FEATURED ARTICLE

Cerebrovascular Reactivity: A New Standardized Brain Stress Test

Lashmi Venkatraghavan, MD1; Joseph A. Fisher, MD1; David J. Mikulis, MD2
1Department of Anaesthesia, University of Toronto, University Health Network, Toronto, ON, Canada.
2Division of Neuroradiology, Joint Department of Medical Imaging, University of Toronto, University Health Network, Toronto, ON, Canada

Lashmi Venkatraghavan
Lashmi Venkatraghavan, MD
Joseph A. Fisher, MD
David J. Mikulis
David J. Mikulis, MD

Background
There is increasing interest in assessment of indices of brain blood flow and its regulation in health and disease.1 Cerebral blood flow regulation can be assessed through use of a reproducible cerebrovascular stress test that measures the sensitivity of cerebral blood flow response to a vasodilator. The magnitude of changes in cerebral blood flow relative to the changes in the vasodilatory stimulus is called cerebrovascular reactivity (CVR) and it has provided insight into normal cerebral vascular physiology and increased knowledge and understanding of cerebral perfusion in various neurovascular disorders.2 Many studies have indicated that impaired CVR is strongly related to the risk of acute ischemia as well as chronic ischemia causing cognitive decline.3,4
     
Over the last 20 years clinicians and researchers have used combinations of different cerebral blood flow measurement techniques and vasodilatory stimuli to measure CVR.1 Commonly used techniques for measuring CBF include transcranial Doppler, positron emission tomography (PET) and Xenon-133 single photon emission CT (SPECT).

However, lack of spatial resolution, risk of radiation and limited availability are some of the disadvantages of these techniques.2 Similarly, intravenous infusion of acetazolamide and hypercapnia (breath-holding or inhaled CO2 ) are the most commonly used vasodilatory stimuli.2 Unfortunately, they lack precise control to allow for reproducibility and are not quantifiable to allow normalization of a change in CBF to the size of the stimulus. This lack of standardization has impeded the development of clinically useful brain stress testing.

New Standardized Brain Stress Test
At the University of Toronto, Canada, we developed a cerebrovascular brain stress test using blood oxygen level dependent (BOLD) MRI signal as a surrogate for cerebral blood flow and precisely controlled end-tidal CO2 (PETCO2) as vasoactive stimuli.5 In the magnetic field, deoxygenated hemoglobin is paramagnetic and weakens the BOLD signal. With no changes in the O₂ consumption, BOLD signal increases with an increase in CBF due to decreased deoxygenated haemoglobin. PETCO2 is controlled by a computerized gas blender (RespirAct™, Thornhill Research Inc., Toronto, Ontario) with a sequential breathing circuit (Fig 1). RespirActTM is unique in that it can control alveolar ventilation enabling targeted reproducible changes in PETCO2 and PETCO2 levels, independent of the subjects’ minute ventilation. These changes can be induced within three breaths and are accurate to within +/- 1 mmHg (Fig 2).6,7 This device is Health Canada approved for research studies and currently in use in many centers in North America.

Controlling PETCO2 during BOLD-MRI enables whole brain mapping of the cerebrovascular reactivity. Using BOLD-MRI, change in blood flow per unit change in PETCO2 is measured. Color images are then created to help visualize changes in CVR: areas of brain with good cerebrovascular reactivity (increase in CBF with hypercapnia) are assigned a red color and areas with poor cerebrovascular reactivity indicate inadequate response or paradoxical decrease in CBF with vasodilation indicating intracerebral steal are assigned blue color (Fig 3).5

Unique features of our standardized brain stress test and the clinical applications are presented in Textboxes 1 and 2.

Textbox 1: Unique Features of Our Brain Stress Test

Textbox 1

Textbox 2: Potential Applications of Brain Stress Test

Textbox 2

Figure 1: Components of the RespirAct TM Device

Figure 1

Figure 2: Precision and accuracy of different patterns of hypercapnic stimulus (square wave followed by a ramp). Other patterns including boxcars, and sinusoids can be generated. PETO2 and PETCO2 patterns can be executed simultaneously and independent of each other.

Figure 2

Figure 3:  Normal and abnormal CVR color maps. CVR color scale corresponds to the direction and magnitude of the correlation.  Top - Example of a normal CVR. Bottom - Example of an individual with L internal carotid (ICA) occlusion with entire left hemisphere showing hemodynamic impairment (Blue - Intracerebral steal).

Figure 3

Figure 4: Long-term follow up CVR maps in a 52-year-old patient with Left MCA stenosis showing reproducibility of the test.

Figure 4

References

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  2. Juttukonda MR, Donahue MJ. Neuroimaging of vascular reserve in patients with cerebrovascular diseases. NeuroImage. 2017; 17: 30828–5.
  3. Reinhard M, Schwarzer G, Briel M, Altamura C, et al. Cerebrovascular reactivity predicts stroke in high-grade carotid artery disease. Neurology. 2014;83:1424-1431.
  4. Balucani C, Viticchi G, Falsetti L, Silvestrini M. Cerebral hemodynamics and cognitive performance in bilateral asymptomatic carotid stenosis. Neurology. 2012;79:1788-1795.
  5. Fisher JA, Venkatraghavan L, Mikulis DJ. Magnetic Resonance Imaging-Based Cerebrovascular Reactivity and Hemodynamic Reserve. Stroke. 2018 Aug;49(8):2011-2018.
  6. Ito S, Mardimae A, Han J, Duffin J, et al. Non-invasive prospective targeting of arterial PCO2 in subjects at rest. J Physiol 2008; 586: 3675-82.
  7. Fisher JA, Iscoe S, Duffin J. Sequential gas delivery provides precise control of alveolar gas exchange. Respir Physiol Neurobiol. 2016; 225:60-69.
  8. Mandell DM, Han JS, Poublanc J, Crawley AP, et al. Quantitative measurement of cerebrovascular reactivity by blood oxygen level-dependent MR imaging in patients with intracranial stenosis: preoperative cerebrovascular reactivity predicts the effect of extracranial-intracranial bypass surgery. AJNR Am J Neuroradiol. 2011; 32:721-727.
  9. Sam K, Crawley AP, Conklin J, Poublanc J, et al. Development of white matter hyperintensity is preceded by reduced cerebrovascular reactivity. Annals of Neurology. 2016: 80:277-85.
  10. De costa CL, Fierstra J, Fisher JA, Mikulis DJ,  et al.  BOLD MRI and early impairment of cerebrovascular reserve after aneurysmal subarachnoid hemorrhage. J. Magn Reson. Imaging 2014; 40:972-979.
  11. Mutch WAC, Ellis MJ, Ryner LN, Graham MR, et al. Brain magnetic resonance imaging co2 stress testing in adolescent postconcussion syndrome. J Neurosurg. 2016;0:1-13.
  12. Ryan CM, Battisti-Charbonney A, Sobczyk O, Mikulis DJ, et al. Evaluation of Cerebrovascular Reactivity in Subjects with and without Obstructive Sleep Apnea. J Stroke Cerebrovasc Dis. 2018 ;27:162-168.

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