Energetically costly functional network dynamics in cognitively impaired multiple sclerosis patients

Background and objectives. Patients with multiple sclerosis (MS) often experience cognitive impairment, and this is related to structural disconnection and subsequent functional reorganization. It is not clear how specific patterns of functional reorganization might make it harder for cognitively impaired (CI) MS patients to dynamically adapt how brain regions communicate, which is crucial for normal cognition. To identify patterns relevant to cognitive impairment in MS, we performed a temporally detailed analysis of connectivity state transitions and quantified the effort associated with such dynamic alterations. Methods. Resting-state functional and diffusion MRI was acquired from 95 controls and 330 MS patients (mean disease duration: 15 years) in a cross-sectional design, of whom 86 were classified as CI (≥2/7 domains Z < −2) and 65 as mildly CI (≥2/7 domains Z < −1.5) based on the performance on an expanded Brief Repeatable Battery of Neuropsychological Tests. Four functional connectivity states were determined using K-means clustering of moment-to-moment co-fluctuations (i.e., edge time series), and the resulting state sequence was used to characterize the frequency of transitions between network configurations. The control energy associated with the transitions between states was then calculated using the structural network of each subject with network control theory. Results. CI patients transition less frequently between connectivity states. Relative to the time spent in a particular state, CI patients specifically transition less from a weakly connected and highly modular state (i.e., the weakly connected state) to a more integrated state that featured strong involvement of the visual network (i.e., the visual network state), but more in the opposite direction. CI patients also required more control energy to transition between states. Discussion. This study showed that it became more effortful for MS patients with cognitive impairment to dynamically change the organization of the functional network, providing an intuitive understanding of why these transitions occur less frequently in some patients. In particular, transitions between the weakly connected state and the more integrated visual network state were relevant for cognition in these patients. The findings highlight a possible underpinning of disturbed cognition in MS patients and also provide novel avenues for studying and possibly improving network dynamics. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by Eurostars-EUREKA and the Dutch MS Research Foundation, grant numbers 08-650, 13-820 and 14-358e. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The institutional ethics review board of the Amsterdam UMC gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Anonymized data, not published in the article, will be shared on reasonable request from a qualified investigator. Code is available on GitHub: https://github.com/taabroeders/research-projects/tree/main/states_2024.