State-dependent signatures of anti-N-methyl-d-aspartate receptor encephalitis

Traditional static functional connectivity analyses have shown distinct functional network alterations in patients with anti-N-methyl-d-aspartate receptor encephalitis. Here, we use a dynamic functional connectivity approach that increases the temporal resolution of connectivity analyses from minutes to seconds. We hereby explore the spatiotemporal variability of large-scale brain network activity in anti-N-methyl-d-aspartate receptor encephalitis and assess the discriminatory power of functional brain states in a supervised classification approach. We included resting-state functional magnetic resonance imaging data from 57 patients and 61 controls to extract four discrete connectivity states and assess state-wise group differences in functional connectivity, dwell time, transition frequency, fraction time and occurrence rate. Additionally, for each state, logistic regression models with embedded feature selection were trained to predict group status in a leave-one-out cross-validation scheme. Compared to controls, patients exhibited diverging dynamic functional connectivity patterns in three out of four states mainly encompassing the default-mode network and frontal areas. This was accompanied by a characteristic shift in the dwell time pattern and higher volatility of state transitions in patients. Moreover, dynamic functional connectivity measures were associated with disease severity and positive and negative schizophrenia-like symptoms. Predictive power was highest in dynamic functional connectivity models and outperformed static analyses, reaching up to 78.6% classification accuracy. By applying time-resolved analyses, we disentangle state-specific functional connectivity impairments and characteristic changes in temporal dynamics not detected in static analyses, offering new perspectives on the functional reorganization underlying anti-N-methyl-d-aspartate receptor encephalitis. Finally, the correlation of dynamic functional connectivity measures with disease symptoms and severity demonstrates a clinical relevance of spatiotemporal connectivity dynamics in anti-N-methyl-d-aspartate receptor encephalitis

Functional connectivity dynamics reflect disability and multi-domain clinical impairment in patients with relapsing-remitting multiple sclerosis

BACKGROUND & AIM: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system associated with deficits in cognitive and motor functioning. While structural brain changes such as demyelination are an early hallmark of the disease, a characteristic profile of functional brain alterations in early MS is lacking. Functional neuroimaging studies at various disease stages have revealed complex and heterogeneous patterns of aberrant functional connectivity (FC) in MS, with previous studies largely being limited to a static account of FC. Thus, it remains unclear how time-resolved FC relates to variance in clinical disability status in early MS. We here aimed to characterize brain network organization in early MS patients with time-resolved FC analysis and to explore the relationship between disability status, multi-domain clinical outcomes and altered network dynamics. METHODS: Resting-state functional MRI (rs-fMRI) data were acquired from 101 MS patients and 101 age- and sex-matched healthy controls (HC). Based on the Expanded Disability Status Score (EDSS), patients were split into two sub-groups: patients without clinical disability (EDSS = 1, n = 36) and patients with mild to moderate levels of disability (EDSS = 2, n = 39). Five dynamic FC states were extracted from whole-brain rs-fMRI data. Group differences in static and dynamic FC strength, across-state overall connectivity, dwell time, transition frequency, modularity, and global connectivity were assessed. Patients' impairment was quantified as custom clinical outcome z-scores (higher: worse) for the domains depressive symptoms, fatigue, motor, vision, cognition, total brain atrophy, and lesion load. Correlation analyses between functional measures and clinical outcomes were performed with Spearman partial correlation analyses controlling for age. RESULTS: Patients with mild to moderate levels of disability exhibited a more widespread spatiotemporal pattern of altered FC and spent more time in a high-connectivity, low-occurrence state compared to patients without disability and HCs. Worse symptoms in all clinical outcome domains were positively associated with EDSS scores. Furthermore, depressive symptom severity was positively related to functional dynamics as measured by state-specific global connectivity and default mode network connectivity with attention networks, while fatigue and motor impairment were related to reduced frontoparietal network connectivity with the basal ganglia. CONCLUSIONS: Despite comparably low impairment levels in early MS, we identified distinct connectivity alterations between patients with mild to moderate disability and those without disability, and these changes were sensitive to clinical outcomes in multiple domains. Furthermore, time-resolved analysis uncovered alterations in network dynamics and clinical correlations that remained undetected with conventional static analyses, showing that accounting for temporal dynamics helps disentangle the relationship between functional alterations, disability status, and symptoms in early MS

Preserved white matter microstructure in adolescent patients with atypical anorexia nervosa

Objective: Patients with atypical anorexia nervosa (AN) are often in the normal-weight range at presentation; however, signs of starvation and medical instability are not rare. White matter (WM) microstructural correlates of atypical AN have not yet been investigated, leaving an important gap in our knowledge regarding the neural pathogenesis of this disorder. Method: We investigated WM microstructural integrity in 25 drug-naïve adolescent patients with atypical AN and 25 healthy controls, using diffusion tensor imaging (DTI) with a tract-based spatial statistics (TBSS) approach. Psychological variables related to the eating disorder and depressive symptoms were also evaluated by administering the eating disorder examination questionnaire (EDE-Q) and the Montgomery–Åsberg depression rating scale (MADRS-S) respectively, to all participants. Results: Patients and controls were in the normal-weight range and did not differ from the body mass index standard deviations for their age. No between groups difference in WM microstructure could be detected. Discussion: Our findings support the hypothesis that brain structural alterations may not be associated to early-stage atypical AN. These findings also suggest that previous observations of alterations in WM microstructure in full syndrome AN may constitute state-related consequences of severe weight loss. Whether the preservation of WM structure is a pathogenetically discriminant feature of atypical AN or only an effect of a less severe nutritional disturbance, will have to be verified by future studies on larger samples, possibly directly comparing AN and atypical AN

Dynamic changes in white matter microstructure in anorexia nervosa: Findings from a longitudinal study

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

Increased flexibility of brain dynamics in patients with multiple sclerosis

Patients with multiple sclerosis consistently show widespread changes in functional connectivity. Yet, alterations are heterogeneous across studies, underscoring the complexity of functional reorganization in multiple sclerosis. Here, we aim to provide new insights by applying a time-resolved graph-analytical framework to identify a clinically relevant pattern of dynamic functional connectivity reconfigurations in multiple sclerosis. Resting-state data from 75 patients with multiple sclerosis (N = 75, female:male ratio of 3:2, median age: 42.0 ± 11.0 years, median disease duration: 6 ± 11.4 years) and 75 age- and sex-matched controls (N = 75, female:male ratio of 3:2, median age: 40.2 ± 11.8 years) were analysed using multilayer community detection. Local, resting-state functional system and global levels of dynamic functional connectivity reconfiguration were characterized using graph-theoretical measures including flexibility, promiscuity, cohesion, disjointedness and entropy. Moreover, we quantified hypo- and hyper-flexibility of brain regions and derived the flexibility reorganization index as a summary measure of whole-brain reorganization. Lastly, we explored the relationship between clinical disability and altered functional dynamics. Significant increases in global flexibility (t = 2.38, PFDR = 0.024), promiscuity (t = 1.94, PFDR = 0.038), entropy (t = 2.17, PFDR = 0.027) and cohesion (t = 2.45, PFDR = 0.024) were observed in patients and were driven by pericentral, limbic and subcortical regions. Importantly, these graph metrics were correlated with clinical disability such that greater reconfiguration dynamics tracked greater disability. Moreover, patients demonstrate a systematic shift in flexibility from sensorimotor areas to transmodal areas, with the most pronounced increases located in regions with generally low dynamics in controls. Together, these findings reveal a hyperflexible reorganization of brain activity in multiple sclerosis that clusters in pericentral, subcortical and limbic areas. This functional reorganization was linked to clinical disability, providing new evidence that alterations of multilayer temporal dynamics play a role in the manifestation of multiple sclerosis