Studies of resting state functional MRI (rs-fRMI) are increasingly focused on "dynamics", or on those properties of brain activation that manifest and vary on timescales shorter than the scan's full ...duration. This shift in focus has led to a flurry of interest in developing hypothesis testing frameworks and null models applicable to the dynamical setting. Thus far however, these efforts have been weakened by a number of crucial shortcomings that are outlined and discussed in this article. We focus here on aspects of recently proposed null models that, we argue, are poorly formulated relative to the hypotheses they are designed to test, i.e., their potential role in separating functionally relevant BOLD signal dynamics from noise or intermittent background and maintenance type processes is limited by factors that are fundamental rather than merely quantitative or parametric. In this short position paper, we emphasize that (1) serious care must be exercised in building null models for rs-fMRI dynamics from distributionally stationary univariate or multivariate timeseries, i.e., timeseries whose values are each independently drawn from one pre-specified probability distribution; and (2) measures such as kurtosis that quantify over-concentration of observed values in the far tails of some reference distribution may not be particularly suitable for capturing signal features most plausibly contributing to functionally relevant brain dynamics. Other metrics targeted, for example, at capturing the type of epochal signal variation that is often viewed as a signature of brain responsiveness to stimuli or experimental tasks, could play a more scientifically clarifying role. As we learn more about the phenomenon of functionally relevant brain dynamics and its imaging correlates, scientifically meaningful null hypotheses and well-tuned null models will naturally emerge. We also revisit the important concept of distributional stationarity, discuss how it manifests within realizations vs. across multiple realizations, and provide guidance on the benefits and limitations of employing this type of stationarity in modeling the absence of functionally relevant temporal dynamics in resting state fMRI. We hope that the discussions herein are useful, and promote thoughtful consideration of these important issues.
•An association between Alzheimer’s disease genetic rinks with static and dynamic functional network connectivity was observed.•Participants with higher risk of Alzheimer’s disease showed less visual ...sensory connectivity.•Participants with lower risk of Alzheimer’s disease showed more cognitive control network connectivity.•Sex has a significant contribution in the link between Alzheimer’s disease genetic risks with static and dynamic functional network connectivity.
Apolipoprotein E (APOE) polymorphic alleles are genetic factors associated with Alzheimer’s disease (AD) risk. Although previous studies have explored the link between AD genetic risk and static functional network connectivity (sFNC), to the best of our knowledge, no previous studies have evaluated the association between dynamic FNC (dFNC) and AD genetic risk. Here, we examined the link between sFNC, dFNC, and AD genetic risk with a data-driven approach. We used rs-fMRI, demographic, and APOE data from cognitively normal individuals (N = 886) between 42 and 95 years of age (mean = 70 years). We separated individuals into low, moderate, and high-risk groups. Using Pearson correlation, we calculated sFNC across seven brain networks. We also calculated dFNC with a sliding window and Pearson correlation. The dFNC windows were partitioned into three distinct states with k-means clustering. Next, we calculated the proportion of time each subject spent in each state, called occupancy rate or OCR and frequency of visits. We compared both sFNC and dFNC features across individuals with different genetic risks and found that both sFNC and dFNC are related to AD genetic risk. We found that higher AD risk reduces within-visual sensory network (VSN) sFNC and that individuals with higher AD risk spend more time in a state with lower within-VSN dFNC. We also found that AD genetic risk affects whole-brain sFNC and dFNC in women but not men. In conclusion, we presented novel insights into the links between sFNC, dFNC, and AD genetic risk.
New techniques to investigate functional network connectivity in resting state functional magnetic resonance imaging data have recently emerged. One novel approach, called meta-state analysis, goes ...beyond the mere cross-correlation of time courses of distinct brain areas and explores temporal dynamism in more detail, allowing for connectivity states to overlap in time and capturing global dynamic behavior. Previous studies have shown that patients with chronic schizophrenia exhibit reduced neural dynamism compared to healthy controls, but it is not known whether these alterations extend to earlier phases of the illness. In this study, we analyzed individuals at clinical high-risk (CHR, n = 53) for developing psychosis, patients in an early stage of schizophrenia (ESZ, n = 58), and healthy controls (HC, n = 70). ESZ individuals exhibit reduced neural dynamism across all domains compared to HC. CHR individuals also show reduced neural dynamism but only in 2 out of 4 domains investigated. Overall, meta-state analysis adds information about dynamic fluidity of functional connectivity.
Spontaneous low-frequency fluctuations in the blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (MRI) signal have been shown to reflect neural synchrony between brain regions. ...A "default network" of spontaneous low-frequency fluctuations has been described in healthy volunteers during stimulus-independent thought. Negatively correlated with this network are regions activated during attention-demanding tasks. Both these networks involve brain regions and functions that have been linked with schizophrenia in previous research. The present study examined spontaneous slow fluctuations in the BOLD signal at rest, as measured by correlation with low-frequency oscillations in the posterior cingulate, in 17 schizophrenic patients, and 17 comparable healthy volunteers. Healthy volunteers demonstrated correlation between spontaneous low-frequency fluctuations of the BOLD signal in the posterior cingulate and fluctuations in the lateral parietal, medial prefrontal, and cerebellar regions, similar to previous reports. Schizophrenic patients had significantly less correlation between spontaneous slow activity in the posterior cingulate and that in the lateral parietal, medial prefrontal, and cerebellar regions. Connectivity of the posterior cingulate was found to vary with both positive and negative symptoms in schizophrenic patients. Because these data suggest significant abnormalities in resting-state neural networks in schizophrenia, further investigations of spontaneous slow fluctuations of the BOLD signal seem warranted in this population.
Alzheimer's disease (AD) is the most common age-related dementia that promotes a decline in memory, thinking, and social skills. The initial stages of dementia can be associated with mild symptoms, ...and symptom progression to a more severe state is heterogeneous across patients. Recent work has demonstrated the potential for functional network mapping to assist in the prediction of symptomatic progression. However, this work has primarily used static functional connectivity (sFC) from resting-state functional magnetic resonance imaging. Recently, dynamic functional connectivity (dFC) has been recognized as a powerful advance in functional connectivity methodology to differentiate brain network dynamics between healthy and diseased populations.
Group independent component analysis was applied to extract 17 components within the cognitive control network (CCN) from 1385 individuals across varying stages of AD symptomology. We estimated dFC among 17 components within the CCN, followed by clustering the dFCs into 3 recurring brain states, and then estimated a hidden Markov model and the occupancy rate for each subject. Then, we investigated the link between CCN dFC features and AD progression. Also, we investigated the link between sFC and AD progression and compared its results with dFC results.
Progression of AD symptoms was associated with increases in connectivity within the middle frontal gyrus. Also, the very mild AD (vmAD) showed less connectivity within the inferior parietal lobule (in both sFC and dFC) and between this region and the rest of CCN (in dFC analysis). Also, we found that within-middle frontal gyrus connectivity increases with AD progression in both sFC and dFC results. Finally, comparing with vmAD, we found that the normal brain spends significantly more time in a state with lower within-middle frontal gyrus connectivity and higher connectivity between the hippocampus and the rest of CCN, highlighting the importance of assessing the dynamics of brain connectivity in this disease.
Our results suggest that AD progress not only alters the CCN connectivity strength but also changes the temporal properties in this brain network. This suggests the temporal and spatial pattern of CCN as a biomarker that differentiates different stages of AD.
Independent component analysis (ICA) is a widely applied technique to derive functionally connected brain networks from fMRI data. Group ICA (GICA) and Independent Vector Analysis (IVA) are ...extensions of ICA that enable users to perform group fMRI analyses; however a full comparison of the performance limits of GICA and IVA has not been investigated. Recent interest in resting state fMRI data with potentially higher degree of subject variability makes the evaluation of the above techniques important. In this paper we compare component estimation accuracies of GICA and an improved version of IVA using simulated fMRI datasets. We systematically change the degree of inter-subject spatial variability of components and evaluate estimation accuracy over all spatial maps (SMs) and time courses (TCs) of the decomposition. Our results indicate the following: (1) at low levels of SM variability or when just one SM is varied, both GICA and IVA perform well, (2) at higher levels of SM variability or when more than one SMs are varied, IVA continues to perform well but GICA yields SM estimates that are composites of other SMs with errors in TCs, (3) both GICA and IVA remove spatial correlations of overlapping SMs and introduce artificial correlations in their TCs, (4) if number of SMs is over estimated, IVA continues to perform well but GICA introduces artifacts in the varying and extra SMs with artificial correlations in the TCs of extra components, and (5) in the absence or presence of SMs unique to one subject, GICA produces errors in TCs and IVA estimates are accurate. In summary, our simulation experiments (both simplistic and realistic) and our holistic analyses approach indicate that IVA produces results that are closer to ground truth and thereby better preserves subject variability. The improved version of IVA is now packaged into the GIFT toolbox (http://mialab.mrn.org/software/gift).
Functional connectivity of the resting-state (RS) brain is a vehicle to study brain dysconnectivity aspects of diseases such as schizophrenia and bipolar. Methods that are developed to measure ...functional connectivity are based on the underlying hypotheses regarding the actual nature of RS-connectivity including evidence of temporally dynamic versus static RS-connectivity and evidence of frequency-specific versus hemodynamically-driven connectivity over a wide frequency range. This study is derived by these observations of variation of RS-connectivity in temporal and frequency domains and evaluates such characteristics of RS-connectivity in clinical population and jointly in temporal and frequency domains (the
). We base this study on the hypothesis that by studying functional connectivity of schizophrenia patients and comparing it to the one of healthy controls in the spectro-temporal domain we might be able to make new observations regarding the differences and similarities between diseased and healthy brain connectivity and such observations could be obscured by studies which investigate such characteristics separately. Interestingly, our results include, but are not limited to, a spectrally localized (mostly mid-range frequencies) modular dynamic connectivity pattern in which sensory motor networks are anti-correlated with visual, auditory and sub-cortical networks in schizophrenia, as well as evidence of lagged dependence between default-mode and sensory networks in schizophrenia. These observations are unique to the proposed augmented domain of connectivity analysis. We conclude this study by arguing not only resting-state connectivity has structured spectro-temporal variability, but also that studying properties of connectivity in this joint domain reveals distinctive group-based differences and similarities between clinical and healthy populations.
Schizophrenia (SZ) is a severe mental disorder that arises from abnormal neurodevelopment, caused by genetic and environmental factors. SZ often involves distortions in reality perception and it is ...widely associated with alterations in brain connectivity. In the present work, we used Human Induced Pluripotent Stem Cells (hiPSCs)-derived neuronal cultures to study neural communicational dynamics during early development in SZ. We conducted gene and protein expression profiling, calcium imaging recordings, and applied a mathematical model to quantify the dynamism of functional connectivity (FC) in hiPSCs-derived neuronal networks. Along the neurodifferentiation process, SZ networks displayed altered gene expression of the glutamate receptor-related proteins
HOMER1
and
GRIN1
compared to healthy control (HC) networks, suggesting a possible tendency to develop hyperexcitability. Resting-state FC in neuronal networks derived from HC and SZ patients emerged as a dynamic phenomenon exhibiting connectivity configurations reoccurring in time (hub states). Compared to HC, SZ networks were less thorough in exploring different FC configurations, changed configurations less often, presented a reduced repertoire of hub states and spent longer uninterrupted time intervals in this less diverse universe of hubs. Our results suggest that alterations in the communicational dynamics of SZ emerging neuronal networks might contribute to the previously described brain FC anomalies in SZ patients, by compromising the ability of their neuronal networks for rapid and efficient reorganization through different activity patterns.
Patterns of resting state fMRI functional network connectivity in schizophrenia patients have been shown to differ markedly from those of healthy controls. While some studies have explored ...connectivity within fixed frequency bands, the question of network phase synchrony across disparate frequency bands, or cross-frequency connectivity , has remained surprisingly underexplored. Computational modeling at the neuronal scale however has long acknowledged the existence of coupled fast and slow subsystems. Here, we present preliminary evidence that cross-frequency coupling exists at the network level, that it patterns in meaningful ways over functional domains, and that this patterning differs between the healthy population and individuals with diagnosed schizophrenia.
Many studies have analyzed resting state functional magnetic resonance imaging (rs-fMRI) dynamic functional network connectivity (dFNC) data to elucidate the effects of neurological and ...neuropsychiatric disorders upon the interactions of brain regions over time. Existing studies often use either machine learning classification or clustering algorithms. Additionally, several studies have used clustering algorithms to extract features related to brain states trajectories that can be used to train interpretable classifiers. However, the combination of explainable dFNC classifiers followed by clustering algorithms is highly underutilized. In this study, we show how such an approach can be used to study the effects of schizophrenia (SZ) upon brain activity. Specifically, we train an explainable deep learning model to classify between individuals with SZ and healthy controls. We then cluster the resulting explanations, identifying discriminatory states of dFNC. We lastly apply several novel measures to quantify aspects of the classifier explanations and obtain additional insights into the effects of SZ upon brain network dynamics. Specifically, we uncover effects of schizophrenia upon subcortical, sensory, and cerebellar network interactions. We also find that individuals with SZ likely have reduced variability in overall brain activity and that the effects of SZ may be temporally localized. In addition to uncovering effects of SZ upon brain network dynamics, our approach could provide novel insights into a variety of neurological and neuropsychiatric disorders in future dFNC studies.
•Cluster classifier explanations to identify discriminatory states of dFNC activity.•Identify effects of schizophrenia on subcortical, sensory, and cerebellar networks.•Identify reduced variability and temporally localized effects of schizophrenia.•Propose approach applicable to many neurological and neuropsychiatric disorders.
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