Blood Oxygen Level-dependent Hemodynamic Response 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.

Characterization of the blood oxygen level dependent hemodynamic response function in human subcortical regions with high spatiotemporal resolution.

Subcortical brain regions are absolutely essential for normal human function. These phylogenetically early brain regions play critical roles in human behaviors such as the orientation of attention, arousal, and the modulation of sensory signals to cerebral cortex. Despite the critical health importance of subcortical brain regions, there has been a dearth of research on their neurovascular responses. Blood oxygen level dependent (BOLD) functional MRI (fMRI) experiments can help fill this gap in our understanding. The BOLD hemodynamic response function (HRF) evoked by brief (<4 s) neural activation is crucial for the interpretation of fMRI results because linear analysis between neural activity and the BOLD response relies on the HRF. Moreover, the HRF is a consequence of underlying local blood flow and oxygen metabolism, so characterization of the HRF enables understanding of neurovascular and neurometabolic coupling. We measured the subcortical HRF at 9.4T and 3T with high spatiotemporal resolution using protocols that enabled reliable delineation of HRFs in individual subjects. These results were compared with the HRF in visual cortex. The HRF was faster in subcortical regions than cortical regions at both field strengths. There was no significant undershoot in subcortical areas while there was a significant post-stimulus undershoot that was tightly coupled with its peak amplitude in cortex. The different BOLD temporal dynamics indicate different vascular dynamics and neurometabolic responses between cortex and subcortical nuclei.

Normalization of mediotemporal and prefrontal activity, and mediotemporal-striatal connectivity, may underlie antipsychotic effects of cannabidiol in psychosis.

Recent evidence suggests that cannabidiol (CBD), a non-intoxicating ingredient present in cannabis extract, has an antipsychotic effect in people with established psychosis. However, the effect of CBD on the neurocognitive mechanisms underlying psychosis is unknown. Patients with established psychosis on standard antipsychotic treatment were studied on separate days at least one week apart, to investigate the effects of a single dose of orally administered CBD (600 mg) compared to a matched placebo (PLB), using a double-blind, randomized, PLB-controlled, repeated-measures, within-subject cross-over design. Three hours after taking the study drug participants were scanned using a block design functional magnetic resonance imaging (fMRI) paradigm, while performing a verbal paired associate learning task. Fifteen psychosis patients completed both study days, 13 completed both scanning sessions. Nineteen healthy controls (HC) were also scanned using the same fMRI paradigm under identical conditions, but without any drug administration. Effects of CBD on brain activation measured using the blood oxygen level-dependent hemodynamic response fMRI signal were studied in the mediotemporal, prefrontal, and striatal regions of interest. Compared to HC, psychosis patients under PLB had altered prefrontal activation during verbal encoding, as well as altered mediotemporal and prefrontal activation and greater mediotemporal-striatal functional connectivity during verbal recall. CBD attenuated dysfunction in these regions such that activation under its influence was intermediate between the PLB condition and HC. CBD also attenuated hippocampal-striatal functional connectivity and caused trend-level symptom reduction in psychosis patients. This suggests that normalization of mediotemporal and prefrontal dysfunction and mediotemporal-striatal functional connectivity may underlie the antipsychotic effects of CBD.

Dynamics of the cerebral blood flow response to brief neural activity in human visual cortex

The blood oxygen-level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal depends on an interplay of cerebral blood flow (CBF), oxygen metabolism, and cerebral blood volume. Despite wide usage of BOLD fMRI, it is not clear how these physiological components create the BOLD signal. Here, baseline CBF and its dynamics evoked by a brief stimulus (2 s) in human visual cortex were measured at 3T. We found a stereotypical CBF response: immediate increase, rising to a peak a few second after the stimulus, followed by a significant undershoot. The BOLD hemodynamic response function (HRF) was also measured in the same session. Strong correlations between HRF and CBF peak responses indicate that the flow responses evoked by neural activation in nearby gray matter drive the early HRF. Remarkably, peak CBF and HRF were also strongly modulated by baseline perfusion. The CBF undershoot was reliable and significantly correlated with the HRF undershoot. However, late-time dynamics of the HRF and CBF suggest that oxygen metabolism can also contribute to the HRF undershoot. Combined measurement of the CBF and HRF for brief neural activation is a useful tool to understand the temporal dynamics of neurovascular and neurometabolic coupling.

Neural Responsivity to Food Cues in Patients With Unmedicated First-Episode Psychosis

ImportanceSchizophrenia is associated with a reduced life expectancy of 15 to 20 years owing to a high prevalence of cardiometabolic disorders. Obesity, a key risk factor for the development of cardiometabolic alterations, is more prevalent in individuals with schizophrenia. Although obesity is linked to the altered reward processing of food cues, no studies have investigated this link in schizophrenia without the confounds of antipsychotics and illness chronicity.ObjectiveTo investigate neural responsivity to food cues in first-episode psychosis without the confounds of antipsychotic medication or illness chronicity.Design, Setting, and ParticipantsA case-control study was conducted from January 31, 2015, to September 30, 2018, in London, United Kingdom, of 29 patients with first-episode psychosis who were not taking antipsychotic medication and 28 matched controls.Main Outcomes and MeasuresParticipants completed a food cue paradigm while undergoing a functional magnetic resonance imaging scan. Neural activation was indexed using the blood oxygen level–dependent hemodynamic response. The Dietary Instrument for Nutrition Education was used to measure diet, and the International Physical Activity Questionnaire was used to measure exercise.ResultsThere were no significant differences in age, sex, or body mass index between the 29 patients (25 men and 4 women; mean [SD] age, 26.1 [4.8] years) and 28 controls (22 men and 6 women; mean [SD] age, 26.4 [5.5] years). Relative to controls, patients consumed more saturated fat (t46 = –3.046; P = .004) and undertook less high-intensity (U = 304.0; P = .01) and low-intensity (U = 299.5; P = .005) weekly exercise. There were no group differences in neural responses to food vs nonfood cues in whole-brain or region-of-interest analyses of the nucleus accumbens, insula, or hypothalamus. Body mass index was inversely correlated with the mean blood oxygen level–dependent signal in the nucleus accumbens in response to food vs nonfood cues in controls (R = –0.499; P = .01) but not patients (R = 0.082; P = .70).Conclusions and RelevanceRelative to controls, patients with first-episode psychosis who were not taking antipsychotic medication consumed more saturated fat and showed an altered association between body mass index and neural response to food cues in the absence of differences in neural responses to food cues. These findings highlight how maladaptive eating patterns and alterations in the association between body mass index and neural responses to food cues are established early in the course of schizophrenia.

BOLD hemodynamic response function changes significantly with healthy aging

Functional magnetic resonance imaging (fMRI) has been used to infer age-differences in neural activity from the hemodynamic response function (HRF) that characterizes the blood-oxygen-level-dependent (BOLD) signal over time. BOLD literature in healthy aging lacks consensus in age-related HRF changes, the nature of those changes, and their implications for measurement of age differences in brain function. Between-study discrepancies could be due to small sample sizes, analysis techniques, and/or physiologic mechanisms. We hypothesize that, with large sample sizes and minimal analysis assumptions, age-related changes in HRF parameters could reflect alterations in one or more components of the neural-vascular coupling system. To assess HRF changes in healthy aging, we analyzed the large population-derived dataset from the Cambridge Center for Aging and Neuroscience (CamCAN) study (Shafto et al., 2014). During scanning, 74 younger (18–30 years of age) and 173 older participants (54–74 years of age) viewed two checkerboards to the left and right of a central fixation point, simultaneously heard a binaural tone, and responded via right index finger button-press. To assess differences in the shape of the HRF between younger and older groups, HRFs were estimated using FMRIB's Linear Optimal Basis Sets (FLOBS) to minimize a priori shape assumptions. Group mean HRFs were different between younger and older groups in auditory, visual, and motor cortices. Specifically, we observed increased time-to-peak and decreased peak amplitude in older compared to younger adults in auditory, visual, and motor cortices. Changes in the shape and timing of the HRF in healthy aging, in the absence of performance differences, support our hypothesis of age-related changes in the neural-vascular coupling system beyond neural activity alone. More precise interpretations of HRF age-differences can be formulated once these physiologic factors are disentangled and measured separately.

Effect of Cannabidiol on Medial Temporal, Midbrain, and Striatal Dysfunction in People at Clinical High Risk of Psychosis

Cannabidiol (CBD) has antipsychotic effects in humans, but how these are mediated in the brain remains unclear. To investigate the neurocognitive mechanisms that underlie the therapeutic effects of CBD in psychosis. In this parallel-group, double-blind, placebo-controlled randomized clinical trial conducted at the South London and Maudsley NHS Foundation Trust in London, United Kingdom, 33 antipsychotic medication-naive participants at clinical high risk (CHR) of psychosis and 19 healthy control participants were studied. Data were collected from July 2013 to October 2016 and analyzed from November 2016 to October 2017. A total of 16 participants at CHR of psychosis received a single oral dose of 600 mg of CBD, and 17 participants at CHR received a placebo. Control participants were not given any drug. All participants were then studied using functional magnetic resonance imaging (fMRI) while performing a verbal learning task. Brain activation during verbal encoding and recall, indexed using the blood oxygen level-dependent hemodynamic response fMRI signal. Of the 16 participants in the CBD group, 6 (38%) were female, and the mean (SD) age was 22.43 (4.95) years; of 17 in the placebo group, 10 (59%) were female, and the mean (SD) age was 25.35 (5.24) years; and of 19 in the control group, 8 (42%) were female, and the mean (SD) age was 23.89 (4.14) years. Brain activation (indexed using the median sum of squares ratio of the blood oxygen level-dependent hemodynamic response effects model component to the residual sum of squares) was analyzed in 15 participants in the CBD group, 16 in the placebo group, and 19 in the control group. Participants receiving placebo had reduced activation relative to controls in the right caudate during encoding (placebo: median, -0.027; interquartile range [IQR], -0.041 to -0.016; control: median, 0.020; IQR, -0.022 to 0.056; P < .001) and in the parahippocampal gyrus and midbrain during recall (placebo: median, 0.002; IQR, -0.016 to 0.010; control: median, 0.035; IQR, 0.015 to 0.039; P < .001). Within these 3 regions, activation in the CBD group was greater than in the placebo group but lower than in the control group (parahippocampal gyrus/midbrain: CBD: median, -0.013; IQR, -0.027 to 0.002; placebo: median, -0.007; IQR, -0.019 to 0.008; control: median, 0.034; IQR, 0.005 to 0.059); the level of activation in the CBD group was thus intermediate to that in the other 2 groups. There were no significant group differences in task performance. Cannabidiol may partially normalize alterations in parahippocampal, striatal, and midbrain function associated with the CHR state. As these regions are critical to the pathophysiology of psychosis, the influence of CBD at these sites could underlie its therapeutic effects on psychotic symptoms. isrctn.org Identifier: ISRCTN46322781.

Reliability of the depth-dependent high-resolution BOLD hemodynamic response in human visual cortex and vicinity

Functional magnetic resonance imaging (fMRI) often relies on a hemodynamic response function (HRF), the stereotypical blood oxygen level dependent (BOLD) response elicited by a brief (<4s) stimulus. Early measurements of the HRF used coarse spatial resolutions (≥3mm voxels) that would generally include contributions from white matter, gray matter, and the extra-pial compartment (the space between the pial surface and skull including pial blood vessels) within each voxel. To resolve these contributions, high-resolution fMRI (0.9-mm voxels) was performed at 3T in early visual cortex and its apposed white-matter and extra-pial compartments. The results characterized the depth dependence of the HRF and its reliability during nine fMRI sessions. Significant HRFs were observed in white-matter and extra-pial compartments as well as in gray matter. White-matter HRFs were faster and weaker than in the gray matter, while extra-pial HRFs were comparatively slower and stronger. Depth trends of the HRF peak amplitude were stable throughout a broad depth range that included all three compartments for each session. Across sessions, however, the depth trend of HRF peak amplitudes was stable only in the white matter and deep-intermediate gray matter, while there were strong session-to-session variations in the superficial gray matter and the extra-pial compartment. Thus, high-resolution fMRI can resolve significant and dynamically distinct HRFs in gray matter, white matter, and extra-pial compartments.

Multiple sclerosis-related white matter microstructural change alters the BOLD hemodynamic response

Multiple sclerosis (MS) results in inflammatory damage to white matter microstructure. Prior research using blood-oxygen-level dependent (BOLD) imaging indicates MS-related alterations to brain function. What is currently unknown is the extent to which white matter microstructural damage influences BOLD signal in MS. Here we assessed changes in parameters of the BOLD hemodynamic response function (HRF) in patients with relapsing-remitting MS compared to healthy controls. We also used diffusion tensor imaging to assess whether MS-related changes to the BOLD-HRF were affected by changes in white matter microstructural integrity. Our results showed MS-related reductions in BOLD-HRF peak amplitude. These MS-related amplitude decreases were influenced by individual differences in white matter microstructural integrity. Other MS-related factors including altered reaction time, limited spatial extent of BOLD activity, elevated lesion burden, or lesion proximity to regions of interest were not mediators of group differences in BOLD-HRF amplitude. Results are discussed in terms of functional hyperemic mechanisms and implications for analysis of BOLD signal differences.

Reproducing the Hemoglobin Saturation Profile, a Marker of the Blood Oxygenation Level Dependent (BOLD) fMRI Effect, at the Microscopic Level.

The advent of functional MRI in the mid-1990s has catalyzed progress pertaining to scientific discoveries in neuroscience. With the prospect of elucidating the physiological aspect of the Blood Oxygenation Level Dependent (BOLD) effect we present a computational capillary-tissue system capable of mapping venous hemoglobin saturation— a marker of the BOLD hemodynamic response. Free and facilitated diffusion and convection for hemoglobin and oxygen are considered in the radial and axial directions. Hemoglobin reaction kinetics are governed by the oxyhemoglobin dissociation curve. Brain activation, mimicked by dynamic transitions in cerebral blood velocity (CBv) and oxidative metabolism (CMRO2), is simulated by normalized changes in m = (ΔCBv/CBv)/(ΔCMRO2/CMRO2) of values 2, 3 and 4. Venous hemoglobin saturation profiles and peak oxygenation results, for m = 2, based upon a 50% and a 25% increase in CBv and CMRO2, respectively, lie within physiological limits exhibiting excellent correlation with the BOLD signal, for short-duration stimuli. Our analysis suggests basal CBv and CMRO2 values of 0.6 mm/s and 200 μmol/100g/min. Coupled CBv and CMRO2 responses, for m = 3 and m = 4, overestimate peak hemoglobin saturation, confirming the system’s responsiveness to changes in hematocrit, CBv and CMRO2. Finally, factoring in neurovascular effects, we show that no initial dip will be observed unless there is a time delay in the onset of increased CBv relative to CMRO2.

Neural and hemodynamic responses to optogenetic and sensory stimulation in the rat somatosensory cortex.

Introducing optogenetics into neurovascular research can provide novel insights into the cell-specific control of the hemodynamic response. To generalize findings from molecular approaches, it is crucial to determine whether light-activated circuits have the same effect on the vasculature as sensory-activated ones. For that purpose, rats expressing channelrhodopsin (ChR2) specific to excitatory glutamatergic neurons were used to measure neural activity, blood flow, hemoglobin-based optical intrinsic signal, and blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) during optogenetic and sensory stimulation. The magnitude of the evoked hemodynamic responses was monotonically correlated with optogenetic stimulus strength. The BOLD hemodynamic response function was consistent for optogenetic and sensory stimuli. The relationship between electrical activities and hemodynamic responses was comparable for optogenetic and sensory stimuli, and better explained by the local field potential (LFP) than the firing rate. The LFP was well correlated with cerebral blood flow, moderately with cerebral blood volume, and less with deoxyhemoglobin (dHb) level. The presynaptic firing rate had little impact on evoking vascular response. Contribution of the postsynaptic LFP to the blood flow response induced by optogenetic stimulus was further confirmed by the application of glutamate receptor antagonists. Overall, neurovascular coupling during optogenetic control of glutamatergic neurons largely conforms to that of a sensory stimulus.

Altered Hemodynamics and Regional Cerebral Blood Flow in Patients With Hemodynamically Significant Stenoses

Blood oxygen level-dependent (BOLD) contrast largely depends on changes in cerebral blood flow (CBF). Because cerebrovascular disease may result in altered CBF, we assessed the temporal dynamics and magnitude of the BOLD response in patients with major arterial stenoses. Seven patients with hemodynamically significant stenoses affecting the anterior circulation (primarily left internal carotid and middle cerebral arteries) were compared with 7 neurologically healthy subjects. Continuous arterial spin-labeled perfusion MRI was used to measure resting CBF globally and within various vascular distributions. The BOLD response was acquired during a visually guided bilateral handball squeeze task while motor performance was recorded by a pressure transducer. Baseline CBF was reduced in bilateral middle cerebral artery and left anterior cerebral artery territories in patients. A prolonged BOLD hemodynamic response was observed in patients in bilateral primary motor cortices but not visual cortex. Patients also exhibited a larger early negative BOLD response, or "initial dip," in left primary motor cortex. There were no differences in motor performance between groups, suggesting behavioral differences were not primarily responsible for the characteristics of the BOLD response. An initial deoxygenation followed by a delayed hyperemic BOLD response was observed in patients, although resting flow values were not within an ischemic range. A simple visuomotor BOLD activation paradigm can reflect alterations in the hemodynamic response in patients with hemodynamically significant stenoses.

Temporal resolving power of spin echo and gradient echo fMRI at 3T with apparent diffusion coefficient compartmentalization

The temporal resolving power of blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) at 3T was investigated in the visual and auditory cortices of the human brain. By using controlled temporal delays and selective visual hemifield stimulation, regions with similar (left vs. right occipital cortex) and different (occipital cortex vs. auditory cortex) vascular architectures were compared. Estimates of the time-to-peak (TTP) of the BOLD hemodynamic response function (hrf) were obtained using a spin echo (SE) sequence and compared to those acquired using a traditional gradient echo (GE) sequence. The hrf TTP in the visual cortex was found to be 4.73 s and 4.21 s for GE and SE, respectively. The auditory cortex response was significantly delayed, with TTPs of 4.95 s and 4.51 s for GE and SE, respectively. The GE response was able to resolve visual stimuli separated by 250 ms, whereas SE could resolve stimuli 500 ms apart. Apparent-diffusion-coefficient (ADC) compartmentalization of the BOLD signal was applied to restrict the vascular sensitivity of the SE and GE sequences. Limiting the response to voxels with ADCs < 0.8 x 10(-3) mm(2)/s improved the temporal resolving power of GE and SE BOLD to 125 ms and 250 ms, respectively.