A longitudinal prospective research design applied in this project was motivated by the specific focus on post stroke recovery, i.e. the study of change over time. This design enabled the evaluation of how the implemented novel measures related to i) time and to ii) clinically assessed motor impairments at baseline and iii) imaging measures of stroke lesion
characteristics. This design also enabled the evaluation of predictive strength of selected factors of interest and the study of their interrelationships in motor control functions.
This thesis involved novel measures across impairment and activity levels of ICF. However, we did not use kinematic measures of arm movements in this project that may have revealed
knowledge on control of upper limb movements (Kwakkel et al., 2019). Kinematic measures have been proposed to evaluate movement quality and would have contributed additional understanding of reaching and grasping (Kwakkel et al., 2017). However, including kinematic measures was not possible in this project since the test battery was already comprehensive and additional time for further assessments was not possible. We also chose measures easy to implement early after stroke in patients with severe motor impairment. In hindsight a more detailed measurement of cognitive domains such as attention and working memory would also have been of interest (Mullick et al., 2015).
The study of neural correlates incorporated distinct structural and functional MRI techniques.
Integrity of the CST was assessed using the weighted CST lesion load (wCST-LL) metric, representing the volume of overlap between the patient’s lesion map and a probabilistic CST template (wCST-LL), derived from diffusion tensor images of healthy control subjects (Birchenall et al., 2019; Zhu et al., 2010). We also used VLSM to correlate lesion location with motor control impairments. Other measures of CST integrity are also available such as TMS for the assessment of motor evoked potentials (MEPs) and DTI measures of fractional anisotropy ratio (Bigourdan et al., 2016; Jin, Guo, Zhang, & Chen, 2017; K. H. Kim et al., 2015). To date, there is a lack of evidence supporting superiority of one method over another (Hoonhorst et al., 2018). The methods selected proved feasible in all patients and
corroborated each other (VLSM confirming findings regarding CST integrity based on CST lesion load calculations). However, neuroimaging derived measures require technical and analytical resources that are not yet generally implemented clinically in post stroke rehabilitation services. Automatized MRI processing steps could be of benefit requiring minimal input from a radiologist. Further standardization of the analysis procedure could represent a quick and ready manner to obtain a measure of CST injury, easier to obtain than TMS and with fewer processing steps than DTI. However, which neuroimaging and or neurophysiological method that can offer the most feasible and reliable estimate of CST integrity remains to be determined (Boyd et al., 2017).
Another study limitation was the sample size in this project. A total of 89 patients were followed-up longitudinally (61 in Study I, 80 in Study II). A larger sample would have increased power and may have improved the capacity to detect additional predictors and perform extended multivariable prediction models with improved precision of estimates. This would have aided study of sub-groups with impairment specific profiles. However, the present sample size still enabled small but significant contribution to multivariable prediction models, such as the categorical two-point discrimination variable explaining a few additional percent of variance. Despite comprehensive and time consuming assessment protocol, including MRI examination, there were few cases lost to follow up for known reasons. Data was incomplete in some cases, due to inherent properties of the assessment scales (e.g. floor effects in kinetic measures) and also due to excluded imaging data due to for example movement artefacts. In addition, the studied cohort was relatively young, as compared to the overall stroke population and epidemiological trends point to increasing future demands on post stroke care and rehabilitation in adult stroke patients below ~70 years of age. Whilst
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study of a younger cohort has some advantages in terms of likely lower likelihood that co-morbidity impacts on findings, it does limit generalization of the finding; before the findings based on this young cohort may be translated to other age groups, further validation is required.
Previous prediction models, such as the PREP2 algorithm, have primarily been aimed at quick and feasible prediction of three or six month outcome based on factors obtained during the first hours or first week, i.e. in the acute phase after stroke (Bernhardt et al., 2016; Rosso
& Lamy, 2020). The overall aim of this thesis was to identify key determinants for hand motor outcome and recovery up to six month post stroke, based on data obtained in the early subacute phase, i.e. 2-6 weeks after stroke onset. At this time point the purpose of prediction and the medical context for implementation differ from the acute phase, when high numbers of patients pass through a stroke unit and time for qualified decision making is limited, and coarse outcome predictions are often quite appropriate as a basis for the clinical decisions to be made at that time point. However, on the in-patient rehabilitation unit, prediction would ideally aid decisions regarding individualized rehabilitation planning and interventions, and as such requires a deepened understanding of factors critical for successful recovery and optimized outcome. Ideally, initial predictions would be successively refined by measurement across time. Findings from this thesis are a stepping stone towards the development of
individualized predictions and therapies of the future. Findings will also support the necessary stratification in clinical trials that will be needed to evaluate rehabilitation interventions. A summary of key findings and conclusion is given below.
7 CONCLUSIONS
In this longitudinal prospective research project of arm and hand motor recovery after stroke, a combination of fine-grained measures of sensorimotor impairment and activity performance were applied in combination with commonly used clinical scales and a multimodal
neuroimaging protocol. These specific and nuanced assessments allowed for further
delineation and understanding of the heterogeneous impairment and recovery profiles among stroke survivors, across multiple ICF levels.
Identified key predictors:
i) hand spasticity severity, with potential to predict limitations in hand motor recovery and secondary complications over time,
ii) the clinically assessed FMA-SAFE score and measures of sensory and cognitive impairment, were highly predictive of unimanual sensorimotor function and bimanual activity performance,
iii) force release was highly predictive of grip and release capability,
iv) the MRI derived measure of CST integrity (wCST-LL) was highly predictive of arm and hand sensorimotor recovery across all ICF levels, including detailed measures of force control
v) other cortico-striatal motor pathways were specifically predictive of force release,
vi) resting state functional connectivity, which contributed with some additional predictive information in addition to other factors.
Altogether, this thesis generated an improved understanding regarding force generation and force control functions of the hand, their interrelationship over time and coherence with clinically assessed outcome and recovery after stroke. Moreover, this thesis advances our knowledge regarding longitudinal recovery and prediction of grasp and release capability.
Further, this thesis provides the first detailed comparison of unimanual and bimanual recovery and their predictors after stroke. Increased understanding of factors contributing to variability in stroke recovery could contribute to development of new treatment paradigms with more specific targets for evaluation in clinical trials. This cohort represents a younger stroke population and the findings need further external validation in other age groups and in larger cohorts.
8 ACKNOWLEDGEMENTS
This thesis is the sum of effort, dedication and commitment by many, over several years. To all of you, I am forever grateful.
To the patients who participated in the studies of this thesis, and to your family members who also contributed in many ways, I would like to express my sincere gratitude. For your effort and hard work, for your courage and for sharing your knowledge and experience and for sharing your valuable time, you have my deepest thanks.
My profound thanks to all members of the control group in study II. Your readiness to volunteer and to share your time is greatly appreciated.
To the members of the data-collection team, Birgitta Johansson, Gaia Valentina Pennati, Sahil Bhaskar, Mia Reistedt, and Karin Weber for hard work and invaluable support, especially at times when I´ve lost my way, and you´ve guided me back on track as true friends, thank you from the bottom of my heart.
Through the years, the Division of Rehabilitation Medicine at Danderyd Hospital has
embraced this project and carried it forward with incessant support. For this I want to say my deepest thanks. At the very beginning of this project, when the challenges were many, invaluable contributions and support were given by many, that saw to that research and clinical activities could work together, and enrich one another. For this I want to express my gratitude to Jörgen Borg, Marie-Louise Schult, Jean-Luc af Geierstam, Christian Andersen, Kristian Borg, Vera Häglund, Charikleia Pappas, Eva Kedvik and Carin Persson. A special thanks also to Karola Ollas, Anne Åvall and Agneta Tamwelius.
To the Division of Radiology at Danderyd Hospital, for continued support for this project, I would like to say my deepest thanks. Evaldas Laurencikas, thank you for always being there with help and support. This work could not have been done without you. Lars Nilsson and Patrick Beijner, thank you for always finding solutions, for taking such good care of our patients at the MRI examination, and simply always doing your best. Thank you!
As a doctoral student, you must seek knowledge and advice. So you go to the library. And there you find it. Because at the library, you also find the most helpful, knowledgeable and service-minded people. Then, the struggle of learning turns into a pleasure and for this I am forever grateful. At the University Library of Karolinska Institutet and the Medical Library at Danderyd Hospital, there is where it happens.
It has been such a fortune to find you, fellow doctoral students at The Rehabilitation Medicine clinic. Thank you Ann-Christine Persson, Gabriella Markovic, Christian
Oldenburg, Giedré Matusevičienė, Christina Sargénius Landahl, Märta Berthold and Gaia Pennati. With all my affection, Anneli Wall and Helena Hybbinette, for all good times, thank you. You made all the difference to me and I couldn´t have done this without you. I would
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also like to thank Marika Möller and Monika Löfgren for inviting room and spirit for fruitful discussions and learning.
I would like to give my sincere gratitude to all the members of the medical teams, at the in-patient and out-in-patient clinics, for investing your time and knowledge into this project. Your expertise and high standards have made all the difference for this research and encouraged and inspired me. A special thanks to Isa Gustin, for your invaluable investment of time and knowledge. Hanna Bergling, you´re missed! At numerous times, you´ve been a life-saver.
Thank you! A special thanks to all nurses and assistant nurses for always being there for the patients, for helping out with endless practical things that made this research possible, for your interest in this work and for your willingness to contribute, I want to say my sincere gratitude.
Johan Gäverth, thank you for being too good to be true, for your readiness to help out and for your kind patience when you´ve spotted that question mark on my forehead! A special thanks also to Anders Fagergren, for finding the time when there is no time, it has been incredibly valuable.
For you, the best physios and colleagues one can whish for, I am immensely grateful. You´ve been my safe place, where I always long to go. Your trust and faith in me and in this work have been so valuable to me. Thank you! Maria Sandgren, my sincere thanks for your faith in me.
I want to say my sincere thanks to my home department KIDS. For your assistance and advise whatever the question, Åsa Misic, Malin Wirf, Håkan Wallén, Siw Svensson, Thomas Pettersson, Nina Ringart, and not least, Erik Näslund, thank you!
To the research team in Paris, for your welcoming ways, for generously sharing your
knowledge and expertise, for all good times on travel, exploring science as well as good food and drink, for all good memories, thank you!
The four papers included in this thesis did not come to life without you. Cherished
co-authors, I am immensely proud and thankful for sharing authorship with you. I have learnt so much and I´ve appreciated every part of our correspondence over refinement of message and meaning. Thank you! A special thanks to Lena Krumlinde Sundholm, for bringing your valuable knowledge and expertise into this project, and to all of us in the clinic.
Sverker Johansson, thank you for your mentorship and incredible generosity and for believing in me. For always inviting courage and inspiration, I am forever grateful.
Kenth Malmström and Elisabeth Ginsburg, your shared values are my compass still. To all collegues at Erstagårdskliniken, not least Birgitta Olsson, Karin Broms and Kristina Westman, for all you´ve taught me, for love and friendship, thank you.
I would like to express my gratitude to Stroke-Riksförbundet, NEURO, Lars Hedlund for generous financial support to this research. And not least, my sincere gratitude to Promobilia
Foundation, for important financial support to this research, and for an assigned research grant, that enabled the completion of this thesis. I cannot say how proud I am.
Special thanks to Tony and Erik Iivonen, for opening a new world of music to me, for sharing your affection for music and for guidance in the art of playing the accordion (bimanually!).
You´ve helped me find new inspiration and a key to creativity good energy and peace of mind.
To all members of our research-group at Danderyd, Jörgen Borg, Gaia Pennati, Anna
Creamux, Hanna Bergling, Anneli Wall, Beatrice Felixon, Disa Sommerfelt, Påvel Lindberg and Susanne Palmcrantz. Exploring the paths of literature and science, collecting and
discussing data, your willingness to helping out when technology crash, thank you for sharing your knowledge and expertise, for all the joy of working together.
To my supervisors Jörgen Borg, Alison Godbolt and Påvel Lindberg, how can I express my gratitude. Your guidance and support has been immensely valuable to me. The opportunity to learn from you, has been so gratifying. Thank you for being so generous, for your patience and for always bringing hope and inspiration.
It came to be so that the last months of my doctoral studies coincided with deep sorrow due to the sudden loss of by beloved farther. To all of you who has been there for me, and especially you Påvel, thank you for helping me through.
My singing, creative, dancing, mountain tracking, extended family, you are my water, nourishment and sunshine, thanks to you I will grow back as a stronger plant. And all my love to you LisaLotta, my very own life gardener!
Käraste Tyresö-töser, thank you for lifelong support and friendship. Thank you PO, for always being there and for always believing in me. To my affectionate First Aid Kit, Lovisa-Lo och Lu, Elin, Ghina and Elis, how proud I am of you, and happy I am for you. Erikssou for being such a good friend. Kaoken Körm Cerenius, I am forever grateful for our
friendship, I have learnt so much from you, about life and also how to be the very best physiotherapist I can ever be.
Sist men inte minst vill jag tacka dig min älskade mamma, och mina syskon Joakim och Helena med familjer, och dig min allra käraste Lova för att ni finns, och dig min älskade pappa, för att du alltid funnits.
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