revealed a negative correlation between the functional connectivity of the right insular cortex and left anterior cingulate cortex and the total score of TAS, as well as difficulty identifying feelings and difficulty describing feeling subscores, indicating that the higher the scores, the weaker the functional connectivity between these regions (T = -3.830, p = 0.0013, R = -0.5180). This correlation remained significant even after controlling for anxiety and depression using partial correlation analysis. CONCLUSION: The present study revealed differences in the activity of the Saliency Network at rest as measured by ASL, which were independent of anxiety and depression, and varied depending on the severity of alexithymia. This functional change may underlie the neural basis of decreased emotional processing observed in alexithymia. These findings may contribute to the elucidation of the neural mechanisms of alexithymia, which can lead to social impairments, and suggest the usefulness of ASL measurement as a biomarker of alexithymia.

Daily physical complaints and hippocampal function: an fMRI study of pain modulation by anxiety.

Pain is a popular physical complaint in human. It is known that experimental anxiety modulates pain processing through hippocampal amplification, whereas it is not known whether a similar experimental reaction is related to daily physical complaints known as 'somatization'. The purpose of this study is to investigate the neural correlates of pain modulation induced by anxiety, particularly in the hippocampus, and how individual differences in this neural reaction relate to somatization. We measured neural response to noxious electrical stimulations, as well as the response to the preceding visual anticipatory cues (which induced low anxiety or high anxiety), by functional magnetic resonance imaging (fMRI). Individual daily physical symptoms were assessed by using the somatization subscale of the Symptom Checklist 90 revised (SCL-90-R). Correlation coefficients between the neural activations and the somatization scores were calculated. We found that manifestation of daily physical symptoms was related to smaller differences in hippocampus activation between high and low anxiety states, suggesting that the ability of the hippocampus to distinguish anxiety states was weakened by the chronic condition that caused the daily physical symptoms. The proper inhibition of neural activation in low anxiety states in the hippocampus and the anterior insula was observed to occur in companionship with lower daily physical complaints. These findings indicate that anxiety's alteration of the network that includes the hippocampus and that is associated with pain modulation underlies the manifestation of somatization.

Eating Disorder Neuroimaging Initiative (EDNI): a multicentre prospective cohort study protocol for elucidating the neural effects of cognitive-behavioural therapy for eating disorders.

INTRODUCTION: Anorexia nervosa is a refractory psychiatric disorder with a mortality rate of 5.9% and standardised mortality ratio of 5.35, which is much higher than other psychiatric disorders. The standardised mortality ratio of bulimia nervosa is 1.49; however, it is characterised by suicidality resulting in a shorter time to death. While there is no current validated drug treatment for eating disorders in Japan, cognitive-behavioural therapy (CBT) is a well-established and commonly used treatment. CBT is also recommended in the Japanese Guidelines for the Treatment of Eating Disorders (2012) and has been covered by insurance since 2018. However, the neural mechanisms responsible for the effect of CBT have not been elucidated, and the use of biomarkers such as neuroimaging data would be beneficial. METHODS AND ANALYSIS: The Eating Disorder Neuroimaging Initiative is a multisite prospective cohort study. We will longitudinally collect data from 72 patients with eating disorders (anorexia nervosa and bulimia nervosa) and 70 controls. Data will be collected at baseline, after 21-41 sessions of CBT and 12 months later. We will assess longitudinal changes in neural circuit function, clinical data, gene expression and psychological measures by therapeutic intervention and analyse the relationship among them using machine learning methods. ETHICS AND DISSEMINATION: The study was approved by The Ethical Committee of the National Center of Neurology and Psychiatry (A2019-072). We will obtain written informed consent from all patients who participate in the study after they had been fully informed about the study protocol. All imaging, demographic and clinical data are shared between the participating sites and will be made publicly available in 2024. TRIAL REGISTRATION NUMBER: UMIN000039841.

Neural correlates of body comparison and weight estimation in weight-recovered anorexia nervosa: a functional magnetic resonance imaging study.

BACKGROUND: The neural mechanisms underlying body dissatisfaction and emotional problems evoked by social comparisons in patients with anorexia nervosa (AN) are currently unclear. Here, we elucidate patterns of brain activation among recovered patients with AN (recAN) during body comparison and weight estimation with functional magnetic resonance imaging (fMRI). METHODS: We used fMRI to examine 12 patients with recAN and 13 healthy controls while they performed body comparison and weight estimation tasks with images of underweight, healthy weight, and overweight female bodies. In the body comparison task, participants rated their anxiety levels while comparing their own body with the presented image. In the weight estimation task, participants estimated the weight of the body in the presented image. We used between-group region of interest (ROI) analyses of the blood oxygen level dependent (BOLD) signal to analyze differences in brain activation patterns between the groups. In addition, to investigate activation outside predetermined ROIs, we performed an exploratory whole-brain analysis to identify group differences. RESULTS: We found that, compared to healthy controls, patients with recAN exhibited significantly greater activation in the pregenual anterior cingulate cortex (pgACC) when comparing their own bodies with images of underweight female bodies. In addition, we found that, compared with healthy controls, patients with recAN exhibited significantly smaller activation in the middle temporal gyrus corresponding to the extrastriate body area (EBA) when comparing their own bodies, irrespective of weight, during self-other comparisons of body shape. CONCLUSIONS: Our findings from a group of patients with recAN suggest that the pathology of AN may lie in an inability to regulate negative affect in response to body images via pgACC activation during body comparisons. The findings also suggest that altered body image processing in the brain persists even after recovery from AN.

Gut Dysbiosis in Patients with Anorexia Nervosa.

Anorexia nervosa (AN) is a psychological illness with devastating physical consequences; however, its pathophysiological mechanism remains unclear. Because numerous reports have indicated the importance of gut microbiota in the regulation of weight gain, it is reasonable to speculate that AN patients might have a microbial imbalance, i.e. dysbiosis, in their gut. In this study, we compared the fecal microbiota of female patients with AN (n = 25), including restrictive (ANR, n = 14) and binge-eating (ANBP, n = 11) subtypes, with those of age-matched healthy female controls (n = 21) using the Yakult Intestinal Flora-SCAN based on 16S or 23S rRNA-targeted RT-quantitative PCR technology. AN patients had significantly lower amounts of total bacteria and obligate anaerobes including those from the Clostridium coccoides group, Clostridium leptum subgroup, and Bacteroides fragilis group than the age-matched healthy women. Lower numbers of Streptococcus were also found in the AN group than in the control group. In the analysis based on AN subtypes, the counts of the Bacteroides fragilis group in the ANR and ANBP groups and the counts of the Clostridium coccoides group in the ANR group were significantly lower than those in the control group. The detection rate of the Lactobacillus plantarum subgroup was significantly lower in the AN group than in the control group. The AN group had significantly lower acetic and propionic acid concentrations in the feces than the control group. Moreover, the subtype analysis showed that the fecal concentrations of acetic acid were lower in the ANR group than in the control group. Principal component analysis confirmed a clear difference in the bacterial components between the AN patients and healthy women. Collectively, these results clearly indicate the existence of dysbiosis in the gut of AN patients.

The reliability and validity of the Japanese version of the Levels of Emotional Awareness Scale (LEAS-J).

BACKGROUND: The Levels of Emotional Awareness Scale (LEAS) was developed to assess five levels of emotional awareness: bodily sensations, action tendencies, single emotions, blends of emotion, and combinations of blends. It is a paper and pencil performance questionnaire that presents 20 emotion-evoking scenes. We developed a Japanese version of the LEAS (LEAS-J), and its reliability and validity were examined. METHODS: The LEAS-J level was independently assessed by two researchers who scored each response according to the LEAS scoring manual. High inter-rater reliability and internal consistency were obtained for the LEAS-J. Measures were socioeconomic status, LEAS-J, Toronto Alexithymia Scale-20 (TAS-20), Interpersonal Reactivity Index (IRI), and NEO Five-Factor Inventory (NEO-FFI). TAS-20, IRI and NEO-FFI were the measures used to explore the construct validity of LEAS-J, as it was predicted that higher scores on the LEAS-J would be related to fewer alexithymic features, greater empathetic ability, and a greater sense of cooperation with others. Questionnaires were completed by 344 university students. RESULTS: The criterion-referenced validity was determined: a significant negative relationship was found with the externally-oriented thinking scores of TAS-20, and positive relationships were found with fantasy, perspective taking, and empathic concern on IRI and with extraversion, openness to experience, and agreeableness on NEO-FFI. CONCLUSIONS: Consistent with our expectations, the findings provide evidence that the LEAS-J has good reliability and validity. In addition, women had significantly higher scores than men on LEAS-J, showing that the gender difference identified in the original LEAS was cross-culturally consistent.

The longitudinal BMI pattern and body composition of patients with anorexia nervosa who require urgent hospitalization: A case control study.

BACKGROUND: The prevention of serious physical complications in anorexia nervosa (AN) patients is important. The purpose of this study is to clarify which physical and social factors are related to the necessity for urgent hospitalization of anorexia nervosa (AN) patients in a long-term starvation state. We hypothesized that the change of longitudinal BMI, body composition and social background would be useful as an index of the necessity for urgent hospitalization. METHODS: AN patients were classified into; urgent hospitalization, due to disturbance of consciousness or difficulty walking(n = 17); planned admission (n = 96); and outpatient treatment only groups (n = 136). The longitudinal BMI pattern and the clinical features of these groups were examined. In the hospitalization groups, comparison was done of body composition variation and the social background, including the educational level and advice from family members. RESULTS: After adjusting for age and duration of illness, the BMI of the urgent hospitalization group was lower than that of the other groups at one year before hospitalization (P < 0.01) and decreased more rapidly (P < 0.01). Urgent hospitalization was associated with the fat free mass (FFM) (P < 0.01). Between the groups, no considerable difference in social factors was found. CONCLUSIONS: The longitudinal pattern of BMI and FFM may be useful for understanding the severity in AN from the viewpoint of failure of the homeostasis system.