Statistical inference of dynamic resting‐state functional connectivity using hierarchical observation modeling

Spontaneous fluctuations of blood‐oxygenation level‐dependent functional magnetic resonance imaging (BOLD fMRI) signals are highly synchronous between brain regions that serve similar functions. This provides a means to investigate functional networks; however, most analysis techniques assume functional connections are constant over time. This may be problematic in the case of neurological disease, where functional connections may be highly variable. Recently, several methods have been proposed to determine moment‐to‐moment changes in the strength of functional connections over an imaging session (so called dynamic connectivity). Here a novel analysis framework based on a hierarchical observation modeling approach was proposed, to permit statistical inference of the presence of dynamic connectivity. A two‐level linear model composed of overlapping sliding windows of fMRI signals, incorporating the fact that overlapping windows are not independent was described. To test this approach, datasets were synthesized whereby functional connectivity was either constant (significant or insignificant) or modulated by an external input. The method successfully determines the statistical significance of a functional connection in phase with the modulation, and it exhibits greater sensitivity and specificity in detecting regions with variable connectivity, when compared with sliding‐window correlation analysis. For real data, this technique possesses greater reproducibility and provides a more discriminative estimate of dynamic connectivity than sliding‐window correlation analysis. Hum Brain Mapp 37:4566–4580, 2016. © 2016 Wiley Periodicals, Inc.     

An average sliding window correlation method for dynamic functional connectivity

Sliding window correlation (SWC) is utilized in many studies to analyze the temporal characteristics of brain connectivity. However, spurious artifacts have been reported in simulated data using this technique. Several suggestions have been made through the development of the SWC technique. Recently, it has been proposed to utilize a SWC window length of 100 s given that the lowest nominal fMRI frequency is 0.01 Hz. The main pitfall is the loss of temporal resolution due to a large window length. In this work, we propose an average sliding window correlation (ASWC) approach that presents several advantages over the SWC. One advantage is the requirement for a smaller window length. This is important because shorter lengths allow for a more accurate estimation of transient dynamicity of functional connectivity. Another advantage is the behavior of ASWC as a tunable high pass filter. We demonstrate the advantages of ASWC over SWC using simulated signals with configurable functional connectivity dynamics. We present analytical models explaining the behavior of ASWC and SWC for several dynamic connectivity cases. We also include a real data example to demonstrate the application of the new method. In summary, ASWC shows lower artifacts and resolves faster transient connectivity fluctuations, resulting in a lower mean square error than in SWC.     

Impact of acute sleep deprivation on dynamic functional connectivity states

Sleep deprivation (SD) could amplify the temporal fluctuation of spontaneous brain activities that reflect different arousal levels using a dynamic functional connectivity (dFC) approach. Therefore, we intended to evaluate the test–retest reliability of dFC characteristics during rested wakefulness (RW), and to explore how the properties of these dynamic connectivity states were affected by extended durations of acute sleep loss (28/52 hr). We acquired resting‐state fMRI and neuropsychological datasets in two independent studies: (a) twice during RW and once after 28 hr of SD (n = 15) and (b) after 52 hr of SD and after 14 hr of recovery sleep (RS; n = 14). Sliding‐window correlations approach was applied to estimate their covariance matrices and corresponding three connectivity states were generated. The test–retest reliability of dFC properties demonstrated mean dwell time and fraction of connectivity states were reliable. After SD, the mean dwell time of a specific state, featured by strong subcortical–cortical anticorrelations, was significantly increased. Conversely, another globally hypoconnected state was significantly decreased. Subjective sleepiness and objective performances were separately positive and negative correlated with the increased and decreased state. Two brain connectivity states and their alterations might be sufficiently sensitive to reflect changes in the dynamics of brain mental activities after sleep loss.     

Disentangling dynamic networks: Separated and joint expressions of functional connectivity patterns in time

Resting‐state functional connectivity (FC) is highly variable across the duration of a scan. Groups of coevolving connections, or reproducible patterns of dynamic FC (dFC), have been revealed in fluctuating FC by applying unsupervised learning techniques. Based on results from k‐means clustering and sliding‐window correlations, it has recently been hypothesized that dFC may cycle through several discrete FC states. Alternatively, it has been proposed to represent dFC as a linear combination of multiple FC patterns using principal component analysis. As it is unclear whether sparse or nonsparse combinations of FC patterns are most appropriate, and as this affects their interpretation and use as markers of cognitive processing, the goal of our study was to evaluate the impact of sparsity by performing an empirical evaluation of simulated, task‐based, and resting‐state dFC. To this aim, we applied matrix factorizations subject to variable constraints in the temporal domain and studied both the reproducibility of ensuing representations of dFC and the expression of FC patterns over time. During subject‐driven tasks, dFC was well described by alternating FC states in accordance with the nature of the data. The estimated FC patterns showed a rich structure with combinations of known functional networks enabling accurate identification of three different tasks. During rest, dFC was better described by multiple FC patterns that overlap. The executive control networks, which are critical for working memory, appeared grouped alternately with externally or internally oriented networks. These results suggest that combinations of FC patterns can provide a meaningful way to disentangle resting‐state dFC. Hum Brain Mapp 35:5984–5995, 2014. © 2014 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.     

Altered brain functional network dynamics in obsessive–compulsive disorder

Obsessive–compulsive disorder (OCD) is a debilitating and disabling neuropsychiatric disorder, whose neurobiological basis remains unclear. Although traditional static resting‐state magnetic resonance imaging (rfMRI) studies have found aberrant functional connectivity (FC) in OCD, alterations in whole‐brain FC and topological properties in the context of brain dynamics remain relatively unexplored. The rfMRI data of 29 patients with OCD and 40 healthy controls were analyzed using group independent component analysis to obtain independent components (ICs) and a sliding‐window approach to generate dynamic functional connectivity (dFC) matrices. dFC patterns were clustered into three reoccurring states, and state transition metrics were obtained. Then, graph‐theory methods were applied to dFC matrices to calculate the variability of network topological organization. The occurrence of a state (State 1) with the highest modularity index and lowest mean FC between networks was increased significantly in OCD, and the fractional time in brain State 1 was positively correlated with anxiety level in patients. State 1 was characterized by having positive connections within default mode (DMN) and salience networks (SAN), and negative coupling between the two networks. Additionally, ICs belonging to DMN and SAN showed lower temporal variability of nodal degree centrality and efficiency in patients, which was related to longer illness duration and higher current obsession ratings. Our results provide evidence of clinically relevant aberrant dynamic brain activity in OCD. Increased functional segregation among networks and impaired functional flexibility in connections among brain regions in DMN and SAN may play important roles in the neuropathology of OCD.     

Transient states of network connectivity are atypical in autism: A dynamic functional connectivity study

There is ample evidence of atypical functional connectivity (FC) in autism spectrum disorders (ASDs). However, transient relationships between neural networks cannot be captured by conventional static FC analyses. Dynamic FC (dFC) approaches have been used to identify repeating, transient connectivity patterns (“states”), revealing spatiotemporal network properties not observable in static FC. Recent studies have found atypical dFC in ASDs, but questions remain about the nature of group differences in transient connectivity, and the degree to which states persist or change over time. This study aimed to: (a) describe and relate static and dynamic FC in typical development and ASDs, (b) describe group differences in transient states and compare them with static FC patterns, and (c) examine temporal stability and flexibility between identified states. Resting‐state functional magnetic resonance imaging (fMRI) data were collected from 62 ASD and 57 typically developing (TD) children and adolescents. Whole‐brain, data‐driven regions of interest were derived from group independent component analysis. Sliding window analysis and k‐means clustering were used to explore dFC and identify transient states. Across all regions, static overconnnectivity and increased variability over time in ASDs predominated. Furthermore, significant patterns of group differences emerged in two transient states that were not observed in the static FC matrix, with group differences in one state primarily involving sensory and motor networks, and in the other involving higher‐order cognition networks. Default mode network segregation was significantly reduced in ASDs in both states. Results highlight that dynamic approaches may reveal more nuanced transient patterns of atypical FC in ASDs.     

Dynamic functional connectivity reveals altered variability in functional connectivity among patients with major depressive disorder

Resting‐state fMRI (RS‐fMRI) has become a useful tool to investigate the connectivity structure of mental health disorders. In the case of major depressive disorder (MDD), recent studies regarding the RS‐fMRI have found abnormal connectivity in several regions of the brain, particularly in the default mode network (DMN). Thus, the relevance of the DMN to self‐referential thoughts and ruminations has made the use of the resting‐state approach particularly important for MDD. The majority of such research has relied on the grand averaged functional connectivity measures based on the temporal correlations between the BOLD time series of various brain regions. We, in our study, investigated the variations in the functional connectivity over time at global and local level using RS‐fMRI BOLD time series of 27 MDD patients and 27 healthy control subjects. We found that global synchronization and temporal stability were significantly increased in the MDD patients. Furthermore, the participants with MDD showed significantly increased overall average (static) functional connectivity (sFC) but decreased variability of functional connectivity (vFC) within specific networks. Static FC increased to predominance among the regions pertaining to the default mode network (DMN), while the decreased variability of FC was observed in the connections between the DMN and the frontoparietal network. Hum Brain Mapp 37:2918–2930, 2016. © 2016 Wiley Periodicals, Inc.     

Tools of the trade: estimating time-varying connectivity patterns from fMRI data

Given the dynamic nature of the brain, there has always been a motivation to move beyond ‘static’ functional connectivity, which characterizes functional interactions over an extended period of time. Progress in data acquisition and advances in analytical neuroimaging methods now allow us to assess the whole brain’s dynamic functional connectivity (dFC) and its network-based analog, dynamic functional network connectivity at the macroscale (mm) using fMRI. This has resulted in the rapid growth of analytical approaches, some of which are very complex, requiring technical expertise that could daunt researchers and neuroscientists. Meanwhile, making real progress toward understanding the association between brain dynamism and brain disorders can only be achieved through research conducted by domain experts, such as neuroscientists and psychiatrists. This article aims to provide a gentle introduction to the application of dFC. We first explain what dFC is and the circumstances under which it can be used. Next, we review two major categories of analytical approaches to capture dFC. We discuss caveats and considerations in dFC analysis. Finally, we walk readers through an openly accessible toolbox to capture dFC properties and briefly review some of the dynamic metrics calculated using this toolbox.     

Differential patterns of dynamic functional connectivity variability of striato–cortical circuitry in children with benign epilepsy with centrotemporal spikes

Benign epilepsy with centrotemporal spikes (BECTS) is characterized by abnormal (static) functional interactions among cortical and subcortical regions, regardless of the active or chronic epileptic state. However, human brain connectivity is dynamic and associated with ongoing rhythmic activity. The dynamic functional connectivity (dFC) of the distinct striato–cortical circuitry associated with or without interictal epileptiform discharges (IEDs) are poorly understood in BECTS. Herein, we captured the pattern of dFC using sliding window correlation of putamen subregions in the BECTS (without IEDs, n = 23; with IEDs, n = 20) and sex‐ and age‐matched healthy controls (HCs, n = 28) during rest. Furthermore, we quantified dFC variability using their standard deviation. Compared with HCs and patients without IEDs, patients with IEDs exhibited excessive variability in the dorsal striatal‐sensorimotor circuitry related to typical seizure semiology. By contrast, excessive stability (decreased dFC variability) was found in the ventral striatal–cognitive circuitry (p < .05, GRF corrected). In addition, correlation analysis revealed that the excessive variability in the dorsal striatal‐sensorimotor circuitry was related to highly frequent IEDs (p < .05, uncorrected). Our finding of excessive variability in the dorsal striatal‐sensorimotor circuitry could be an indication of increased sensitivity to regional fluctuations in the epileptogenic zone, while excessive stability in the ventral striatal–cognitive circuitry could represent compensatory mechanisms that prevent or postpone cognitive impairments in BECTS. Overall, the differentiated dynamics of the striato–cortical circuitry extend our understanding of interactions among epileptic activity, striato–cortical functional architecture, and neurocognitive processes in BECTS.     

Realistic models of apparent dynamic changes in resting‐state connectivity in somatosensory cortex

Variations over time in resting‐state correlations in blood oxygenation level‐dependent (BOLD) signals from different cortical areas may indicate changes in brain functional connectivity. However, apparent variations over time may also arise from stationary signals when the sample duration is finite. Recently, a vector autoregressive (VAR) null model has been proposed to simulate real functional magnetic resonance imaging (fMRI) data, which provides a robust stationary model for identifying possible temporal dynamic changes in functional connectivity. In this work, we propose a simpler model that uses a filtered stationary dataset. The filtered stationary model generates statistically stationary time series from random data with a single prescribed correlation coefficient that is calculated as the average over the entire time series. In addition, we propose a dynamic model, which is better able to replicate real fMRI connectivity, estimated from monkey brain studies, than the two stationary models. We compare simulated results using these three models with the behavior of primary somatosensory cortex (S1) networks in anesthetized squirrel monkeys at high field (9.4 T), using a sliding window correlation analysis. We found that at short window sizes, both stationary models reproduced the distribution of correlations of real signals well, but at longer window sizes, a dynamic model reproduced the distribution of correlations of real signals better than the stationary models. While stationary models replicate several features of real data, a close representation of the behavior of resting‐state data acquired from somatosensory cortex of non‐human primates is obtained only when a dynamic correlation is introduced, suggesting dynamic variations in connectivity are real. Hum Brain Mapp 37:3897–3910, 2016. © 2016 Wiley Periodicals, Inc .     

Establishing the resting state default mode network derived from functional magnetic resonance imaging tasks as an endophenotype: A twins study

The resting state default mode network (DMN) has been shown to characterize a number of neurological and psychiatric disorders. Evidence suggests an underlying genetic basis for this network and hence could serve as potential endophenotype for these disorders. Heritability is a defining criterion for endophenotypes. The DMN is measured either using a resting‐state functional magnetic resonance imaging (fMRI) scan or by extracting resting state activity from task‐based fMRI. The current study is the first to evaluate heritability of this task‐derived resting activity. 250 healthy adult twins (79 monozygotic and 46 dizygotic same sex twin pairs) completed five cognitive and emotion processing fMRI tasks. Resting state DMN functional connectivity was derived from these five fMRI tasks. We validated this approach by comparing connectivity estimates from task‐derived resting activity for all five fMRI tasks, with those obtained using a dedicated task‐free resting state scan in an independent cohort of 27 healthy individuals. Structural equation modeling using the classic twin design was used to estimate the genetic and environmental contributions to variance for the resting‐state DMN functional connectivity. About 9–41% of the variance in functional connectivity between the DMN nodes was attributed to genetic contribution with the greatest heritability found for functional connectivity between the posterior cingulate and right inferior parietal nodes (P < 0.001). Our data provide new evidence that functional connectivity measures from the intrinsic DMN derived from task‐based fMRI datasets are under genetic control and have the potential to serve as endophenotypes for genetically predisposed psychiatric and neurological disorders. Hum Brain Mapp 35:3893–3902, 2014. © 2014 Wiley Periodicals, Inc .     

Large‐scale dynamic causal modeling of major depressive disorder based on resting‐state functional magnetic resonance imaging

Major depressive disorder (MDD) is a serious mental illness characterized by dysfunctional connectivity among distributed brain regions. Previous connectome studies based on functional magnetic resonance imaging (fMRI) have focused primarily on undirected functional connectivity and existing directed effective connectivity (EC) studies concerned mostly task‐based fMRI and incorporated only a few brain regions. To overcome these limitations and understand whether MDD is mediated by within‐network or between‐network connectivities, we applied spectral dynamic causal modeling to estimate EC of a large‐scale network with 27 regions of interests from four distributed functional brain networks (default mode, executive control, salience, and limbic networks), based on large sample‐size resting‐state fMRI consisting of 100 healthy subjects and 100 individuals with first‐episode drug‐naive MDD. We applied a newly developed parametric empirical Bayes (PEB) framework to test specific hypotheses. We showed that MDD altered EC both within and between high‐order functional networks. Specifically, MDD is associated with reduced excitatory connectivity mainly within the default mode network (DMN), and between the default mode and salience networks. In addition, the network‐averaged inhibitory EC within the DMN was found to be significantly elevated in the MDD. The coexistence of the reduced excitatory but increased inhibitory causal connections within the DMNs may underlie disrupted self‐recognition and emotional control in MDD. Overall, this study emphasizes that MDD could be associated with altered causal interactions among high‐order brain functional networks.     

Abnormal brain functional network dynamics in sleep-related hypermotor epilepsy

Aims

This study aimed to use resting-state functional magnetic resonance imaging (rs-fMRI) to determine the temporal features of functional connectivity states and changes in connectivity strength in sleep-related hypermotor epilepsy (SHE).

Methods

High-resolution T1 and rs-fMRI scanning were performed on all the subjects. We used a sliding-window approach to construct a dynamic functional connectivity (dFC) network. The k-means clustering method was performed to analyze specific FC states and related temporal properties. Finally, the connectivity strength between the components was analyzed using network-based statistics (NBS) analysis. The correlations between the abovementioned measures and disease duration were analyzed.

Results

After k-means clustering, the SHE patients mainly exhibited two dFC states. The frequency of state 1 was higher, which was characterized by stronger connections within the networks; state 2 occurred at a relatively low frequency, characterized by stronger connections between networks. SHE patients had greater fractional time and a mean dwell time in state 2 and had a larger number of state transitions. The NBS results showed that SHE patients had increased connectivity strength between networks. None of the properties was correlated with illness duration among patients with SHE.

Conclusion

The patterns of dFC patterns may represent an adaptive and protective mode of the brain to deal with epileptic seizures.     

Real‐time estimation of dynamic functional connectivity networks

Two novel and exciting avenues of neuroscientific research involve the study of task‐driven dynamic reconfigurations of functional connectivity networks and the study of functional connectivity in real‐time. While the former is a well‐established field within neuroscience and has received considerable attention in recent years, the latter remains in its infancy. To date, the vast majority of real‐time fMRI studies have focused on a single brain region at a time. This is due in part to the many challenges faced when estimating dynamic functional connectivity networks in real‐time. In this work, we propose a novel methodology with which to accurately track changes in time‐varying functional connectivity networks in real‐time. The proposed method is shown to perform competitively when compared to state‐of‐the‐art offline algorithms using both synthetic as well as real‐time fMRI data. The proposed method is applied to motor task data from the Human Connectome Project as well as to data obtained from a visuospatial attention task. We demonstrate that the algorithm is able to accurately estimate task‐related changes in network structure in real‐time. Hum Brain Mapp 38:202–220, 2017. © 2016 Wiley Periodicals, Inc.     

Instability of brain connectivity during nonrapid eye movement sleep reflects altered properties of information integration

Nonrapid eye movement (NREM) sleep is associated with fading consciousness in humans. Recent neuroimaging studies have demonstrated the spatiotemporal alterations of the brain functional connectivity (FC) in NREM sleep, suggesting the changes of information integration in the sleeping brain. However, the common stationarity assumption in FC does not satisfactorily explain the dynamic process of information integration during sleep. The dynamic FC (dFC) across brain networks is speculated to better reflect the time‐varying information propagation during sleep. Accordingly, we conducted simultaneous EEG‐fMRI recordings involving 12 healthy men during sleep and observed dFC across sleep stages using the sliding‐window approach. We divided dFC into two aspects: mean dFC (dFC_mean) and variance dFC (dFC_var). A high dFC_mean indicates stable brain network integrity, whereas a high dFC_var indicates instability of information transfer within and between functional networks. For the network‐based dFC, the dFC_var were negatively correlated with the dFC_mean across the waking and three NREM sleep stages. As sleep deepened, the dFC_mean decreased (N0~N1 > N2 > N3), whereas the dFC_var peaked during the N2 stage (N0~N1 < N3 < N2). The highest dFC_var during the N2 stage indicated the unstable synchronizations across the entire brain. In the N3 stage, the overall disrupted network integration was observed through the lowest dFC_mean and elevated dFC_var, compared with N0 and N1. Conclusively, when the network specificity (dFC_mean) breaks down, the consciousness dissipates with increasing variability of information exchange (dFC_var).     

Dynamic functional connectivity impairments in idiopathic rapid eye movement sleep behavior disorder

IntroductionPrevious functional magnetic resonance imaging (fMRI) studies typically analyzed static functional connectivity (sFC) to reveal the pathophysiology of iRBD and overlooked the dynamic nature of brain activity. Thus, we aimed to explore whether iRBD showed abnormalities of brain network dynamics using the dynamic functional connectivity (dFC) approach.MethodsResting-state fMRI data from 33 iRBD patients and 38 matched healthy controls were analyzed using an independent component analysis, sliding window correlation and k-means clustering. Relationships between clinical symptoms and abnormal dFC were evaluated using Spearman's correlation analysis.ResultsFour distinct connectivity states were identified to characterize and compare dFC patterns. We demonstrated that iRBD had fewer occurrences and a shorter dwell time in the infrequent and strongly connected State 1, but with more occurrences and a longer dwell time in the frequent and sparsely connected State 2. In addition, iRBD patients showed significantly decreased FC in certain dFC states compared to healthy controls. More importantly, the impairments in the temporal properties of State 2 were found to be associated RBDSQ scores in the patient group.ConclusionsThis study detected dFC impairments in iRBD patients and provided new insights into the pathophysiology of iRBD, which might contribute to the development of disease-modifying drugs in future clinical trials.     

Intrinsic functional connectivity variance and state‐specific under‐connectivity in autism

Autism spectrum disorder (ASD) is a neurodevelopmental condition associated with altered brain connectivity. Previous neuroimaging research demonstrates inconsistent results, particularly in studies of functional connectivity in ASD. Typically, these inconsistent findings are results of studies using static measures of resting‐state functional connectivity. Recent work has demonstrated that functional brain connections are dynamic, suggesting that static connectivity metrics fail to capture nuanced time‐varying properties of functional connections in the brain. Here we used a dynamic functional connectivity approach to examine the differences in the strength and variance of dynamic functional connections between individuals with ASD and healthy controls (HCs). The variance of dynamic functional connections was defined as the respective standard deviations of the dynamic functional connectivity strength across time. We utilized a large multicenter dataset of 507 male subjects (209 with ASD and 298 HC, from 6 to 36 years old) from the Autism Brain Imaging Data Exchange (ABIDE) to identify six distinct whole‐brain dynamic functional connectivity states. Analyses demonstrated greater variance of widespread long‐range dynamic functional connections in ASD (P < 0.05, NBS method) and weaker dynamic functional connections in ASD (P < 0.05, NBS method) within specific whole‐brain connectivity states. Hypervariant dynamic connections were also characterized by weaker connectivity strength in ASD compared with HC. Increased variance of dynamic functional connections was also related to ASD symptom severity (ADOS total score) (P < 0.05), and was most prominent in connections related to the medial superior frontal gyrus and temporal pole. These results demonstrate that greater intraindividual dynamic variance is a potential biomarker of ASD. Hum Brain Mapp 38:5740–5755, 2017. © 2017 Wiley Periodicals, Inc.     

Dynamic frontostriatal functional peak connectivity (in alcohol use disorder)

Alcohol use disorder (AUD) is associated with changes in frontostriatal connectivity, but functional magnetic resonance imaging (fMRI) functional connectivity (FC) approaches are usually not adapted to these circuits. We developed a circuit‐specific fMRI analysis approach to detect dynamic changes in frontostriatal FC inspired by medial‐ventral‐rostral to lateral‐dorsal‐caudal frontostriatal gradients originally identified in nonhuman primate tract‐tracing data. In our PeaCoG (“ pea k co nnectivity on a g radient”) approach we use information about the location of strongest FC on empirical frontostriatal connectivity gradients. We have recently described a basic PeaCoG version with conventional FC, and now developed a dynamic PeaCoG approach with sliding‐window FC. In resting state data of n = 66 AUD participants and n = 40 healthy controls we continue here the analyses that we began with the basic version. Our former result of an AUD‐associated ventral shift in right orbitofrontal cortex PeaCoG is consistently detected in the dynamic approach. Temporospatial variability of dynamic PeaCoG in the left dorsolateral prefrontal cortex is reduced in AUD and associated with self‐efficacy to abstain and days of abstinence. Our method has the potential to provide insight into the dynamics of frontostriatal circuits, which has so far been relatively unexplored, and into their role in mental disorders and normal cognition.     

Structural and functional brain network correlates of depressive symptoms in premanifest Huntington's disease

Depression is common in premanifest Huntington's disease (preHD) and results in significant morbidity. We sought to examine how variations in structural and functional brain networks relate to depressive symptoms in premanifest HD and healthy controls. Brain networks were constructed using diffusion tractography (70 preHD and 81 controls) and resting state fMRI (92 preHD and 94 controls) data. A sub‐network associated with depression was identified in a data‐driven fashion and network‐based statistics was used to investigate which specific connections correlated with depression scores. A replication analysis was then performed using data from a separate study. Correlations between depressive symptoms with increased functional connectivity and decreased structural connectivity were seen for connections in the default mode network (DMN) and basal ganglia in preHD. This study reveals specific connections in the DMN and basal ganglia that are associated with depressive symptoms in preHD. Hum Brain Mapp 38:2819–2829, 2017. © 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.     

Dynamic functional network connectivity in Huntington's disease and its associations with motor and cognitive measures

Dynamic functional network connectivity (dFNC) is an expansion of traditional, static FNC that measures connectivity variation among brain networks throughout scan duration. We used a large resting‐state fMRI (rs‐fMRI) sample from the PREDICT‐HD study (N = 183 Huntington disease gene mutation carriers [HDgmc] and N = 78 healthy control [HC] participants) to examine whole‐brain dFNC and its associations with CAG repeat length as well as the product of scaled CAG length and age, a variable representing disease burden. We also tested for relationships between functional connectivity and motor and cognitive measurements. Group independent component analysis was applied to rs‐fMRI data to obtain whole‐brain resting state networks. FNC was defined as the correlation between RSN time‐courses. Dynamic FNC behavior was captured using a sliding time window approach, and FNC results from each window were assigned to four clusters representing FNC states, using a k‐means clustering algorithm. HDgmc individuals spent significantly more time in State‐1 (the state with the weakest FNC pattern) compared to HC. However, overall HC individuals showed more FNC dynamism than HDgmc. Significant associations between FNC states and genetic and clinical variables were also identified. In FNC State‐4 (the one that most resembled static FNC), HDgmc exhibited significantly decreased connectivity between the putamen and medial prefrontal cortex compared to HC, and this was significantly associated with cognitive performance. In FNC State‐1, disease burden in HDgmc participants was significantly associated with connectivity between the postcentral gyrus and posterior cingulate cortex, as well as between the inferior occipital gyrus and posterior parietal cortex.