Jennifer M Watchmaker1, Blaise deB Frederick2,3, Meher R Juttukonda1, Sarah K Lants1, Larry T Davis1, Matthew R Fusco4, and Manus J Donahue1,5,6
1Radiology & Radiological Sciences, Vanderbilt University, Nashville, TN, United States, 2Mclean Hospital, Brain Imaging Center, Belmont, MA, United States, 3Department of Psychiatry, Harvard Medical School, Boston, MA, United States, 4Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, TN, United States, 5Department of Psychiatry, Vanderbilt University Medical Center, Nashville, TN, United States, 6Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, United States
Synopsis
Structural
and BOLD-weighted hemodynamic imaging was performed in patients with
intracranial steno-occlusion due to moyamoya disease before and after surgical
revascularization. A novel data-driven time-delay analysis was performed using cross-correlation
of functional imaging data to find the time at which maximum correlation occurs
between the BOLD signal from each voxel and a reference regressor. This provides
a novel metric of hemodynamic impairment (lagtime) that may be indicative of
vascular smooth muscle dysfunction and therefore delayed reactivity. We found
that in patients with successful revascularization on angiography, lagtimes
decreased, and in patients with unsuccessful revascularization and progressive disease,
lagtimes increased.
Purpose
The overall goal of this work is to implement
novel analysis tools to separately quantify cerebrovascular reactivity (CVR)
magnitude and CVR response time and to use this information to evaluate
functional differences in collateral vessels before and after surgical
revascularization. More specifically, recent
elegant optical imaging work in anesthetized rats has revealed that endothelial
disruption significantly attenuates the functional hyperemia response1, and more recently it has been shown that neo-angiogenic
collateral vessels in patients with cerebrovascular disease may have
distinct vasoactive properties relative to healthy vessels2. These findings suggest that not only the
magnitude of the change in blood volume and flow of parenchyma, commonly
referred to as CVR, but also the time for parenchymal vessels to respond
maximally to vasoactive stimuli or progressive reductions in cerebral perfusion
pressure, may represent distinct features of parenchymal health. To investigate
this possibility, we implemented a novel, data-driven time regression analysis
of CVR data in patients with non-atherosclerotic intracranial stenosis (i.e.,
moyamoya disease) before and after surgical revascularization in sequence with
catheter angiography. The goal was to understand the relationship between the
structure of collateral vessel formation from angiography and the function of
these collateral vessels from hemodynamic MRI. Methods
Patients
(n=15) with at least one imaging time point before and after revascularization
were included and post revascularization MRI scans were obtained (13.9 ± 5.2
months) following surgery at the time when follow-up imaging was
clinically-indicated. Images were acquired at 3T (Philips), including standard
T1-weighted, FLAIR, and DWI, together with hypercapnic (180s/180s
normocapnia/5%-hypercapnia repeated once) gradient echo BOLD (spatial
resolution=3.4x3.4x5 mm3; TR=2s; measurements=450). Data were preprocessed3 (slice time correction, motion correction) and registered
to the T1-weighted image and to an MNI atlas. Lagtimes were calculated using RapidTiDe4, which performs time-delay cross-correlation analysis of
functional imaging data to find the time at which maximum correlation occurs between
BOLD signal from each voxel in a given time series compared to a reference
regressor (Figure 1). A refined global
regressor was used as the reference regressor and was determined for each
functional imaging dataset. Maximum CVR was also determined, which
corresponded to the z-statistic at the time of the voxel-wise lagtime, and was normalized
to a healthy occipital region. Vascular stenosis was assessed by digital subtraction angiography (DSA) and graded by a radiologist. Success was graded based
on amount of middle cerebral artery (MCA) territory revascularized (0=no
revascularization; 1=<1/3 MCA territory; 2=1/3 – 2/3 MCA territory; 3=>2/3
MCA territory).
Results
In n=15 patients, 20 indirect
revascularization procedures were performed with varied outcomes on
post-surgery DSA (grading categories 0/1/2/3 corresponding to 1/5/8/6
procedures, respectively). Hemodynamic MRI imaging was performed which provided additional
spatial information not apparent from angiography alone. Figure 2 shows an
example of a patient who has significant stenosis and lenticulostriate
collaterals consistent with advanced moyamoya (Figure 2A) who underwent
surgical revascularization. On post-surgical DSA, there are an abundance of collaterals (Figure 2B, yellow arrow). CVR imaging (Figure 2C) shows improvement in the
right hemisphere, whereas maximum CVR (Figure 2D) does not change. The lagtimes
(Figure 2E) decrease in the operative hemisphere, and interestingly also in the
contralateral hemisphere. The lagtime changes in this patient are shown as
individual histograms (Figure 2F), and a trend for decrease in longer lagtimes
can be seen in the scans following surgical revascularization that resulted in robust collateral formation. Additional
subjects (Figure 3) show regional differences largely consistent with
vasculopathy and revascularization success, with CVR magnitude being more
constant and symmetric relative to CVR response time.
Discussion
Time-delay processing
of BOLD data may provide additional information beyond more qualitative measures
such as z-statistic or signal change measurements. The global decrease in
lagtimes observed following successful revascularization can potentially be
explained by the known effect of revascularization on not only the surgical
hemisphere, but also the contralateral hemisphere5. Whole brain lagtimes are delayed in moyamoya
disease prior to surgical revascularization, as evidenced on histogram analysis
of lagtimes wherein the majority of the voxels have lagtimes exceeding 10
seconds. Of note, lagtimes greatly exceed
arterial circulation times (ACT) even in patients with steno-occlusion and
delayed filling (wherein ACT ~3 seconds for patients with advanced moyamoya)6, and may represent unique measures of smooth
muscle reactivity to hypercapnic stimuli, which can be evaluated when
moderate-to-long stimulus durations of 60s or more are used. Additionally, this
data-driven approach may reduce the need for EtCO2 traces, which can
have substantial delays and sampling errors.
Conclusion
Reactivity time
(lagtime) and maximum reactivity are potentially unique and non-overlapping
indicators of impairment and collateral vessel health. Acknowledgements
No acknowledgement found.References
1. Chen
BR, Kozberg MG, et al. A critical role for the
vascular endothelium in functional neurovascular coupling in the brain. J Am Heart Assoc. 2014;3:e000787
2.
Roach BA, Donahue MJ, Davis LT,
et al. Interrogating the functional correlates
of collateralization in patients with intracranial stenosis using multimodal
hemodynamic imaging. AJNR Am J
Neuroradiol. 2016;37:1132-1138
3. Smith SM, Jenkinson M,
Woolrich MW, et al. Advances in
functional and structural mr image analysis and implementation as fsl. Neuroimage. 2004;23 Suppl 1:S208-219
4.
Donahue MJ, Strother MK,
Lindsey KP, et al. Time delay processing of
hypercapnic fmri allows quantitative parameterization of cerebrovascular
reactivity and blood flow delays. J Cereb
Blood Flow Metab. 2016;36:1767-1779
5. Sam K, Poublanc J, Sobczyk
O, et al. Assessing the effect of
unilateral cerebral revascularisation on the vascular reactivity of the
non-intervened hemisphere: A retrospective observational study. BMJ Open. 2015;5:e006014
6. Donahue MJ, Ayad M, Moore
R, et al. Relationships between hypercarbic
reactivity, cerebral blood flow, and arterial circulation times in patients
with moyamoya disease. J Magn Reson
Imaging. 2013;38:1129-1139