Breath-Hold Blood Oxygen Level-Dependent MRI: A Tool for the Assessment of Cerebrovascular Reserve in Children with Moyamoya Disease

BACKGROUND AND PURPOSE: There is a critical need for a reliable and clinically feasible imaging technique that can enable prognostication and selection for revascularization surgery in children with Moyamoya disease. Blood oxygen level-dependent MR imaging assessment of cerebrovascular reactivity, using voluntary breath-hold hypercapnic challenge, is one such simple technique. However, its repeatability and reliability in children with Moyamoya disease are unknown. The current study sought to address this limitation. MATERIALS AND METHODS: Children with Moyamoya disease underwent dual breath-hold hypercapnic challenge blood oxygen level-dependent MR imaging of cerebrovascular reactivity in the same MR imaging session. Within-day, within-subject repeatability of cerebrovascular reactivity estimates, derived from the blood oxygen level-dependent signal, was computed. Estimates were associated with demographics and intellectual function. Interrater reliability of a qualitative and clinically applicable scoring scheme was assessed. RESULTS: Twenty children (11 males; 12.1 ± 3.3 years) with 30 MR imaging sessions (60 MR imaging scans) were included. Repeatability was "good" on the basis of the intraclass correlation coefficient (0.70 ± 0.19). Agreement of qualitative scores was "substantial" (κ = 0.711), and intrarater reliability of scores was "almost perfect" (κ = 0.83 and 1). Younger participants exhibited lower repeatability (P = .027). Repeatability was not associated with cognitive function (P > .05). However, abnormal cerebrovascular reactivity was associated with slower processing speed (P = .015). CONCLUSIONS: Breath-hold hypercapnic challenge blood oxygen level-dependent MR imaging is a repeatable technique for the assessment of cerebrovascular reactivity in children with Moyamoya disease and is reliably interpretable for use in clinical practice. Standardization of such protocols will allow further research into its application for the assessment of ischemic risk in childhood cerebrovascular disease

Measuring vascular reactivity with breath-holds after stroke: a method to aid interpretation of group-level BOLD signal changes in longitudinal fMRI studies

Blood oxygenation level-dependent (BOLD) contrast functional magnetic resonance imaging (fMRI) is a widely used technique to map brain function, and to monitor its recovery after stroke. Since stroke has a vascular etiology, the neurovascular coupling between cerebral blood flow and neural activity may be altered, resulting in uncertainties when interpreting longitudinal BOLD signal changes. The purpose of this study was to demonstrate the feasibility of using a recently validated breath-hold task in patients with stroke, both to assess group level changes in cerebrovascular reactivity (CVR) and to determine if alterations in regional CVR over time will adversely affect interpretation of task-related BOLD signal changes. Three methods of analyzing the breath-hold data were evaluated. The CVR measures were compared over healthy tissue, infarcted tissue and the peri-infarct tissue, both sub-acutely (∼2 weeks) and chronically (∼4 months). In this cohort, a lack of CVR differences in healthy tissue between the patients and controls indicates that any group level BOLD signal change observed in these regions over time is unlikely to be related to vascular alterations. CVR was reduced in the peri-infarct tissue but remained unchanged over time. Therefore, although a lack of activation in this region compared with the controls may be confounded by a reduced CVR, longitudinal group-level BOLD changes may be more confidently attributed to neural activity changes in this cohort. By including this breath-hold-based CVR assessment protocol in future studies of stroke recovery, researchers can be more assured that longitudinal changes in BOLD signal reflect true alterations in neural activity

Separating vascular and neuronal effects of age on fMRI BOLD signals.

Accurate identification of brain function is necessary to understand the neurobiology of cognitive ageing, and thereby promote well-being across the lifespan. A common tool used to investigate neurocognitive ageing is functional magnetic resonance imaging (fMRI). However, although fMRI data are often interpreted in terms of neuronal activity, the blood oxygenation level-dependent (BOLD) signal measured by fMRI includes contributions of both vascular and neuronal factors, which change differentially with age. While some studies investigate vascular ageing factors, the results of these studies are not well known within the field of neurocognitive ageing and therefore vascular confounds in neurocognitive fMRI studies are common. Despite over 10 000 BOLD-fMRI papers on ageing, fewer than 20 have applied techniques to correct for vascular effects. However, neurovascular ageing is not only a confound in fMRI, but an important feature in its own right, to be assessed alongside measures of neuronal ageing. We review current approaches to dissociate neuronal and vascular components of BOLD-fMRI of regional activity and functional connectivity. We highlight emerging evidence that vascular mechanisms in the brain do not simply control blood flow to support the metabolic needs of neurons, but form complex neurovascular interactions that influence neuronal function in health and disease. This article is part of the theme issue 'Key relationships between non-invasive functional neuroimaging and the underlying neuronal activity'.This work is supported by the British Academy (PF160048), the Guarantors of Brain (G101149), the Wellcome Trust (103838), the Medical Research Council (SUAG/051 G101400; and SUAG/046 G101400), European Union’s Horizon 2020 (732592) and the Cambridge NIHR Biomedical Research Centre

A dual-center validation of the PIRAMD scoring system for assessing the severity of ischemic Moyamoya disease

Prior Infarcts, Reactivity, and Angiography in Moyamoya Disease (PIRAMD) is a recently proposed imaging-based scoring system that incorporates the severity of disease and its impact on parenchymal hemodynamics in order to better support clinical management and evaluate response to intervention. In particular, PIRAMD may have merit in identifying symptomatic patients that may benefit most from revascularization. Our aim was to validate the PIRAMD scoring system

Effects of normobaric hypoxia on the activation of motor and visual cortex areas in functional magnetic resonance imaging (fMRI)

Aims: Hypoxia due to high altitude or otherwise altered fraction of inspired O2 affects cerebral mechanisms. Human brain function can be assessed indirectly via examination of local changes in haemodynamics in fMRI. The aim of this study was to examine if adaptation to normobaric hypoxia determines divergent activation in the brain regions supplied by the main cerebral arterial vessels. Methods: Visual and motor paradigms were used to shed light on the activation of different brain regions in fMRI under normobaric hypoxic conditions in 16 healthy male subjects. Hypoxia was produced by reducing the percentage of O2 in an inhaled gas mixture resulting in normobaric hypoxia with an FiO2 of 13 %. Participants had to complete a total of 3 MRI sessions to study different oxygen conditions: normoxia (FiO2 = 0.21, normal pressure), short-time (7 ± 1 min, FiO2 = 0.13, normal pressure), longtime hypoxia (8 h and 29 ± 24 min, FiO2 = 0.13, normal pressure). Each session lasted approximately 30 min, consisting of two fMRI runs (1 visual task, 1 motor task) which were pseudo-randomized between participants, followed by the structural sequence. Cerebral symptoms of AMS were assessed by means of the LLS and it was examined if symptomatic AMS has consequences on brain activation patterns measured as ∆S values. Results: Mean ∆S during normoxia was 2.43 ± 0.80 % due to motor stimulation, and 3.49 ± 1.41 % due to visual stimulation. During motor stimulation, the mean signal change due to short-time hypoxia was 0.55 ± 0.30 % and 0.82 ± 0,62 % due to longtime hypoxia. During visual stimulation, the mean signal change due to short-time hypoxia was 1.79 ± 0.69 %. Long-time hypoxia led to a mean signal change of 2.02 ± 1.18 %. Repeated ANOVA measures with factors task (motor, visual) and the hypoxic conditions (short-time hypoxia, long-time hypoxia) showed a main effect of task (F (1,15) = 52.10, p < 0.001), but no main effect of the hypoxic condition (F (1, 15) = 1.79, p = ns). Conclusions: Hypoxia led to diminished cerebral activation during motor and visual stimulation in spite of a preserved cerebral function. The oxygenation changes associated with brain activation seem more influential on the motor area, rather than the visual cortex. Therefore, the capability of the human brain to acclimatise to chronic hypoxic conditions may vary in the motor and the visual system.Ziele: Hypoxie aufgrund großer Höhe oder eines anderweitig veränderten Anteils von eingeatmetem O2-Gehalts beeinflusst zerebrale Mechanismen. Die menschliche Gehirnfunktion kann indirekt über den Nachweis lokaler hämodynamischer Veränderungen im fMRT bestimmt werden. Das Ziel dieser Studie war es, zu untersuchen, ob die Anpassung an normobare Hypoxie eine unterschiedliche Aktivierung in von den drei Hauptgefäßen versorgten Gehirnregionen erzeugt. Methoden: Bei 16 gesunden, männlichen Probanden wurden visuelle und motorische Testparadigmen angewendet, um die Aktivierung verschiedener Hirnregionen im fMRT unter normobaren, hypoxischen Bedingungen aufzuklären. Hypoxie wurde mit Hilfe eines sauerstoffreduzierten Gasgemischs (O2-Anteil 13%) erzeugt. Die Probanden mussten insgesamt 3 MRT-Sitzungen absolvieren, um verschiedene Sauerstoffzustände zu untersuchen: Normoxie (FiO2 = 0,21), Kurzzeithypoxie (7 ± 1 min Hypoxie, FiO2 = 0,13), Langzeithypoxie (8 h und 29 ± 24 min Hypoxie, FiO2 = 0,13). Jede Sitzung dauerte ca. 30 min und bestand aus je zwei fMRI-Durchgängen (1 visuelle Aufgabe, 1 motorische Aufgabe). Die zerebralen Symptome einer Höhenkrankheit wurden mittels des LLS bewertet und der Einfluss einer Höhenkrankheit auf die Gehirnaktivierungsmuster im fMRT untersucht. Resultate: Die mittlere BOLD-Signalveränderung während Normoxie betrug bei motorischer Stimulation 2,43 ± 0,80% und bei visueller Stimulation 3,49 ± 1,41%. Bei motorischer Stimulation betrug sie nach Kurzzeithypoxie 0,55 ± 0,30% und 0,82 ± 0,62% nach Langzeithypoxie. Bei visueller Stimulation betrug die mittlere Signaländerung aufgrund von Kurzzeithypoxie 1,79 ± 0,69 und aufgrund Langzeithypoxie 2,02 ± 1,18%. ANOVA-Messungen mit den Faktoren Aufgabe (motorisch, visuell) und hypoxische Bedingungen (Kurzzeithypoxie, Langzeithypoxie) zeigten einen Effekt der Aufgabe (F (1, 15) = 52.10, p <0.001), aber keinen Effekt der hypoxischen Bedingung (F (1, 15) = 1,79, p = ns) auf die BOLD Signalwertänderungen. Schlussfolgerungen: Hypoxie führte zu einer verminderten Hirnaktivität im fMRT bei motorischer und visueller Stimulation trotz erhaltener Hirnfunktion. Die mit der Gehirnaktivierung verbundenen Veränderungen der Oxygenierung scheinen eher Einfluss auf den motorischen Bereich als den visuellen Kortex zu haben. Die Adaptationsfähigkeit an chronische hypoxische Zustände scheint sich demzufolge zwischen dem motorischen und dem visuellen System zu unterscheiden

Protocol-dependence of middle cerebral artery dilation to modest hypercapnia.

There is a need for improved understanding of how different cerebrovascular reactivity (CVR) protocols affect vascular cross-sectional area (CSA) to reduce error in CVR calculations when measures of vascular CSA are not feasible. In human participants, we delivered ∼±4 mm Hg end-tidal partial pressure of CO2 (PETCO2) relative to baseline through controlled delivery, and measured changes in middle cerebral artery (MCA) CSA (7 Tesla magnetic resonance imaging (MRI)), blood velocity (transcranial Doppler and Phase contrast MRI), and calculated CVR based on a 3-minute steady-state (+4 mm Hg PETCO2) and a ramp (-3 to +4 mm Hg of PETCO2). We observed that (1) the MCA did not dilate during the ramp protocol (slope for CSA across time P \u3e 0.05; R2 = 0.006), but did dilate by ∼7% during steady-state hypercapnia (P \u3c 0.05); and (2) MCA blood velocity CVR was not different between ramp and steady-state hypercapnia protocols (ramp: 3.8 ± 1.7 vs. steady-state: 4.0 ± 1.6 cm/s/mm Hg), although calculated MCA blood flow CVR was ∼40% greater during steady-state hypercapnia than during ramp (P \u3c 0.05) with the discrepancy due to MCA CSA changes during steady-state hypercapnia. We propose that a ramp model, across a delta of -3 to +4 mm Hg PETCO2, may provide an alternative approach to collecting CVR measures in young adults with transcranial Doppler when CSA measures are not feasible. Novelty: We optimized a magnetic resonance imaging sequence to measure dynamic middle cerebral artery (MCA) cross-sectional area (CSA). A ramp model of hypercapnia elicited similar MCA blood velocity reactivity as the steady-state model while maintaining MCA CSA

Cerebrovascular reactivity measurements using 3T BOLD MRI and a fixed inhaled CO2 gas challenge: Repeatability and impact of processing strategy

Introduction: Cerebrovascular reactivity (CVR) measurements using blood oxygen level dependent (BOLD) magnetic resonance imaging (MRI) are commonly used to assess the health of cerebral blood vessels, including in patients with cerebrovascular diseases; however, evidence and consensus regarding reliability and optimal processing are lacking. We aimed to assess the repeatability, accuracy and precision of voxel- and region-based CVR measurements at 3 T using a fixed inhaled (FI) CO2 stimulus in a healthy cohort.Methods: We simulated the effect of noise, delay constraints and voxel- versus region-based analysis on CVR parameters. Results were verified in 15 healthy volunteers (28.1±5.5 years, female: 53%) with a test-retest MRI experiment consisting of two CVR scans. CVR magnitude and delay in grey matter (GM) and white matter were computed for both analyses assuming a linear relationship between the BOLD signal and time-shifted end-tidal CO2 (EtCO2) profile.Results: Test-retest repeatability was high [mean (95% CI) inter-scan difference: −0.01 (−0.03, −0.00) %/mmHg for GM CVR magnitude; −0.3 (−1.2,0.6) s for GM CVR delay], but we detected a small systematic reduction in CVR magnitude at scan 2 versus scan 1, accompanied by a greater EtCO2 change [±1.0 (0.4,1.5) mmHg] and lower heart rate [−5.5 (−8.6,−2.4] bpm]. CVR magnitude estimates were higher for voxel- versus region-based analysis [difference in GM: ±0.02 (0.01,0.03) %/mmHg]. Findings were supported by simulation results, predicting a positive bias for voxel-based CVR estimates dependent on temporal contrast-to-noise ratio and delay fitting constraints and an underestimation for region-based CVR estimates.Discussion: BOLD CVR measurements using FI stimulus have good within-day repeatability in healthy volunteers. However, measurements may be influenced by physiological effects and the analysis protocol. Voxel-based analyses should be undertaken with care due to potential for systematic bias; region-based analyses are more reliable in such cases

Cerebral haemodynamics during experimental intracranial hypertension.

Intracranial hypertension is a common final pathway in many acute neurological conditions. However, the cerebral haemodynamic response to acute intracranial hypertension is poorly understood. We assessed cerebral haemodynamics (arterial blood pressure, intracranial pressure, laser Doppler flowmetry, basilar artery Doppler flow velocity, and vascular wall tension) in 27 basilar artery-dependent rabbits during experimental (artificial CSF infusion) intracranial hypertension. From baseline (∼9 mmHg; SE 1.5) to moderate intracranial pressure (∼41 mmHg; SE 2.2), mean flow velocity remained unchanged (47 to 45 cm/s; p = 0.38), arterial blood pressure increased (88.8 to 94.2 mmHg; p < 0.01), whereas laser Doppler flowmetry and wall tension decreased (laser Doppler flowmetry 100 to 39.1% p < 0.001; wall tension 19.3 to 9.8 mmHg, p < 0.001). From moderate to high intracranial pressure (∼75 mmHg; SE 3.7), both mean flow velocity and laser Doppler flowmetry decreased (45 to 31.3 cm/s p < 0.001, laser Doppler flowmetry 39.1 to 13.3%, p < 0.001), arterial blood pressure increased still further (94.2 to 114.5 mmHg; p < 0.001), while wall tension was unchanged (9.7 to 9.6 mmHg; p = 0.35).This animal model of acute intracranial hypertension demonstrated two intracranial pressure-dependent cerebroprotective mechanisms: with moderate increases in intracranial pressure, wall tension decreased, and arterial blood pressure increased, while with severe increases in intracranial pressure, an arterial blood pressure increase predominated. Clinical monitoring of such phenomena could help individualise the management of neurocritical patients.The authors would acknowledge Dr Hugh Richards and Dr Stefan Piechnik who contributed to data collection. JD is supported by a Woolf Fisher scholarship. GVV is supported by an A.G. Leventis Foundation Scholarship, and a Charter Studentship from St Edmund’s College, Cambridge. XYL is supported by Bill Gates Scholarship, and DC is supported by a Cambridge Commonwealth, European & International Trust Scholarship (University of Cambridge).This is the author accepted manuscript. The final version is available from SAGE via https://doi.org/10.1177/0271678X1663906