Neuronal activation induced BOLD and CBF responses upon acetazolamide administration in patients with steno-occlusive artery disease
Graphical abstract
Introduction
In patients with ischemic stroke and steno-occlusive disease of the vertebral and basilar arteries (VBAs) it is difficult to assess which patients are at risk for future stroke and should be treated with an endovascular or surgical procedure. This is crucial as the risk of early recurrent stroke is high in these patients (Gulli et al., 2013, Markus et al., 2013). An important parameter that could predict the risk of recurrent stroke is the cerebrovascular reactivity (CVR), the vasodilatory response of the cerebral resistance vessels. By measuring cerebral blood flow (CBF) before and after a vasodilatory challenge the CVR is measured and the cerebral autoregulative status can be assessed (Detre et al., 1999). As a vasodilatory challenge acetazolamide (ACZ) can be used which acts as a carbonic anhydrase inhibitor that increases the baseline CBF due to vasodilation — the degree of which gives information regarding the CVR (Russell et al., 1990, Vorstrup et al., 1984). In addition, hemodynamic compromise caused by diseased arteries can be assessed by applying a neuronal stimulus (Amemiya et al., 2012). Besides vasodilatation this will also increase the cerebral metabolic rate of oxygen (CMRO2) which may impede interpretation of the results.
For inferring neuronal activation, the most widely used imaging technique is blood-oxygenation-level-dependent (BOLD) MRI and is also becoming increasingly popular for assessing CVR (Donahue et al., 2012, Lythgoe et al., 1999, Mandell et al., 2008, Yezhuvath et al., 2009, Van Der Zande et al., 2005). The rationale for using the BOLD signal is that it reflects underlying changes in CBF that carry information regarding neurovascular coupling and CVR. Furthermore, BOLD MRI has a high image SNR allowing rich spatial and temporal information compared to other modalities for measuring CVR and activation. However, CVR measurements using BOLD MRI are only useful in an experimental design where the BOLD signal returns to baseline (and thereby can be corrected for signal drift). Therefore, BOLD CVR measurements upon ACZ administration is not a suitable option due to the long return to baseline.
The BOLD signal does not only reflect purely CBF changes, but is also modulated by changes in cerebral blood volume (CBV) and CMRO2. An increase in CBF leads to removal of deoxyhemoglobin from the local vasculature, resulting in an increase of the BOLD signal. Dilation of blood vessels (CBV increase) and increases in CMRO2 lead to more deoxyhemoglobin resulting in a BOLD signal decrease. Ultimately, the dynamic interplay of changes in CBF, CBV and CMRO2 will produce the resultant BOLD response. In healthy conditions, increased excitatory neuronal activation evokes a positive BOLD response as the relative increase in CBF is larger than the increase in CMRO2 and CBV.
Several studies have investigated BOLD responses in the human brain using vasoactive challenges such as neuronal stimuli, hypercapnia or ACZ administration in healthy subjects (Brown et al., 2003) and patients with hemodynamic impairment (Amemiya et al., 2012, Blicher et al., 2012, Hamzei et al., 2003, Murata et al., 2006, Rossini et al., 2004). In patients with cerebrovascular disease it has been demonstrated that uncoupling between changes in CBF, CBV and CMRO2 can lead to discrepant BOLD responses compared to healthy subjects (Blicher et al., 2012). This can complicate correct interpretation of neuronal activation when solely using BOLD MRI. On the other hand, discrepant BOLD responses can yield clinically relevant hemodynamic and metabolic information. In the above study by Blicher et al. only neuronal activation was evaluated in patients with cerebrovascular disease (Blicher et al., 2012). It remains unclear whether vascular stimuli, either in isolation or in conjunction with neuronal stimuli, may yield important information concerning the vascular and metabolic status of cortical tissue in these patients.
Here, we investigated BOLD and CBF responses in patients with VBA steno-occlusive disease. Specifically, we evoked neuronal BOLD and CBF responses in the visual cortex before and after a vasodilatory challenge using ACZ. We observe that combined measurements of CBF and BOLD contain crucial information in this population, and that solely BOLD or CBF cannot correctly assess the activation and condition of the vasculature and surrounding tissue.
Section snippets
Subjects and procedure
All patients (n = 8, age = 62 ± 6 years (mean ± standard deviation)) with recent (1–10 months) ischemic stroke or transient ischemic attack (TIA) in the perfusion territory of the VBAs provided written informed consent in accordance with the Declaration of Helsinki 2008 to participate in the study which was approved by the Institutional Review Board of the Utrecht University Medical Center. Diagnosis and grading of the VBA stenosis or occlusion were performed with either computed tomography or magnetic
Results
An overview of the demographic and clinical characteristics of the patients with steno-occlusive disease is shown in Table 1.
Fig. 1 shows the results of the CBF and BOLD responses from the activation-based ROI for the pre-ACZ and post-ACZ situation. Reported are the baseline CBF (CBF0), the functional CBF (ΔCBF) and BOLD response (ΔBOLD) for the group average (Figs. 1A–C) and per subject (Figs. 1D–F). Post-ACZ an overall increase in baseline CBF of approximately 50% (P < 0.005 Fig. 2A) and a
Discussion
The present study shows a reduced functional BOLD response after acetazolamide in the visual cortex of patients with steno-occlusive disease of the vertebral and basilar arteries, whereas the CBF response remained relatively similar. In 3 of 8 cases this effect was even more prominent as visual activation revealed cortical areas with substantial negative BOLD changes with concurrent positive CBF changes. These phenomena will have implications when assessing neuronal activation and neurovascular
Conclusions
The application of both functional and vasodilatory stimuli can provide useful information on neurovascular coupling in patients with cerebrovascular disease. We found that upon acetazolamide administration the visual activation induced BOLD response is reduced, or even negative (3 out of 8 subjects), whereas the CBF response remained relatively similar (but small) in patients with VBA steno-occlusive disease. These findings likely indicate an altered neurovascular and non-linear
Acknowledgments
This project was partly funded by NIH/NINDS 5R01 NS078828.
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