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Task-phase fMRI evidencing cognitive improvement post carotid angioplasty and stenting (CAS) – initial findings of a follow-up study
Betty Chinda1,2, Simon Liang3, William Siu4, George Medvedev5, and Xiaowei Song1,2
1Department of Biomedical Physiology & Kinesiology, Simon Fraser University, Burnaby, BC, Canada, 2Health Research and Innovation, Fraser Health Authority, Surrey, BC, Canada, 3Department of Medicine, University of British Columbia, Vancouver, BC, Canada, 4Department of Radiology, Royal Columbian Hospital, New Westminster, BC, Canada, 5Department of Neurology, Royal Columbian Hospital, New Westminster, BC, Canada

Synopsis

This longitudinal task-phase fMRI study aims to provide direct evidence of possible effects of Carotid angioplasty and stenting (CAS) on cognition. The initial phase enrolled patients with severe carotid stenosis (≥70% stenosis) who had MRI scans pre-CAS and two-month post-CAS. At each scan, patients completed two fMRI sessions while performing a working memory task. Improved cerebral perfusion to areas supplied by carotid arteries following CAS was correlated with improved cognitive function in working memory performance along with increased fMRI activations in the re-perfused vascular territory especially in frontal and temporal lobes and reduced in the contralateral hemisphere.

Introduction

The narrowing of the carotid arteries with plaque formation (carotid stenosis) represents a major risk factor for ischemic stroke and cognitive impairments especially when severe (≥70% stenosis).1-2 Carotid angioplasty and stenting (CAS) is a standard clinical treatment to reduce stroke risk. 3 The cognitive effect of CAS remains largely unknown. Current clinical standard evaluates primarily the successful completion of the procedure by assessing correct stent placement and perioperative complications such as 30-day stroke rate and death. 4 Previous research has mostly relied on paper-based cognitive tests to study the cognitive impact of CAS while the few functional MRI (fMRI) studies were only conducted at resting phase. 5-11 Both traditional cognitive tests and the resting-state fMRI data lacked the ability to detect the brain functional changes in solving cognitive problems that require the application of task-phase fMRI. This study aims to provide direct evidence of possible effects of CAS on cognition, using task-phase blood-oxygen level dependent (BOLD) fMRI.

Methods

This study built is on top of standard clinical care. Patients with carotid stenosis scheduled for CAS as part of standard care, had MRI scans pre-CAS and two-month post-CAS. The initial findings involved two patients. Case 1 is a 65-year-old man who had severe (>95%) flow-limiting stenosis in the right carotid artery. Case 2 is an 81-year-old man who had 70% non-flow limiting stenosis in the left carotid artery (Figure 1). At each scan, patients completed two fMRI sessions that lasted for approximately 5 minutes each, while performing a working memory task. The delayed match to sample working memory task was applied, adapted with modification for the study with two levels of task difficulties (Figure 2). The task began with presentation of a stimulus (for encoding), followed by a 2.7 sec delay, and then a response, for which participants were instructed to indicate the stimulus shown before, when it was presented together with a distractor image. 12-13 MRI scans were conducted using a whole-body Philips Ingenia 3.0T CX Quasar Dual MRI system equipped with 32-channel dStream head coil and operated by Release 5.3 (Philips Medical Systems Nederland B.V.). The fMRI utilized an echo planar imaging (GRE-EPI) sequence (TR/TE=2000/30ms, flip angle=90◦, 3x3x3 mm3 voxels covering the whole-brain). High-resolution anatomical T1 images (for co-registration) were acquired. Data were analyzed using FMRI Expert Analysis Toolbox following standard procedures. 14-15 Accuracy, reaction time, and brain activation were analyzed for each patient for possible pre-post CAS changes.

Results

Case 1 showed increased activation in the right (treated-side) frontal and medial temporal lobes post-CAS; which was associated with improvements in accuracy (from 58% to 74%) and task completion rate (from 17% to 72%). Excellent baseline cognitive performance was observed pre-CAS across both the simple and difficult tasks, which was not improved further by the CAS procedure in Case 2. Case 2 completed the tasks pre- and post-CAS with >90% accuracy, while decreased fMRI activation in the contralateral (untreated) hemisphere and mildly increased activation in the left (treated -side) anterior circulation territory were observed post-CAS (Figures 3-5).

Discussion

Improved cerebral perfusion to areas supplied by carotid arteries following CAS was correlated with improved cognitive function in working memory performance along with increased fMRI activations in the re-perfused vascular territory especially in frontal and temporal lobes and reduced in the contralateral hemisphere. However, considerable individual variability between the two cases impacted the cognitive changes observed post-CAS. Higher severity of stenosis with great flow limitation, poorer collateral circulation and lower cognitive reserve pre-CAS was associated with greater cognitive improvements post-CAS in Case 1 compared to Case 2.

Conclusion

This study provided the first task-phase fMRI data demonstrating that CAS improved cognitive function in the re-perfused vascular territory. The finding supports the role of CAS in improving cognitive performance beyond reducing stroke risk. Enlightened by these cases, we hope to further test the cognitive outcomes of artery stenting using task-phase fMRI as described here with increased sample size and more follow-up sessions, involving matched healthy control participants.

Acknowledgements

The authors would like to thank Bob Strain and Kim Crooks-William, patient partners of the research project for their valuable and constructive contributions. We thank the patient participants for volunteering in the study. We thank the SFU ImageTech Lab for approval for the research team to conduct the MRI experiment with three hours of pilot scans at reduced MRI scanner fee charge. The authors acknowledge the Departments of Medical Imaging, Interventional Radiology and Neurology at Royal Columbian Hospital, Department of Evaluation and Research Services, and Surrey Memorial Hospital of Fraser Health for technical and administrative supports.

This work was supported by a research grant from the Royal Columbian Hospital Foundation (G2019-21000). Additional research and scholarship supports were from the Surrey Hospital Foundation (G2017-001), Canadian Institute of Health Research Graduate Scholarship Program and the BC SUPPORT Unit Fraser Centre SPOR initiative.

References

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Figures

Carotid angiogram pre-and post-stenting in anteroposterior and lateral projections: The left figure shows the carotid angiogram for Case 1 with right carotid artery flow-limiting stenosis (>95%, determined using NASCET criteria) while the right figure shows Case 2 with left carotid artery non-flow-limiting stenosis (70%, NASCET criteria). The top and bottom panels show the anteroposterior and lateral projections respectively. In each panel, the left image shows the pre-CAS stenotic artery while the right image shows the post-CAS artery with the stent implanted.

FMRI task design: The delayed match to sample task begins with the study stimulus (encoding), followed by a delay, and then a response time in which participants must correctly select the study stimulus when it is presented together with a distractor. There are two levels of task complexity; a simple (3*3 grid) and a difficult (5*5 grid) task. Each participant had 2 BOLD-fMRI scans to perform both levels of the task. The task is presented in block design with 5 blocks and 6 rest phases. Each block contains 6 stimuli such that a total of 30 responses are collected in each fMRI scan session.

FMRI activation maps: Z statistic images were thresholded using clusters determined by Z>2 (P=0.05). The top panel shows comparison of brain activation of the simple and difficult tasks (pre-and post-CAS); the middle and bottom panels shows subtraction images of the two time-points for the simple and difficult tasks respectively.Case 1 (left) had more activations in the treated right hemisphere post-CAS (green arrows). Case 2 (right) had more fMRI activations post-CAS in the treated left hemisphere (green arrows) and reduced in the contralateral hemisphere (blue arrows).

Strength of brain activation in regions associated with cognition: This figure shows a query into the dorsal frontal cortical network (BA 8 & 46) as well as the medial temporal lobes for both cases on the simple and difficult tasks pre (blue) and post (red) CAS. The bars are the strength of fMRI activation generated by multiplying the mean value and number of the z-thresholded voxel clusters. Case 1 (top) shows increased activations post CAS for all brain regions in the right stented hemisphere. Case 2 (bottom) shows decreased activations post CAS, consistent with the behavioral results.

fMRI Task Performance Pre-and Post CAS: This table shows the results of the fMRI behavioural task (accuracy, reaction time and task completion rates) pre- and post-CAS for both Case 1 (top) and Case 2 (bottom).

Proc. Intl. Soc. Mag. Reson. Med. 29 (2021)
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