Relative Changes In Cerebral Blood Flow Research Articles

Assessing the correlation between resting cerebral blood flow and three different cerebrovascular reactivity stressors

Background: Understanding the regulation of resting cerebral blood flow (CBF) is crucial in the realm of brain health as previous studies indicate reduced CBF is associated with an increased risk of several neurological and cerebrovascular conditions. Concurrently, cerebrovascular reactivity (CVR), which assesses the ability of blood vessels to respond to stimuli, is a valuable indicator of cerebrovascular health, as reduced CVR to increased CO2 is associated with increased stroke, cognitive decline, and mortality risk. Thus, evaluating CVR may serve as a useful tool to understand pathologic brain conditions. In this study, we sought to address these intricacies by examining how the brain responds to different physiological stressors, such as hypercapnia, hyperoxia, and hypoxia. We tested the hypothesis that a) lower resting CBF is associated with reduced CVR-CO2, b) lower resting CBF is associated with reduced CVR-hyperoxia c) lower resting CBF is associated with reduced CVR-hypoxia. Methods: 51 young, healthy adults (19F) were included (23±4 yr). Females were not taking hormonal birth control and studied on days 1-7 of the menstrual cycle. Participants completed a magnetic resonance imaging (MRI) scan and CBF was quantified using arterial spin labeling (ASL). CVR was evaluated using a resting normoxia compared to: hypercapnia (5% CO2; 32M/19F), isocapnic-hyperoxia (100% O2; 8M/7F) and isocapnic hypoxia (80-85±1% oxygen saturation (SpO2); 12M/2F). Relative CVR was calculated by the ratio of %ΔCBF/ΔEnd tidal CO2 (ETCO2) for hypercapnia, %ΔCBF/ΔSpO2 for hypoxia, and hyperoxic reactivity was analyzed as relative CBF change (%Δ). Data were analyzed using correlation with significance set at p<0.05 and are displayed as mean ± SD. Results: ETCO2 increased from 35±3 to 42±3 mmHg during hypercapnia (p<0.05), but did not change significantly during hyperoxia or hypoxia conditions (p>0.05 for both). SpO2 decreased from 98±1% to 84±2 % during hypoxia (p<0.05). There was no significant correlation between resting CBF and CVR-CO2 (r2=0.02, p=0.23), as well as CVR-hyperoxia (r2=0.07, p=0.3). However, lower CVR-hypoxia was significantly correlated with lower resting CBF (r2=0.27; p=0.05). Conclusion: These findings suggest there is an association between resting CBF and hypoxic reactivity, but not hypercapnic or hyperoxic reactivity indicating a single measure of vascular health may not be suffcient to understand cerebrovascular function in health. Further studies with larger and more diverse populations may provide deeper insights into these intricate interactions. Funding NIH R01 HL 150361. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Psilocybin-induced changes in cerebral blood flow are associated with acute and baseline inter-individual differences

Research into the use of psilocybin for the treatment of psychiatric disorders is a growing field. Nevertheless, robust brain–behavior relationships linking psilocybin-induced brain changes to subjective drug-induced effects have not been established. Furthermore, it is unclear if the acute neural effects are dependent on individual heterogeneity in baseline characteristics. To address this, we assessed the effects of three oral doses of psilocybin vs. placebo on cerebral blood flow (CBF) using arterial spin labeling in healthy participants (N = 70; n = 31, 0.16 mg/kg; n = 10, 0.2 mg/kg; n = 29, 0.215 mg/kg). First, we quantified psilocybin-induced changes in relative and absolute CBF. Second, in an exploratory analysis, we assessed whether individual baseline characteristics and subjective psychedelic experience are associated with changes in CBF. Psychological and neurobiological baseline characteristics correlated with the psilocybin-induced reduction in relative CBF and the psilocybin-induced subjective experience. Furthermore, the psilocybin-induced subjective experience was associated with acute changes in relative and absolute CBF. The results demonstrated that inter-individual heterogeneity in the neural response to psilocybin is associated with baseline characteristics and shed light on the mechanisms underlying the psychedelic-induced altered state. Overall, these findings help guide the search for biomarkers, paving the way for a personalized medicine approach within the framework of psychedelic-assisted therapy.

Tau pathology as determinant of changes in atrophy and cerebral blood flow: a multi-modal longitudinal imaging study

PurposeTau pathology is associated with concurrent atrophy and decreased cerebral blood flow (CBF) in Alzheimer’s disease (AD), but less is known about their temporal relationships. Our aim was therefore to investigate the association of concurrent and longitudinal tau PET with longitudinal changes in atrophy and relative CBF.MethodsWe included 61 individuals from the Amsterdam Dementia Cohort (mean age 65.1 ± 7.5 years, 44% female, 57% amyloid-β positive [Aβ +], 26 cognitively impaired [CI]) who underwent dynamic [18F]flortaucipir PET and structural MRI at baseline and 25 ± 5 months follow-up. In addition, we included 86 individuals (68 CI) who only underwent baseline dynamic [18F]flortaucipir PET and MRI scans to increase power in our statistical models. We obtained [18F]flortaucipir PET binding potential (BPND) and R1 values reflecting tau load and relative CBF, respectively, and computed cortical thickness from the structural MRI scans using FreeSurfer. We assessed the regional associations between i) baseline and ii) annual change in tau PET BPND in Braak I, III/IV, and V/VI regions and cortical thickness or R1 in cortical gray matter regions (spanning the whole brain) over time using linear mixed models with random intercepts adjusted for age, sex, time between baseline and follow-up assessments, and baseline BPND in case of analyses with annual change as determinant. All analyses were performed in Aβ− cognitively normal (CN) individuals and Aβ+ (CN and CI) individuals separately.ResultsIn Aβ+ individuals, greater baseline Braak III/IV and V/VI tau PET binding was associated with faster cortical thinning in primarily frontotemporal regions. Annual changes in tau PET were not associated with cortical thinning over time in either Aβ+ or Aβ− individuals. Baseline tau PET was not associated with longitudinal changes in relative CBF, but increases in Braak III/IV tau PET over time were associated with increases in parietal relative CBF over time in Aβ + individuals.ConclusionWe showed that higher tau load was related to accelerated cortical thinning, but not to decreases in relative CBF. Moreover, tau PET load at baseline was a stronger predictor of cortical thinning than change of tau PET signal.

Cerebral Metabolic Stress Improves after Voxelotor Treatment in Pediatric Sickle Cell Disease

Introduction In sickle cell disease (SCD), hemoglobin S rapidly forms intracellular polymers in the deoxygenated state, resulting in red blood cell sickling, hemolysis, and vaso-occlusion. These changes alter cerebral perfusion and dramatically increase risk for neurocognitive deficits and stroke (Bush et al., 2014; Wang et al., 2021). Voxelotor (Oxbryta®) is an inhibitor of HbS polymerization that has been shown to significantly improve anemia and reduce hemolysis in sickle cell disease. However, it is unknown whether these changes are accompanied by improvements in perfusion and reductions in cerebral metabolic stress. Here we employ two novel optical techniques known as frequency-domain near-infrared spectroscopy (FDNIRS) and diffuse correlation spectroscopy (DCS) to non-invasively monitor regional changes in oxygen extraction fraction (OEF), cerebral blood flow (CBF), and cerebral metabolic rate of oxygen (CMRO2) as markers of cerebral metabolic stress in a pilot cohort of children with SCD beginning voxelotor. Our primary objective was to test the hypothesis that voxelotor decreases CBF, OEF, and CMRO2 from pre-treatment levels. We also explored the relationship between CBF, OEF, and CMRO2 and hemoglobin. Methods Children ages 4 to 17 years old with SCD (HbSS or HbS-thalassemia) were enrolled at Children's Healthcare of Atlanta. Participants who met study criteria started open label voxelotor at recommended dose. Participants were monitored prior to treatment initiation, as well as at weeks 4, 8, and 12 weeks. At each study visit, laboratory measurements of anemia (CBC, Retic) and FDNIRS/DCS measurements of regional cerebral blood flow, oxygen extraction fraction, and oxygen metabolism were made (Lee et al., 2022). Transcranial Doppler ultrasound (TCD, middle cerebral artery, internal carotid artery, and carotid bifurcations) along with markers of hemolysis (LDH, T.Bili) were performed at weeks 0 and 12. Paired Wilcoxon signed-rank tests were used to test whether all measures were significantly different from pre-treatment levels. Linear mixed-effects regression models with random-intercept at the patient level were used to examine the association of the relative change in each outcome measure (OEF, CBF, and CMRO2) from pre-treatment levels and delta changes in laboratory data. These models were two-level and accounted for repeated measures nested within each patient. Results Ten of the 12 recruited patients met study criteria. All patients were HbSS on stable dose of hydroxyurea (Table 1). Following initiation of voxelotor, the median (interquartile range, IQR) blood hemoglobin levels increased by 1.2 (0.4, 1.5) g/dL at week 4 (p=0.023); these increases persisted at weeks 8 and 12. Bilirubin was significantly decreased at week 12 (p=0.008), and LDH increased, although the trend was not statistically significant (p=0.24). While TCD velocities were unchanged at week 12, significant decreases in OEF, CBF, and CMRO2 were observed by week 4 (all p < 0.05) that persisted at weeks 8 and 12 (Table 2). Across all time points, relative changes in OEF, CBF, and CMRO2 from pre-treatment levels were inversely associated with changes in hemoglobin (p = 0.0015, 0.071, and 0.020, respectively). Discussion Non-invasive FDNIRS/DCS was used to successfully measure changes in regional cerebral blood flow and oxygen utilization in response to treatment with voxelotor. Results suggest that voxelotor treatment in children with SCD reduces cerebral metabolic stress by improving oxygen delivery to the tissue. Work is ongoing to validate these measurements with MRI. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Concurrent CBF and BOLD fMRI with dual-echo spiral simultaneous multi-slice acquisitions at 7T

Measurement of cerebral blood flow (CBF) using the Arterial Spin Labeling (ASL) technique is a desirable fMRI approach due to the higher specificity of CBF to the site of neural activation. However, ASL has inherent limitations, such as a low signal-to-noise ratio (SNR) and low coverage/resolution due to the limited readout window following the labeling. Recently, ASL has been implemented at ultra-high field (UHF) strengths in an attempt to mitigate the SNR challenges. Even though ASL intrinsically allows concurrent acquisition of CBF and BOLD contrasts, a compromise in the echo time (TE) for either of the contrasts is inevitable with single-echo acquisitions. Long durations of the Cartesian EPI readout do not allow for multi-echo acquisitions for resolutions ≤2 mm where both contrasts can be acquired at their optimal TE at UHF. With its higher acquisition efficiency, single-shot spiral imaging provides a promising alternative to EPI, and with a dual-echo, out-in trajectory allows both CBF and BOLD contrasts to be acquired at their respective optimal TE. In this work, we implemented a dual-echo spiral out-in ASL sequence with simultaneous multi-slice (SMS) readout for increased coverage, and validated its application to fMRI with a visuomotor paradigm. Conventional Cartesian EPI acquisitions with matched parameters served as a reference. The dual-echo spiral ASL acquisitions resulted in robust CBF and BOLD activations maps. The absolute and relative CBF changes measured with the dual-echo spiral readout were in agreement with previous reports in the literature as well as the reference Cartesian acquisitions. The BOLD response amplitude was higher compared to the Cartesian acquisitions, attributable to a more optimal TE of the second echo. In conclusion, dual-echo spiral out-in SMS acquisition shows promise for concurrent acquisitions of BOLD and non-BOLD contrasts that require a short TE, with no loss in temporal resolution.

Impaired Cerebral Autoregulation After Subarachnoid Hemorrhage: A Quantitative Assessment Using a Mouse Model.

Subarachnoid hemorrhage (SAH) is a common form of hemorrhagic stroke associated with high rates of mortality and severe disability. SAH patients often develop severe neurological deficits days after ictus, events attributed to a phenomenon referred to as delayed cerebral ischemia (DCI). Recent studies indicate that SAH-induced DCI results from a multitude of cerebral circulatory disturbances including cerebral autoregulation malfunction. Cerebral autoregulation incorporates the influence of blood pressure (BP) on arterial diameter in the homeostatic regulation of cerebral blood flow (CBF), which is necessary for maintaining constant brain perfusion during physiological swings in systemic BP. In this study, we quantitatively examined the impact of SAH on cerebral autoregulation using a mouse endovascular perforation model and a newly developed approach combining absolute and relative CBF measurements. This method enables a direct quantitative comparison of cerebral autoregulation between individual animals (e.g., SAH vs. control or sham-operated mice), which cannot be done solely using relative CBF changes by laser Doppler flowmetry. Here, absolute CBF was measured via injection of fluorescent microspheres at a baseline BP. In separate groups of animals, in vivo laser Doppler flowmetry was used to measure relative CBF changes over a range of BP using phlebotomy and the pressor phenylephrine to lower and raise BP, respectively. Absolute CBF measurements from microspheres were then used to calibrate laser Doppler measurements to calculate the relationship between CBF and BP, i.e., “cerebral autoregulation curves.” Un-operated and sham-operated groups exhibited similar cerebral autoregulatory curves, showing comparable levels of relatively constant CBF over a range of BP from ~80 mmHg to ~130 mmHg. In contrast, SAH animals exhibited a narrower autoregulatory range of BP, which was primarily due to a decrease in the upper limit of BP whereby cerebral autoregulation was maintained. Importantly, SAH animals also exhibited a marked decrease in CBF throughout the entire range of BP. In sum, this study provides evidence of the dramatic reduction in cortical CBF and the diminished range of autoregulation after SAH. Furthermore, this novel methodology should pave the way for future studies examining pathological mechanisms and/or therapeutic strategies targeting impaired cerebral autoregulation, a pathology common to many cardiovascular and cerebrovascular disorders.

Predicting PET Cerebrovascular Reserve with Deep Learning by Using Baseline MRI: A Pilot Investigation of a Drug-Free Brain Stress Test.

Background Cerebrovascular reserve (CVR) may be measured by using an acetazolamide test to clinically evaluate patients with cerebrovascular disease. However, acetazolamide use may be contraindicated and/or undesirable in certain clinical settings. Purpose To predict CVR images generated from acetazolamide vasodilation with a deep learning network by using only images before acetazolamide administration. Materials and Methods Simultaneous oxygen 15 (15O)-labeled water PET/MRI before and after acetazolamide injection were retrospectively analyzed for patients with Moyamoya disease and healthy control participants from April 2017 to May 2019. Inputs to deep learning models were perfusion-based images (arterial spin labeling [ASL]), structural scans (T2 fluid-attenuated inversion-recovery, T1), and brain location. Two models, that is, 15O-labeled water PET cerebral blood flow (CBF) and MRI (PET-plus-MRI model) before acetazolamide administration and only MRI (MRI-only model) before acetazolamide administration, were trained and tested with sixfold cross-validation. The models learned to predict a voxelwise relative CBF change (rΔCBF) map by using rΔCBF measured with PET due to acetazolamide as ground truth. Quantitative analysis included image quality metrics (peak signal-to-noise ratio, root mean square error, and structural similarity index), as well as comparison between the various methods by using correlation and Bland-Altman analyses. Identification of vascular territories with impaired rΔCBF was evaluated by using receiver operating characteristic metrics. Results Thirty-six participants were included: 24 patients with Moyamoya disease (mean age ± standard deviation, 41 years ± 12; 17 women) and 12 age-matched healthy control participants (mean age, 39 years ± 16; nine women). The rΔCBF maps predicted by both deep learning models demonstrated better image quality metrics than did ASL (all P < .001 in patients) and higher correlation coefficient with PET than with ASL (PET-plus-MRI model, 0.704; MRI-only model, 0.690 vs ASL, 0.432; both P < .001 in patients). Both models also achieved high diagnostic performance in identifying territories with impaired rΔCBF (area under receiver operating characteristic curve, 0.95 for PET-plus-MRI model [95% confidence interval: 0.90, 0.99] and 0.95 for MRI-only model [95% confidence interval: 0.91, 0.98]). Conclusion By using only images before acetazolamide administration, PET-plus-MRI and MRI-only deep learning models predicted cerebrovascular reserve images without the need for vasodilator injection. © RSNA, 2020 Online supplemental material is available for this article.

Cerebral Blood Flow Autoregulation in Hypertensive Models of Pregnancy

Cerebral blood flow (CBF) autoregulation is a robust protective mechanism that maintains constant blood flow during changes in perfusion pressure. Although it is well known that major cardiovascular adaptations occur during normal pregnancies, the cerebral vascular adaptations that occur during pregnancy, especially in the setting of hypertensive pregnancies, are poorly understood. Hypertension is typically associated with normal autoregulatory function in the cerebral circulation, although the upper and lower limits of the autoregulatory curve are shifted to higher blood pressures. Previous studies in pregnant Sprague Dawley (SD) rats show that the cerebral autoregulatory curve is shifted to higher pressures compared to nonpregnant rats. The impact of preexisting hypertension on cerebral blood flow autoregulation has not been examined. The current study was performed to test the hypothesis that CBF autoregulation is impaired during pregnancy in the presence of underlying hypertension.Dahl salt‐sensitive (Dahl S) and spontaneously hypertensive (SHR) rats, 19–22 weeks of age, were used because they spontaneously develop hypertension without additional challenges. Female rats were mated with same strain males, and gestational day 1 (G1) of pregnancy was defined by the detection of sperm histologically from a vaginal swab. CBF was assessed on G18–20 in rats anesthetized with Inactin. Briefly, catheters were placed in the femoral artery and vein to monitor blood pressure and continuously and administer phenylephrine, respectively.Laser Doppler flow probes were positioned above two closed cranial windows 3–4 mm lateral and 2mm distal to Bregma to assess relative changes in CBF in response to increases in blood pressure.Linear regression analysis of CBF autoregulatory curves shows significant differences between pregnant and virgin rats across strains (★★, p&lt;0.0001) and between strains in the pregnant rats (★★, p&lt;0.0001, Figure). No significant differences in slopes were observed between strains in the virgin rats.Contrary to our hypothesis, these data show that CBF autoregulation was enhanced during pregnancy in two different models of spontaneous hypertension. Previous studies from our laboratory showed increased vascular and blood brain barrier permeability in pregnant Dahl S rats when compared to virgin littermates. Therefore, these data suggest an uncoupling of cerebral vascular permeability from CBF autoregulation in this model of superimposed preeclampsia.Future studies will investigate the role of pregnancy specific circulating factors that contribute to these changes and their implications on cerebrovascular function.Support or Funding InformationKJM was supported by 5T32HL105324‐09. Work was supported by 1R01HL137673 to MRG, HL136684to MJR, and R01HL134711 to JMS.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Simultaneous infrared thermal imaging and laser speckle imaging of brain temperature and cerebral blood flow in rats.

.Infrared thermal imaging of brain temperature changes is useful for evaluating cortical activity and disease states, such as stroke. However, the changes depend on a balance between changes in heat generation from metabolism and in heat convection related to blood flow. To discriminate between these effects and gain a clearer understanding of neurovascular metabolic coupling, brain temperature imaging must be improved to measure temperature and blood flow simultaneously. We develop an imaging technique that shows a two-dimensional (2-D) distribution of absolute brain temperature and relative cerebral blood flow changes in anesthetized rats by combining infrared thermal imaging with laser speckle imaging. The changes in brain metabolism and cerebral blood flow are achieved using two different anesthetics (isoflurane and -chloralose) to evaluate our system. Isoflurane increased cerebral blood flow but decreased metabolism, whereas -chloralose decreased both parameters. This technique enables simultaneous visualization of brain surface changes in temperature and cerebral blood flow in the same regions. This imaging system will permit further study of neurovascular metabolic coupling in normal and diseased brains.

Network-wise cerebral blood flow redistribution after 20 Hz rTMS on left dorso-lateral prefrontal cortex

The repetitive application of transcranial magnetic stimulation (rTMS) on left dorsolateral prefrontal cortex (DLPFC) has been consistently shown to be beneficial for treating various neuropsychiatric or neuropsychological disorders, but its neural mechanisms still remain unclear. The purpose of this study was to measure the effects of high-frequency left DLPFC rTMS using cerebral blood flow (CBF) collected from 40 young healthy subjects before and after applying 20 Hz left DLPFC rTMS or SHAM stimulations. Relative CBF (rCBF) changes before and after 20 Hz rTMS or SHAM were assessed with paired-t test. The results show that 20 Hz DLPFC rTMS induced CBF redistribution in the default mode network, including increased rCBF in left medial temporal cortex (MTC)/hippocampus, but reduced rCBF in precuneus and cerebellum. Meanwhile, SHAM stimulation didn’t produce any rCBF changes. After controlling SHAM effects, only the rCBF increase in MTC/hippocampus remained. Those data suggest that the beneficial effects of high-frequency rTMS may be through a within-network rCBF redistribution.

Reduction of BOLD interference in pseudo-continuous arterial spin labeling: towards quantitative fMRI

Fluctuations in blood-oxygenation level dependent (BOLD) signal and perfusion affect the quantification of changes in cerebral blood flow (CBF), coupled to neuronal activity, in arterial spin labeling (ASL). Subtraction methods for control and labeled MR images (i.e. pair-wise, surround subtraction, and subtraction of sinc-interpolated images), postulated to mitigate this interference in pseudo-continuous ASL (pCASL), were evaluated by comparison with quantitative 15O-water PET. At rest, a good agreement in the CBF values was found between PET and MRI for each of the subtraction methods. Stimulation of the visual system resulted in a regional CBF increase in the occipital lobe, which was detectable in both modalities. Bland–Altman analysis showed a systematic underestimation of the CBF values during activation in MRI. Evaluation of the relative CBF change induced by neuronal stimulation showed good inter-modality agreement for the three subtraction methods. Perfusion data obtained with each subtraction method followed the stimulation paradigm without significant differences in the correlation patterns or in the time lag between stimulation and perfusion response. Comparison to the gold standard confirmed the detectability of a neuronal stimulation pattern by pCASL. The results indicate that the combined use of background suppression and short TE reduces the BOLD-weighting in the pCASL signal.

A comparison study between the saturation-recovery-T1 and CASL MRI methods for quantitative CBF imaging

The saturation-recovery (SR)-T1 MRI method for quantitatively imaging cerebral blood flow (CBF) change (ΔCBF) concurrently with the blood oxygenation level dependence (BOLD) alteration has been recently developed and validated by simultaneous measurement of relative CBF change using laser Doppler flowmetry (LDF) in rats at 9.4T. In this study, ΔCBF induced by mildly transient hypercapnia and measured by the SR-T1 MRI method was rigorously compared with an established perfusion MRI method—continuous arterial spin labeling (CASL) approach in normal and preclinical middle cerebral artery occlusion (MCAo) rat models. The results show an excellent agreement between ΔCBF values measured with these two imaging methods. Moreover, the intrinsic longitudinal relaxation rate (R1int) was experimentally determined in vivo in normal rat brains at 9.4T by comparing two independent measures of the apparent longitudinal relaxation rate (R1app) and CBF measured by the CSAL approach across a wide range of perfusion. In turn, the R1int constant can be employed to calculate the CBF value based on the R1app measurement in healthy brain. This comparison study validates the fundamental relationship for linking brain tissue water R1app and cerebral perfusion, demonstrates the feasibility of imaging and quantifying both CBF and its change using the SR-T1 MRI method in vivo.

The absolute CBF response to activation is preserved during elevated perfusion: Implications for neurovascular coupling measures

Functional magnetic resonance imaging (fMRI) techniques in which the blood oxygenation level dependent (BOLD) and cerebral blood flow (CBF) response to a neural stimulus are measured, can be used to estimate the fractional increase in the cerebral metabolic rate of oxygen consumption (CMRO2) that accompanies evoked neural activity. A measure of neurovascular coupling is obtained from the ratio of fractional CBF and CMRO2 responses, defined as n, with the implicit assumption that relative rather than absolute changes in CBF and CMRO2 adequately characterise the flow-metabolism response to neural activity. The coupling parameter n is important in terms of its effect on the BOLD response, and as potential insight into the flow-metabolism relationship in both normal and pathological brain function. In 10 healthy human subjects, BOLD and CBF responses were measured to test the effect of baseline perfusion (modulated by a hypercapnia challenge) on the coupling parameter n during graded visual stimulation. A dual-echo pulsed arterial spin labelling (PASL) sequence provided absolute quantification of CBF in baseline and active states as well as relative BOLD signal changes, which were used to estimate CMRO2 responses to the graded visual stimulus. The absolute CBF response to the visual stimuli were constant across different baseline CBF levels, meaning the fractional CBF responses were reduced at the hyperperfused baseline state. For the graded visual stimuli, values of n were significantly reduced during hypercapnia induced hyperperfusion. Assuming the evoked neural responses to the visual stimuli are the same for both baseline CBF states, this result has implications for fMRI studies that aim to measure neurovascular coupling using relative changes in CBF. The coupling parameter n is sensitive to baseline CBF, which would confound its interpretation in fMRI studies where there may be significant differences in baseline perfusion between groups. The absolute change in CBF, as opposed to the change relative to baseline, may more closely match the underlying increase in neural activity in response to a stimulus.

Functional response of cerebral blood flow induced by somatosensory stimulation in rats with subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) is often accompanied by cerebral vasospasm (CVS), which is the phenomenon of narrowing of large cerebral arteries, and then can produce delayed ischemic neurological deficit (DIND) such as lateralized sensory dysfunction. CVS was regarded as a major contributor to DIND in patients with SAH. However, therapy for preventing vasospasm after SAH to improve the outcomes may not work all the time. It is important to find answers to the relationship between CVS and DIND after SAH. How local cerebral blood flow (CBF) is regulated during functional activation after SAH still remains poorly understood, whereas, the regulation of CBF may play an important role in weakening the impact of CVS on cortex function. Therefore, it is worthwhile to evaluate the functional response of CBF in the activated cortex in an SAH animal model. Most evaluation of the effect of SAH is presently carried out by neurological behavioral scales. The functional imaging of cortical activation during sensory stimulation may help to reflect the function of the somatosensory cortex more locally than the behavioral scales do. We investigated the functional response of CBF in the somatosensory cortex induced by an electrical stimulation to contralateral forepaw via laser speckle imaging in a rat SAH model. Nineteen Sprague-Dawley rats from two groups (control group, n=10 and SAH group, n=9) were studied. SAH was induced in rats by double injection of autologous blood into the cisterna magna after CSF aspiration. The same surgical procedure was applied in the control group without CSF aspiration or blood injection. Significant CVS was found in the SAH group. Meanwhile, we observed a delayed peak of CBF response in rats with SAH compared with those in the control group, whereas no significant difference was found in magnitude, duration, and areas under curve of relative CBF changes between the two groups. The results suggest that the regulation function of local CBF during functional activation induced by somatosensory stimulation might not be seriously impaired in the somatosensory cortex of rats with SAH. Therefore, our findings might help to understand the clinical phenomenon that DIND might not occur even when CVS was found in SAH patients.

Continuous Optical Monitoring of Cerebral Hemodynamics During Head-of-Bed Manipulation in Brain-Injured Adults

Head-of-bed manipulation is commonly performed in the neurocritical care unit to optimize cerebral blood flow (CBF), but its effects on CBF are rarely measured. This pilot study employs a novel, non-invasive instrument combining two techniques, diffuse correlation spectroscopy (DCS) for measurement of CBF and near-infrared spectroscopy (NIRS) for measurement of cerebral oxy- and deoxy-hemoglobin concentrations, to monitor patients during head-of-bed lowering. Ten brain-injured patients and ten control subjects were monitored continuously with DCS and NIRS while the head-of-bed was positioned first at 30° and then at 0°. Relative CBF (rCBF) and concurrent changes in oxy- (ΔHbO2), deoxy- (ΔHb), and total-hemoglobin concentrations (ΔTHC) from left/right frontal cortices were monitored for 5 min at each position. Patient and control response differences were assessed. rCBF, ΔHbO2, and ΔTHC responses to head lowering differed significantly between brain-injured patients and healthy controls (P < 0.02). For patients, rCBF changes were heterogeneous, with no net change observed in the group average (0.3 ± 28.2 %, P = 0.938). rCBF increased in controls (18.6 ± 9.4 %, P < 0.001). ΔHbO2, ΔHb, and ΔTHC increased with head lowering in both groups, but to a larger degree in brain-injured patients. rCBF correlated moderately with changes in cerebral perfusion pressure (R = 0.40, P < 0.001), but not intracranial pressure. DCS/NIRS detected differences in CBF and oxygenation responses of brain-injured patients versus controls during head-of-bed manipulation. This pilot study supports the feasibility of continuous bedside measurement of cerebrovascular hemodynamics with DCS/NIRS and provides the rationale for further investigation in larger cohorts.

High-Resolution fMRI Reveals Laminar Differences in Neurovascular Coupling between Positive and Negative BOLD Responses

The six cortical layers have distinct anatomical andphysiological properties, like different energy use and different feedforward and feedback connectivity. It is not known if and how layer-specific neural processes are reflected in the fMRI signal. To address this question we used high-resolution fMRI to measure BOLD, CBV, and CBF responses to stimuli that elicit positive and negative BOLD signals in macaque primary visual cortex. We found that regions with positive BOLD responses had parallel increases in CBV and CBF, whereas areas with negative BOLD responses showed a decrease in CBF but an increase in CBV. For positive BOLD responses, CBF and CBV increased in the center of the cortex, but for negative BOLD responses, CBF decreased superficially while CBV increased in the center. Our findings suggest different mechanisms for neurovascular coupling for BOLD increases and decreases, aswell as laminar differences in neurovascular coupling.

Early postoperative changes in cerebral oxygen metabolism following neonatal cardiac surgery: Effects of surgical duration

The early postoperative period following neonatal cardiac surgery is a time of increased risk for brain injury, yet the mechanisms underlying this risk are unknown. To understand these risks more completely, we quantified changes in postoperative cerebral metabolic rate of oxygen (CMRO(2)), oxygen extraction fraction (OEF), and cerebral blood flow (CBF) compared with preoperative levels by using noninvasive optical modalities. Diffuse optical spectroscopy and diffuse correlation spectroscopy were used concurrently to derive cerebral blood flow and oxygen utilization postoperatively for 12 hours. Relative changes in CMRO(2), OEF, and CBF were quantified with reference to preoperative data. A mixed-effect model was used to investigate the influence of total support time and deep hypothermic circulatory arrest duration on relative changes in CMRO(2), OEF, and CBF. Relative changes in CMRO(2), OEF, and CBF were assessed in 36 patients, 21 with single-ventricle defects and 15 with 2-ventricle defects. Among patients with single-ventricle lesions, deep hypothermic circulatory arrest duration did not affect relative changes in CMRO(2), CBF, or OEF (P> .05). Among 2-ventricle patients, total support time was not a significant predictor of relative changes in CMRO(2) or CBF (P > .05), although longer total support time was associated significantly with greater increases in relative change of postoperative OEF (P=.008). Noninvasive diffuse optical techniques were used to quantify postoperative relative changes in CMRO(2), CBF, and OEF for the first time in this observational pilot study. Pilot data suggest that surgical duration does not account for observed variability in the relative change in CMRO(2), and that more comprehensive clinical studies using the new technology are feasible and warranted to elucidate these issues further.

Peri-infarct flow transients predict outcome in rat focal brain ischemia

Spreading depolarizations are accompanied by transient changes in cerebral blood flow (CBF). In a post hoc analysis of previously studied control rats we analyzed CBF time courses after middle cerebral artery occlusion in the rat in order to test whether intra-ischemic flow, reperfusion, and different parameters of peri-infarct flow transients (PIFTs) (amplitude, number) can predict outcome. Sprague–Dawley rats anesthetized with either halothane (n=23) or isoflurane (n=32) underwent 90-min filament occlusion of the middle cerebral artery followed by 72h of reperfusion. The infarct size was determined by 2,3,5-triphenyltetrazolium chloride staining. Relative CBF changes were monitored by laser Doppler flowmetry at 4–5mm lateral, and 1–2mm posterior to Bregma. An additional filament occlusion study (n=12) was performed to validate that PIFTs were coupled to direct current shifts of spreading depolarization. The PIFT-direct current shift study revealed that every PIFT was associated with a negative direct current shift typical of spreading depolarization. Post-hoc analysis showed that the number of PIFTs, especially with the combination of intra-ischemic level of flow, can predict the development of cortical infarcts. These findings show that PIFTs can serve as an early biomarker in predicting outcome in preclinical animal studies.

Correlation between the arterial pulse wave of the cerebral microcirculation and CBF during breath holding and hyperventilation in human

ObjectiveTo evaluate if relative changes in the amplitude of the arterial pulse wave of the cerebral microcirculation (APWCM) measured by near-infrared spectroscopy (NIRS) may provide information about relative changes of cerebral blood flow (CBF) in cerebral cortex. MethodsIn 10 healthy human volunteers, through simultaneous recording of the APWCM amplitude by means of NIRS and the mean blood flow velocity (MBFV) of middle cerebral artery by means of transcranial Doppler (TCD) at rest and during breath holding and hyperventilation, we evaluate a possible correlation between relative changes of the mean APWCM amplitude and relative changes of MBFV. ResultsWe found a significant linear correlation: breath holding: R2 0.84, p<0.001, hyperventilation: R2 0.81, p<0.001. ConclusionThe relative changes of the mean APWCM amplitude seem able to provide information about relative changes of CBF of cerebral cortex in healthy adult humans during breath holding and hyperventilation. SignificanceAPWCM detected by NIRS, a safe, repeatable, inexpensive technology and at the bedside may improve the study of cerebral cortex microcirculation in neurological diseases.

Calibrating the BOLD signal during a motor task using an extended fusion model incorporating DOT, BOLD and ASL data.

Multimodal imaging improves the accuracy of the localization and the quantification of brain activation when measuring different manifestations of the hemodynamic response associated with cerebral activity. In this study, we incorporated cerebral blood flow (CBF) changes measured with arterial spin labeling (ASL), Diffuse Optical Tomography (DOT) and blood oxygen level-dependent (BOLD) recordings to reconstruct changes in oxy- (ΔHbO(2)) and deoxyhemoglobin (ΔHbR). Using the Grubb relation between relative changes in CBF and cerebral blood volume (CBV), we incorporated the ASL measurement as a prior to the total hemoglobin concentration change (ΔHbT). We applied this ASL fusion model to both synthetic data and experimental multimodal recordings during a 2-s finger-tapping task. Our results show that the new approach is very powerful in estimating ΔHbO(2) and ΔHbR with high spatial and quantitative accuracy. Moreover, our approach allows the computation of baseline total hemoglobin concentration (HbT(0)) as well as of the BOLD calibration factor M on a single subject basis. We obtained an average HbT(0) of 71 μM, an average M value of 0.18 and an average increase of 13% in cerebral metabolic rate of oxygen (CMRO(2)), all of which are in agreement with values previously reported in the literature. Our method yields an independent measurement of M, which provides an alternative measurement to validate the hypercapnic calibration of the BOLD signal.