Blood Oxygenation Level-dependent Oscillations Research Articles

Detectability and cortical depth dependence of stimulus-driven high-frequency BOLD oscillations in the human primary somatosensory and motor cortex

Abstract In functional magnetic resonance imaging (fMRI), neural activity is inferred from the associated hemodynamic response. However, the degree to which hemodynamics can track dynamic changes in neuronal activity, and thus the ultimate temporal resolution of fMRI, remains unknown. To evaluate the detectability of stimulus-driven high-frequency blood oxygenation level dependent (BOLD) signal oscillations in functionally and vascularly distinct cerebral cortical areas, stimuli up to 0.5 Hz were used to evoke activation in the primary somatosensory and motor cortex. Despite their functional and vascular differences, a similar frequency dependence was observed in both cortical areas. We then proceeded to investigate these signals at different levels of the cortical vascular hierarchy, using cortical depth as a proxy. We observed that, above 0.33 Hz, the BOLD response amplitude decreased faster with increasing frequency near the pial surface than in the parenchyma, suggesting that, in addition to exhibiting high spatial specificity, parenchymal signals—accessible with high spatial resolution imaging—also attenuate less rapidly when the stimulus frequency is increased. In addition, as the stimulus frequency increased, we observed larger relative phase differences in the BOLD oscillations across cortical depths. When averaged across depths, these signals can thus interfere destructively, suggesting that high spatial resolutions can avoid this phase cancellation and thereby aid in the detection of rapid BOLD oscillations.

Analysis of Respiratory Sinus Arrhythmia and Directed Information Flow between Brain and Body Indicate Different Management Strategies of fMRI-Related Anxiety

Respiratory sinus arrhythmia (RSA) denotes decrease of cardiac beat-to-beat intervals (RRI) during inspiration and RRI increase during expiration, but an inverse pattern (termed negative RSA) was also found in healthy humans with elevated anxiety. It was detected using wave-by-wave analysis of cardiorespiratory rhythms and was considered to reflect a strategy of anxiety management involving the activation of a neural pacemaker. Results were consistent with slow breathing, but contained uncertainty at normal breathing rates (0.2-0.4 Hz). We combined wave-by-wave analysis and directed information flow analysis to obtain information on anxiety management at higher breathing rates. We analyzed cardiorespiratory rhythms and blood oxygen level-dependent (BOLD) signals from the brainstem and cortex in 10 healthy fMRI participants with elevated anxiety. Three subjects with slow respiratory, RRI, and neural BOLD oscillations showed 57 ± 26% negative RSA and significant anxiety reduction by 54 ± 9%. Six participants with breathing rate of ~0.3 Hz showed 41 ± 16% negative RSA and weaker anxiety reduction. They presented significant information flow from RRI to respiration and from the middle frontal cortex to the brainstem, which may result from respiration-entrained brain oscillations, indicating another anxiety management strategy. The two analytical approaches applied here indicate at least two different anxiety management strategies in healthy subjects.

FMRI spectral signatures of sleep

Sleep can be distinguished from wake by changes in brain electrical activity, typically assessed using electroencephalography (EEG). The hallmark of nonrapid-eye-movement (NREM) sleep is the shift from high-frequency, low-amplitude wake EEG to low-frequency, high-amplitude sleep EEG dominated by spindles and slow waves. Here we identified signatures of sleep in brain hemodynamic activity, using simultaneous functional MRI (fMRI) and EEG. We found that, at the transition from wake to sleep, fMRI blood oxygen level-dependent (BOLD) activity evolved from a mixed-frequency pattern to one dominated by two distinct oscillations: a low-frequency (<0.1 Hz) oscillation prominent in light sleep and correlated with the occurrence of spindles, and a high-frequency oscillation (>0.1 Hz) prominent in deep sleep and correlated with the occurrence of slow waves. The two oscillations were both detectable across the brain but exhibited distinct spatiotemporal patterns. During the falling-asleep process, the low-frequency oscillation first appeared in the thalamus, then the posterior cortex, and lastly the frontal cortex, while the high-frequency oscillation first appeared in the midbrain, then the frontal cortex, and lastly the posterior cortex. During the waking-up process, both oscillations disappeared first from the thalamus, then the frontal cortex, and lastly the posterior cortex. The BOLD oscillations provide local signatures of spindle and slow wave activity. They may be employed to monitor the regional occurrence of sleep or wakefulness, track which regions are the first to fall asleep or wake up at the wake-sleep transitions, and investigate local homeostatic sleep processes.

Frequency-Specific Blood Oxygen Level Dependent Oscillations Associated With Pain Relief From Ankle Acupuncture in Patients With Chronic Low Back Pain.

Objective: Recent advances in brain imaging have deepened our knowledge of the neural activity in distinct brain areas associated with acupuncture analgesia. However, there has not been conclusive research into the frequency-specific resting-state functional changes associated with acupuncture analgesia in patients with chronic pain. Here, we aimed to characterize changes across multiple frequencies of resting-state cortical activity associated with ankle acupuncture stimulation (AAS) in patients with chronic low back pain (CLBP) and healthy controls.Methods: Twenty seven patients with CLBP and Twenty five age- and gender-matched healthy volunteers were enrolled in the study. Participants received tactile sham acupuncture (TSA) and AAS, respectively. The whole-brain amplitude of low-frequency fluctuation (ALFF) in the range 0.01–0.25 Hz was assessed for changes associated with each intervention. Further, a visual analog scale (VAS) was used to collect subjective measures of pain intensity in patients. Linear mixed-effect modeling (LME) was used to examine the mean ALFF values of AAS and TSA between patients and healthy controls.Results: The ALFF was modulated in the default mode network (an increase in the medial prefrontal cortex, and a decrease in the cerebellum/posterior ingulate/parahippocampus, P < 0.01, corrected) in both patients and controls. Decreased ALFF in the bilateral insular was frequency-dependent. Modulations in the cerebellum and right insular were significantly correlated with VAS pain score after AAS (P < 0.01).Conclusion: Hence, frequency-specific resting-state activity in the cerebellum and insular was correlated to AAS analgesia. Our frequency-specific analysis of ALFF may provide novel insights related to pain relief from acupuncture.

Verification of a Central Pacemaker in Brain Stem by Phase-Coupling Analysis Between HR Interval- and BOLD-Oscillations in the 0.10-0.15 Hz Frequency Band.

The origin of slow intrinsic oscillations in resting states of functional magnetic resonance imaging (fMRI) signals is still a matter of debate. The present study aims to test the hypothesis that slow blood oxygenation level-dependent (BOLD) oscillations with frequency components greater than 0.10 Hz result from a central neural pacemaker located in the brain stem. We predict that a central oscillator modulates cardiac beat-to-beat interval (RRI) fluctuations rapidly, with only a short neural lag around 0.3 s. Spontaneous BOLD fluctuations in the brain stem, however, are considerably delayed due to the hemodynamic response time of about ∼2–3 s. In order to test these predictions, we analyzed the time delay between slow RRI oscillations from thorax and BOLD oscillations in the brain stem by calculating the phase locking value (PLV). Our findings show a significant time delay of 2.2 ± 0.2 s between RRI and BOLD signals in 12 out of 23 (50%) participants in axial slices of the pons/brain stem. Adding the neural lag of 0.3 s to the observed lag of 2.2 s we obtain 2.5 s, which is the time between neural activity increase and BOLD increase, termed neuro-BOLD coupling. Note, this time window for neuro-BOLD coupling in awake humans is surprisingly of similar size as in awake head-fixed adult mice (Mateo et al., 2017).

An Experimental Investigation of White Matter Venous Hemodynamics: Basic Physiology and Disruption in Neuroinflammatory Disease.

The white matter is highly vascularised by the cerebral venous system. In this paper, we describe a unique blood oxygen-level dependent (BOLD) signal within the white matter using functional MRI and spatial independent components analysis. The signal is characterized by a narrow peak frequency band between 0.05 and 0.1 Hz. Hypercapnia, induced transient increases in white matter venous BOLD that disrupted the oscillation indicative of a vasocontractile mechanism. Comparison of the white matter venous BOLD oscillations between 14 healthy subjects and 18 people with perivenular inflammation due to multiple sclerosis (MS), revealed loss of power in the white matter venous BOLD signal in the peak frequency band (patients = 6.70 ± 0.94 dB/Hz vs. controls = 7.64 ± 0.71 dB/Hz; p = 0.006). In MS, lower power was associated with greater levels of neuroinflammatory activity (R = −0.64, p = 0.006). Using a signal modeling technique, we assessed the anatomical distribution of white matter venous BOLD signal abnormalities and detected reduced power in the periventricular white matter, a region of known venous damage in MS. These results demonstrate a novel link between neuroinflammation and vascular physiological dysfunction in the cerebral white matter, and could indicate enduring loss of vascular compliance associated with imperfect repair of blood-brain barrier damage after resolution of acute neuroinflammation.

Neural oscillations in human auditory cortex revealed by fast fMRI during auditory perception

Previous work pointed to the neural and functional significance of infraslow neural oscillations below 1 ​Hz that can be detected and precisely located with fast functional magnetic resonance imaging (fMRI). While previous work demonstrated this significance for brain dynamics during very low-level sensory stimulation, we here provide the first evidence for the detectability and functional significance of infraslow oscillatory blood oxygenation level-dependent (BOLD) responses to auditory stimulation by the sociobiological relevant and more complex category of voices. Previous work pointed to a specific area of the mammalian auditory cortex (AC) that is sensitive to vocal signals as quantified by activation levels. Here we show, by using fast fMRI, that the human voice-sensitive AC prioritizes vocal signals not only in terms of activity level but also in terms of specific infraslow BOLD oscillations. We found unique sustained and transient oscillatory BOLD patterns in the AC for vocal signals. For transient oscillatory patterns, vocal signals showed faster peak oscillatory responses across all AC regions. Furthermore, we identified an exclusive sustained oscillatory component for vocal signals in the primary AC. Fast fMRI thus demonstrates the significance and richness of infraslow BOLD oscillations for neurocognitive mechanisms in social cognition as demonstrated here for the sociobiological relevance of voice processing.

Scale-invariant rearrangement of resting state networks in the human brain under sustained stimulation

Brain activity at rest is characterized by widely distributed and spatially specific patterns of synchronized low-frequency blood-oxygenation level-dependent (BOLD) fluctuations, which correspond to physiologically relevant brain networks. This network behaviour is known to persist also during task execution, yet the details underlying task-associated modulations of within- and between-network connectivity are largely unknown. In this study we exploited a multi-parametric and multi-scale approach to investigate how low-frequency fluctuations adapt to a sustained n-back working memory task. We found that the transition from the resting state to the task state involves a behaviourally relevant and scale-invariant modulation of synchronization patterns within both task-positive and default mode networks. Specifically, decreases of connectivity within networks are accompanied by increases of connectivity between networks. In spite of large and widespread changes of connectivity strength, the overall topology of brain networks is remarkably preserved. We show that these findings are strongly influenced by connectivity at rest, suggesting that the absolute change of connectivity (i.e., disregarding the baseline) may not be the most suitable metric to study dynamic modulations of functional connectivity. Our results indicate that a task can evoke scale-invariant, distributed changes of BOLD fluctuations, further confirming that low frequency BOLD oscillations show a specialized response and are tightly bound to task-evoked activation.

Synchronization of intrinsic 0.1-Hz blood-oxygen-level-dependent oscillations in amygdala and prefrontal cortex in subjects with increased state anxiety.

Low‐frequency oscillations with a dominant frequency at 0.1 Hz are one of the most influential intrinsic blood‐oxygen‐level‐dependent (BOLD) signals. This raises the question if vascular BOLD oscillations (originating from blood flow in the brain) and intrinsic slow neural activity fluctuations (neural BOLD oscillations) can be differentiated. In this study, we report on two different approaches: first, on computing the phase‐locking value in the frequency band 0.07–0.13 Hz between heart beat‐to‐beat interval (RRI) and BOLD oscillations and second, between multiple BOLD oscillations (functional connectivity) in four resting states in 23 scanner‐naïve, anxious healthy subjects. The first method revealed that vascular 0.1‐Hz BOLD oscillations preceded those in RRI signals by 1.7 ± 0.6 s and neural BOLD oscillations lagged RRI oscillations by 0.8 ± 0.5 s. Together, vascular BOLD oscillations preceded neural BOLD oscillations by ~90° or ~2.5 s. To verify this discrimination, connectivity patterns of neural and vascular 0.1‐Hz BOLD oscillations were compared in 26 regions involved in processing of emotions. Neural BOLD oscillations revealed significant phase‐coupling between amygdala and medial frontal cortex, while vascular BOLD oscillations showed highly significant phase‐coupling between amygdala and multiple regions in the supply areas of the anterior and medial cerebral arteries. This suggests that not only slow neural and vascular BOLD oscillations can be dissociated but also that two strategies may exist to optimize regulation of anxiety, that is increased functional connectivity between amygdala and medial frontal cortex, and increased cerebral blood flow in amygdala and related structures.

Age-associated patterns in gray matter volume, cerebral perfusion and BOLD oscillations in children and adolescents.

Healthy brain development involves changes in brain structure and function that are believed to support cognitive maturation. However, understanding how structural changes such as grey matter thinning relate to functional changes is challenging. To gain insight into structure-function relationships in development, the present study took a data driven approach to define age-related patterns of variation in gray matter volume (GMV), cerebral blood flow (CBF) and blood-oxygen level dependent (BOLD) signal variation (fractional amplitude of low-frequency fluctuations; fALFF) in 59 healthy children aged 7-18 years, and examined relationships between modalities. Principal components analysis (PCA) was applied to each modality in parallel, and participant scores for the top components were assessed for age associations. We found that decompositions of CBF, GMV and fALFF all included components for which scores were significantly associated with age. The dominant patterns in GMV and CBF showed significant (GMV) or trend level (CBF) associations with age and a strong spatial overlap, driven by increased signal intensity in default mode network (DMN) regions. GMV, CBF and fALFF additionally showed components accounting for 3-5% of variability with significant age associations. However, these patterns were relatively spatially independent, with small-to-moderate overlap between modalities. Independence of age effects was further demonstrated by correlating individual subject maps between modalities: CBF was significantly less correlated with GMV and fALFF in older children relative to younger. These spatially independent effects of age suggest that the parallel decline observed in global GMV and CBF may not reflect spatially synchronized processes. Hum Brain Mapp 38:2398-2407, 2017. © 2017 Wiley Periodicals, Inc.

Distinction between Neural and Vascular BOLD Oscillations and Intertwined Heart Rate Oscillations at 0.1 Hz in the Resting State and during Movement.

In the resting state, blood oxygen level-dependent (BOLD) oscillations with a frequency of about 0.1 Hz are conspicuous. Whether their origin is neural or vascular is not yet fully understood. Furthermore, it is not clear whether these BOLD oscillations interact with slow oscillations in heart rate (HR). To address these two questions, we estimated phase-locking (PL) values between precentral gyrus (PCG) and insula in 25 scanner-naïve individuals during rest and stimulus-paced finger movements in both hemispheres. PL was quantified in terms of time delay and duration in the frequency band 0.07 to 0.13 Hz. Results revealed both positive and negative time delays. Positive time delays characterize neural BOLD oscillations leading in the PCG, whereas negative time delays represent vascular BOLD oscillations leading in the insula. About 50% of the participants revealed positive time delays distinctive for neural BOLD oscillations, either with short or long unilateral or bilateral phase-locking episodes. An expected preponderance of neural BOLD oscillations was found in the left hemisphere during right-handed movement and unexpectedly in the right hemisphere during rest. Only neural BOLD oscillations were significantly associated with heart rate variability (HRV) in the 0.1-Hz range in the first resting state. It is well known that participating in magnetic resonance imaging (MRI) studies may be frightening and cause anxiety. In this respect it is important to note that the most significant hemispheric asymmetry (p<0.002) with a right-sided dominance of neural BOLD and a left-sided dominance of vascular BOLD oscillations was found in the first resting session in the scanner-naïve individuals. Whether the enhanced left-sided perfusion (dominance of vascular BOLD) or the right-sided dominance of neural BOLD is related to the increased level of anxiety, attention or stress needs further research.

Central sensitization-related changes of effective and functional connectivity in the rat inflammatory trigeminal pain model

Central sensitization is a key mechanism in the pathology of several neuropathic pain disorders. We aimed to investigate the underlying brain connectivity changes in a rat model of chronic pain.Non-noxious whisker stimulation was used to evoke blood-oxygen-level-dependent (BOLD) responses in a block-design functional Magnetic Resonance Imaging (fMRI) experiment on 9.4T. Measurements were repeated two days and one week after injecting complete Freund’s adjuvant into the rats’ whisker pad.We found that acute pain reduced activation in the barrel cortex, most probably due to a plateau effect. After one week, increased activation of the anterior cingulate cortex was found. Analyses of effective connectivity driven by stimulus-related activation revealed that chronic pain-related central sensitization manifested as a widespread alteration in the activity of the somatosensory network. Changes were mainly mediated by the anterior cingulate cortex and the striatum and affected the somatosensory and motor cortices and the superior colliculus. Functional connectivity analysis of nested BOLD oscillations justified that the anterior cingular–somatosensory interplay is a key element of network changes. Additionally, a decreased cingulo-motor functional connectivity implies that alterations also involve the output tract of the network.Our results extend the knowledge about the role of the cingulate cortex in the chronification of pain and indicate that integration of multiple connectivity analysis could be fruitful in studying the central sensitization in the pain matrix.

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.

Modeling the contribution of neuron-astrocyte cross talk to slow blood oxygenation level-dependent signal oscillations

A consistent and prominent feature of brain functional magnetic resonance imaging (fMRI) data is the presence of low-frequency (<0.1 Hz) fluctuations of the blood oxygenation level-dependent (BOLD) signal that are thought to reflect spontaneous neuronal activity. In this report we provide modeling evidence that cyclic physiological activation of astroglial cells produces similar BOLD oscillations through a mechanism mediated by intracellular Ca(2+) signaling. Specifically, neurotransmission induces pulses of Ca(2+) concentration in astrocytes, resulting in increased cerebral perfusion and neuroactive transmitter release by these cells (i.e., gliotransmission), which in turn stimulates neuronal activity. Noticeably, the level of neuron-astrocyte cross talk regulates the periodic behavior of the Ca(2+) wave-induced BOLD fluctuations. Our results suggest that the spontaneous ongoing activity of neuroglial networks is a potential source of the observed slow fMRI signal oscillations.

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.

Resting States Affect Spontaneous BOLD Oscillations in Sensory and Paralimbic Cortex

The brain exhibits spontaneous neural activity that depends on the behavioral state of the organism. We asked whether the blood oxygenation level-dependent (BOLD) signal reflects these modulations. BOLD was measured under three steady-state conditions: while subjects kept their eyes closed, kept their eyes open, or while fixating. The BOLD spectral density was calculated across brain voxels and subjects. Visual, sensory-motor, auditory, and retrosplenial cortex showed modulations of the BOLD spectral density by resting state type. All modulated regions showed greater spontaneous BOLD oscillations in the eyes closed than the eyes open or fixation conditions, suggesting that the differences were endogenously driven. Next, we examined the pattern of correlations between regions whose ongoing BOLD signal was modulated by resting state type. Regional neuronal correlations were estimated using an analytic procedure from the comparison of BOLD-BOLD covariances in the fixation and eyes closed conditions. Most regions were highly correlated with one another, with the exception of the primary visual cortices, which showed low correlations with the other regions. In conclusion, changes in resting state were associated with synchronous modulations of spontaneous BOLD oscillations in cortical sensory areas driven by two spatially overlapping, but temporally uncorrelated signals.