Smartphone Keyboard Interaction Monitoring as an Unobtrusive Method to Approximate Rest-Activity Patterns: Experience Sampling Study Investigating Interindividual and Metric-Specific Variations.

BACKGROUND: Sleep is an important determinant of individuals' health and behavior during the wake phase. Novel research methods for field assessments are required to enable the monitoring of sleep over a prolonged period and across a large number of people. The ubiquity of smartphones offers new avenues for detecting rest-activity patterns in everyday life in a noninvasive an inexpensive manner and on a large scale. Recent studies provided evidence for the potential of smartphone interaction monitoring as a novel tracking method to approximate rest-activity patterns based on the timing of smartphone activity and inactivity throughout the 24-hour day. These findings require further replication and more detailed insights into interindividual variations in the associations and deviations with commonly used metrics for monitoring rest-activity patterns in everyday life. OBJECTIVE: This study aimed to replicate and expand on earlier findings regarding the associations and deviations between smartphone keyboard-derived and self-reported estimates of the timing of the onset of the rest and active periods and the duration of the rest period. Moreover, we aimed to quantify interindividual variations in the associations and time differences between the 2 assessment modalities and to investigate to what extent general sleep quality, chronotype, and trait self-control moderate these associations and deviations. METHODS: Students were recruited to participate in a 7-day experience sampling study with parallel smartphone keyboard interaction monitoring. Multilevel modeling was used to analyze the data. RESULTS: In total, 157 students participated in the study, with an overall response rate of 88.9% for the diaries. The results revealed moderate to strong relationships between the keyboard-derived and self-reported estimates, with stronger associations for the timing-related estimates (ß ranging from .61 to .78) than for the duration-related estimates (ß=.51 and ß=.52). The relational strength between the time-related estimates was lower, but did not substantially differ for the duration-related estimates, among students experiencing more disturbances in their general sleep quality. Time differences between the keyboard-derived and self-reported estimates were, on average, small (<0.5 hours); however, large discrepancies were also registered for quite some nights. The time differences between the 2 assessment modalities were larger for both timing-related and rest duration-related estimates among students who reported more disturbances in their general sleep quality. Chronotype and trait self-control did not significantly moderate the associations and deviations between the 2 assessment modalities. CONCLUSIONS: We replicated the positive potential of smartphone keyboard interaction monitoring for estimating rest-activity patterns among populations of regular smartphone users. Chronotype and trait self-control did not significantly influence the metrics' accuracy, whereas general sleep quality did: the behavioral proxies obtained from smartphone interactions appeared to be less powerful among students who experienced lower general sleep quality. The generalization and underlying process of these findings require further investigation.

Disease severity classification using passively collected smartphone-based keystroke dynamics within multiple sclerosis.

Multiple Sclerosis (MS) is a progressive demyelinating disease of the central nervous system characterised by a wide range of motor and non-motor symptoms. The level of disability of people with MS (pwMS) is based on a wide range of clinical measures, though their frequency of evaluation and inaccuracies coming from objective and self-reported evaluations limits these assessments. Alternatively, remote health monitoring through devices can offer a cost-efficient solution to gather more reliable, objective measures continuously. Measuring smartphone keyboard interactions is a promising tool since typing and, thus, keystroke dynamics are likely influenced by symptoms that pwMS can experience. Therefore, this paper aims to investigate whether keyboard interactions gathered on a person's smartphone can provide insight into the clinical status of pwMS leveraging machine learning techniques. In total, 24 Healthy Controls (HC) and 102 pwMS were followed for one year. Next to continuous data generated via smartphone interactions, clinical outcome measures were collected and used as targets to train four independent multivariate binary classification pipelines in discerning pwMS versus HC and estimating the level of disease severity, manual dexterity and cognitive capabilities. The final models yielded an AUC-ROC in the hold-out set above 0.7, with the highest performance obtained in estimating the level of fine motor skills (AUC-ROC=0.753). These findings show that keyboard interactions combined with machine learning techniques can be used as an unobtrusive monitoring tool to estimate various levels of clinical disability in pwMS from daily activities and with a high frequency of sampling without increasing patient burden.

The Use of Smartphone Keystroke Dynamics to Passively Monitor Upper Limb and Cognitive Function in Multiple Sclerosis: Longitudinal Analysis.

BACKGROUND: Typing on smartphones, which has become a near daily activity, requires both upper limb and cognitive function. Analysis of keyboard interactions during regular typing, that is, keystroke dynamics, could therefore potentially be utilized for passive and continuous monitoring of function in patients with multiple sclerosis. OBJECTIVE: To determine whether passively acquired smartphone keystroke dynamics correspond to multiple sclerosis outcomes, we investigated the association between keystroke dynamics and clinical outcomes (upper limb and cognitive function). This association was investigated longitudinally in order to study within-patient changes independently of between-patient differences. METHODS: During a 1-year follow-up, arm function and information processing speed were assessed every 3 months in 102 patients with multiple sclerosis with the Nine-Hole Peg Test and Symbol Digit Modalities Test, respectively. Keystroke-dynamics data were continuously obtained from regular typing on the participants' own smartphones. Press-and-release latency of the alphanumeric keys constituted the fine motor score cluster, while latency of the punctuation and backspace keys constituted the cognition score cluster. The association over time between keystroke clusters and the corresponding clinical outcomes was assessed with linear mixed models with subjects as random intercepts. By centering around the mean and calculating deviation scores within subjects, between-subject and within-subject effects were distinguished. RESULTS: Mean (SD) scores for the fine motor score cluster and cognition score cluster were 0.43 (0.16) and 0.94 (0.41) seconds, respectively. The fine motor score cluster was significantly associated with the Nine-Hole Peg Test: between-subject ß was 15.9 (95% CI 12.2-19.6) and within-subject ß was 6.9 (95% CI 2.0-11.9). The cognition score cluster was significantly associated with the Symbol Digit Modalities Test between subjects (between-subject ß -11.2, 95% CI -17.3 to -5.2) but not within subjects (within-subject ß -0.4, 95% CI -5.6 to 4.9). CONCLUSIONS: Smartphone keystroke dynamics were longitudinally associated with multiple sclerosis outcomes. Worse arm function corresponded with longer latency in typing both across and within patients. Worse processing speed corresponded with higher latency in using punctuation and backspace keys across subjects. Hence, keystroke dynamics are a potential digital biomarker for remote monitoring and predicting clinical outcomes in patients with multiple sclerosis. TRIAL REGISTRATION: Netherlands Trial Register NTR7268; https://trialsearch.who.int/Trial2.aspx?TrialID=NTR7268.

Structure-function coupling as a correlate and potential biomarker of cognitive impairment in multiple sclerosis.

Multiple sclerosis (MS) features extensive connectivity changes, but how structural and functional connectivity relate, and whether this relation could be a useful biomarker for cognitive impairment in MS is unclear. This study included 79 MS patients and 40 healthy controls (HCs). Patients were classified as cognitively impaired (CI) or cognitively preserved (CP). Structural connectivity was determined using diffusion MRI and functional connectivity using resting-state magnetoencephalography (MEG) data (theta, alpha1, and alpha2 bands). Structure-function coupling was assessed by correlating modalities, and further explored in frequency bands that significantly correlated with whole-brain structural connectivity. Functional correlates of short- and long-range structural connections (based on tract length) were then specifically assessed. Receiving operating curve analyses were performed on coupling values to identify biomarker potential. Only the theta band showed significant correlations between whole-brain structural and functional connectivity (rho = -0.26, p = 0.023, only in MS). Long-range structure-function coupling was stronger in CI patients compared to HCs (p = 0.005). Short-range coupling showed no group differences. Structure-function coupling was not a significant classifier of cognitive impairment for any tract length (short-range area under the curve (AUC) = 0.498, p = 0.976, long-range AUC = 0.611, p = 0.095). Long-range structure-function coupling was stronger in CI MS compared to HCs, but more research is needed to further explore this measure as biomarkers in MS.

Smartphone-derived keystroke dynamics are sensitive to relevant changes in multiple sclerosis.

BACKGROUND: To investigate smartphone keystroke dynamics (KD), derived from regular typing, on sensitivity to relevant change in disease activity, fatigue, and clinical disability in multiple sclerosis (MS). METHODS: Preplanned interim analysis of a cohort study with 102 MS patients assessed at baseline and 3-month follow-up for gadolinium-enhancing lesions on magnetic resonance imaging, relapses, fatigue and clinical disability outcomes. Keyboard interactions were unobtrusively collected during typing using the Neurokeys App. From these interactions 15 keystroke features were derived and aggregated using 16 summary and time series statistics. Responsiveness of KD to clinical anchor-based change was assessed by calculating the area under the receiver operating characteristic curve (AUC). The optimal cut-point was used to determine the minimal clinically important difference (MCID) and compared to the smallest real change (SRC). Commonly used clinical measures were analyzed for comparison. RESULTS: A total of 94 patients completed the follow-up. The five best performing keystroke features had AUC-values in the range 0.72-0.78 for change in gadolinium-enhancing lesions, 0.67-0.70 for the Checklist Individual Strength Fatigue subscale, 0.66-0.79 for the Expanded Disability Status Scale, 0.69-0.73 for the Ambulation Functional System, and 0.72-0.75 for Arm function in MS Questionnaire. The MCID of these features exceeded the SRC on group level. KD had higher AUC-values than comparative clinical measures for the study outcomes, aside from ambulatory function. CONCLUSIONS: Keystroke dynamics demonstrated good responsiveness to changes in disease activity, fatigue, and clinical disability in MS, and detected important change beyond measurement error on group level. Responsiveness of KD was better than commonly used clinical measures.

The cerebellum and its network: Disrupted static and dynamic functional connectivity patterns and cognitive impairment in multiple sclerosis.

BACKGROUND: The impact of cerebellar damage and (dys)function on cognition remains understudied in multiple sclerosis. OBJECTIVE: To assess the cognitive relevance of cerebellar structural damage and functional connectivity (FC) in relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS). METHODS: This study included 149 patients with early RRMS, 81 late RRMS, 48 SPMS and 82 controls. Cerebellar cortical imaging included fractional anisotropy, grey matter volume and resting-state functional magnetic resonance imaging (MRI). Cerebellar FC was assessed with literature-based resting-state networks, using static connectivity (that is, conventional correlations), and dynamic connectivity (that is, fluctuations in FC strength). Measures were compared between groups and related to disability and cognition. RESULTS: Cognitive impairment (CI) and cerebellar damage were worst in SPMS. Only SPMS showed cerebellar connectivity changes, compared to early RRMS and controls. Lower static FC was seen in fronto-parietal and default-mode networks. Higher dynamic FC was seen in dorsal and ventral attention, default-mode and deep grey matter networks. Cerebellar atrophy and higher dynamic FC together explained 32% of disability and 24% of cognitive variance. Higher dynamic FC was related to working and verbal memory and to information processing speed. CONCLUSION: Cerebellar damage and cerebellar connectivity changes were most prominent in SPMS and related to worse CI.

Increased functional sensorimotor network efficiency relates to disability in multiple sclerosis.

BACKGROUND: Network abnormalities could help explain physical disability in multiple sclerosis (MS), which remains poorly understood. OBJECTIVE: This study investigates functional network efficiency changes in the sensorimotor system. METHODS: We included 222 MS patients, divided into low disability (LD, Expanded Disability Status Scale (EDSS) ⩽3.5, n = 185) and high disability (HD, EDSS ⩾6, n = 37), and 82 healthy controls (HC). Functional connectivity was assessed between 23 sensorimotor regions. Measures of efficiency were computed and compared between groups using general linear models corrected for age and sex. Binary logistic regression models related disability status to local functional network efficiency (LE), brain volumes and demographics. Functional connectivity patterns of regions important for disability were explored. RESULTS: HD patients demonstrated significantly higher LE of the left primary somatosensory cortex (S1) and right pallidum compared to LD and HC, and left premotor cortex compared to HC only. The logistic regression model for disability (R2 = 0.38) included age, deep grey matter volume and left S1 LE. S1 functional connectivity was increased with prefrontal and secondary sensory areas in HD patients, compared to LD and HC. CONCLUSION: Clinical disability in MS associates with functional sensorimotor increases in efficiency and connectivity, centred around S1, independent of structural damage.

Sleep characteristics across the lifespan in 1.1 million people from the Netherlands, United Kingdom and United States: a systematic review and meta-analysis.

We aimed to obtain reliable reference charts for sleep duration, estimate the prevalence of sleep complaints across the lifespan and identify risk indicators of poor sleep. Studies were identified through systematic literature search in Embase, Medline and Web of Science (9 August 2019) and through personal contacts. Eligible studies had to be published between 2000 and 2017 with data on sleep assessed with questionnaires including ≥100 participants from the general population. We assembled individual participant data from 200,358 people (aged 1-100 years, 55% female) from 36 studies from the Netherlands, 471,759 people (40-69 years, 55.5% female) from the United Kingdom and 409,617 people (≥18 years, 55.8% female) from the United States. One in four people slept less than age-specific recommendations, but only 5.8% slept outside of the 'acceptable' sleep duration. Among teenagers, 51.5% reported total sleep times (TST) of less than the recommended 8-10 h and 18% report daytime sleepiness. In adults (≥18 years), poor sleep quality (13.3%) and insomnia symptoms (9.6-19.4%) were more prevalent than short sleep duration (6.5% with TST < 6 h). Insomnia symptoms were most frequent in people spending ≥9 h in bed, whereas poor sleep quality was more frequent in those spending <6 h in bed. TST was similar across countries, but insomnia symptoms were 1.5-2.9 times higher in the United States. Women (≥41 years) reported sleeping shorter times or slightly less efficiently than men, whereas with actigraphy they were estimated to sleep longer and more efficiently than man. This study provides age- and sex-specific population reference charts for sleep duration and efficiency which can help guide personalized advice on sleep length and preventive practices.

Long-range connections are more severely damaged and relevant for cognition in multiple sclerosis.

An efficient network such as the human brain features a combination of global integration of information, driven by long-range connections, and local processing involving short-range connections. Whether these connections are equally damaged in multiple sclerosis is unknown, as is their relevance for cognitive impairment and brain function. Therefore, we cross-sectionally investigated the association between damage to short- and long-range connections with structural network efficiency, the functional connectome and cognition. From the Amsterdam multiple sclerosis cohort, 133 patients (age = 54.2 ± 9.6) with long-standing multiple sclerosis and 48 healthy controls (age = 50.8 ± 7.0) with neuropsychological testing and MRI were included. Structural connectivity was estimated from diffusion tensor images using probabilistic tractography (MRtrix 3.0) between pairs of brain regions. Structural connections were divided into short- (length < quartile 1) and long-range (length > quartile 3) connections, based on the mean distribution of tract lengths in healthy controls. To determine the severity of damage within these connections, (i) fractional anisotropy as a measure for integrity; (ii) total number of fibres; and (iii) percentage of tract affected by lesions were computed for each connecting tract and averaged for short- and long-range connections separately. To investigate the impact of damage in these connections for structural network efficiency, global efficiency was computed. Additionally, resting-state functional connectivity was computed between each pair of brain regions, after artefact removal with FMRIB's ICA-based X-noiseifier. The functional connectivity similarity index was computed by correlating individual functional connectivity matrices with an average healthy control connectivity matrix. Our results showed that the structural network had a reduced efficiency and integrity in multiple sclerosis relative to healthy controls (both P < 0.05). The long-range connections showed the largest reduction in fractional anisotropy (z = -1.03, P < 0.001) and total number of fibres (z = -0.44, P < 0.01), whereas in the short-range connections only fractional anisotropy was affected (z = -0.34, P = 0.03). Long-range connections also demonstrated a higher percentage of tract affected by lesions than short-range connections, independent of tract length (P < 0.001). Damage to long-range connections was more strongly related to structural network efficiency and cognition (fractional anisotropy: r = 0.329 and r = 0.447. number of fibres r = 0.321 and r = 0.278. and percentage of lesions: r = -0.219; r = -0.426, respectively) than damage to short-range connections. Only damage to long-distance connections correlated with a more abnormal functional network (fractional anisotropy: r = 0.226). Our findings indicate that long-range connections are more severely affected by multiple sclerosis-specific damage than short-range connections. Moreover compared to short-range connections, damage to long-range connections better explains network efficiency and cognition.

Cortical atrophy accelerates as cognitive decline worsens in multiple sclerosis.

OBJECTIVE: To determine which pathologic process could be responsible for the acceleration of cognitive decline during the course of multiple sclerosis (MS), using longitudinal structural MRI, which was related to cognitive decline in relapsing-remitting MS (RRMS) and progressive MS (PMS). METHODS: A prospective cohort of 230 patients with MS (179 RRMS and 51 PMS) and 59 healthy controls was evaluated twice with 5-year (mean 4.9, SD 0.94) interval during which 22 patients with RRMS converted to PMS. Annual rates of cortical and deep gray matter atrophy as well as lesion volume increase were computed on longitudinal (3T) MRI data and correlated to the annual rate of cognitive decline as measured using an extensive cognitive evaluation at both time points. RESULTS: The deep gray matter atrophy rate did not differ between PMS and RRMS (-0.82%/year vs -0.71%/year, p = 0.11), while faster cortical atrophy was observed in PMS (-0.87%/year vs -0.48%/year, p < 0.01). Similarly, faster cognitive decline was observed in PMS compared to RRMS (p < 0.01). Annual cognitive decline was related to the rate of annual lesion volume increase in stable RRMS (r = -0.17, p = 0.03) to the rate of annual deep gray matter atrophy in converting RRMS (r = 0.50, p = 0.02) and annual cortical atrophy in PMS (r = 0.35, p = 0.01). CONCLUSIONS: These results indicate that cortical atrophy and cognitive decline accelerate together during the course of MS. Substrates of cognitive decline shifted from worsening lesional pathology in stable RRMS to deep gray matter atrophy in converting RRMS and to accelerated cortical atrophy in PMS only.

Reduced Network Dynamics on Functional MRI Signals Cognitive Impairment in Multiple Sclerosis.

Background Previous studies have demonstrated extensive functional network disturbances in patients with multiple sclerosis (MS), showing a less efficient brain network. Recent studies indicate that the dynamic properties of the brain network show a strong correlation with cognitive function. Purpose To investigate network dynamics on functional MRI in cognitively impaired patients with MS. Materials and Methods In secondary analysis of prospectively acquired data, with imaging performed between 2008 and 2012, differences in regional functional network dynamics (ie, eigenvector centrality dynamics) between cognitively impaired and cognitively preserved participants with MS were investigated. Functional network dynamics were computed on images from functional MRI (3 T) by using a sliding-window approach. Cognitively impaired and preserved groups were compared by using a clusterwise permutation-based method. Results The study included 96 healthy control subjects and 332 participants with MS (including 226 women and 106 men; median age, 48.1 years ± 11.0). Among the 332 participants with MS, 87 were cognitively impaired and 180 had preserved cognitive function; mildly impaired patients (n = 65) were excluded. The cognitively impaired group included a higher proportion of men compared with the cognitively preserved group (35 of 87 [40%] vs 48 of 180 [27%], respectively; P = .02) and had a higher mean age (51.1 years vs 46.3 years, respectively; P < .01). The clusterwise permutation-based comparison at P less than .05 showed reduced centrality dynamics in default-mode, frontoparietal, and visual network regions on functional MRI in cognitively impaired participants versus cognitively preserved participants. A subsequent correlation and hierarchical clustering analysis revealed that the default-mode and visual networks normally demonstrate negatively correlated fluctuations in functional importance (r = -0.23 in healthy control subjects), with an almost complete loss of this negative correlation in cognitively impaired participants compared with cognitively preserved participants (r = -0.04 vs r = -0.14; corrected P = .02). Conclusion As shown on functional MRI, cognitively impaired patients with multiple sclerosis not only demonstrate reduced dynamics in default-mode, frontoparietal, and visual networks, but also show a loss of interplay between default-mode and visual networks. © RSNA, 2019 Online supplemental material is available for this article. See also the article by Eijlers et al and the editorial by Zivadinov and Dwyer in this issue.

Structural network topology relates to tissue properties in multiple sclerosis.

OBJECTIVE: Abnormalities in segregative and integrative properties of brain networks have been observed in multiple sclerosis (MS) and are related to clinical functioning. This study aims to investigate the micro-scale correlates of macro-scale network measures of segregation and integration in MS. METHODS: Eight MS patients underwent post-mortem in situ whole-brain diffusion tensor (DT) imaging and subsequent brain dissection. Macro-scale structural network topology was derived from DT data using graph theory. Clustering coefficient and mean white matter (WM) fiber length were measures of nodal segregation and integration. Thirty-three tissue blocks were collected from five cortical brain regions. Using immunohistochemistry micro-scale tissue properties were evaluated, including, neuronal size, neuronal density, axonal density and total cell density. Nodal network properties and tissue properties were correlated. RESULTS: A negative correlation between clustering coefficient and WM fiber length was found. Higher clustering coefficient was associated with smaller neuronal size and lower axonal density, and vice versa for fiber length. Higher whole-brain WM lesion load was associated with higher whole-brain clustering, shorter whole-brain fiber length, lower neuronal size and axonal density. CONCLUSION: Structural network properties on MRI associate with neuronal size and axonal density, suggesting that macro-scale network measures may grasp cortical neuroaxonal degeneration in MS.

Predicting cognitive decline in multiple sclerosis: a 5-year follow-up study.

Cognitive decline is common in multiple sclerosis and strongly affects overall quality of life. Despite the identification of cross-sectional MRI correlates of cognitive impairment, predictors of future cognitive decline remain unclear. The objective of this study was to identify which MRI measures of structural damage, demographic and/or clinical measures at baseline best predict cognitive decline, during a 5-year follow-up period. A total of 234 patients with clinically definite multiple sclerosis and 60 healthy control subjects were examined twice, with a 5-year interval (mean = 4.9 years, standard deviation = 0.9). An extensive neuropsychological evaluation was performed at both time points and the reliable change index was computed to evaluate cognitive decline. Both whole-brain and regional MRI (3 T) measures were assessed at baseline, including white matter lesion volume, diffusion-based white matter integrity, cortical and deep grey matter volume. Logistic regression analyses were performed to determine which baseline measures best predicted cognitive decline in the entire sample as well as in early relapsing-remitting (symptom duration <10 years), late relapsing-remitting (symptom duration ≥10 years) and progressive phenotypes. At baseline, patients with multiple sclerosis had a mean disease duration of 14.8 (standard deviation = 8.4) years and 96/234 patients (41%) were classified as cognitively impaired. A total of 66/234 patients (28%) demonstrated cognitive decline during follow-up, with higher frequencies in progressive compared to relapsing-remitting patients: 18/33 secondary progressive patients (55%), 10/19 primary progressive patients (53%) and 38/182 relapsing-remitting patients (21%). A prediction model that included only whole-brain MRI measures (Nagelkerke R2 = 0.22, P < 0.001) showed cortical grey matter volume as the only significant MRI predictor of cognitive decline, while a prediction model that assessed regional MRI measures (Nagelkerke R2 = 0.35, P < 0.001) indicated integrity loss of the anterior thalamic radiation, lesions in the superior longitudinal fasciculus and temporal atrophy as significant MRI predictors for cognitive decline. Disease stage specific regressions showed that cognitive decline in early relapsing-remitting multiple sclerosis was predicted by white matter integrity damage, while cognitive decline in late relapsing-remitting and progressive multiple sclerosis was predicted by cortical atrophy. These results indicate that patients with more severe structural damage at baseline, and especially cortical atrophy, are more prone to suffer from cognitive decline. New studies now need to further elucidate the underlying mechanisms leading to cortical atrophy, evaluate the value of including cortical atrophy as a possible outcome marker in clinical trials as well as study its potential use in individual patient management.

The importance of hippocampal dynamic connectivity in explaining memory function in multiple sclerosis.

Introduction: Brain dynamics (i.e., variable strength of communication between areas), even at the scale of seconds, are thought to underlie complex human behavior, such as learning and memory. In multiple sclerosis (MS), memory problems occur often and have so far only been related to "stationary" brain measures (e.g., atrophy, lesions, activation and stationary (s) functional connectivity (FC) over an entire functional scanning session). However, dynamics in FC (dFC) between the hippocampus and the (neo)cortex may be another important neurobiological substrate of memory impairment in MS that has not yet been explored. Therefore, we investigated hippocampal dFC during a functional (f) magnetic resonance imaging (MRI) episodic memory task and its relationship with verbal and visuospatial memory performance outside the MR scanner. Methods: Thirty-eight MS patients and 29 healthy controls underwent neuropsychological tests to assess memory function. Imaging (1.5T) was obtained during performance of a memory task. We assessed hippocampal volume, functional activation, and sFC (i.e., FC of the hippocampus with the rest of the brain averaged over the entire scan, using an atlas-based approach). Dynamic FC of the hippocampus was calculated using a sliding window approach. Results: No group differences were found in hippocampal activation, sFC, and dFC. However, stepwise forward regression analyses in patients revealed that lower dFC of the left hippocampus (standardized ß = -0.30; p = .021) could explain an additional 7% of variance (53% in total) in verbal memory, in addition to female sex and larger left hippocampal volume. For visuospatial memory, lower dFC of the right hippocampus (standardized ß = -0.38; p = .013) could explain an additional 13% of variance (24% in total) in addition to higher sFC of the right hippocampus. Conclusion: Low hippocampal dFC is an important indicator for maintained memory performance in MS, in addition to other hippocampal imaging measures. Hence, brain dynamics may offer new insights into the neurobiological mechanisms underlying memory (dys)function.

Determinants of Cognitive Impairment in Patients with Multiple Sclerosis with and without Atrophy.

Purpose To investigate the discrepancy between patients with multiple sclerosis (MS) without atrophy who have already developed cognitive impairment and patients with MS with atrophy who have preserved cognitive function. Materials and Methods This retrospective imaging study, with imaging acquired between 2008 and 2012, included 332 patients with MS (106 men and 226 women; mean age, 48.1 years; range, 23.0-72.5 years) and 96 healthy control participants. Cognitive impairment was defined as cognitive performance of z less than -1.5 compared with that in control participants in greater than or equal to two cognitive domains. Atrophy was defined as cortical and deep gray matter volumes of z less than -1.5 compared with that in control participants. White matter lesions were assessed with T2-imaging, tract fractional anisotropy (ie, integrity) with diffusion MRI, and regional centrality (ie, importance within network) with functional MRI. Within each atrophy group, patients with cognitive impairment and preserved cognitive function were compared and regression analyses were performed to predict cognitive impairment. Results A total of 132 of 328 patients with MS had no atrophy; of these, 42 of 132 (32%) had cognitive impairment. Cognitive impairment in patients without atrophy was predicted by level of education (Wald test, 11.63; P < .01) and posterior cingulate centrality (Wald test, 6.82; P < .01). A total of 65 of 328 patients with MS had atrophy; of these, 49 of 65 (75%) had cognitive impairment. Cognitive impairment in patients with atrophy was predicted by white matter tract fractional anisotropy (Wald test, 4.89; P = .03) and posterior cingulate centrality (Wald test, 7.19; P < .01). Conclusion Cognitive impairment was related to white matter damage, but only in patients with MS with atrophy. In patients without atrophy, a lower level of education was most important for cognitive impairment. Posterior cingulate cortex showed functional abnormalities in all MS groups with cognitive impairment, regardless of atrophy.

Staging of cortical and deep grey matter functional connectivity changes in multiple sclerosis.

OBJECTIVE: Functional connectivity is known to increase as well as decrease throughout the brain in multiple sclerosis (MS), which could represent different stages of the disease. In addition, functional connectivity changes could follow the atrophy pattern observed with disease progression, that is, moving from the deep grey matter towards the cortex. This study investigated when and where connectivity changes develop and explored their clinical and cognitive relevance across different MS stages. METHODS: A cohort of 121 patients with early relapsing-remitting MS (RRMS), 122 with late RRMS and 53 with secondary progressive MS (SPMS) as well as 96 healthy controls underwent MRI and neuropsychological testing. Functional connectivity changes were investigated for (1) within deep grey matter connectivity, (2) connectivity between the deep grey matter and cortex and (3) within-cortex connectivity. A post hoc regional analysis was performed to identify which regions were driving the connectivity changes. RESULTS: Patients with late RRMS and SPMS showed increased connectivity of the deep grey matter, especially of the putamen and palladium, with other deep grey matter structures and with the cortex. Within-cortex connectivity was decreased, especially for temporal, occipital and frontal regions, but only in SPMS relative to early RRMS. Deep grey matter connectivity alterations were related to cognition and disability, whereas within-cortex connectivity was only related to disability. CONCLUSION: Increased connectivity of the deep grey matter became apparent in late RRMS and further increased in SPMS. The additive effect of cortical network degeneration, which was only seen in SPMS, may explain the sudden clinical deterioration characteristic to this phase of the disease.

Increased connectivity of hub networks and cognitive impairment in multiple sclerosis.

OBJECTIVE: To investigate default-mode network (DMN) and frontoparietal network (FPN) dysfunction in cognitively impaired (CI) patients with multiple sclerosis (MS) because these networks strongly relate to cognition and contain most of the hubs of the brain. METHODS: Resting-state fMRI and neuropsychological assessments were performed in 322 patients with MS and 96 healthy controls (HCs). Patients with MS were classified as CI (z score < -2.0 on at least 2 tests; n = 87), mildly cognitively impaired (z score < -1.5 on at least 2 tests and not CI; n = 65), and cognitively preserved (CP; n = 180). Within-network connectivity, connectivity with the rest of the brain, and between-network connectivity were calculated and compared between groups. Connectivity values were normalized for individual means and SDs. RESULTS: Only in CI, both the DMN and FPN showed increased connectivity with the rest of the brain compared to HCs and CP, with no change in within- or between-network connectivity. Regionally, this increased connectivity was driven by the inferior parietal, posterior cingulate, and angular gyri. Increased connectivity with the rest of the brain correlated with worse cognitive performance, namely attention for the FPN as well as information processing speed and working memory for both networks. CONCLUSIONS: In CI patients with MS, the DMN and FPN showed increased connectivity with the rest of the brain, while normal within- and between-network connectivity levels were maintained. These findings indicate that cognitive impairment in MS features disturbed communication of hub-rich networks, but only with the more peripheral (i.e., nonhub) regions of the brain.

Increased default-mode network centrality in cognitively impaired multiple sclerosis patients.

OBJECTIVE: To investigate how changes in functional network hierarchy determine cognitive impairment in multiple sclerosis (MS). METHODS: A cohort consisting of 332 patients with MS (age 48.1 ± 11.0 years, symptom duration 14.6 ± 8.4 years) and 96 healthy controls (HCs; age 45.9 ± 10.4 years) underwent structural MRI, fMRI, and extensive neuropsychological testing. Patients were divided into 3 groups: cognitively impaired (CI; n = 87), mildly cognitively impaired (MCI; n = 65), and cognitively preserved (CP; n = 180). The functional importance of brain regions was quantified with degree centrality, the average strength of the functional connections of a brain region with the rest of the brain, and eigenvector centrality, which adds to this concept by adding additional weight to connections with brain hubs because these are known to be especially important. Centrality values were calculated for each gray matter voxel based on resting-state fMRI data, registered to standard space. Group differences were assessed with a cluster-wise permutation-based method corrected for age, sex, and education. RESULTS: CI patients demonstrated widespread centrality increases compared to both HCs and CP patients, mainly in regions making up the default-mode network. Centrality decreases were similar in all patient groups compared to HCs, mainly in occipital and sensorimotor areas. Results were robust across centrality measures. CONCLUSIONS: Patients with MS with cognitive impairment show hallmark alterations in functional network hierarchy with increased relative importance (centrality) of the default-mode network.

A review and meta-analysis of the enemy release hypothesis in plant-herbivorous insect systems.

A suggested mechanism for the success of introduced non-native species is the enemy release hypothesis (ERH). Many studies have tested the predictions of the ERH using the community approach (native and non-native species studied in the same habitat) or the biogeographical approach (species studied in their native and non-native range), but results are highly variable, possibly due to large variety of study systems incorporated. We therefore focused on one specific system: plants and their herbivorous insects. We performed a systematic review and compiled a large number (68) of datasets from studies comparing herbivorous insects on native and non-native plants using the community or biogeographical approach. We performed a meta-analysis to test the predictions from the ERH for insect diversity (number of species), insect load (number of individuals) and level of herbivory for both the community and biogeographical approach. For both the community and biogeographical approach insect diversity was significantly higher on native than on non-native plants. Insect load tended to be higher on native than non-native plants at the community approach only. Herbivory was not different between native and non-native plants at the community approach, while there was too little data available for testing the biogeographical approach. Our meta-analysis generally supports the predictions from the ERH for both the community and biogeographical approach, but also shows that the outcome is importantly determined by the response measured and approach applied. So far, very few studies apply both approaches simultaneously in a reciprocal manner while this is arguably the best way for testing the ERH.