Jim Gatheral and Mac Robertson Scholarship Final Report 2013/2014

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Phoebe Harrison
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Jim Gatheral and Mac Robertson Scholarship Final Report 2013/2014 About me: I am a British national and medical doctor, training to be a Neurologist.

1 Jim Gatheral and Mac Robertson Scholarship Final Report 2013/2014 About me: I am a British national and medical doctor, training to be a Neurologist. In December 2010, I took up the post of Clinical Research Fellow in Neurology at the University of Glasgow after taking an Out-of-Program for research time from the NHS Neurology Specialist training post. My research interest in stroke led me to be a co-investigator for a first-in-man fully regulated clinical trial investigating the feasibility and safety of human neural stem cells (hnsc) in chronic stroke. Professor Keith Muir is the principal investigator and my supervisor. During my final year of PhD studies, I was awarded the 2013/2014 Jim Gatheral ( 2,222) and Mac Robertson ( 1,988) Scholarship totaling My visit was to Washington University in St. Louis, Missouri, USA from November 2013 to January Background Research: My PhD research is in the area of novel regenerative therapy for ischaemic stroke, in particular to investigate the safety, feasibility and explore neuroimaging biomarkers of intracranial implantation of human neural stem cells. We have recruited 11 patients with stable disability following an ischaemic stroke at least 6 months previously. Two months after recruitment patients received one injection of CTX0E03 hnsc around the putamen on the side of the cerebral infarct. Longitudinal assessments over 2 years included baseline clinical assessments, blood tests and magnetic resonance brain imaging (MRI) and repeated at month 1 and 12 after implantation. Structural neuroimaging is of limited value in predicting functional recovery. Newer functional brain imaging that help to map physiological activity and understand coordinated activity of large scale brain networks are needed to define brain response to novel therapies and improve clinical predictions. Application of mathematical models is the basis to analyse MR imaging data and help solve real world clinical questions. 1

2 Why did I apply for this scholarship? Functional MR imaging is a growing field with newer approaches to acquiring and analysing magnetic resonance imaging data. Altered neuro-anatomical brain imaging from patients with chronic stroke adds an additional complexity for analysing softwares. One way of getting around this is by masking the brain lesion. I had liaised with Dr.Corbetta and planned a collaboration to share our knowledge of the novel therapy while simultaneously I learn imaging analysis techniques. This necessitated travel to Washington University and stay in St. Louis for weeks. Details of visit to Washington University in St. Louis, USA: I visited the neuroimaging lab led by Professor Maurizio Corbetta at Washington University in St. Louis, MO, USA and spent 2.5 months from 5 th Nov 2013 to 12 th Jan I gave a talk in the first week detailing about my research and aims of my visit. I had a workstation for my use and was able to work on locally collected data to learn the techniques and also on the data collected in Glasgow. Dr.Corbetta and I agreed to focus on motor network to begin with. Before statistical analysis, I had to prepare the raw data so that it was analysable. This involved a series of pre-processing 1. Pre-processing: The raw data recorded from the MRI scanner had to go through a series of pre-processing steps that involved 14 different levels. This was automated by using a software script running on a Linux workstation. First the raw DICOM data (scanner standard format) was converted to a 4-dimensional floating point (4dfp) format. To negate patient movement effects the images were realigned so as to make sure a point in brain space is the same throughout the data. The brain was then normalized, a step very important to make sure the different sized brains are all within a common space again to make sure a point in brain space is the same throughout the data. Some of the final steps included transforming the functional data to a brain atlas space and applying the individual lesions to this, so all sequences are merged into one common space to apply statistical tests. 2

3 Fig 1: Example of a stroke lesion (yellow) mask. 2. The fmri brain data is actually a collection of many small 3 dimensional cuboids called voxels. Within each voxel there is a series of MR signals across a given time. We can run statistical correlations to explore which of these voxel signals correlate by time there by concluding that the better correlated ones are functionally relevant or connected. To do this we can identify a set of voxels (seeds) and check its connectivity against the whole brain voxels. From prior knowledge, I explored the motor cortex seeds and studied the whole brain connectivity. Unfortunately I did not find any significant change after multiple comparisons correction over the time points that we have acquired the data. Fig 2: Example of connectivity maps with seeds in left & right central sulcus. 3. Since our subjects have been injected with neural stem cells close to their putamen, I thought of investigating the lesional putamen s whole brain voxel-wise connectivity. Individual lesion and normal putamen had to be manually segmented and then converted to a region-of-interest in the atlas space. Whole brain voxel-wise connectivity was done and group maps generated at baseline, month and month12. Statistical student t tests were run at every voxel between the time points with significant increased connectivity observed between lesional putamen and bilateral caudate and contralateral thalamus. There was decreased connectivity to ipsilateral parietal cortex. At 12 months, reduced contralateral 3

4 parietal cortex connectivity was seen, compared to baseline but no significant regions compared to 1 month. Contralateral putamen connectivity negatively correlated with weak arm Ashworth scores. Fig 4: Clinical correlation with arm spasticity scores. 4. I have also processed motor task fmri and diffusion tensor imaging data and currently analysing some aspects via remote VPN access to Washington University servers from Glasgow. Impact of Scholarship: Analyses of resting state functional MRI is a vital part of my PhD research. Learning cutting edge techniques does not come easy and forging collaborations with other research centres is vital for advancing knowledge. The joint scholarship awarded to me was vital since it gave me the requested full funding and paved the way to visit a centre of excellence, learn new approaches and exchange ideas. This near 3 month stint will certainly be the highlight of my 3.5 year postgraduate research experience. 4

I submitted an abstract from work done during this visit to the 2014 European Stroke Conference and it has been accepted for an oral presentation, scheduled in May2014.

5 I submitted an abstract from work done during this visit to the 2014 European Stroke Conference and it has been accepted for an oral presentation, scheduled in May2014. I intend to work further on this and submit a manuscript for peer review and publish a journal article. At a personal level, I thoroughly enjoyed meeting new people, understanding some aspects of their culture and visiting new cities. Budweiser Brewery 5

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