Resting-state Blood Oxygenation Level-dependent Research Articles

Association between neurovascular coupling and neural signals in the resting state as revealed by a combined fMRI and magnetoencephalography study in humans.

The blood oxygenation level-dependent (BOLD) activation reflects hemodynamic events mediated by neurovascular coupling. During task performance, the BOLD hemodynamic response in a relevant area is mainly driven by the high levels of synaptic activity (reflected in local field potentials, LFPs) but, in contrast, during a task-free, resting state, the contribution to BOLD of such neural events is small, as expected by the comparatively (to the task state) low level of neural events. Concomitant recording of BOLD and LFP at rest in animal experiments has estimated the neural contribution to BOLD to ∼10%. Such experiments have not been performed in humans. As an approximation, we recorded (in the same subject, n = 57 healthy participants) at a task-free, resting state the BOLD signal and, in a different session, the magnetoencephalographic (MEG) signal, which reflects purely neural (synaptic) events. We then calculated the turnover of these signals by computing the successive moment-to-moment difference in the BOLD and MEG time series and retaining the median of the absolute value of the differenced series (BOLD and TMEG, respectively). The correlation between normalized turnovers of BOLD (TBOLD) and turnovers of MEG (TMEG) was r = 0.336 (r2 = 0.113; P = 0.011). These results estimate that 11.3% of the variance in TBOLD can be explained by the variance in TMEG. This estimate is close to the aforementioned estimate obtained by direct recordings in animal experiments. NEW & NOTEWORTHY Here, we report on a weak positive association between turnovers of blood oxygenation level-dependent (TBOLD) and magnetoencephalographic (TMEG) signals in 57 healthy human subjects in a resting, task-free state. More specifically, we found that the purely neural TMEG accounted for 11.1% of the TBOLD, a percentage remarkably close to that found between resting-state local field potentials (LFPs) and BOLD recorded concurrently in animal experiments.

Stronger influence of systemic than local hemodynamic-vascular factors on resting-state BOLD functional connectivity

Correlated fluctuations in the blood oxygenation level dependent (BOLD) signal of resting-state functional MRI (i.e., BOLD-functional connectivity, BOLD-FC) reflect a spectrum of neuronal and non-neuronal processes. In particular, there are multiple hemodynamic-vascular influences on BOLD-FC on both systemic (e.g., perfusion delay) and local levels (e.g., neurovascular coupling). While the influence of individual factors has been studied extensively, combined and comparative studies of systemic and local hemodynamic-vascular factors on BOLD-FC are scarce, notably in humans. We employed a multi-modal MRI approach to investigate and compare distinct hemodynamic-vascular processes and their impact on homotopic BOLD-FC in healthy controls and patients with unilateral asymptomatic internal carotid artery stenosis (ICAS). Asymptomatic ICAS is a cerebrovascular disorder, in which neuronal functioning is largely preserved but hemodynamic-vascular processes are impaired, mostly on the side of stenosis. Investigated indicators for local hemodynamic-vascular processes comprise capillary transit time heterogeneity (CTH) and cerebral blood volume (CBV) from dynamic susceptibility contrast (DSC) MRI, and cerebral blood flow (CBF) from pseudo-continuous arterial spin labeling (pCASL). Indicators for systemic processes are time-to-peak (TTP) from DSC MRI and BOLD lags from functional MRI. For each of these parameters, their influence on BOLD-FC was estimated by a comprehensive linear mixed model. Equally across groups, we found that individual mean BOLD-FC, local (CTH, CBV, and CBF) and systemic (TTP and BOLD lag) hemodynamic-vascular factors together explain 40.7% of BOLD-FC variance, with 20% of BOLD-FC variance explained by hemodynamic-vascular factors, with an about two-times larger contribution of systemic versus local factors. We conclude that regional differences in blood supply, i.e., systemic perfusion delays, exert a stronger influence on BOLD-FC than impairments in local neurovascular coupling.

A Novel Finding in Cerebral Blood Flow in Patients with Sickle Cell Disease Using Bold Functional MRI

Background: Sickle cell disease (SCD) is an inherited blood disorder which is associated with acute and chronic pain, as well as other vascular complications such as arterial steno-occlusion, stroke, and silent cerebral infarction. Alterations of cerebral blood flow have been found to be associated with different painful stages in SCD, thus cerebral blood flow might be correlated with the disease severity determined by varied pain conditions in SCD. Blood oxygen level dependent (BOLD) imaging is a blood-related contrast technology in functional magnetic resonance imaging (fMRI). We have previously demonstrated the feasibility of using low frequency oscillation (LFO) in BOLD fMRI to track the hemodynamic features of the blood flow with maximum cross-correlation coefficient (MCCC) and the Delay Time (i.e., blood arrival time at different brain regions) (Tong et al., JCBFM. 2017). Positive MCCC value was found between the LFO BOLD signals extracted from the global mean (GMean, averaged signal across the whole brain) and the superior sagittal sinus (SSS) in our previous findings (Tong et al., JCBFM. 2018). In this study, we aim to use LFO BOLD signals to explore the cerebral hemodynamic features with MCCCs and their associations with hematological and disease severity related outcomes in patients with SCD. Methods: Ten subjects with SCD aged 14-43 years old (5 HbSS, 3 HbSC, 1 HbSB+, 1 HbB0) and 10 age- and sex-matched controls from a publicly available dataset Human Connectome Project (HCP) (Essen et al., Neuroimage, 2013) were included for data analysis. T1-weighted and resting-state BOLD fMRI (repetition time (TR)=1.05 sec) were collected using a 3T SIEMENS (Prisma) scanner. A BOLD fMRI dataset with TR of 0.72 sec from healthy subjects was used as control. All the BOLD fMRI data were preprocessed using FSL to correct the motion artifact. The SSS region was identified in the T1-weighted image using FSL. The corresponding SSS mask was then applied in the BOLD fMRI image to extract the BOLD fMRI signals in the SSS region. The GMean BOLD signal was averaged across the whole brain. BOLD fMRI Signals were demeaned and band-pass filtered (0.01-0.1 Hz) to acquire the LFO signals. Cross-correlation between the SSS-LFO signal and GMean-LFO signal was performed to calculate the MCCC and their corresponding Delay Time. Correlations between the MCCCs of the two LFO signals (from SSS and GMean) and each hematological index were further performed. Results: Consistent with the healthy control in our previous findings, half of the patients (3 HbSC, 1 HbSB+, and 1 HbSS) presented positive MCCC values. However, interestingly, negative MCCC values were found from another half of the patients (4 HbSS and 1 HbB0, Figure 1, p < 0.05 for all subjects). Notably, all patients with HbSC presented positive MCCC values that are similar to controls whereas 4 out 5 patients with HbSS (80%) were found to have negative MCCC values. More importantly, higher percentages of HbS and lower total Hgb (HbS(%): r=-0.73, p=0.03; Hgb(GM/dL): r=0.69, p=0.03) were found to be significantly associated with the negative MCCC values. Conclusions: We found a never-before-seen negative MCCC signature between the BOLD fMRI signals in the SSS and the GMean in a subset of patients with SCD compared with healthy controls. This might indicate a significant change in cerebral blood flow in a subset of patients with SS disease compared with SC and controls. Importantly, we further observed that this never-before-seen negative MCCC signature is highly associated with the percentage of the HbS and total Hgb that are known to be correlated with disease severity. This might be due to the microvascular shunting (Juttukonda et al., JCBFM, 2019) that exists in patients who have high percentage of HbS. This study is the first to associate BOLD fMRI derived hemodynamic metrics with disease severity related outcomes in SCD. This never-before-seen anti-correlation MCCC signature may have tremendous promise as a novel biomarker for SCD severity and differentiate pain characteristics in different sickle cell phenotypes, and further investigation in larger number of subjects is needed to understand variations between SCD phenotypes and its relationship to clinical outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Cerebral neurovascular alterations in stable chronic obstructive pulmonary disease: a preliminary fMRI study.

Cognitive impairment (CI) is very common in patients with chronic obstructive pulmonary disease (COPD). Cerebral structural and functional abnormalities have been reported in cognitively impaired patients with COPD, and the neurovascular coupling changes are rarely investigated. To address this issue, arterial spin labeling (ASL) and resting-state blood oxygenation level dependent (BOLD) fMRI techniques were used to determine whether any neurovascular changes in COPD patients. Forty-five stable COPD patients and forty gender- and age-matched healthy controls were recruited. Furthermore, resting-state BOLD fMRI and ASL were acquired to calculate degree centrality (DC) and cerebral blood flow (CBF) respectively. The CBF-DC coupling and CBF/DC ratio were compared between the two groups. COPD patients showed abnormal CBF, DC and CBF/DC ratio in several regions. Moreover, lower CBF/DC ratio in the left lingual gyrus negatively correlated with naming scores, lower CBF/DC ratio in medial frontal cortex/temporal gyrus positively correlated with the Montreal Cognitive Assessment (MoCA), visuospatial/executive and delayed recall scores. These findings may provide new potential insights into neuropathogenesis of cognition decline in stable COPD patients.

Impaired Neurovascular Function Underlies Poor Neurocognitive Outcomes and Is Associated with Nitric Oxide Bioavailability in Congenital Heart Disease.

We use a non-invasive MRI proxy of neurovascular function (pnvf) to assess the ability of the vasculature to supply baseline metabolic demand, to compare pediatric and young adult congenital heart disease (CHD) patients to normal referents and relate the proxy to neurocognitive outcomes and nitric oxide bioavailability. In a prospective single-center study, resting-state blood-oxygen-level-dependent (BOLD) and arterial spin labeling (ASL) MRI scans were successfully obtained from 24 CHD patients (age = 15.4 ± 4.06 years) and 63 normal referents (age = 14.1 ± 3.49) years. Pnvf was computed on a voxelwise basis as the negative of the ratio of functional connectivity strength (FCS) estimated from the resting-state BOLD acquisition to regional cerebral blood flow (rCBF) as estimated from the ASL acquisition. Pnvf was used to predict end-tidal CO2 (PETCO2) levels and compared to those estimated from the BOLD data. Nitric oxide availability was obtained via nasal measurements (nNO). Pnvf was compared on a voxelwise basis between CHD patients and normal referents and correlated with nitric oxide availability and neurocognitive outcomes as assessed via the NIH Toolbox. Pnvf was shown as highly predictive of PETCO2 using theoretical modeling. Pnvf was found to be significantly reduced in CHD patients in default mode network (DMN, comprising the ventromedial prefrontal cortex and posterior cingulate/precuneus), salience network (SN, comprising the insula and dorsal anterior cingulate), and central executive network (CEN, comprising posterior parietal and dorsolateral prefrontal cortex) regions with similar findings noted in single cardiac ventricle patients. Positive correlations of Pnvf in these brain regions, as well as the hippocampus, were found with neurocognitive outcomes. Similarly, positive correlations between Pnvf and nitric oxide availability were found in frontal DMN and CEN regions, with particularly strong correlations in subcortical regions (putamen). Reduced Pnvf in CHD patients was found to be mediated by nNO. Mediation analyses further supported that reduced Pnvf in these regions underlies worse neurocognitive outcome in CHD patients and is associated with nitric oxide bioavailability. Impaired neuro-vascular function, which may be non-invasively estimated via combined arterial-spin label and BOLD MR imaging, is a nitric oxide bioavailability dependent factor implicated in adverse neurocognitive outcomes in pediatric and young adult CHD.

Genome-wide association study of the human brain functional connectome reveals strong vascular component underlying global network efficiency

Complex brain networks play a central role in integrating activity across the human brain, and such networks can be identified in the absence of any external stimulus. We performed 10 genome-wide association studies of resting state network measures of intrinsic brain activity in up to 36,150 participants of European ancestry in the UK Biobank. We found that the heritability of global network efficiency was largely explained by blood oxygen level-dependent (BOLD) resting state fluctuation amplitudes (RSFA), which are thought to reflect the vascular component of the BOLD signal. RSFA itself had a significant genetic component and we identified 24 genomic loci associated with RSFA, 157 genes whose predicted expression correlated with it, and 3 proteins in the dorsolateral prefrontal cortex and 4 in plasma. We observed correlations with cardiovascular traits, and single-cell RNA specificity analyses revealed enrichment of vascular related cells. Our analyses also revealed a potential role of lipid transport, store-operated calcium channel activity, and inositol 1,4,5-trisphosphate binding in resting-state BOLD fluctuations. We conclude that that the heritability of global network efficiency is largely explained by the vascular component of the BOLD response as ascertained by RSFA, which itself has a significant genetic component.

Resting-state neural signal variability in women with depressive disorders

Aberrant activity and connectivity in default mode (DMN), frontoparietal (FPN), and salience (SN) network regions is well-documented in depression. Recent neuroimaging research suggests that altered variability in the blood oxygen level-dependent (BOLD) signal may disrupt normal network integration and be an important novel predictor of psychopathology. However, no studies have yet determined the relationship between resting-state BOLD signal variability and depressive disorders nor applied BOLD signal variability features to the classification of depression history using machine learning (ML). We collected resting-state fMRI data for 79 women with different depression histories: no history, past history, and current depressive disorder. We tested voxelwise differences in BOLD signal variability related to depression group and severity. We also investigated whether BOLD signal variability of DMN, FPN, and SN regions could predict depression history group using a supervised random forest ML model. Results indicated that individuals with any history of depression had significantly decreased BOLD signal variability in the left and right cerebellum and right parietal cortex (pFWE <0.05). Furthermore, greater depression severity was also associated with reduced BOLD signal variability in the cerebellum. A random forest model classified participant depression history with 74% accuracy, with the ventral anterior cingulate cortex of the DMN as the most important variable in the model. These findings provide novel support for resting-state BOLD signal variability as a marker of neural dysfunction in depression and implicate decreased neural signal variability in the pathophysiology of depression.

Static and dynamic BOLD fMRI components along white matter fibre tracts and their dependence on the orientation of the local diffusion tensor axis relative to the B0-field

Recent studies have reported functional MRI (fMRI) activation within cerebral white matter (WM) using blood-oxygenation-level-dependent (BOLD) contrast. Many blood vessels in WM run parallel to the fibre bundles, and other studies observed dependence of susceptibility contrast-based measures of blood volume on the local orientation of the fibre bundles relative to the magnetic field or B0 axis. Motivated by this, we characterized the dependence of gradient-echo BOLD fMRI on fibre orientation (estimated by the local diffusion tensor) relative to the B0 axis to test whether the alignment between bundles and vessels imparts an orientation dependence on resting-state BOLD fluctuations in the WM. We found that the baseline signal level of the T2*-weighted data is 11% higher in voxels containing fibres parallel to B0 than those containing perpendicular fibres, consistent with a static influence of either fibre or vessel orientation on local T2* values. We also found that BOLD fluctuations in most bundles exhibit orientation effects expected from oxygenation changes, with larger amplitudes from voxels containing perpendicular fibres. Different magnitudes of this orientation effect were observed across the major WM bundles, with inferior fasciculus, corpus callosum and optic radiation exhibiting 14–19% higher fluctuations in voxels containing perpendicular compared to parallel fibres.

Resting-state BOLD functional connectivity depends on the heterogeneity of capillary transit times in the human brain A combined lesion and simulation study about the influence of blood flow response timing

Functional connectivity (FC) derived from blood oxygenation level dependent (BOLD) functional magnetic resonance imaging at rest (rs-fMRI), is commonly interpreted as indicator of neuronal connectivity. In a number of brain disorders, however, metabolic, vascular, and hemodynamic impairments can be expected to alter BOLD-FC independently from neuronal activity. By means of a neurovascular coupling (NVC) model of BOLD-FC, we recently demonstrated that aberrant timing of cerebral blood flow (CBF) responses may influence BOLD-FC. In the current work, we support and extend this finding by empirically linking BOLD-FC with capillary transit time heterogeneity (CTH), which we consider as an indicator of delayed and broadened CBF responses. We assessed 28 asymptomatic patients with unilateral high-grade internal carotid artery stenosis (ICAS) as a hemodynamic lesion model with largely preserved neurocognitive functioning and 27 age-matched healthy controls. For each participant, we obtained rs-fMRI, arterial spin labeling, and dynamic susceptibility contrast MRI to study the dependence of left-right homotopic BOLD-FC on local perfusion parameters. Additionally, we investigated the dependency of BOLD-FC on CBF response timing by detailed simulations. Homotopic BOLD-FC was negatively associated with increasing CTH differences between homotopic brain areas. This relation was more pronounced in asymptomatic ICAS patients even after controlling for baseline CBF and relative cerebral blood volume influences. These findings match simulation results that predict an influence of delayed and broadened CBF responses on BOLD-FC. Results demonstrate that increasing CTH differences between homotopic brain areas lead to BOLD-FC reductions. Simulations suggest that CTH increases correspond to broadened and delayed CBF responses to fluctuations in ongoing neuronal activity.

Alterations in Functional Network Topology Within Normal Hemispheres Contralateral to Anterior Circulation Steno-Occlusive Disease: A Resting-State BOLD Study.

The purpose of this study was to assess spatially remote effects of hemodynamic impairment on functional network topology contralateral to unilateral anterior circulation steno-occlusive disease (SOD) using resting-state blood oxygen level-dependent (BOLD) imaging, and to investigate the relationships between network connectivity and cerebrovascular reactivity (CVR), a measure of hemodynamic stress. Twenty patients with unilateral, chronic anterior circulation SOD and 20 age-matched healthy controls underwent resting-state BOLD imaging. Five-minute standardized baseline BOLD acquisition was followed by acetazolamide infusion to measure CVR. The BOLD baseline was used to analyze network connectivity contralateral to the diseased hemispheres of SOD patients. Compared to healthy controls, reduced network degree (z-score = −1.158 ± 1.217, P < 0.001, false discovery rate (FDR) corrected), local efficiency (z-score = −1.213 ± 1.120, P < 0.001, FDR corrected), global efficiency (z-score = −1.346 ± 1.119, P < 0.001, FDR corrected), and enhanced modularity (z-score = 1.000 ± 1.205, P = 0.002, FDR corrected) were observed in the contralateral, normal hemispheres of SOD patients. Network degree (P = 0.089, FDR corrected; P = 0.027, uncorrected) and nodal efficiency (P = 0.089, FDR corrected; P = 0.045, uncorrected) showed a trend toward a positive association with CVR. The results indicate remote abnormalities in functional connectivity contralateral to the diseased hemispheres in patients with unilateral SOD, despite the absence of macrovascular disease or demonstrable hemodynamic impairment. The clinical impact of remote functional disruptions requires dedicated investigation but may portend far reaching consequence for even putatively unilateral cerebrovascular disease.

The altered multiscale dynamics of spontaneous brain activity in depression with Parkinson’s disease

BackgroundDepression is one typical mood disorder in Parkinson’s disease (DPD). The alterations in the resting-state brain activities are believed to be associated with DPD. These resting-state activities are regulated by neurophysiological components over multiple temporal scales. The multiscale dynamics of these spontaneous fluctuations are thus complex, but not well-characterized.ObjectiveTo characterize the complexity of the spontaneous blood-oxygen-level-dependent (BOLD) of fMRI in DPD. We hypothesized that (1) compared to non-depression PD (NDPD), the complexity in DPD would be lower; and (2) the diminished complexity would be associated with lower connections/communications between brain regions.MethodsTwenty-nine participants (10 in DPD and 19 in NDPD) who were naïve to medications completed a resting-sate functional MRI scan. The BOLD complexity within each voxel was calculated by using multiscale entropy (MSE). The complexity of the whole brain and each of the 90 regions parcellated following automated-anatomical-labeling template was then obtained by averaging voxel-wised complexity across all brain regions or within each region. The level of connections of regions with diminished complexity was measured by their own global functional connectivity (FC).ResultsAs compared to NDPD patients, the whole-brain complexity and complexity in 18 regions were significantly lower in DPD (F > 16.3, p < 0.0005). Particularly, in eight of the 18 regions, lower complexity was associated with lower global FC (Beta = 0.333 ~ 0.611, p = 0.000 ~ 0.030).ConclusionThe results from this pilot study suggest that the resting-state BOLD complexity may provide critical knowledge into the pathology of DPD. Future studies are thus warranted to confirm the findings of this study.

Dynamic variations of resting-state BOLD signal spectra in white matter

Recent studies have demonstrated that the mathematical model used for analyzing and interpreting fMRI data in gray matter (GM) is inappropriate for detecting or describing blood-oxygenation-level-dependent (BOLD) signals in white matter (WM). In particular the hemodynamic response function (HRF) which serves as the regressor in general linear models is different in WM compared to GM. We recently reported measurements of the frequency contents of resting-state signal time courses in WM that showed distinct power spectra which depended on local structural-vascular-functional associations. In addition, multiple studies of GM have revealed how functional connectivity between regions, as measured by the correlation between BOLD time series, varies dynamically over time. We therefore investigated whether and how BOLD signals from WM in a resting state varied over time. We measured voxel-wise spectrograms, which reflect the time-varying spectral patterns of WM time courses. The results suggest that the spectral patterns are non-stationary but could be categorized into five modes that recurred over time. These modes showed distinct spatial distributions of their occurrences and durations, and the distributions were highly consistent across individuals. In addition, one of the modes exhibited a strong coupling of its occurrence between GM and WM across individuals, and two communities of WM voxels were identified according to the hierarchical structures of transitions among modes. Moreover, these modes are coupled to the shape of instantaneous HRFs. Our findings extend previous studies and reveal the non-stationary nature of spectral patterns of BOLD signals over time, providing a spatial-temporal-frequency characterization of resting-state signals in WM.

Gaining insight into the neural basis of resting-state fMRI signal

The blood oxygenation level-dependent (BOLD)-based resting-state functional magnetic resonance imaging (rsfMRI) has been widely used as a non-invasive tool to map brain-wide connectivity architecture. However, the neural basis underpinning the resting-state BOLD signal remains elusive. In this study, we combined simultaneous calcium-based fiber photometry with rsfMRI in awake animals to examine the relationship of the BOLD signal and spiking activity at the resting state. We observed robust couplings between calcium and BOLD signals in the dorsal hippocampus as well as other distributed areas in the default mode network (DMN), suggesting that the calcium measurement can reliably predict the rsfMRI signal. In addition, using the calcium signal recorded as the ground truth, we assessed the impacts of different rsfMRI data preprocessing pipelines on functional connectivity mapping. Overall, our results provide important evidence suggesting that spiking activity measured by the calcium signal plays a key role in the neural mechanism of resting-state BOLD signal.

Relationships between correlated spikes, oxygen and LFP in the resting-state primate

Resting-state functional MRI (rsfMRI) provides a view of human brain organization based on correlation patterns of blood oxygen level dependent (BOLD) signals recorded across the whole brain. The neural basis of resting-state BOLD fluctuations and their correlation remains poorly understood. We simultaneously recorded oxygen level, spikes, and local field potential (LFP) at multiple sites in awake, resting monkeys. Following a spike, the average local oxygen and LFP voltage responses each resemble a task-driven BOLD response, with LFP preceding oxygen by 0.5 s. Between sites, features of the long-range correlation patterns of oxygen, LFP, and spikes are similar to features seen in rsfMRI. Most of the variance shared between sites lies in the infraslow frequency band (0.01–0.1 Hz) and in the infraslow envelope of higher-frequency bands (e.g. gamma LFP). While gamma LFP and infraslow LFP are both strong correlates of local oxygen, infraslow LFP explains significantly more of the variance shared between correlated oxygen signals than any other electrophysiological signal. Together these findings are consistent with a causal relationship between infraslow LFP and long-range oxygen correlations in the resting state.

BOLD asynchrony elucidates tumor burden in IDH-mutated gliomas.

Gliomas comprise the most common type of primary brain tumor, are highly invasive, and often fatal. IDH-mutated gliomas are particularly challenging to image and there is currently no clinically accepted method for identifying the extent of tumor burden in these neoplasms. This uncertainty poses a challenge to clinicians who must balance the need to treat the tumor while sparing healthy brain from iatrogenic damage. The purpose of this study was to investigate the feasibility of using resting-state blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to detect glioma-related asynchrony in vascular dynamics for distinguishing tumor from healthy brain. Twenty-four stereotactically localized biopsies were obtained during open surgical resection from ten treatment-naïve patients with IDH-mutated gliomas who received standard-of-care preoperative imaging as well as echo-planar resting-state BOLD fMRI. Signal intensity for BOLD asynchrony and standard-of-care imaging was compared to cell counts of total cellularity (H&E), tumor density (IDH1 & Sox2), cellular proliferation (Ki67), and neuronal density (NeuN), for each corresponding sample. BOLD asynchrony was directly related to total cellularity (H&E, P = 4 × 10-5), tumor density (IDH1, P = 4 × 10-5; Sox2, P = 3 × 10-5), cellular proliferation (Ki67, P = .002), and inversely related to neuronal density (NeuN, P = 1 × 10-4). Asynchrony in vascular dynamics, as measured by resting-state BOLD fMRI, correlates with tumor burden and provides a radiographic delineation of tumor boundaries in IDH-mutated gliomas.

Cerebrovascular Reactivity Mapping Using Resting-State BOLD Functional MRI in Healthy Adults and Patients with Moyamoya Disease.

Background Cerebrovascular reserve, the potential capacity of brain tissue to receive more blood flow when needed, is a desirable marker in evaluating ischemic risk. However, current measurement methods require acetazolamide injection or hypercapnia challenge, prompting a clinical need for resting-state (RS) blood oxygen level-dependent (BOLD) functional MRI data to measure cerebrovascular reactivity (CVR). Purpose To optimize and evaluate an RS CVR MRI technique and demonstrate its relationship to neurosurgical treatment. Materials and Methods In this HIPAA-compliant study, RS BOLD functional MRI data collected in 170 healthy controls between December 2008 and September 2010 were retrospectively evaluated to identify the optimal frequency range of temporal filtering on the basis of spatial correlation with the reference standard CVR map obtained with CO2 inhalation. Next, the optimized RS method was applied in a new, prospective cohort of 50 participants with Moyamoya disease who underwent imaging between June 2014 and August 2019. Finally, CVR values were compared between brain hemispheres with and brain hemispheres without revascularization surgery by using Mann-Whitney U test. Results A total of 170 healthy controls (mean age ± standard deviation, 51 years ± 20; 105 women) and 100 brain hemispheres of 50 participants with Moyamoya disease (mean age, 41 years ± 12; 43 women) were evaluated. RS CVR maps based on a temporal filtering frequency of [0, 0.1164 Hz] yielded the highest spatial correlation (r = 0.74) with the CO2 inhalation CVR results. In patients with Moyamoya disease, 77 middle cerebral arteries (MCAs) had stenosis. RS CVR in the MCA territory was lower in the group that did not undergo surgery (n = 30) than in the group that underwent surgery (n = 47) (mean, 0.407 relative units [ru] ± 0.208 vs 0.532 ru ± 0.182, respectively; P = .006), which is corroborated with the CO2 inhalation CVR data (mean, 0.242 ru ± 0.273 vs 0.437 ru ± 0.200; P = .003). Conclusion Cerebrovascular reactivity mapping performed by using resting-state blood oxygen level-dependent functional MRI provided a task-free method to measure cerebrovascular reserve and depicted treatment effect of revascularization surgery in patients with Moyamoya disease comparable to that with the reference standard of CO2 inhalation MRI. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Wolf and Ware in this issue.

Lower Cerebrovascular Reactivity Contributed to White Matter Hyperintensity-Related Cognitive Impairment: A Resting-State Functional MRI Study.

Impaired cerebrovascular reactivity (CVR) plays an important role in the pathophysiology of white matter hyperintensities (WMHs). The pathogenesis of CVR in the development of WMH-related cognitive impairment (CI) remains poorly understood. To detect the CVR status in WMH subjects with/without CI by using a resting-state blood oxygenation level-dependent (BOLD) approach and to explore the mediating relationships among CVR, WMH, and cognitive level. Prospective. Subjects with moderate to severe WMH (with CI [WMH-CI], n = 68; without CI [WMH-no-CI, n = 63) as well as normal controls (NCs, n = 87). 3.0T with gradient-recalled echoplanar imaging and 3D fluid-attenuated inversion recovery. The CVR, WMH volume, and cognitive level were assessed. The CVR map was derived using BOLD signal obtained from resting-state functional MRI data. CVR maps were compared among the three groups. Partial correlation analyses were performed to correlate impaired CVR with WMH volume and cognitive test scores. Mediation analysis was conducted to determine whether WMH acted as a mediating factor between CVR and cognitive function. Compared with the NC group, both WMH groups showed reduced CVR in the left hemisphere (P < 0.05). The WMH-CI group showed further decreased CVR in the left frontal area, when compared with the WMH-no-CI group (P < 0.05). In the WMH-CI group, the lower CVR in left frontal area was a strong indicator of poor performance on general cognition (r = 0.311), executive function (r = 0.362), and information processing speed (r = 0.399) (all P < 0.05). Periventricular WMH (PWMH) volume mediated these correlations, the β and 95% bootstrap confidence intervals were (0.5097, [0.1498,1.1385]), (-0.4081, [-1.0256,-0.1363]), and (-0.5576, [-1.4666,-0.1538]), respectively. WMH-CI subjects showed a greater reduction of CVR derived from a resting-state BOLD approach in the left frontal area than WMH-no-CI subjects. Cognition was highly dependent on the integrity of cerebrovascular reactivity and mediated by PWMH burden. 4 TECHNICAL EFFICACY: Stage 2.

Reduced Dynamic Complexity of BOLD Signals Differentiates Mild Cognitive Impairment From Normal Aging.

Mild cognitive impairment (MCI) is characterized as a transitional phase between cognitive decline associated with normal aging and Alzheimer’s disease (AD). Resting-state functional magnetic resonance imaging (fMRI) measuring blood oxygenation level-dependent (BOLD) signals provides complementary information considered essential for understanding disease progression. Previous studies suggested that multi-scale entropy (MSE) analysis quantifying the complexity of BOLD signals is a novel and promising method for investigating neurodegeneration associated with cognitive decline in different stages of MCI. Therefore, the current study used MSE to explore the changes in the complexity of resting-state brain BOLD signals in patients with early MCI (EMCI) and late MCI (LMCI). We recruited 345 participants’ data from the Alzheimer’s Disease Neuroimaging Initiative database, including 176 normal control (NC) subjects, 87 patients with EMCI and 82 patients with LMCI. We observed a significant reduction of brain signal complexity toward regularity in the left fusiform gyrus region in the EMCI group and in the rostral anterior cingulate cortex in the LMCI group. Our results extend prior work by revealing that significant reductions of brain BOLD signal complexity can be detected in different stages of MCI independent of age, sex and regional atrophy. Notably, the reduction of BOLD signal complexity in the rostral anterior cingulate cortex was significantly associated with greater risk of progression to AD. The present study thus identified MSE as a potential imaging biomarker for the early diagnosis of pre-clinical Alzheimer’s disease and provides further insights into the neuropathology of cognitive decline in prodromal AD.

PROSPECTIVE MEASURES OF INTRA-REGION BRAIN REGULARITY DIFFERENTIATES ACL INJURED AND UNINJURED ATHLETES

Background:Anterior cruciate ligament (ACL) injuries are debilitating for athletes. While numerous motor and biomechanical deficits contribute to the inciting ACL injury mechanism, the limited knowledge about the underlying neural drivers of these deficits has impeded intervention development to reduce ACL injury rates. A prospective investigation using functional magnetic resonance imaging (fMRI) in female soccer players revealed decreased connectivity between the primary somatosensory cortex and cerebellum for athletes that went on to ACL injury athletes compared to their healthy teammates. Although information about inter-region connectivity patterns is informative, this finding does elucidate the individual, intra-region brain activity that may be further underlie ACL injury mechanisms.Hypothesis/Purpose:The purpose of this study was to prospectively investigate the intra-region regularity of the blood oxygen-level dependent (BOLD) signal activity in 25 knee-related regions of interests (ROI) between athletes who sustained an ACL injury and matched controls.Methods:Adolescent female soccer athletes were evaluated using fMRI to capture resting-state brain connectivity prior to their competitive season. Two of these athletes (16.0±0yrs, 169.0±2.8cm, 60.1±8.3kg) later experienced an ACL injury and were matched to eight uninjured teammates (15.9±0.8yrs, 164.0±4.9cm, 58.3±7.6kg). Standard fMRI data processing was used to determine resting-state BOLD signal activity in 25 knee-related ROIs. Sample entropy (SampEn) was then used to quantify the regularity of each individual ROI. A lower SampEn value indicates a ROI’s BOLD signal activity was more regular (predictable) and a higher value indicates a signal’s activity was more irregular (unpredictable). T-tests—with a Bonferroni correction for the familywise error rate (p < .002)—were used to compare SampEn values between both groups for all 25 ROIs.Results:ACL injured athletes (M = 0.35±0.01) exhibited higher SampEn values in the left primary motor cortex than matched, uninjured athletes (M = 0.29±0.02; t(8)=4.62, p=.0017, d=3.65).Conclusion:Athletes who sustained an ACL injury exhibited less regularity in BOLD signal activity of the left primary motor cortex. As the primary motor cortex serves as the final destination in the brain before efferent information is sent to the spinal cord to initiate movement, decreased BOLD signal regularity in this region may alter such cortical-spinal transmission. Considering ACL injuries often occur during unpredictable environments, irregular activity of motor cortex activity may dampen an athlete’s ability to sustain a safe knee position. These findings may help to guide development of brain-driven biofeedback training to promote adaptive neuroplasticity that ‘pushes’ the motor cortex towards more regular activity.Figure 1.Shown above is the location of the left primary motor cortex (indicated by the black circle to the left). In Panel A, a BOLD signal from an athlete who went on to injure her ACL is presented. In Panel B, a BOLD signal from an athlete who did not injure her ACL is shown.

Resting State BOLD Variability Is Linked to White Matter Vascular Burden in Healthy Aging but Not in Older Adults With Subjective Cognitive Decline.

Background: Alzheimer’s disease (AD) is the leading cause of dementia. A lack of curative treatments and a rapidly aging global population have amplified the need for early biomarkers of the disease process. Recent advances suggest that subjective cognitive decline (SCD) may be one of the earliest symptomatic markers of the AD cascade. Previous studies have identified changes in variability in the blood-oxygen-level-dependent (BOLD) signal in patients with AD, with a possible association between BOLD variability and cerebrovascular factors in the aging brain. The objective of the current study was to determine whether changes in BOLD variability can be identified in individuals with SCD, and whether this signal may be associated with markers of cerebrovascular integrity in SCD and older adults without memory complaints.Method: Data were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database from 19 participants with SCD and 19 similarly-aged controls. For each participant, a map of BOLD signal variability (SDBOLD) was computed as the standard deviation of the BOLD time-series at each voxel. Group comparisons were performed to examine differences in resting-state SDBOLD in SCD vs. healthy controls. Relationships were then examined between participant SDBOLD maps and neuroimaging markers of white matter vascular infarcts in each group separately.Results: Between-group comparisons showed no significant differences in whole-brain SDBOLD in individuals with SCD and controls. In the healthy aging group, higher white matter hyperintensity (WMH) burden was associated with greater SDBOLD in right temporal regions (p < 0.05), and lower scores on a measure of global executive functioning. These associations were not identified in individuals with SCD.Conclusion: The current study underscores previous evidence for a relationship between SDBOLD and white matter vascular infarcts in the healthy aging brain. The findings also provide evidence for a dissociable relationship between healthy aging and SCD, such that in healthy controls, increased WMH is associated with declines in executive function that is not observed in older adults who present with memory complaints. Further multimodal work is needed to better understand the contributions of vascular pathology to the BOLD signal, and its potential relationship with pathological aging.