Effects of Aerobic Exercise on the Cerebral Arterial System, Cognitive, and Motor Function in Post-stroke Patients.

Background: Stroke is the second leading cause of death and disability worldwide and in Hong Kong, 6.2% of all registered deaths in 2020 were due to cerebrovascular disease. Exercise training has the potential to improve the deconditioned hemodynamic, motor, and cognitive functions associated with stroke.

Purpose: The proposed study seeks to investigate the effects of AET on the large intracranial and extracranial cerebral arteries' morphological and haemodynamic features and the cognitive and motor functions in post-stroke chronic patients. Additionally, the study seeks to compare the cerebral arteries' features between post-stroke patients and age-matched controls without stroke. Furthermore, the project seeks to assess the association between the cerebrovascular system changes and the cognitive and motor function changes in post-stroke patients undergoing AET.

Study Design: A Randomised controlled trial (RCT) in which the post-stroke patients will be randomly assigned into three groups consisting of a control group and two AET interventional groups (treadmill and cycle ergometer). Each group will target sample size of 20 participants. The target dosage for the two AET modes will consist of 1.) a session duration=30mins, 2.) frequency=3times/week, 3.) high intensity=(60-84% heart rate reserve (HHR).4.) Types=Treadmill and cycle ergometer 5.) overall program duration=3months.

Data collection methods: Quantitative data on the cerebral arteries' haemodynamic and morphological features will be assessed using duplex carotid ultrasound (DCUS) and transcranial Doppler (TCD) ultrasound techniques. Montreal cognitive assessment (HK) version and six-minute walk test (6MWT) will assess cognitive and motor functions respectively. The data will be assessed at three time periods of during the 3 months AET program

Significance of the study: The study has the potential to inform the clinical decision making process on the usefulness of AET in improving post-stroke chronic patients. Results on associations will provide a basis for future work in chronic stroke Rehabilitation functional outcome prediction models based on DCUS and TCD ultrasound imaging techniques.

Stroke is a medical condition defined as the "rapidly developing clinical signs of focal (or global) disturbance of cerebral function, with symptoms lasting 24 hours or longer or leading to death, with no apparent cause other than of vascular origin". It is characterized by the deconditioned hemodynamic, motor, and cognitive functions among other things. The condition poses a serious economic and social burden worldwide as it is the second leading cause of death and disability. In China, stroke is ranked the number three cause of death following malignant tumors and heart disease with a reported death rate of 149.5 per 100,000 and accounting for 1.57 million deaths in 2018 whereas, in Hong Kong, 6.2% of all registered deaths in 2020 were attributed to cerebrovascular disease.

To mitigate the challenges and burden associated with stroke, preventative measures such as advocating for healthy living to control the stroke risk factors have been suggested. However, despite the presence of such measures, it cannot be argued that stroke occurrence is inevitable as evidenced by the above statistics. There is a need, therefore, to come up with robust and efficient stroke treatment and management approaches aimed at preventing stroke recurrence and improving the survival and quality of life of post-stroke patients. Rehabilitation is one such non-pharmacological, therapeutic intervention that is aimed at restoring the lost function in the various domains associated with stroke. Since Ischemic stroke is a consequence of inadequate blood flow and oxygen to the brain due to thromboembolic occlusion, the rehabilitation techniques should therefore target to improve the health status of the cerebral arteries (intracranial and extracranial) and restore the cognitive and motor function to achieve positive post-stroke outcomes. Among the various rehabilitation techniques, Aerobic exercise training (AET) defined as "structured exercise programs that involve the rhythmical movement of large muscles for sustained periods", has the potential to restore the deconditioned hemodynamic, cognitive and motor function that characterizes the presence of stroke and treadmill training(TT) together with cycle ergometer are two such common types of AET.

The principal mechanism by which AET may improve cerebrovascular blood flow is through increased production of nitric oxide (NO), a known mediator of endothelial function. NO is reported to have anti-atherogenic properties that may prevent plaque buildup in the blood vessels, hence has the potential to promote positive cerebrovascular morphological changes within the large intracranial and extracranial arteries in ischemic stroke patients, key attributes necessary for the improvement of post-stroke patients' quality of life and in preventing stroke recurrence. There is however limited information on the potential reduction in the atherosclerotic plaque among chronic stroke patients undergoing AET. Duplex carotid ultrasound (DCUS) and transcranial Doppler ultrasound (TCD) are two non-invasive and non-ionizing techniques that can be used to assess the haemodynamic and morphological changes within the extracranial and intracranial cerebral arteries respectively. Despite cerebral hemodynamics having been demonstrated to play an important role in the occurrence of ischemic brain damage, only limited attempts have been made to interrogate the underlying haemodynamic changes within the intracranial and extracranial cerebral arteries that are brought about by AET in post-stroke patients and how these are associated with the possible changes in both motor and cognitive function. The few studies that have assessed the potential cerebrovascular system beneficial effects of AET have reported contradictory findings.

Despite the contradictory findings, it is imperative to note that these studies have focused on assessing the effects of exercise training on only a single hemodynamic parameter, the mean flow velocity from (TCD) and there is paucity of evidence on its effect on the extracranial cerebral arteries hemodynamic and morphological features. Additionally, Carotid ultrasonography scanning techniques have evolved over the recent years with new techniques such as carotid arterial stiffness analysis, three-dimensional(3D) vessel wall imaging, computer assisted image analysis (CAIA) emerging and these methods have been concluded to reliably and accurately assess the extracranial cerebral vessel's morphology in other populations apart from chronic stroke patients, hence have the potential to better monitor and provide a holistic assessment of the changes that may occur in the extracranial cerebral arteries in post stroke patients undergoing aerobic exercise training.

Considering the above mentioned diversified and contradictory background, coupled with the emerging of advanced ultrasonography techniques, the need to further interrogate the possible value of AET in improving cerebral arteries' haemodynamics and morphology as well as cognitive and motor function in post-stroke patients using robust study designs, incorporating evidence based prescription, whilst utilising a multi-parametric approach incorporating, novel CUS techniques to assess the primary outcomes cannot be overemphasized. The following aims were formulated based on the above background information.

The purpose of the study is to investigate the effects of AET on the large intracranial and extracranial cerebral arteries as assessed by novel, multi-parametric Duplex Carotid ultrasound (DCUS) techniques and transcranial Doppler (TCD) ultrasound, and on the cognitive and motor functions in post-stroke chronic patients. Additionally, the study seeks to compare the morphological and hemodynamic features of the large intracranial and extracranial cerebral arteries between post stroke patients and age-matched controls without stroke as determined by DCUS and TCD ultrasound.

The study is a quantitative, prospective randomised controlled trial study involving chronic stroke adult patients and age matched non stroke subjects and will be undertaken at the ultrasound laboratory of the Hong Kong Polytechnic University from January 2023 to August 2024. Ethical approval was obtained from the Institutional Review Board (IRB) of the Hong Kong Polytechnic University (Ref: HSEARS20220714001). Informed consent will be obtained from the patients whilst a coding system will be used to ensure the confidentiality and anonymity of the research subjects. Probability sampling involving a simple random technique will be employed. Assuming a medium effect size of 0.5, α of 0.05, statistical power of 80% and a 17% dropout rate, to achieve the objective of comparing the large intracranial and extracranial cerebral arteries morphological and haemodynamic features between the post stroke patients and the age-matched non stroke subjects a sample size of 120 subjects is targeted (60 stroke patients and 60 Non stroke) as calculated from the G\* Power software using the t-test (Difference between two independent means). Based on an effect size of 0.59, α of 0.05, statistical power of 80%, and a 15% dropout rate, a minimum sample size of 13 subjects in each of the three post-stroke groups undergoing AET is required, as calculated from the G\* Power software using the F test (one-way fixed effects ANOVA).

Post stroke chronic patients of Chinese origin with mild to moderate disability who can undertake the two AET are targeted to be included in the study. Since age is a confounding variable in post-stroke recovery, only patients greater than 50 years old, with \> 6months from time of stroke onset (chronic stroke patients). To cater for the clinical factor of stroke subtype only subjects with ischemic stroke which is the most common stroke subtype will be recruited. Patients with insufficient bone windows to allow for TCD assessment and those with substantial cardiovascular risk factors to perform AET will also be excluded from the study.

Carotid ultrasound and transcranial Doppler ultrasound machines will be used to examine the large extracranial and intracranial arteries' haemodynamic and morphological features respectively. Treadmill and Cycle ergometer equipment will be used for the AET. The carotid protocol will involve assessing the extracranial carotid artery morphological parameters using novel approaches such as 3D degree of arterial stenosis assessment, arterial stiffness analysis, and automated CIMT analysis, whereas the haemodynamic features (mean flow velocity (MFV), peak systolic velocity (PSV), end diastolic velocity (EDV), resistive index (RI), and pulsatility index (PI) will also be assessed. The TCD ultrasound protocols will involve scanning of the bilateral middle cerebral arteries (MCA) through the transtemporal window. The spectral Doppler parameters (MFV, PSV, EDV, PI, and RI.) will be measured.

The target dosage for the two AET modes will consist of 1.) a session duration=30mins, 2.) frequency=3times/week, 3.) high intensity=(60-84% heart rate reserve (HHR).4.) Types=Treadmill and cycle ergometer 5.)overall program duration=3months.

IBM SPSS (Statistical Package for the Social Science) version 25 statistical package will be used for data analysis in this study. Both descriptive and inferential statistics will be utilized. The repeated measures ANOVA or non-parametric equivalent Friedman test will be used to perform an intra-group assessment of the outcome measures whereas One Way ANOVA will perform the between group analysis. The statistical significance will be considered at p\<0.05. The standardized mean difference (SMD) will be used to quantify the treatment benefits or effect of the AET. The effects size shall be categorized as small (0.2-0.5), medium (0.5-0.8) or large (≥0.8).

Significance of the study.

Knowledge on the possible improvement in the large intracranial and extracranial arteries haemodynamic and morphological features in post stroke patients following AET can provide a measure of the effectiveness of the AET in improving the health outcomes of post-stroke patients, and thus assist in the clinical management of these patients. The use of novel, multi-parametric ultrasound-based approaches such as 3D arterial stenosis, arterial stiffness, and automated CIMT analysis in this subject group will set baseline values that can be useful for future research. The study results will also inform the therapists and clinicians on the AET modality that is more effective in improving the cerebral arteries haemodynamic and morphological features and the cognitive and motor functional outcomes in post-stroke patients. The improvement of neurocognitive and motor functioning in post stroke patients has important public health implications as this reduce the socioeconomic burden associated with the further deterioration of neurocognitive function that has been associated with increased risk of dementia and high mortality rates.

Eligibility Criteria:
Inclusion Criteria:

1. Inclusion criteria post stroke group

   1. Post stroke adult patients of Chinese origin, who are 50 years old or above,
   2. Time of stroke onset \>6months (chronic),
   3. Mild to moderate disability to be able to undertake aerobic exercise training (treadmill and stationery cycling),
   4. Not participating in a structured aerobic exercise training.
2. Inclusion criteria Non stroke group.

   1. Adults of Chinese origin who are 50 years old or above,
   2. No history of stroke or Transient Ischemic stroke (TIA).

Exclusion Criteria:

1. Exclusion criteria post- stroke group

   1. Non-Chinese nationals,
   2. Time of stroke onset\<6months,
   3. Below 50 years of age,
   4. Currently participating in a structured aerobic exercise training,
   5. Cannot perform treadmill walking or stationery cycling, and
   6. Allergic to ultrasound gel.
2. Exclusion criteria Non-stroke group.

   1. History of stroke or TIA.,
   2. Non-Chinese nationals,
   3. Below 50 years of age, and
   4. Allergic to ultrasound gel.