Association of body-mass index with physiological brain pulsations across adulthood - a fast fMRI study.

BACKGROUND/OBJECTIVE: Obesity is a risk factor for several brain-related health issues, and high body-mass index (BMI) is associated with an increased risk for several neurological conditions, including cognitive decline and dementia. Cardiovascular, respiratory, and vasomotor brain pulsations have each been shown to drive intracranial cerebrovascular fluid (CSF) flow, which is linked to the brain metabolite efflux that sustains homeostasis. While these three physiological pulsations are demonstrably altered in numerous brain diseases, there is no previous investigation of the association between physiological brain pulsations and BMI. SUBJECTS/METHODS: We measured the amplitudes of the physiological brain pulsations using amplitude of low frequency fluctation (ALFF) based method with resting-state functional magnetic resonance imaging via high temporal resolution whole-brain magnetic resonance encephalography (MREG) in 115 healthy subjects. We next undertook multiple linear regression to model the BMI effect voxel-wise whole-brain on very low frequency (VLF), respiration, cardiovascular, and respiratory induced modulation of cardiovascular pulsation amplitudes with age, pulse pressure, and gender as nuisance variables. RESULTS: In our study population, BMI was positively associated with the amplitudes of vasomotor, respiratory, and respiratory induced modulations of cardiovascular pulsations (p < 0.05), while negatively associated with the amplitudes of cardiovascular pulsations (p < 0.05). CONCLUSIONS: The findings suggest that BMI is a significant factor in alterations of cardiovascular pulsation of neurofluids. As physiological pulsations are the drivers of CSF flow and subsequent metabolite clearance, these results emphasize the need for further research into the mechanisms through which obesity affects brain clearance.

Synchronous functional magnetic resonance eye imaging, video ophthalmoscopy, and eye surface imaging reveal the human brain and eye pulsation mechanisms.

The eye possesses a paravascular solute transport pathway that is driven by physiological pulsations, resembling the brain glymphatic pathway. We developed synchronous multimodal imaging tools aimed at measuring the driving pulsations of the human eye, using an eye-tracking functional eye camera (FEC) compatible with magnetic resonance imaging (MRI) for measuring eye surface pulsations. Special optics enabled integration of the FEC with MRI-compatible video ophthalmoscopy (MRcVO) for simultaneous retinal imaging along with functional eye MRI imaging (fMREye) of the BOLD (blood oxygen level dependent) contrast. Upon optimizing the fMREye parameters, we measured the power of the physiological (vasomotor, respiratory, and cardiac) eye and brain pulsations by fast Fourier transform (FFT) power analysis. The human eye pulsated in all three physiological pulse bands, most prominently in the respiratory band. The FFT power means of physiological pulsation for two adjacent slices was significantly higher than in one-slice scans (RESP1 vs. RESP2; df = 5, p = 0.045). FEC and MRcVO confirmed the respiratory pulsations at the eye surface and retina. We conclude that in addition to the known cardiovascular pulsation, the human eye also has respiratory and vasomotor pulsation mechanisms, which are now amenable to study using non-invasive multimodal imaging of eye fluidics.

Effect of sleep deprivation and NREM sleep stage on physiological brain pulsations.

Introduction: Sleep increases brain fluid transport and the power of pulsations driving the fluids. We investigated how sleep deprivation or electrophysiologically different stages of non-rapid-eye-movement (NREM) sleep affect the human brain pulsations. Methods: Fast functional magnetic resonance imaging (fMRI) was performed in healthy subjects (n = 23) with synchronous electroencephalography (EEG), that was used to verify arousal states (awake, N1 and N2 sleep). Cardiorespiratory rates were verified with physiological monitoring. Spectral power analysis assessed the strength, and spectral entropy assessed the stability of the pulsations. Results: In N1 sleep, the power of vasomotor (VLF < 0.1 Hz), but not cardiorespiratory pulsations, intensified after sleep deprived vs. non-sleep deprived subjects. The power of all three pulsations increased as a function of arousal state (N2 > N1 > awake) encompassing brain tissue in both sleep stages, but extra-axial CSF spaces only in N2 sleep. Spectral entropy of full band and respiratory pulsations decreased most in N2 sleep stage, while cardiac spectral entropy increased in ventricles. Discussion: In summary, the sleep deprivation and sleep depth, both increase the power and harmonize the spectral content of human brain pulsations.

Infra-slow fluctuations in cortical potentials and respiration drive fast cortical EEG rhythms in sleeping and waking states.

OBJECTIVE: Infra-slow fluctuations (ISF, 0.008-0.1 Hz) characterize hemodynamic and electric potential signals of human brain. ISFs correlate with the amplitude dynamics of fast (>1 Hz) neuronal oscillations, and may arise from permeability fluctuations of the blood-brain barrier (BBB). It is unclear if physiological rhythms like respiration drive or track fast cortical oscillations, and the role of sleep in this coupling is unknown. METHODS: We used high-density full-band electroencephalography (EEG) in healthy human volunteers (N = 21) to measure concurrently the ISFs, respiratory pulsations, and fast neuronal oscillations during periods of wakefulness and sleep, and to assess the strength and direction of their phase-amplitude coupling. RESULTS: The phases of ISFs and respiration were both coupled with the amplitude of fast neuronal oscillations, with stronger ISF coupling being evident during sleep. Phases of ISF and respiration drove the amplitude dynamics of fast oscillations in sleeping and waking states, with different contributions. CONCLUSIONS: ISFs in slow cortical potentials and respiration together significantly determine the dynamics of fast cortical oscillations. SIGNIFICANCE: We propose that these slow physiological phases play a significant role in coordinating cortical excitability, which is a fundamental aspect of brain function.

Increased interictal synchronicity of respiratory related brain pulsations in epilepsy.

Respiratory brain pulsations have recently been shown to drive electrophysiological brain activity in patients with epilepsy. Furthermore, functional neuroimaging indicates that respiratory brain pulsations have increased variability and amplitude in patients with epilepsy compared to healthy individuals. To determine whether the respiratory drive is altered in epilepsy, we compared respiratory brain pulsation synchronicity between healthy controls and patients. Whole brain fast functional magnetic resonance imaging was performed on 40 medicated patients with focal epilepsy, 20 drug-naïve patients and 102 healthy controls. Cerebrospinal fluid associated respiratory pulsations were used to generate individual whole brain respiratory synchronization maps, which were compared between groups. Finally, we analyzed the seizure frequency effect and diagnostic accuracy of the respiratory synchronization defect in epilepsy. Respiratory brain pulsations related to the verified fourth ventricle pulsations were significantly more synchronous in patients in frontal, periventricular and mid-temporal regions, while the seizure frequency correlated positively with synchronicity. The respiratory brain synchronicity had a good diagnostic accuracy (ROCAUC = 0.75) in discriminating controls from medicated patients. The elevated respiratory brain synchronicity in focal epilepsy suggests altered physiological effect of cerebrospinal fluid pulsations possibly linked to regional brain water dynamics involved with interictal brain physiology.

Physiological instability is linked to mortality in primary central nervous system lymphoma: A case-control fMRI study.

Primary central nervous system lymphoma (PCNSL) is an aggressive brain disease where lymphocytes invade along perivascular spaces of arteries and veins. The invasion markedly changes (peri)vascular structures but its effect on physiological brain pulsations has not been previously studied. Using physiological magnetic resonance encephalography (MREGBOLD ) scanning, this study aims to quantify the extent to which (peri)vascular PCNSL involvement alters the stability of physiological brain pulsations mediated by cerebral vasculature. Clinical implications and relevance were explored. In this study, 21 PCNSL patients (median 67y; 38% females) and 30 healthy age-matched controls (median 63y; 73% females) were scanned for MREGBOLD signal during 2018-2021. Motion effects were removed. Voxel-by-voxel Coefficient of Variation (CV) maps of MREGBOLD signal was calculated to examine the stability of physiological brain pulsations. Group-level differences in CV were examined using nonparametric covariate-adjusted tests. Subject-level CV alterations were examined against control population Z-score maps wherein clusters of increased CV values were detected. Spatial distributions of clusters and findings from routine clinical neuroimaging were compared [contrast-enhanced, diffusion-weighted, fluid-attenuated inversion recovery (FLAIR) data]. Whole-brain mean CV was linked to short-term mortality with 100% sensitivity and 100% specificity, as all deceased patients revealed higher values (n = 5, median 0.055) than surviving patients (n = 16, median 0.028) (p < .0001). After adjusting for medication, head motion, and age, patients revealed higher CV values (group median 0.035) than healthy controls (group median 0.024) around arterial territories (p ≤ .001). Abnormal clusters (median 1.10 × 105 mm3 ) extended spatially beyond FLAIR lesions (median 0.62 × 105 mm3 ) with differences in volumes (p = .0055).

Cardiovascular Pulsatility Increases in Visual Cortex Before Blood Oxygen Level Dependent Response During Stimulus.

The physiological pulsations that drive tissue fluid homeostasis are not well characterized during brain activation. Therefore, we used fast magnetic resonance encephalography (MREG) fMRI to measure full band (0-5 Hz) blood oxygen level-dependent (BOLDFB) signals during a dynamic visual task in 23 subjects. This revealed brain activity in the very low frequency (BOLDVLF) as well as in cardiac and respiratory bands. The cardiovascular hemodynamic envelope (CHe) signal correlated significantly with the visual BOLDVLF response, considered as an independent signal source in the V1-V2 visual cortices. The CHe preceded the canonical BOLDVLF response by an average of 1.3 (± 2.2) s. Physiologically, the observed CHe signal could mark increased regional cardiovascular pulsatility following vasodilation.

Human NREM Sleep Promotes Brain-Wide Vasomotor and Respiratory Pulsations.

The physiological underpinnings of the necessity of sleep remain uncertain. Recent evidence suggests that sleep increases the convection of cerebrospinal fluid (CSF) and promotes the export of interstitial solutes, thus providing a framework to explain why all vertebrate species require sleep. Cardiovascular, respiratory and vasomotor brain pulsations have each been shown to drive CSF flow along perivascular spaces, yet it is unknown how such pulsations may change during sleep in humans. To investigate these pulsation phenomena in relation to sleep, we simultaneously recorded fast fMRI, magnetic resonance encephalography (MREG), and electroencephalography (EEG) signals in a group of healthy volunteers. We quantified sleep-related changes in the signal frequency distributions by spectral entropy analysis and calculated the strength of the physiological (vasomotor, respiratory, and cardiac) brain pulsations by power sum analysis in 15 subjects (age 26.5 ± 4.2 years, 6 females). Finally, we identified spatial similarities between EEG slow oscillation (0.2-2 Hz) power and MREG pulsations. Compared with wakefulness, nonrapid eye movement (NREM) sleep was characterized by reduced spectral entropy and increased brain pulsation intensity. These effects were most pronounced in posterior brain areas for very low-frequency (≤0.1 Hz) vasomotor pulsations but were also evident brain-wide for respiratory pulsations, and to a lesser extent for cardiac brain pulsations. There was increased EEG slow oscillation power in brain regions spatially overlapping with those showing sleep-related MREG pulsation changes. We suggest that reduced spectral entropy and enhanced pulsation intensity are characteristic of NREM sleep. With our findings of increased power of slow oscillation, the present results support the proposition that sleep promotes fluid transport in human brain.SIGNIFICANCE STATEMENT We report that the spectral power of physiological brain pulsation mechanisms driven by vasomotor, respiration, and cardiac rhythms in human brain increase during sleep, extending previous observations of their association with glymphatic brain clearance during sleep in rodents. The magnitudes of increased pulsations follow the rank order of vasomotor greater than respiratory greater than cardiac pulsations, with correspondingly declining spatial extents. Spectral entropy, previously known as vigilance and as an anesthesia metric, decreased during NREM sleep compared with the awake state in very low and respiratory frequencies, indicating reduced signal complexity. An EEG slow oscillation power increase occurring in the early sleep phase (NREM 1-2) spatially overlapped with pulsation changes, indicating reciprocal mechanisms between those measures.

Spectral analysis of physiological brain pulsations affecting the BOLD signal.

Physiological pulsations have been shown to affect the global blood oxygen level dependent (BOLD) signal in human brain. While these pulsations have previously been regarded as noise, recent studies show their potential as biomarkers of brain pathology. We used the extended 5 Hz spectral range of magnetic resonance encephalography (MREG) data to investigate spatial and frequency distributions of physiological BOLD signal sources. Amplitude spectra of the global image signals revealed cardiorespiratory envelope modulation (CREM) peaks, in addition to the previously known very low frequency (VLF) and cardiorespiratory pulsations. We then proceeded to extend the amplitude of low frequency fluctuations (ALFF) method to each of these pulsations. The respiratory pulsations were spatially dominating over most brain structures. The VLF pulsations overcame the respiratory pulsations in frontal and parietal gray matter, whereas cardiac and CREM pulsations had this effect in central cerebrospinal fluid (CSF) spaces and major blood vessels. A quasi-periodic pattern (QPP) analysis showed that the CREM pulsations propagated as waves, with a spatiotemporal pattern differing from that of respiratory pulsations, indicating them to be distinct intracranial physiological phenomenon. In conclusion, the respiration has a dominant effect on the global BOLD signal and directly modulates cardiovascular brain pulsations.

The variability of functional MRI brain signal increases in Alzheimer's disease at cardiorespiratory frequencies.

Biomarkers sensitive to prodromal or early pathophysiological changes in Alzheimer's disease (AD) symptoms could improve disease detection and enable timely interventions. Changes in brain hemodynamics may be associated with the main clinical AD symptoms. To test this possibility, we measured the variability of blood oxygen level-dependent (BOLD) signal in individuals from three independent datasets (totaling 80 AD patients and 90 controls). We detected a replicable increase in brain BOLD signal variability in the AD populations, which constituted a robust biomarker for clearly differentiating AD cases from controls. Fast BOLD scans showed that the elevated BOLD signal variability in AD arises mainly from cardiovascular brain pulsations. Manifesting in abnormal cerebral perfusion and cerebrospinal fluid convection, present observation presents a mechanism explaining earlier observations of impaired glymphatic clearance associated with AD in humans.

Respiratory-related brain pulsations are increased in epilepsy-a two-centre functional MRI study.

Resting-state functional MRI has shown potential for detecting changes in cerebral blood oxygen level-dependent signal in patients with epilepsy, even in the absence of epileptiform activity. Furthermore, it has been suggested that coefficient of variation mapping of fast functional MRI signal may provide a powerful tool for the identification of intrinsic brain pulsations in neurological diseases such as dementia, stroke and epilepsy. In this study, we used fast functional MRI sequence (magnetic resonance encephalography) to acquire ten whole-brain images per second. We used the functional MRI data to compare physiological brain pulsations between healthy controls (n = 102) and patients with epilepsy (n = 33) and furthermore to drug-naive seizure patients (n = 9). Analyses were performed by calculating coefficient of variation and spectral power in full band and filtered sub-bands. Brain pulsations in the respiratory-related frequency sub-band (0.11-0.51 Hz) were significantly (P < 0.05) increased in patients with epilepsy, with an increase in both signal variance and power. At the individual level, over 80% of medicated and drug-naive seizure patients exhibited areas of abnormal brain signal power that correlated well with the known clinical diagnosis, while none of the controls showed signs of abnormality with the same threshold. The differences were most apparent in the basal brain structures, respiratory centres of brain stem, midbrain and temporal lobes. Notably, full-band, very low frequency (0.01-0.1 Hz) and cardiovascular (0.8-1.76 Hz) brain pulses showed no differences between groups. This study extends and confirms our previous results of abnormal fast functional MRI signal variance in epilepsy patients. Only respiratory-related brain pulsations were clearly increased with no changes in either physiological cardiorespiratory rates or head motion between the subjects. The regional alterations in brain pulsations suggest that mechanisms driving the cerebrospinal fluid homeostasis may be altered in epilepsy. Magnetic resonance encephalography has both increased sensitivity and high specificity for detecting the increased brain pulsations, particularly in times when other tools for locating epileptogenic areas remain inconclusive.

Dynamic lag analysis reveals atypical brain information flow in autism spectrum disorder.

This study investigated whole-brain dynamic lag pattern variations between neurotypical (NT) individuals and individuals with autism spectrum disorder (ASD) by applying a novel technique called dynamic lag analysis (DLA). The use of 3D magnetic resonance encephalography data with repetition time = 100 msec enables highly accurate analysis of the spread of activity between brain networks. Sixteen resting-state networks (RSNs) with the highest spatial correlation between NT individuals (n = 20) and individuals with ASD (n = 20) were analyzed. The dynamic lag pattern variation between each RSN pair was investigated using DLA, which measures time lag variation between each RSN pair combination and statistically defines how these lag patterns are altered between ASD and NT groups. DLA analyses indicated that 10.8% of the 120 RSN pairs had statistically significant (P-value <0.003) dynamic lag pattern differences that survived correction with surrogate data thresholding. Alterations in lag patterns were concentrated in salience, executive, visual, and default-mode networks, supporting earlier findings of impaired brain connectivity in these regions in ASD. 92.3% and 84.6% of the significant RSN pairs revealed shorter mean and median temporal lags in ASD versus NT, respectively. Taken together, these results suggest that altered lag patterns indicating atypical spread of activity between large-scale functional brain networks may contribute to the ASD phenotype. Autism Res 2020, 13: 244-258. © 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. LAY SUMMARY: Autism spectrum disorder (ASD) is characterized by atypical neurodevelopment. Using an ultra-fast neuroimaging procedure, we investigated communication across brain regions in adults with ASD compared with neurotypical (NT) individuals. We found that ASD individuals had altered information flow patterns across brain regions. Atypical patterns were concentrated in salience, executive, visual, and default-mode network areas of the brain that have previously been implicated in the pathophysiology of the disorder.

Sampling Rate Effects on Resting State fMRI Metrics.

Low image sampling rates used in resting state functional magnetic resonance imaging (rs-fMRI) may cause aliasing of the cardiorespiratory pulsations over the very low frequency (VLF) BOLD signal fluctuations which reflects to functional connectivity (FC). In this study, we examine the effect of sampling rate on currently used rs-fMRI FC metrics. Ultra-fast fMRI magnetic resonance encephalography (MREG) data, sampled with TR 0.1 s, was downsampled to different subsampled repetition times (sTR, range 0.3-3 s) for comparisons. Echo planar k-space sampling (TR 2.15 s) and interleaved slice collection schemes were also compared against the 3D single shot trajectory at 2.2 s sTR. The quantified connectivity metrics included stationary spatial, time, and frequency domains, as well as dynamic analyses. Time domain methods included analyses of seed-based functional connectivity, regional homogeneity (ReHo), coefficient of variation, and spatial domain group level probabilistic independent component analysis (ICA). In frequency domain analyses, we examined fractional and amplitude of low frequency fluctuations. Aliasing effects were spatially and spectrally analyzed by comparing VLF (0.01-0.1 Hz), respiratory (0.12-0.35 Hz) and cardiac power (0.9-1.3 Hz) FFT maps at different sTRs. Quasi-periodic pattern (QPP) of VLF events were analyzed for effects on dynamic FC methods. The results in conventional time and spatial domain analyses remained virtually unchanged by the different sampling rates. In frequency domain, the aliasing occurred mainly in higher sTR (1-2 s) where cardiac power aliases over respiratory power. The VLF power maps suffered minimally from increasing sTRs. Interleaved data reconstruction induced lower ReHo compared to 3D sampling (p < 0.001). Gradient recalled echo-planar imaging (EPI BOLD) data produced both better and worse metrics. In QPP analyses, the repeatability of the VLF pulse detection becomes linearly reduced with increasing sTR. In conclusion, the conventional resting state metrics (e.g., FC, ICA) were not markedly affected by different TRs (0.1-3 s). However, cardiorespiratory signals showed strongest aliasing in central brain regions in sTR 1-2 s. Pulsatile QPP and other dynamic analyses benefit linearly from short TR scanning.

3D Multi-Resolution Optical Flow Analysis of Cardiovascular Pulse Propagation in Human Brain.

The brain is cleaned from waste by glymphatic clearance serving a similar purpose as the lymphatic system in the rest of the body. Impairment of the glymphatic brain clearance precedes protein accumulation and reduced cognitive function in Alzheimer's disease (AD). Cardiovascular pulsations are a primary driving force of the glymphatic brain clearance. We developed a method to quantify cardiovascular pulse propagation in the human brain with magnetic resonance encephalography (MREG). We extended a standard optical flow estimation method to three spatial dimensions, with a multi-resolution processing scheme. We added application-specific criteria for discarding inaccurate results. With the proposed method, it is now possible to estimate the propagation of cardiovascular pulse wavefronts from the whole brain MREG data sampled at 10 Hz. The results show that on average the cardiovascular pulse propagates from major arteries via cerebral spinal fluid spaces into all tissue compartments in the brain. We present an example, that cardiovascular pulsations are significantly altered in AD: coefficient of variation and sample entropy of the pulse propagation speed in the lateral ventricles change in AD. These changes are in line with the theory of glymphatic clearance impairment in AD. The proposed non-invasive method can assess a performance indicator related to the glymphatic clearance in the human brain.

Breath hold effect on cardiovascular brain pulsations - A multimodal magnetic resonance encephalography study.

Ultra-fast functional magnetic resonance encephalography (MREG) enables separate assessment of cardiovascular, respiratory, and vasomotor waves from brain pulsations without temporal aliasing. We examined effects of breath hold- (BH) related changes on cardiovascular brain pulsations using MREG to study the physiological nature of cerebrovascular reactivity. We used alternating 32 s BH and 88 s resting normoventilation (NV) to change brain pulsations during MREG combined with simultaneously measured respiration, continuous non-invasive blood pressure, and cortical near-infrared spectroscopy (NIRS) in healthy volunteers. Changes in classical resting-state network BOLD-like signal and cortical blood oxygenation were reproduced based on MREG and NIRS signals. Cardiovascular pulsation amplitudes of MREG signal from anterior cerebral artery, oxygenated hemoglobin concentration in frontal cortex, and blood pressure decreased after BH. MREG cardiovascular pulse amplitudes in cortical areas and sagittal sinus increased, while cerebrospinal fluid and white matter remained unchanged. Respiratory centers in the brainstem - hypothalamus - thalamus - amygdala network showed strongest increases in cardiovascular pulsation amplitude. The spatial propagation of averaged cardiovascular impulses altered as a function of successive BH runs. The spread of cardiovascular pulse cycles exhibited a decreasing spatial similarity over time. MREG portrayed spatiotemporally accurate respiratory network activity and cardiovascular pulsation dynamics related to BH challenges at an unpreceded high temporal resolution.

Altered physiological brain variation in drug-resistant epilepsy.

INTRODUCTION: Functional magnetic resonance imaging (fMRI) combined with simultaneous electroencephalography (EEG-fMRI) has become a major tool in mapping epilepsy sources. In the absence of detectable epileptiform activity, the resting state fMRI may still detect changes in the blood oxygen level-dependent signal, suggesting intrinsic alterations in the underlying brain physiology. METHODS: In this study, we used coefficient of variation (CV) of critically sampled 10 Hz ultra-fast fMRI (magnetoencephalography, MREG) signal to compare physiological variance between healthy controls (n = 10) and patients (n = 10) with drug-resistant epilepsy (DRE). RESULTS: We showed highly significant voxel-level (p < 0.01, TFCE-corrected) increase in the physiological variance in DRE patients. At individual level, the elevations range over three standard deviations (σ) above the control mean (µ) CVMREG values solely in DRE patients, enabling patient-specific mapping of elevated physiological variance. The most apparent differences in group-level analysis are found on white matter, brainstem, and cerebellum. Respiratory (0.12-0.4 Hz) and very-low-frequency (VLF = 0.009-0.1 Hz) signal variances were most affected. CONCLUSIONS: The CVMREG increase was not explained by head motion or physiological cardiorespiratory activity, that is, it seems to be linked to intrinsic physiological pulsations. We suggest that intrinsic brain pulsations play a role in DRE and that critically sampled fMRI may provide a powerful tool for their identification.

Combined spatiotemporal ICA (stICA) for continuous and dynamic lag structure analysis of MREG data.

This study investigated lag structure in the resting-state fMRI by applying a novel independent component (ICA) method to magnetic resonance encephalography (MREG) data. Briefly, the spatial ICA (sICA) was used for defining the frontal and back nodes of the default mode network (DMN), and the temporal ICA (tICA), which is enabled by the high temporal resolution of MREG (TR=100ms), was used to separate both neuronal and physiological components of these two spatial map regions. Subsequently, lag structure was investigated between the frontal (DMNvmpf) and posterior (DMNpcc) DMN nodes using both conventional method with all-time points and a sliding-window approach. A rigorous noise exclusion criterion was applied for tICs to remove physiological pulsations, motion and system artefacts. All the de-noised tICs were used to calculate the null-distributions both for expected lag variability over time and over subjects. Lag analysis was done for the three highest correlating denoised tICA pairs. Mean time lag of 0.6s (± 0.5 std) and mean absolute correlation of 0.69 (± 0.08) between the highest correlating tICA pairs of DMN nodes was observed throughout the whole analyzed period. In dynamic 2min window analysis, there was large variability over subjects as ranging between 1-10sec. Directionality varied between these highly correlating sources an average 28.8% of the possible number of direction changes. The null models show highly consistent correlation and lag structure between DMN nodes both in continuous and dynamic analysis. The mean time lag of a null-model over time between all denoised DMN nodes was 0.0s and, thus the probability of having either DMNpcc or DMNvmpf as a preceding component is near equal. All the lag values of highest correlating tICA pairs over subjects lie within the standard deviation range of a null-model in whole time window analysis, supporting the earlier findings that there is a consistent temporal lag structure across groups of individuals. However, in dynamic analysis, there are lag values exceeding the threshold of significance of a null-model meaning that there might be biologically meaningful variation in this measure. Taken together the variability in lag and the presence of high activity peaks during strong connectivity indicate that individual avalanches may play an important role in defining dynamic independence in resting state connectivity within networks.