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.

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.

Dynamic Changes in Local Brain Connectivity and Activity: A Longitudinal Study in Adolescent Anorexia Nervosa.

BACKGROUND: Resting-state functional connectivity analysis has been used to study disruptions in neural circuitries underlying eating disorder symptoms. Research has shown resting-state functional connectivity to be altered during the acute phase of anorexia nervosa (AN), but little is known about the biological mechanisms underlying neural changes associated with weight restoration. The goal of the current study was to investigate longitudinal changes in regional homogeneity (ReHo) among neighboring voxels, degree centrality (DC) (a voxelwise whole brain correlation coefficient), voxel-mirrored homotopic connectivity (VMHC) (measuring the synchronization between hemispheres), and the fractional amplitude of low-frequency fluctuations associated with weight gain during AN treatment. METHODS: Resting-state functional connectivity data were acquired and analyzed from a sample of 174 female volunteers: 87 underweight patients with AN that were scanned before treatment and again after at least 12% body mass index increase, as well as 87 age-matched healthy control participants. RESULTS: Longitudinal changes in ReHo, DC, VMHC, and the fractional amplitude of low-frequency fluctuations were observed in most regions identified to differ between patients with AN before treatment and healthy control participants. However, the degree of normalization varied for each parameter, ranging from 9% of all clusters in DC to 66% in VMHC. Longitudinal changes in ReHo and VMHC showed a linear association weight gain. CONCLUSIONS: Resting-state functional magnetic resonance imaging measures, including ReHo, DC, VMHC, and the fractional amplitude of low-frequency fluctuations, show varying degrees of recovery after short-term weight restoration. Although only some of these changes were related to weight gain, our results provide an overall positive message, suggesting that weight restoration is associated with changes in functional brain measures that point toward normalization.

Structural brain abnormalities and aggressive behaviour in schizophrenia: Mega-analysis of data from 2095 patients and 2861 healthy controls via the ENIGMA consortium.

Background: Schizophrenia is associated with an increased risk of aggressive behaviour, which may partly be explained by illness-related changes in brain structure. However, previous studies have been limited by group-level analyses, small and selective samples of inpatients and long time lags between exposure and outcome. Methods: This cross-sectional study pooled data from 20 sites participating in the international ENIGMA-Schizophrenia Working Group. Sites acquired T1-weighted and diffusion-weighted magnetic resonance imaging scans in a total of 2095 patients with schizophrenia and 2861 healthy controls. Measures of grey matter volume and white matter microstructural integrity were extracted from the scans using harmonised protocols. For each measure, normative modelling was used to calculate how much patients deviated (in z-scores) from healthy controls at the individual level. Ordinal regression models were used to estimate the associations of these deviations with concurrent aggressive behaviour (as odds ratios [ORs] with 99% confidence intervals [CIs]). Mediation analyses were performed for positive symptoms (i.e., delusions, hallucinations and disorganised thinking), impulse control and illness insight. Aggression and potential mediators were assessed with the Positive and Negative Syndrome Scale, Scale for the Assessment of Positive Symptoms or Brief Psychiatric Rating Scale. Results: Aggressive behaviour was significantly associated with reductions in total cortical volume (OR [99% CI] = 0.88 [0.78, 0.98], p = .003) and global white matter integrity (OR [99% CI] = 0.72 [0.59, 0.88], p = 3.50 × 10-5) and additional reductions in dorsolateral prefrontal cortex volume (OR [99% CI] = 0.85 [0.74, 0.97], p =.002), inferior parietal lobule volume (OR [99% CI] = 0.76 [0.66, 0.87], p = 2.20 × 10-7) and internal capsule integrity (OR [99% CI] = 0.76 [0.63, 0.92], p = 2.90 × 10-4). Except for inferior parietal lobule volume, these associations were largely mediated by increased severity of positive symptoms and reduced impulse control. Conclusions: This study provides evidence that the co-occurrence of positive symptoms, poor impulse control and aggressive behaviour in schizophrenia has a neurobiological basis, which may inform the development of therapeutic interventions.

Dynamic Amygdala Nuclei Alterations in Relation to Weight Status in Anorexia Nervosa Are Mediated by Leptin.

OBJECTIVE: The amygdaloid complex is a subcortical limbic group of distinct nuclei. In a previous patient-control study, differential amygdala nuclei alterations were found in acute anorexia nervosa (AN); rostral-medial nuclei involved in fear and reward processing were substantially reduced in volume and associated with hypoleptinemia, a key neuroendocrine characteristic of AN. Here, longitudinal amygdala nuclei alterations in AN were investigated in relation to weight status and their associations with leptin levels. METHOD: T1-weighted structural magnetic resonance imaging scans were longitudinally processed with FreeSurfer. Amygdala nuclei volumes in young female patients with acute AN before and after short-term weight restoration (n = 110, >14% body mass index increase over 3 months) and female participants with a history of AN (n = 79, long-term [mean 5 years] weight recovered) were compared with female healthy control participants (n = 271) using linear mixed effects models. RESULTS: Rostral-medially clustered amygdala nuclei volumes, accessory basal, cortical, medial nuclei, and corticoamygdaloid transition, increased during short-term weight restoration (Cohen's d range 0.18-0.30). However, volumetric normalization across nuclei was heterogeneous. Right cortical, medial nuclei, bilateral corticoamygdaloid transitions, and anterior amygdaloid areas were only partially normalized following short-term weight restoration. Right anterior amygdaloid area remained reduced after long-term weight recovery compared with control participants (d = 0.36). Leptin increase, accompanying short-term weight restoration, mediated the effect of weight gain on volumetric increase in left corticoamygdaloid transition and bilateral medial nuclei. CONCLUSION: Rostral-medially clustered amygdala nuclei show pronounced volumetric increase but incomplete normalization in AN during and after short-term weight restoration. Leptin increase may be relevant for the recovery of specific amygdala nuclei in addition to nutritional rehabilitation, indicating links between amygdala substructure and leptin dynamics of potential pathophysiological and clinical relevance in AN. PLAIN LANGUAGE SUMMARY: The amygdala plays a critical role in processing fearful and rewarding stimuli, and alterations in the amygdala are associated with anorexia nervosa. In this study, the authors measured amygdala nuclei volumes in female patients with acute anorexia nervosa undergoing weight-restoration treatment (n = 110), long-term weight-recovered individuals with anorexia (n = 79), and healthy control participants (n = 271). Structural magnetic resonance imaging revealed that volumes of specific nuclei, clustered in the rostral-medial amygdala, were substantially reduced in acute anorexia nervosa and only partially normalized following weight restoration treatment. Residual reductions in volume persisted even after long-term weight-recovery, compared to healthy control participants. Short-term weight restoration was associated with increases in the neurohormone leptin, and increasing leptin levels were found to mediate the positive impact of weight gain on increased amygdala volume over the treatment course. DIVERSITY & INCLUSION STATEMENT: We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper received support from a program designed to increase minority representation in science. We actively worked to promote sex and gender balance in our author group. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list. While citing references scientifically relevant for this work, we also actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our reference list. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.

Explicating the role of amygdala substructure alterations in the link between hypoleptinemia and rumination in anorexia nervosa.

OBJECTIVE: The amygdaloid complex plays a pivotal role in emotion processing and has been associated with rumination transdiagnostically. In anorexia nervosa (AN), we previously observed differential reductions of amygdala nuclei volumes (rostral-medial cluster substantially affected) and, in another study, elevated food-/weight-related rumination. Both amygdala volumes and rumination frequency correlated with characteristically suppressed leptin levels in AN. Thus, we hypothesized that amygdala nuclei alterations might be associated with AN-related rumination and potentially mediate the leptin-rumination relationship in AN. METHODS: Rumination (food-/weight-related) was assessed using ecological momentary assessment for a 14-day period. We employed frequentist and Bayesian linear mixed effects models in females with AN (n = 51, 12-29 years, majority admitted to inpatient treatment) and age-matched healthy females (n = 51) to investigate associations between rostral-medial amygdala nuclei volume alterations (accessory basal, cortical, medial nuclei, corticoamygdaloid transitions) and rumination. We analyzed mediation effects using multi-level structural equation models. RESULTS: Reduced right accessory basal and cortical nuclei volumes predicted more frequent weight-related rumination in AN; both nuclei fully mediated the effect of leptin on weight-related rumination. In contrast, we found robust evidence for the absence of amygdala nuclei volume effects on rumination in healthy females. CONCLUSION: This study provides first evidence for the relevance of specific amygdala substructure reductions regarding cognitive symptom severity in AN and points toward novel mechanistic insight into the relationship between hypoleptinemia and rumination, which might involve the amygdaloid complex. Our findings in AN may have important clinical value with respect to understanding the beneficial neuropsychiatric effects of leptin (treatment) in AN and potentially other psychiatric conditions such as depression.

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

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

Active phase field crystal systems with inertial delay and underdamped dynamics.

Active matter systems often are well approximated as overdamped, meaning that any inertial momentum is immediately dissipated by the environment. On the other hand, especially for macroscopic systems but also for many mesoscopic ones particle mass can become relevant for the dynamics. For such systems we recently proposed an underdamped continuum model which captures translationally inertial dynamics via two contributions. First, convection and second a damping time scale of inertial motion. In this paper, we ask how both of these features influence the collective behavior compared to overdamped dynamics by studying the example of the active phase field crystal model. We first focus on the case of suppressed convection to study the role of the damping time. We quantify that the relaxation process to the steady collective motion state is considerably prolonged with damping time due to the increasing occurrence of transient groups of circularly moving density peaks. Finally, we illustrate the fully underdamped case with convection. Instead of collective motion of density peaks we then find a coexistence of constant high and low density phases reminiscent of motility-induced phase separation.

Mean field approach of dynamical pattern formation in underdamped active matter with short-ranged alignment and distant anti-alignment interactions.

Many active matter systems, especially on the microscopic scale, are well approximated as overdamped, meaning that any inertial momentum is immediately dissipated by the environment. On the other hand, especially for macroscopic active systems but also for many mesoscopic systems the time scale of translational inertial motion can become large enough to be relevant for the dynamics. This raises the question how collective dynamics and the resulting states in active matter are influenced by inertia. Therefore, we propose a coarse-grained continuum model for underdamped active matter based on a mean field description for passive systems. Furthermore, as an example, we apply the model to a system with interactions that support an alignment on short distances and an anti-alignment on longer length scales as known in the context of pattern formation due to orientational interactions. Our numerical calculations of the under- and overdamped dynamics both predict a structured laning state. However, activity induced convective flows that are only present in the underdamped model destabilize this state when the anti-alignment is weakened, leading to a collective motion state which does not occur in the overdamped limit. A turbulent transition regime between the two states can be characterized by strong density fluctuations and the absence of global ordering.

Heat leakage in overdamped harmonic systems.

We investigate the occurrence of heat leakages in overdamped nonequilibrium Brownian harmonic systems. We exactly compute the underdamped and overdamped stochastic heats exchanged with the bath for a sudden frequency or temperature switch. We show that the underdamped heat reduces to the corresponding overdamped expression in the limit of large friction for the isothermal process. However, we establish that this is not the case for the isochoric transformation. We microscopically derive the additionally generated heat leakage and relate its origin to the initial relaxation of the velocity of the system. Our results highlight the limitations of the overdamped approximation for the evaluation of the stochastic heat in systems with changing bath temperature.