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.

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.

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).

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.

The relative brain signal variability increases in the behavioral variant of frontotemporal dementia and Alzheimer's disease but not in schizophrenia.

Overlapping symptoms between Alzheimer's disease (AD), behavioral variant of frontotemporal dementia (bvFTD), and schizophrenia (SZ) can lead to misdiagnosis and delays in appropriate treatment, especially in cases of early-onset dementia. To determine the potential of brain signal variability as a diagnostic tool, we assessed the coefficient of variation of the BOLD signal (CVBOLD) in 234 participants spanning bvFTD (n = 53), AD (n = 17), SZ (n = 23), and controls (n = 141). All underwent functional and structural MRI scans. Data unveiled a notable increase in CVBOLD in bvFTD patients across both datasets (local and international, p < 0.05), revealing an association with clinical scores (CDR and MMSE, r = 0.46 and r = -0.48, p < 0.0001). While SZ and control group demonstrated no significant differences, a comparative analysis between AD and bvFTD patients spotlighted elevated CVBOLD in the frontopolar cortices for the latter (p < 0.05). Furthermore, CVBOLD not only presented excellent diagnostic accuracy for bvFTD (AUC 0.78-0.95) but also showcased longitudinal repeatability. During a one-year follow-up, the CVBOLD levels increased by an average of 35% in the bvFTD group, compared to a 2% increase in the control group (p < 0.05). Our findings suggest that CVBOLD holds promise as a biomarker for bvFTD, offering potential for monitoring disease progression and differentiating bvFTD from AD and SZ.

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.

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.

Increased very low frequency pulsations and decreased cardiorespiratory pulsations suggest altered brain clearance in narcolepsy.

Background: Narcolepsy is a chronic neurological disease characterized by daytime sleep attacks, cataplexy, and fragmented sleep. The disease is hypothesized to arise from destruction or dysfunction of hypothalamic hypocretin-producing cells that innervate wake-promoting systems including the ascending arousal network (AAN), which regulates arousal via release of neurotransmitters like noradrenalin. Brain pulsations are thought to drive intracranial cerebrospinal fluid flow linked to brain metabolite transfer that sustains homeostasis. This flow increases in sleep and is suppressed by noradrenalin in the awake state. Here we tested the hypothesis that narcolepsy is associated with altered brain pulsations, and if these pulsations can differentiate narcolepsy type 1 from healthy controls. Methods: In this case-control study, 23 patients with narcolepsy type 1 (NT1) were imaged with ultrafast fMRI (MREG) along with 23 age- and sex-matched healthy controls (HC). The physiological brain pulsations were quantified as the frequency-wise signal variance. Clinical relevance of the pulsations was investigated with correlation and receiving operating characteristic analysis. Results: We find that variance and fractional variance in the very low frequency (MREGvlf) band are greater in NT1 compared to HC, while cardiac (MREGcard) and respiratory band variances are lower. Interestingly, these pulsations differences are prominent in the AAN region. We further find that fractional variance in MREGvlf shows promise as an effective bi-classification metric (AUC = 81.4%/78.5%), and that disease severity measured with narcolepsy severity score correlates with MREGcard variance (R = -0.48, p = 0.0249). Conclusions: We suggest that our novel results reflect impaired CSF dynamics that may be linked to altered glymphatic circulation in narcolepsy type 1.

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.

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.

Atypical Inter-Network Deactivation Associated With the Posterior Default-Mode Network in Autism Spectrum Disorder.

Previous studies have suggested that atypical deactivation of functional brain networks contributes to the complex cognitive and behavioral profile associated with autism spectrum disorder (ASD). However, these studies have not considered the temporal dynamics of deactivation mechanisms between the networks. In this study, we examined (a) mutual deactivation and (b) mutual activation-deactivation (i.e., anticorrelated) time-lag patterns between resting-state networks (RSNs) in young adults with ASD (n = 20) and controls (n = 20) by applying the recently defined dynamic lag analysis (DLA) method, which measures time-lag variations peak-by-peak between the networks. In order to achieve temporally accurate lag patterns, the brain imaging data was acquired with a fast functional magnetic resonance imaging (fMRI) sequence (TR = 100 ms). Group-level independent component analysis was used to identify 16 RSNs for the DLA. We found altered mutual deactivation timings in ASD in (a) three of the deactivated and (b) two of the transiently anticorrelated (activated-deactivated) RSN pairs, which survived the strict threshold for significance of surrogate data. Of the significant RSN pairs, 80% included the posterior default-mode network (DMN). We propose that temporally altered deactivation mechanisms, including timings and directionality, between the posterior DMN and RSNs mediating processing of socially relevant information may contribute to the ASD phenotype. LAY SUMMARY: To understand autistic traits on a neural level, we examined temporal fluctuations in information flow between brain regions in young adults with autism spectrum disorder (ASD) and controls. We used a fast neuroimaging procedure to investigate deactivation mechanisms between brain regions. We found that timings and directionality of communication between certain brain regions were temporally altered in ASD, suggesting atypical deactivation mechanisms associated with the posterior default-mode network.

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.