Resting-state Blood Oxygenation Level-dependent Research Articles

Relating Intrinsic Low-Frequency BOLD Cortical Oscillations to Cognition in Schizophrenia.

The amplitude of low-frequency fluctuations (ALFF) in the blood oxygenation level-dependent (BOLD) signal during resting-state fMRI reflects the magnitude of local low-frequency BOLD oscillations, rather than interregional connectivity. ALFF is of interest to studies of cognition because fluctuations in spontaneous intrinsic brain activity relate to, and possibly even constrain, task-evoked brain responses in healthy people. Lower ALFF has been reported in schizophrenia, but the cognitive correlates of these reductions remain unknown. Here, we assess relationships between ALFF and attention and working memory in order to establish the functional relevance of intrinsic BOLD oscillatory power alterations with respect to specific cognitive impairments in schizophrenia. As part of the multisite FBIRN study, resting-state fMRI data were collected from schizophrenia subjects (SZ; n=168) and healthy controls (HC; n=166). Voxelwise fractional ALFF (fALFF), a normalized ALFF measure, was regressed on neuropsychological measures of sustained attention and working memory in SZ and HC to identify regions showing either common slopes across groups or slope differences between groups (all findings p<0.01 height, p<0.05 family-wise error cluster corrected). Poorer sustained attention was associated with smaller fALFF in the left superior frontal cortex and bilateral temporoparietal junction in both groups, with additional relationships in bilateral posterior parietal, posterior cingulate, dorsal anterior cingulate (ACC), and right dorsolateral prefrontal cortex (DLPFC) evident only in SZ. Poorer working memory was associated with smaller fALFF in bilateral ACC/mPFC, DLPFC, and posterior parietal cortex in both groups. Our findings indicate that smaller amplitudes of low-frequency BOLD oscillations during rest, measured by fALFF, were significantly associated with poorer cognitive performance, sometimes similarly in both groups and sometimes only in SZ, in regions known to subserve sustained attention and working memory. Taken together, these data suggest that the magnitude of resting-state BOLD oscillations shows promise as a biomarker of cognitive function in health and disease.

Metabolic and vascular origins of the BOLD effect: Implications for imaging pathology and resting-state brain function.

The blood oxygenation level-dependent (BOLD) phenomenon has profoundly revolutionized neuroscience, with applications ranging from normal brain development and aging, to brain disorders and diseases. While the BOLD effect represents an invaluable tool to map brain function, it does not measure neural activity directly; rather, it reflects changes in blood oxygenation resulting from the relative balance between cerebral oxygen metabolism (through neural activity) and oxygen supply (through cerebral blood flow and volume). As such, there are cases in which BOLD signals might be dissociated from neural activity, leading to misleading results. The emphasis of this review is to develop a critical perspective for interpreting BOLD results, through a comprehensive consideration of BOLD's metabolic and vascular underpinnings. We demonstrate that such an understanding is especially important under disease or resting conditions. We also describe state-of-the-art acquisition and analytical techniques to reveal physiological information on the mechanisms underlying measured BOLD signals. With these goals in mind, this review is structured to provide a fundamental understanding of: 1) the physiological and physical sources of the BOLD contrast; 2) the extraction of information regarding oxidative metabolism and cerebrovascular reactivity from the BOLD signal, critical to investigating neuropathology; and 3) the fundamental importance of metabolic and vascular mechanisms for interpreting resting-state BOLD measurements.

Associations of resting-state fMRI functional connectivity with flow-BOLD coupling and regional vasculature.

There has been tremendous interest in applying functional magnetic resonance imaging-based resting-state functional connectivity (rs-fcMRI) measurements to the study of brain function. However, a lack of understanding of the physiological mechanisms of rs-fcMRI limits their ability to interpret rs-fcMRI findings. In this work, the authors examine the regional associations between rs-fcMRI estimates and dynamic coupling between the blood oxygenation level-dependent (BOLD) and cerebral blood flow (CBF), as well as resting macrovascular volume. Resting-state BOLD and CBF data were simultaneously acquired using a dual-echo pseudocontinuous arterial spin labeling (pCASL) technique, whereas macrovascular volume fraction was estimated using time-of-flight MR angiography. Functional connectivity within well-known functional networks—including the default mode, frontoparietal, and primary sensory-motor networks—was calculated using a conventional seed-based correlation approach. They found the functional connectivity strength to be significantly correlated with the regional increase in CBF-BOLD coupling strength and inversely proportional to macrovascular volume fraction. These relationships were consistently observed within all functional networks considered. Their findings suggest that highly connected networks observed using rs-fcMRI are not likely to be mediated by common vascular drainage linking distal cortical areas. Instead, high BOLD functional connectivity is more likely to reflect tighter neurovascular connections, attributable to neuronal pathways.

The relationship between glucose metabolism, resting-state fMRI BOLD signal, and GABAA-binding potential: a preliminary study in healthy subjects and those with temporal lobe epilepsy.

Glucose metabolism has been associated with magnitude of blood oxygen level-dependent (BOLD) signal and connectivity across subjects within the default mode and dorsal attention networks. Similar correlations within subjects across the entire brain remain unexplored. [(18)F]-fluorodeoxyglucose positron emission tomography ([(18)F]-FDG PET), [(11)C]-flumazenil PET, and resting-state functional magnetic resonance imaging (fMRI) scans were acquired in eight healthy individuals and nine with temporal lobe epilepsy (TLE). Regional metabolic rate of glucose (rMRGlu) was correlated with amplitude of low frequency fluctuations (ALFFs) in the fMRI signal, global fMRI connectivity (GC), regional homogeneity (ReHo), and gamma-aminobutyric acid A-binding potential (GABAA BP(ND)) across the brain. Partial correlations for ALFFs, GC, and ReHo with GABAA BP(ND) were calculated, controlling for rMRGlu. In healthy subjects, significant positive correlations were observed across the brain between rMRGlu and ALFF, ReHo and GABAA BP(ND), and between ALFFs and GABAA BP(ND), controlling for rMRGlu. Brain-wide correlations between rMRGlu and ALFFs were significantly lower in TLE patients, and correlations between rMRGlu and GC were significantly greater in TLE than healthy subjects. These results indicate that the glutamatergic and GABAergic systems are coupled across the healthy human brain, and that ALFF is related to glutamate use throughout the healthy human brain. TLE may be a disorder of altered long-range connectivity in association with glutamate function.

Mapping the end-tidal CO2 response function in the resting-state BOLD fMRI signal: Spatial specificity, test–retest reliability and effect of fMRI sampling rate

The blood oxygenation level dependent (BOLD) signal measures brain function indirectly through physiological processes and hence is susceptible to global physiological changes. Specifically, fluctuations in end-tidal CO2 (PETCO2), in addition to cardiac rate variation (CRV), and respiratory volume per time (RVT) variations, have been known to confound the resting-state fMRI (rs-fMRI) signal. Previous studies addressed the resting-state fMRI response function to CRV and RVT, but no attempt has been made to directly estimate the voxel-wise response function to PETCO2. Moreover, the potential interactions among PETCO2, CRV, and RVT necessitate their simultaneous inclusion in a multi-regression model to estimate the PETCO2 response. In this study, we use such a model to estimate the voxel-wise PETCO2 response functions directly from rs-fMRI data of nine healthy subjects. We also characterized the effect of sampling rate (TR=2seconds vs. 323ms) on the temporal and spatial variability of the PETCO2 response function in addition to that of CRV and RVT. In addition, we assess the test–retest reproducibility of the response functions to PETCO2, CRV and RVT. We found that despite overlaps across their spatial patterns, PETCO2 explains a unique portion of the rs-fMRI signal variance compared to RVT and CRV. We also found the shapes of the estimated responses are very similar between long- and short-TR data, although responses estimated from short-TR data have higher reproducibility.

Designing hyperbolic secant excitation pulses to reduce signal dropout in gradient-echo echo-planar imaging.

To design hyperbolic secant (HS) excitation pulses to reduce signal dropout in the orbitofrontal and inferior temporal regions in gradient-echo echo-planar imaging (GE-EPI) for functional MRI (fMRI) applications. An algorithm based on Bloch simulations optimizes the HS pulse parameters needed to give the desired signal response across the range of susceptibility gradients observed in the human head (approximately ±250 μT·m(-1) ). The impact of the HS pulse on the signal, temporal signal-to-noise ratio, blood oxygen level-dependent (BOLD) sensitivity, and ability to detect resting state BOLD signal changes was assessed in six healthy male volunteers at 3T. The optimized HS pulse (μ = 4.25, β = 3040 Hz, A0 = 12.3 μT, Δf = 4598 Hz) had a near uniform signal response for through-plane susceptibility gradients in the range ±250 μT·m(-1) . Signal, temporal signal-to-noise ratio, BOLD sensitivity, and the detectability of resting state networks were all partially recovered in the orbitofrontal and inferior temporal regions; however, there were signal losses of up to 50% in regions of homogeneous field (and signal loss from in-plane susceptibility gradients remained). The HS pulse reduced signal dropout and could be used to acquire task and resting state fMRI data without loss of spatial coverage or temporal resolution.

Contralateral interictal spikes are related to tapetum damage in left temporal lobe epilepsy.

In temporal lobe epilepsy (TLE), the epileptogenic focus is focal and unilateral in the majority of patients. A key characteristic of focal TLE is the presence of subclinical epileptiform activity in both the ictal and contralateral "healthy" hemisphere. Such interictal activity is clinically important, as it may reflect the spread of pathology, potentially leading to secondary epileptogenesis. The role played by white matter pathways in this process is unknown. We compared three interhemispheric white matter tracts (anterior commissure, fornix, and tapetum) to determine the pathway most associated with the presence of contralateral interictal spikes. Forty patients with unilateral left or right TLE were categorized based on the presence or absence of contralateral interictal spikes. Analyses of variance (ANOVAs) were run on diffusion properties from each tract. The analyses revealed that patients with left TLE and with bilateral interictal spikes had lower fractional anisotropy (FA) and higher mean diffusivity (MD) in the tapetum. Patients with right TLE did not show this effect. No significant associations with bilateral activity were observed for the other tracts. Blood oxygen level-dependent (BOLD) functional connectivity data revealed that homotopic lateral, not mesial, temporal areas were reliably correlated in bilateral patients, independent of ictal side. Our results indicate that, among the tracts investigated, only the tapetum was associated with contralateral epileptiform activity, implicating this structure in seizures and possible secondary epileptogenesis. We describe two mechanisms that might explain this association (the interruption of inhibitory signals or the toxic effect of carrying epileptiform signals toward the healthy hemisphere), but also acknowledge other rival factors that may be at work. We also report that patients with TLE with bilateral spikes had increased lateral bitemporal lobe connectivity. Our current results can be seen as bringing together important functional and structural data to elucidate the basis of contralateral interictal activity in focal, unilateral epilepsy. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Perfusion MRI indexes variability in the functional brain effects of theta-burst transcranial magnetic stimulation.

Transcranial Magnetic Stimulation (TMS) is an important tool for testing causal relationships in cognitive neuroscience research. However, the efficacy of TMS can be variable across individuals and difficult to measure. This variability is especially a challenge when TMS is applied to regions without well-characterized behavioral effects, such as in studies using TMS on multi-modal areas in intrinsic networks. Here, we examined whether perfusion fMRI recordings of Cerebral Blood Flow (CBF), a quantitative measure sensitive to slow functional changes, reliably index variability in the effects of stimulation. Twenty-seven participants each completed four combined TMS-fMRI sessions during which both resting state Blood Oxygen Level Dependent (BOLD) and perfusion Arterial Spin Labeling (ASL) scans were recorded. In each session after the first baseline day, continuous theta-burst TMS (TBS) was applied to one of three locations: left dorsolateral prefrontal cortex (L dlPFC), left anterior insula/frontal operculum (L aI/fO), or left primary somatosensory cortex (L S1). The two frontal targets are components of intrinsic networks and L S1 was used as an experimental control. CBF changes were measured both before and after TMS on each day from a series of interleaved resting state and perfusion scans. Although TBS led to weak selective increases under the coil in CBF measurements across the group, individual subjects showed wide variability in their responses. TBS-induced changes in rCBF were related to TBS-induced changes in functional connectivity of the relevant intrinsic networks measured during separate resting-state BOLD scans. This relationship was selective: CBF and functional connectivity of these networks were not related before TBS or after TBS to the experimental control region (S1). Furthermore, subject groups with different directions of CBF change after TBS showed distinct modulations in the functional interactions of targeted networks. These results suggest that CBF is a marker of individual differences in the effects of TBS.

Lewy body compared with Alzheimer dementia is associated with decreased functional connectivity in resting state networks

Resting state functional magnetic resonance imaging (fMRI) was used to measure whole brain functional connectivity within specific networks hypothesised to be more affected in dementia with Lewy bodies (DLB) (a disease characterised by prominent attentional deficits, spontaneous motor features of parkinsonism and depression) than in Alzheimer׳s disease (AD) and controls. This study involved 68 subjects (15 DLB, 13 AD and 40 controls) who were scanned using resting state BOLD (blood-oxygen-level-dependent) fMRI on a 3T MRI scanner. Functional connectivity was measured using a model-free independent component analysis approach that consisted of temporally concatenating the resting state fMRI data of all study subjects and investigating group differences using a back-reconstruction procedure. Resting state functional connectivity was affected in the default mode, salience, executive and basal ganglia networks in DLB subjects compared with AD and controls. Functional connectivity was lower in DLB compared with AD and controls in these networks, except for the basal ganglia network, where connectivity was greater in DLB. No resting state networks showed less connectivity in AD compared with DLB or controls. Our results suggest that functional connectivity of resting state networks can identify differences between DLB and AD subjects that may help to explain why DLB subjects have more frequent attentional deficits, parkinsonian symptoms, and depression than those with AD.

The APOE ɛ4 allele affects complexity and functional connectivity of resting brain activity in healthy adults

The apolipoprotein E (APOE) gene is associated with structural and functional brain changes. We have used multiscale entropy (MSE) analysis to detect changes in the complexity of resting blood oxygen level-dependent (BOLD) signals associated with aging and cognitive function. In this study, we further hypothesized that the APOE genotype may affect the complexity of spontaneous BOLD activity in younger and older adults, and such altered complexity may be associated with certain changes in functional connectivity. We conducted a resting-state functional magnetic resonance imaging experiment in a cohort of 100 younger adults (aged 20-39 years; mean 27.2 ± 4.3 years; male/female: 53/47) and 112 older adults (aged 60-79 years; mean 68.4 ± 6.5 years; male/female: 54/58), and applied voxelwise MSE analysis to assess the main effect of APOE genotype on resting-state BOLD complexity and connectivity. Although the main effect of APOE genotype on BOLD complexity was not observed in younger group, we observed that older APOE ɛ4 allele carriers had significant reductions in BOLD complexity in precuneus and posterior cingulate regions, relative to noncarriers. We also observed that reduced BOLD complexity in precuneus and posterior cingulate regions was associated with increased functional connectivity to the superior and inferior frontal gyrus in the older group. These results support the compensatory recruitment hypothesis in older APOE ɛ4 carriers, and confer the impact of the APOE genotype on the temporal dynamics of brain activity in older adults.

Dynamic and static contributions of the cerebrovasculature to the resting-state BOLD signal

Functional magnetic resonance imaging (fMRI) in the resting state, particularly fMRI based on the blood-oxygenation level-dependent (BOLD) signal, has been extensively used to measure functional connectivity in the brain. However, the mechanisms of vascular regulation that underlie the BOLD fluctuations during rest are still poorly understood. In this work, using dual-echo pseudo-continuous arterial spin labeling and MR angiography (MRA), we assess the spatio-temporal contribution of cerebral blood flow (CBF) to the resting-state BOLD signals and explore how the coupling of these signals is associated with regional vasculature. Using a general linear model analysis, we found that statistically significant coupling between resting-state BOLD and CBF fluctuations is highly variable across the brain, but the coupling is strongest within the major nodes of established resting-state networks, including the default-mode, visual, and task-positive networks. Moreover, by exploiting MRA-derived large vessel (macrovascular) volume fraction, we found that the degree of BOLD–CBF coupling significantly decreased as the ratio of large vessels to tissue volume increased. These findings suggest that the portion of resting-state BOLD fluctuations at the sites of medium-to-small vessels (more proximal to local neuronal activity) is more closely regulated by dynamic regulations in CBF, and that this CBF regulation decreases closer to large veins, which are more distal to neuronal activity.

Neurovascular factors in resting-state functional MRI

There has been growing interest in the use of resting-state functional magnetic resonance imaging (rsfMRI) for the assessment of disease and treatment, and a number of studies have reported significant disease-related changes in resting-state blood oxygenation level dependent (BOLD) signal amplitude and functional connectivity. rsfMRI is particularly suitable for clinical applications because the approach does not require the patient to perform a task and scans can be obtained in a relatively short amount of time. However, the mechanisms underlying resting-state BOLD activity are not well understood and thus the interpretation of changes in resting state activity is not always straightforward. The BOLD signal represents the hemodynamic response to neural activity, and changes in resting-state activity can reflect a complex combination of neural, vascular, and metabolic factors. This paper examines the role of neurovascular factors in rsfMRI and reviews approaches for the interpretation and analysis of resting state measures in the presence of confounding factors.

Infraslow LFP correlates to resting-state fMRI BOLD signals

The slow fluctuations of the blood-oxygenation-level dependent (BOLD) signal in resting-state fMRI are widely utilized as a surrogate marker of ongoing neural activity. Spontaneous neural activity includes a broad range of frequencies, from infraslow (<0.5 Hz) fluctuations to fast action potentials. Recent studies have demonstrated a correlative relationship between the BOLD fluctuations and power modulations of the local field potential (LFP), particularly in the gamma band. However, the relationship between the BOLD signal and the infraslow components of the LFP, which are directly comparable in frequency to the BOLD fluctuations, has not been directly investigated. Here we report a first examination of the temporal relation between the resting-state BOLD signal and infraslow LFPs using simultaneous fMRI and full-band LFP recording in rat. The spontaneous BOLD signal at the recording sites exhibited significant localized correlation with the infraslow LFP signals as well as with the slow power modulations of higher-frequency LFPs (1-100 Hz) at a delay comparable to the hemodynamic response time under anesthesia. Infraslow electrical activity has been postulated to play a role in attentional processes, and the findings reported here suggest that infraslow LFP coordination may share a mechanism with the large-scale BOLD-based networks previously implicated in task performance, providing new insight into the mechanisms contributing to the resting state fMRI signal.

Caffeine-Induced Global Reductions in Resting-State BOLD Connectivity Reflect Widespread Decreases in MEG Connectivity

In resting-state functional magnetic resonance imaging (fMRI), the temporal correlation between spontaneous fluctuations of the blood oxygenation level dependent (BOLD) signal from different brain regions is used to assess functional connectivity. However, because the BOLD signal is an indirect measure of neuronal activity, its complex hemodynamic nature can complicate the interpretation of differences in connectivity that are observed across conditions or subjects. For example, prior studies have shown that caffeine leads to widespread reductions in BOLD connectivity but were not able to determine if neural or vascular factors were primarily responsible for the observed decrease. In this study, we used source-localized magnetoencephalography (MEG) in conjunction with fMRI to further examine the origins of the caffeine-induced changes in BOLD connectivity. We observed widespread and significant (p < 0.01) reductions in both MEG and fMRI connectivity measures, suggesting that decreases in the connectivity of resting-state neuro-electric power fluctuations were primarily responsible for the observed BOLD connectivity changes. The MEG connectivity decreases were most pronounced in the beta band. By demonstrating the similarity in MEG and fMRI based connectivity changes, these results provide evidence for the neural basis of resting-state fMRI networks and further support the potential of MEG as a tool to characterize resting-state connectivity.

The effects of respiratory CO2 fluctuations in the resting-state BOLD signal differ between eyes open and eyes closed

Resting fluctuations in arterial CO2 (a cerebral vasodilator) are believed to be an important source of low-frequency blood oxygenation level dependent (BOLD) signal fluctuations. In this study we focus on the two commonly used resting-states in functional magnetic resonance imaging experiments, eyes open and eyes closed, and quantify the degree to which measured spontaneous fluctuations in the partial pressure of end-tidal CO2 (Petco2) relate to BOLD signal time series. A significantly longer latency of BOLD signal changes following Petco2 fluctuations was found in the eyes closed condition compared to with eyes open, which may reveal different intrinsic vascular response delays in CO2 reactivity or an alteration in the net BOLD signal arising from Petco2 fluctuations and altered neural activity with eyes closed. By allowing a spatially varying time delay for the compensation of this temporal difference, a more spatially consistent CO2 correlation map can be obtained. Finally, Granger-causality analysis demonstrated a “causal” relationship between Petco2 and BOLD. The identified dominant Petco2→BOLD directional coupling supports the notion that Petco2 fluctuations are indeed a cause of resting BOLD variance in the majority of subjects.

Resting state BOLD signal periodicity in low-back pain patient's hippocampus

We report here the case of a low-back pain individual who shows rhythmic fluctuations in hippocampal neural activity. Resting state functional magnetic resonance imaging (fMRI) studies record signal over time without extrinsic stimuli and may be used to assess functional connectivity between regions. Functional connectivity can be evaluated by measuring the correlations in spontaneous fluctuations of blood oxygen level dependent (BOLD) signals from different regions across the brain, providing a systems level evaluation of the integration of individual regions within an intrinsic neural network. This case was detected in a study examining opioid treatment effects on the human brain. During our analysis, we discovered that one participant possessed hippocampal BOLD signal fluctuations with exact periodicity, 0.023Hz, pre-treatment and post-treatment. The resting state BOLD signal pattern is strikingly similar to on/off task design BOLD signal time courses, here mimicking 22s on and 22s off. This frequency fluctuation in the BOLD signal persisted beyond the resting state scan and could be seen in both heat-pain and cold-pain task scans, where the tasks paradigms (20s on and 30s off, and 20s on and 32s off, respectively) were not synced with the BOLD signal fluctuations. Additionally, the BOLD signal fluctuations did not correlate with head motion, heart rate, or respiratory rate. Due to the oddity in the BOLD signal observed in the participant's hippocampus, we asked the participant to return for a third scan, over a year after the first scan. We repeated the same resting state functional scan protocol. The 0.023-Hz BOLD signal periodicity within the hippocampus was still observable. This is the first report we know of where someone exhibits such periodicity in the BOLD signal fluctuations in the resting state. We report here the case of a low-back pain individual who shows rhythmic fluctuations in hippocampal neural activity. Resting state functional magnetic resonance imaging (fMRI) studies record signal over time without extrinsic stimuli and may be used to assess functional connectivity between regions. Functional connectivity can be evaluated by measuring the correlations in spontaneous fluctuations of blood oxygen level dependent (BOLD) signals from different regions across the brain, providing a systems level evaluation of the integration of individual regions within an intrinsic neural network. This case was detected in a study examining opioid treatment effects on the human brain. During our analysis, we discovered that one participant possessed hippocampal BOLD signal fluctuations with exact periodicity, 0.023Hz, pre-treatment and post-treatment. The resting state BOLD signal pattern is strikingly similar to on/off task design BOLD signal time courses, here mimicking 22s on and 22s off. This frequency fluctuation in the BOLD signal persisted beyond the resting state scan and could be seen in both heat-pain and cold-pain task scans, where the tasks paradigms (20s on and 30s off, and 20s on and 32s off, respectively) were not synced with the BOLD signal fluctuations. Additionally, the BOLD signal fluctuations did not correlate with head motion, heart rate, or respiratory rate. Due to the oddity in the BOLD signal observed in the participant's hippocampus, we asked the participant to return for a third scan, over a year after the first scan. We repeated the same resting state functional scan protocol. The 0.023-Hz BOLD signal periodicity within the hippocampus was still observable. This is the first report we know of where someone exhibits such periodicity in the BOLD signal fluctuations in the resting state.

Caffeine increases the temporal variability of resting-state BOLD connectivity in the motor cortex

Correlations between spontaneous fluctuations in the blood oxygenation level dependent (BOLD) signal measured with functional MRI are finding increasing use as measures of functional connectivity in the brain, where differences can potentially predict cognitive performance and diagnose disease. Caffeine, which is a widely consumed neural stimulant and vasoactive agent, has been found to decrease the amplitude and correlation of resting-state BOLD fluctuations, and hence is an important factor to consider in functional connectivity studies. However, because the BOLD signal is sensitive to neural and vascular factors, the physiological mechanisms by which caffeine alters spontaneous BOLD fluctuations remain unclear. Resting-state functional connectivity has traditionally been assessed using stationary measures, such as the correlation coefficient between BOLD signals measured across the length of a scan. However, recent work has shown that the correlation of resting-state networks can vary considerably over time, with periods as short as 10 s. In this study, we used a sliding window correlation analysis to assess temporal variations in resting-state functional connectivity of the motor cortex before and after caffeine ingestion. We found that the temporal variability of BOLD correlation was significantly higher following a caffeine dose, with transient periods of strong correlation alternating with periods of low or negative correlation. This phenomenon was primarily due to increased variability in the phase difference between BOLD time courses in the left and right motor cortices. These results indicate that caffeine may cause underlying spontaneous neural fluctuations to go in and out of coherence more frequently, and emphasizes the need to consider non-stationary measures when studying changes in functional connectivity.

Anatomical and Functional Assemblies of Brain BOLD Oscillations

Brain oscillatory activity has long been thought to have spatial properties, the details of which are unresolved. Here we examine spatial organizational rules for the human brain oscillatory activity as measured by blood oxygen level-dependent (BOLD) signal. Resting-state BOLD signal was transformed into frequency space (Welch's method) and averaged across subjects, and its spatial distribution was studied as a function of four frequency bands, spanning the full BOLD bandwidth. The brain showed anatomically constrained distribution of power for each frequency band. This result was replicated on a repository dataset of 195 subjects. Next, we examined larger-scale organization by parceling the neocortex into regions approximating Brodmann areas (BAs). This indicated that BAs of simple function/connectivity (unimodal), versus complex properties (transmodal), are dominated by low-frequency BOLD oscillations, and within the visual ventral stream we observe a graded shift of power to higher-frequency bands for BAs further removed from the primary visual cortex (increased complexity), linking BOLD frequency properties to hodology. Additionally, BOLD oscillation properties for the default mode network demonstrated that it is composed of distinct frequency-dependent regions. When the same analysis was performed on a visual-motor task, frequency-dependent global and voxelwise shifts in BOLD oscillations could be detected at brain sites mostly outside those identified with general linear modeling. Thus, analysis of BOLD oscillations in full bandwidth uncovers novel brain organizational rules, linking anatomical structures and functional networks to characteristic BOLD oscillations. The approach also identifies changes in brain intrinsic properties in relation to responses to external inputs.

Caffeine reduces resting-state BOLD functional connectivity in the motor cortex

In resting-state functional magnetic resonance imaging (fMRI), correlations between spontaneous low-frequency fluctuations in the blood oxygenation level dependent (BOLD) signal are used to assess functional connectivity between different brain regions. Changes in resting-state BOLD connectivity measures are typically interpreted as changes in coherent neural activity across spatially distinct brain regions. However, this interpretation can be complicated by the complex dependence of the BOLD signal on both neural and vascular factors. For example, prior studies have shown that vasoactive agents that alter baseline cerebral blood flow, such as caffeine and carbon dioxide, can significantly alter the amplitude and dynamics of the task-related BOLD response. In this study, we examined the effect of caffeine (200 mg dose) on resting-state BOLD connectivity in the motor cortex across a sample of healthy young subjects ( N = 9). We found that caffeine significantly ( p < 0.05) reduced measures of resting-state BOLD connectivity in the motor cortex. Baseline cerebral blood flow and spectral energy in the low-frequency BOLD fluctuations were also significantly decreased by caffeine. These results suggest that caffeine usage should be carefully considered in the design and interpretation of resting-state BOLD fMRI studies.

Resting-state functional connectivity in animal models: modulations by exsanguination.

We studied the spatiotemporal characteristics of the resting state low frequency fluctuations in functional MRI (fMRI), blood oxygenation level dependent (BOLD) signal in isoflurane-anesthetized rats. fMRI-BOLD measurements at 9.4 Telsa were made during normal and exsanguinated condition previously known to alter cerebral blood flow (CBF) fluctuations in anesthetized rats. fMRI signal time series were low-pass filtered and studied by spectral analysis. During normal conditions, baseline mean arterial pressure (MAP) was 110 +/- 10 mm Hg and low-frequency fluctuations in BOLD signal were observed in the frequency range of 0.01 - 0.125 Hz. Following blood withdrawal (exsanguination), MAP decreased to 68 +/- 7 mm Hg, resulting in an increase in the amplitude of the low-frequency fluctuations in BOLD signal time series and an increase in power at several frequencies between 0.01 and 0.125 Hz. Spatially, the BOLD fluctuations were confined to the cortex and thalamus spanning both hemispheres with sparse presence in the caudate putamen and hippocampus during both normal and exsanguinated states. Spatial distribution of the low frequency fluctuations in BOLD signal, from cross correlation analysis, indicates substantial inter-hemispheric synchrony similar to that observed in the conscious human brain. The behavior of the resting state BOLD signal fluctuations similar to CBF fluctuations during exsanguination indicates a myogenic dependence. Also, a high inter-hemispheric synchrony combined with different phase characteristics of the low frequency BOLD fluctuations particularly in the hippocampus relative to the cortex emphasizes distinct functional networks.