Impairment of cerebral blood flow regulatory mechanisms in stroke: the influence of stroke sub-type, severity and location

Applications accepted all year round

Self-Funded PhD Students Only

About the Project

The Cerebral Haemodynamics in Ageing and Stroke Medicine (CHiASM) Research Group of the Division of Cardiovascular Sciences has an international reputation for leading research on cerebral haemodynamic alterations resulting from ischaemic and/or haemorrhagic stroke. The group’s reputation has been the result of a focused MD/PhD programme in the last 25 years, as well as several intercalated BSc and MSc projects.

The PhD project will investigate the impairment of cerebral blood flow (CBF) regulatory mechanisms in patients with stroke. In particular, the new student will be carrying out a more detailed analysis of the longitudinal evolution of cerebral haemodynamic impairment in patients with haemorrhagic stroke. One key finding from our group (Salinet et al Cerebrovasc Dis Extra 2014;4:186-197), that was subsequently confirmed by other international centres, was that the impairment in CBF regulation following ischaemic stroke has a characteristic time-course that needs to be taken into account in the care plan of these patients. We have reported alterations in the cerebral haemodynamics of patients with haemorrhagic stroke, but detailed description of its temporal evolution remains to be investigated and this key feature of the response of the brain circulation to the haemorrhagic insult should be a priority target in future investigations.

Hypothesis:

Specific hypotheses would apply to the sub-studies of the project, but the overarching hypothesis is that the impairment of CBF regulatory mechanisms following haemorrhagic stroke has a temporal course that is different from what has been reported in ischaemic stroke, and it is dependent on the location and volume of the haematoma.

Research Plan:

The research plan for this project follows similar strategy adopted for previous PhD students to provide suitable training in research methods and to acquire in-depth knowledge of the topic to enable independent problem-solving and original, internationally leading results at the later stages of their research. In summary, the resulting dissertation should involve the following chapters:

1. Introduction – problem identification, state-of-the art knowledge and research proposal.
2. Systematic Review of the literature on the longitudinal changes in cerebral haemodynamics in haemorrhagic stroke (peer-reviewed publication expected). To be registered in PROSPERO.
3. Multivariate modelling study of the CBF regulation response to changes in arterial blood pressure and PaCO2. This will test the hypothesis that a combined hypercapnic-hypocapnic manoeuvre can allow simultaneous extraction of metrics defining both the dynamic cerebral autoregulation and CO2 reactivity in healthy subjects. This sub-study will not require a new ethics committee approval since it will be based on data recently added to the historical CHiASM database of physiological recordings. This sub-study should lead to one or more peer-reviewed publications.
4. Development of suitable respiratory manoeuvres for identification of CO2 reactivity in haemorrhagic stroke patients. In his project, Recent work has demonstrated that a combined hypercapnic-hypocapnic manoeuvre could be an optimal approach for identification of CO2 reactivity, combined with dynamic cerebral autoregulation in healthy subjects. However, the use of 5% CO2, followed by hyperventilation, are not suitable for use in critically ill patients and for this reason alternatives need to be found. In the first sub-study, also to be performed in healthy subjects, alternative manouevres, such as the use of different breathing frequencies and expiratory resistances, will be tested and compared to the original hypercapnic-hypocapnic manoeuvre, that will be used as reference. The sub-study will require Ethics Committee approval that will be sought through the University of Leicester Infonetica system. This sub-study should lead to at least one peer-reviewed publication. The student would receive formal training in physiological measurement including transcranial Doppler ultrasonography via the Leicester Transcranial Doppler training course.
5. Intra-subject variability of CBF regulatory parameters identified from breathing manoeuvres. In this sub-study, the manoeuvre identified as best to replace the reference hypercapnic-hypocapnic manoeuvre, will be adopted in a longitudinal study in 12 healthy subjects, to identify the reliability of four repeated measurements, with a similar design of the study performed by Brodie et al (Clin Sci 2009;116:513-520) but using multivariate modelling, instead of only the metric for dynamic cerebral autoregulation. This sub-study will require Ethical Committee approval through the University of Leicester and will provide key information to interpret the findings of the main study (Chapter 7). This sub-study should lead to at least one peer-reviewed publication.
6. Validation of suitable respiratory manoeuvres for identification of CO2 reactivity in haemorrhagic stroke (ICH) patients. In the second sub-study, the manoeuvre that best approximates the results of the reference hypercapnic-hypocapnic manouevre, identified in Chapter 4, will be adapted to be reproduced as a brief modification of ventilator parameters. This will be validated in a sub-group of 12 ICH patients, taking into consideration its safety, feasibility, acceptance, and reliability of estimated parameters. The sub-study will require Ethical Committee approval that will be sought with an IRAS application. This sub-study should lead to at least one peer-reviewed publication.
7. Identification of the longitudinal evolution of CBF regulatory mechanisms in ICH. This main study of the project will follow up patients with ICH with four repeated measurements during the three month period after hospital admission. The study will recruit a minimum of 36 patients, formed of three sub-groups of 12 patients each with distinct combinations of haematoma location and volume. The sub-study will require Ethical Committee approval that will be sought with an IRAS application. In the eventuality of lack of acceptability of the new respiratory manoeuvre, as tested in the previous sub-study (Chapter 6), estimates of CO2 reactivity will be based on spontaneous fluctuations of end-tidal CO2 as demonstated previously (Panerai et al Am J Physiol Heart Circ Physiol 2012;302:H459-H466). In either case, the corresponding information about the intra-subject variability of derived CBF regulatory metrics will be provided by the sub-study in Chapter 5. This sub-study should lead to at least two peer-reviewed publications.
8. Conclusions – Project main findings, interpretation, limitations and proposals for future work.

Project fees:

• Home - band 20, (2025/26 £15,010 pa, 2026/7 TBC)
• International - band 15, (2025/26 £32,100 pa, 2026/27 £32,900 pa)

Supervisor contact details:

Dr Jatinder Minhas - jm591@le.ac.uk

Prof Panerai - rp9@le.ac.uk