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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 unclear how specific patterns of functional reorganization might make it harder for cognitively impaired (CI) patients with MS to dynamically adapt how brain regions communicate, which is crucial for normal cognition. We aimed to identify dynamic functional network patterns that are relevant to cognitive impairment in MS and investigate whether these patterns can be explained by altered energy costs., Methods: Resting-state functional and diffusion MRI was acquired in a cross-sectional design, as part of the Amsterdam MS cohort. Patients with clinically definitive MS (relapse-free) were classified as CI (≥2/7 domains Z < -2), mildly CI (MCI) (≥2/7 domains Z < -1.5), or cognitively preserved (CP) based on an expanded Brief Repeatable Battery of Neuropsychological Tests. Functional connectivity states were determined using k -means clustering of moment-to-moment cofluctuations (i.e., edge time series), and the resulting state sequence was used to characterize the frequency of transitions. Control energy of the state transitions was calculated using the structural network with network control theory., Results: Imaging and cognitive data were available for 95 controls and 330 patients (disease duration: 15 years; 179 CP, 65 MCI, and 86 CI). We identified a "visual network state," "sensorimotor network state," "ventral attention network state," and "default mode network state." CI patients transitioned less frequently between connectivity states compared with CP (β = -5.78; p = 0.038). Relative to the time spent in a state, CI patients transitioned less from a "default mode network state" to a "visual network state" (β = -0.02; p = 0.004). The CI patients required more control energy to transition between states (β = 0.32; p = 0.007), particularly for the same transition (β = 0.34; p = 0.049)., Discussion: This study showed that it costs more energy for MS patients with cognitive impairment to dynamically change the functional network, possibly explaining why these transitions occur less frequently. In particular, transitions from a default mode network state to a visual network state were relevant for cognition in these patients. To further study the order of events leading to these network disturbances, future work should include longitudinal data across different disease stages.

Anesthetic agents disrupt neurodevelopment in animal models, but evidence in humans is mixed. The morphologic and behavioral changes observed across many species predicted that deficits should be seen in humans, but identifying a phenotype of injury in children has been challenging. It is increasingly clear that in children, a brief or single early anesthetic exposure is not associated with deficits in a range of neurodevelopmental outcomes including broad measures of intelligence. Deficits in other domains including behavior, however, are more consistently reported in humans and also reflect findings from nonhuman primates. The possibility that behavioral deficits are a phenotype, as well as the entire concept of anesthetic neurotoxicity in children, remains a source of intense debate. The purpose of this report is to describe consensus and disagreement among experts, summarize preclinical and clinical evidence, suggest pathways for future clinical research, and compare studies of anesthetic agents to other suspected neurotoxins., (Copyright © 2022, the American Society of Anesthesiologists. All Rights Reserved.)

An important element of designing research studies is the selection of appropriate outcome measures to ensure that the question posed is properly answered given the evidence. The selection of outcome measures is especially important when tackling complex, interdisciplinary problems, where appropriate outcome measures may not be as simple as a blood test or a laboratory value. One such area of study is the research into neurodevelopmental outcomes after early exposure to anesthetic agents. Concern has arisen recently that certain anesthetic agents may be toxic to the developing brain; a public-private partnership, SmartTots, was formed in conjunction with the Food and Drug Administration and various stakeholders to develop safe anesthetic regimens for neonates and infants who require surgery. However, as research has progressed, questions have arisen regarding the best outcome measures to use in order to detect a true effect, as well as the optimal window in which to measure. These issues were discussed in a round table meeting during the SmartTots meeting in September 2017, and a summary of the discussion is presented here.