Compromised resting cerebral metabolism after sport-related concussion: A calibrated MRI study.

Altered resting cerebral blood flow (CBF0) in the acute phase post-concussion may contribute to neurobehavioral deficiencies, often reported weeks after the injury. However, in addition to changes in CBF0, little is known about other physiological mechanisms that may be disturbed within the cerebrovasculature. The aim of this study was to assess whether changes in baseline perfusion following sport-related concussion (SRC) were co-localized with changes in cerebral metabolic demand. Forty-two subjects (15 SRC patients 8.0 ± 4.6 days post-injury and 27 age-matched healthy control athletes) were studied cross-sectionally. CBF0, cerebrovascular reactivity (CVR), resting oxygen extraction (OEF0) and cerebral metabolic rate of oxygen consumption (CMRO2|0) were measured using a combination of hypercapnic and hyperoxic breathing protocols, and the biophysical model developed in calibrated MRI. Blood oxygenation level dependent and perfusion data were acquired simultaneously using a dual-echo arterial spin labelling sequence. SRC patients showed significant decreases in CBF0 spread across the grey-matter (P < 0.05, corrected), and these differences were also confounded by the effects of baseline end-tidal CO2 (P < 0.0001). Lower perfusion was co-localized with reductions in regional CMRO2|0 (P = 0.006) post-SRC, despite finding no group-differences in OEF0 (P = 0.800). Higher CVR within voxels showing differences in CBF was also observed in the SRC group (P = 0.001), compared to controls. Reductions in metabolic demand despite no significant changes in OEF0 suggests that hypoperfusion post-SRC may reflect compromised metabolic function after the injury. These results provide novel insight about the possible pathophysiological mechanisms underlying concussion that may affect the clinical recovery of athletes after sport-related head injuries.

Co-localized impaired regional cerebrovascular reactivity in chronic concussion is associated with BOLD activation differences during a working memory task.

The purpose of this study was to quantify differences in blood oxygen level dependent (BOLD) activation on a working memory task, baseline cerebral blood flow (CBF0), and cerebrovascular reactivity (CVR) between participants with and without a history of concussion. A dual-echo pseudo-continuous arterial spin labelling (pCASL) sequence was performed on a group of 10 subjects with a previous concussion (126 ± 15 days prior) and on a control group (n = 10) during a visual working memory protocol. A separate dual-echo pCASL sequence was used to derive CVR and CBF0 measurements from a boxcar hypercapnic breathing protocol. Brain areas with significant activation differences on the working memory task between groups were identified and combined as an aggregate region of interest for CBF and CVR analyses. Areas of reduced BOLD activation during the working memory task in the concussed group included the ventral anterior cingulate cortex (ACC), the medial temporal gyrus (MTG), and the lateral occipital cortex in two loci. A single area of increased activation was located in the parietal operculum. Further analyses of CBF0 and CVR in these regions revealed reduced CVR in the concussed group in the MTG and ACC, while CBF0 did not differ. The differences in CVR between the two groups in these regions suggest that concussive injury may result in microvascular dysfunction. In turn, the decreased BOLD response during the task could be due to altered neurovascular coupling, rather than an impairment in neural activation alone. However, in other regions associated with working memory, unchanged CBF0 and CVR suggests that neural injury also persists after concussion. In the future, BOLD results should be normalized to CVR in order achieve a clearer understanding of the neural and vascular contributions to the differences in the signal.

A novel perspective to calibrate temporal delays in cerebrovascular reactivity using hypercapnic and hyperoxic respiratory challenges.

Redistribution of blood flow across different brain regions, arising from the vasoactive nature of hypercapnia, can introduce errors when examining cerebrovascular reactivity (CVR) response delays. In this study, we propose a novel analysis method to characterize hemodynamic delays in the blood oxygen level dependent (BOLD) response to hypercapnia, and hyperoxia, as a way to provide insight into transient differences in vascular reactivity between cortical regions, and across tissue depths. A pseudo-continuous arterial spin labeling sequence was used to acquire BOLD and cerebral blood flow simultaneously in 19 healthy adults (12 F; 20 ± 2 years) during boxcar CO2 and O2 gas inhalation paradigms. Despite showing distinct differences in hypercapnia-induced response delay times (P < 0.05; Bonferroni corrected), grey matter regions showed homogenous hemodynamic latencies (P > 0.05) once calibrated for bolus arrival time derived using non-vasoactive hyperoxic gas challenges. Longer hypercapnic temporal delays were observed as the depth of the white matter tissue increased, although no significant differences in response lag were found during hyperoxia across tissue depth, or between grey and white matter. Furthermore, calibration of hypercapnic delays using hyperoxia revealed that deeper white matter layers may be more prone to dynamic redistribution of blood flow, which introduces response lag times ranging between 1 and 3 s in healthy subjects. These findings suggest that the combination of hypercapnic and hyperoxic gas-inhalation MRI can be used to distinguish between differences in CVR that arise as a result of delayed stimulus arrival time (due to the local architecture of the cerebrovasculature), or preferential blood flow distribution. Calibrated response delays to hypercapnia provide important insights into cerebrovascular physiology, and may be used to correct response delays associated with vascular impairment.

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

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

Indication of BOLD-specific venous flow-volume changes from precisely controlled hyperoxic vs. hypercapnic calibration.

Deriving cerebral metabolic rate of oxygen consumption (CMRO(2)) from blood oxygenation level-dependent (BOLD) signals involves a flow-volume parameter (α), reflecting total cerebral blood volume changes, and a calibration constant (M). Traditionally, the former is assumed a fixed value and the latter is measured under alterations in fixed inspired fractional concentrations of carbon dioxide. We recently reported on reductions in M-variability via precise control of end-tidal pressures of both hypercapnic (HC) and hyperoxic (HO) gases. In light of these findings, our aim was to apply the improved calibration alternatives to neuronal activation, making use of their distinct vasoactive natures to evaluate the α-value. Nine healthy volunteers were imaged at 3 T while simultaneously measuring BOLD and arterial spin-labeling signals during controlled, graded, HC, and HO, followed by visual (VC) and sensorimotor cortices (SMC) activation. On the basis of low M- and CMRO(2)-variability, the comparison of these calibration alternatives accurately highlighted a reduced venous flow-volume relationship (α=0.16±0.02, with α(VC)=0.12±0.04, and α(SMC)=0.20±0.02), as appropriate for BOLD modeling.

Improved fMRI calibration: precisely controlled hyperoxic versus hypercapnic stimuli.

The calibration of functional magnetic resonance imaging (fMRI) for the estimation of neuronal activation-induced changes in cerebral metabolic rate of oxygen (CMRO(2)) has been achieved through hypercapnic-induced iso-metabolic increases in cerebral blood flow (CBF). Hypercapnia (HC) has been traditionally implemented through alterations in the fixed inspired fractional concentrations of carbon dioxide (F(I)CO(2)) without otherwise controlling end-tidal partial pressures of carbon dioxide (P(ET)CO(2)) or oxygen (P(ET)O(2)). There are several shortcomings to the use of this manual HC method that may be improved by using precise targeting of P(ET)CO(2) while maintaining iso-oxia. Similarly, precise control of blood gases can be used to induce isocapnic hyperoxia (HO) to reduce venous deoxyhaemoglobin (dHb) and thus increase BOLD signals, without appreciably altering CMRO(2) or CBF. The aim of our study was to use precise end-tidal targeting to compare the calibration of BOLD signals under an isocapnic hyperoxic protocol (HOP) (rises in P(ET)O(2) to 140, 240 and 340 mm Hg from baseline) to that of an iso-oxic hypercapnic protocol (HCP) (rises in P(ET)CO(2) of 3, 5, 7 and 9 mm Hg from baseline). Nine healthy volunteers were imaged at 3T while monitoring end-tidal gas concentrations and simultaneously measuring BOLD and CBF signals, via arterial spin labeling (ASL), during graded HCP and HOP, alternating with normocapnic states in a blocked experimental design. The variability of the calibration constant obtained under HOP (M(HOP)) was 0.3-0.5 that of the HCP one (M(HCP)). In addition, M-variances with precise gas targeting (M(HCP) and M(HOP)) were less than those reported in studies using traditional F(I)CO(2) and F(I)O(2) methods (M(HC) and M(HO), respectively). We conclude that precise controlled gas delivery markedly improves BOLD-calibration for fMRI studies of oxygen metabolism with both the HCP and the more precise HOP-alternative.

Precise control of end-tidal carbon dioxide and oxygen improves BOLD and ASL cerebrovascular reactivity measures.

In-depth investigation of cerebrovascular blood flow and MR mechanisms underlying the blood oxygenation level dependent signal requires precise manipulation of the arterial partial pressure of carbon dioxide and oxygen, measured by their noninvasive surrogates, the end-tidal values. The traditional methodology consists of administering a fixed fractional concentration of inspired CO(2), but this causes a variable ventilatory response across subjects, resulting in different values of end-tidal partial pressures of CO(2) and O(2). In this study, we investigated whether fine control of these end-tidal partial pressures would improve stability and predictability of blood oxygenation level dependent and arterial spin labeling signals for studying cerebrovascular reactivity. In 11 healthy volunteers, we compared the MR signals generated by the traditional fixed fractional concentration of inspired CO(2) method to those of an automated feed-forward system, a simpler, safer, and more compact alternative to dynamic end-tidal forcing systems, designed to target constant end-tidal partial pressures of CO(2) and O(2). We found that near square-wave changes in end-tidal partial pressure of CO(2) of 5, 7.5, and 10 mm Hg (+/-1.01 mm Hg within two to three breaths) and constrained changes in the end-tidal partial pressure of O(2) (<10 mm Hg) induced cerebral vascular reactivity measurements with faster transitions, together with improved stability and gradation, than those achieved with the traditional fixed fractional concentration of inspired CO(2) method.