Neuroimaging Assessment of Cerebrovascular Reactivity in Concussion: Current Concepts, Methodological Considerations, and Review of the Literature

Abstract

Concussion is a form of traumatic brain injury (TBI) that presents with a wide spectrum of subjective symptoms and few objective clinical findings. Emerging research suggests that one of the processes that may contribute to concussion pathophysiology is dysregulation of cerebral blood flow (CBF) leading to a mismatch between CBF delivery and the metabolic needs of the injured brain. Cerebrovascular reactivity (CVR) is defined as the change in CBF in response to a measured vasoactive stimulus. Several magnetic resonance imaging (MRI) techniques can be used as a surrogate measure of CBF in clinical and laboratory studies. In order to provide an accurate assessment of CVR, these sequences must be combined with a reliable, reproducible vasoactive stimulus that can manipulate CBF. Although CVR imaging currently plays a crucial role in the diagnosis and management of many cerebrovascular diseases, only recently have studies begun to apply this assessment tool in patients with concussion. In order to evaluate the quality, reliability, and relevance of CVR studies in concussion, it is important that clinicians and researchers have a strong foundational understanding of the role of CBF regulation in health, concussion, and more severe forms of TBI, and an awareness of the advantages and limitations of currently available CVR measurement techniques. Accordingly, in this review, we (1) discuss the role of CVR in TBI and concussion, (2) examine methodological considerations for MRI-based measurement of CVR, and (3) provide an overview of published CVR studies in concussion patients.

Keywords: blood oxygen level-dependent imaging; carbon dioxide; cerebrovascular reactivity; concussion; magnetic resonance imaging.

Figures

Figure 1

General schema of cerebral perfusion. Intracranial vessels are perfused in parallel in a fractal branching pattern. The net flow in each region is dynamically determined by the net flow resistance of each branch. Under normal conditions, the inflow from major extracranial vessels is not limiting. The flow to each vascular region is controlled by its local factors as shown in the figure. The net effect of regional vascular resistances determines the total cerebral blood flow. However, with a strong global vasodilatory stimulus, the drop in resistance in the collective downstream branches can be reduced to the point where the blood flow in the larger supply vessels is limiting (“fixed minimal resistance” in supply vessel in the figure). Abbreviation: CPP, cerebral perfusion pressure; MAP, mean arterial pressure; ICP, intracranial pressure; PaCO2, arterial partial pressure of carbon dioxide; PaO2, arterial partial pressure of oxygen; Ca++, calcium ions; ACh, acetylcholine; VIP, vasoactive intestinal polypeptide; PGE, prostaglandins.

Figure 2

The effect of a global vasodilatory stimulus on regional blood flow with normal vasculature and with impaired regional vascular response. (A) The normal state at normocapnia. The extent of red color in the vascular beds represents actual blood flow and blue color represents potential blood flow. “++/++” beside vessels represents normal blood flow at rest (++) compared to the flow demand (++). This would be the case for normal vasculature and for vasculature that has branches with reduced vasodilatory capacity. (B) With normal vasculature, hypercapnia stimulates increase blood demand by the vascular beds. The vasodilatory demand of the vascular beds combined exceed that of the main feeding vessel (23), which is limiting, i.e., their flow (+++) does not meet demand (++++). However, the dilatory response capability of each feeding vessel is symmetrical and so is their flow. (C) In the presence of a dysfunctional vessel, a hypercapnic stimulus results in the same demand in the healthy and dysfunctional vessel (i.e., ++++). There is a strong vasodilation in the healthy (upper) branch and a weaker vasodilation in the dysfunctional (lower) branch. The inflow from the main vessel is still limiting (i.e., +++/++++). The direct competition for flow between the vascular beds results in an increased proportion of the flow through the normal vessel (++++) at the expense of the dysfunctional vessel [flow reduced from +++ in (B), to ++]. This is referred to as vascular ‘steal’.

Figure 3

Block design breathing protocol using model-based prospective end-tidal ETCO2 and ETO2 targeting. Triple hypercapnic stimulus during controlled iso-oxic conditions is illustrated. Breath-by-breath confirmation of ETCO2 and ETO2 allows for accurate measurement and interpretation of CVR assessments.

Figure 4

Second-level analysis maps and postconcussion symptom scale scores for healthy control subject and adolescent postconcussion syndrome patient. Second level individual comparisons examined at the p = 0.005 level demonstrate no evidence of abnormal voxels in the healthy control subject compared to the atlas of normal controls (left panel). Quantitative patient-specific alterations in cerebrovascular responsiveness are demonstrated in the adolescent postconcussion syndrome patient (right panel).

Figure 5

Longitudinal assessment of healthy control subject. Second-level analysis in a healthy adolescent imaged 18 months apart and compared to a normal atlas reveals stable CVR assessment. The p-value is 0.005 as in Figure 4.

Figure 6

Longitudinal assessment of adolescent postconcussion syndrome patient. Symptomatic adolescent PCS patient imaged following abnormal formal neuropsychological testing and symptom-limiting threshold on graded aerobic treadmill testing 3 months post-injury [left panel; image reproduced with permission from Journal of Neurosurgery [Mutch et al. (17)]. Patient re-imaged 5 months later following treatment with sub-maximal exercise prescription resulting in symptom, neuropsychological, and physiological recovery (right panel). The p-value is 0.005 as in Figures 4 and 5.