Julie Bernhardt 1,2, Kathryn S Hayward1,2,3, Gert Kwakkel4,5,Nick S Ward6,7, Steven L Wolf8,9, Karen Borschmann1,2,John W Krakauer10, Lara A Boyd3,11, S Thomas Carmichael12,Dale Corbett13,14 and Steven C Cramer15
A major point of agreement of the SRRR expert group was to focus on progress of stroke recovery research in the next decade and beyond. ‘Rehabilitation’ as a blanket term for all therapy-based interventions post-stroke was considered problematic, vague and an impediment to progress. Rehabilitation reflects a process of care, while recovery reflects the extent to which body structure and functions, as well as activities, have returned to their pre-stroke state. With that, the term ‘recovery’ can be represented in two ways: (1) the change (mostly improvement) of a given outcome that is achieved by an individual between two (or more) timepoints, or (2) the mechanism underlying this improvement in terms of behavioural restitution or compensation strategies.6,7 We used the definition of rehabilitation developed by the British Society of Rehabilitation Medicine,8 “a process of active change by which a person who has become disabled acquires the knowledge and skills needed for optimum physical, psychological and social function.” Stroke rehabilitation is most often delivered by a multidisciplinary team, defined by the World Health Organisation (WHO)9 to encompass the coordinated delivery of intervention(s) provided by two or more disciplines in conjunction with medical professionals. This team aims to improve patient symptoms and maximise functional independence and participation (social integration) using a holistic biopsychosocial model, as defined by the International Classification of Functioning Disability (ICF).9
Timeline of stroke recovery
37,38). The first week until the first month post-stroke (acute and early sub-acute) is a critical time for neural plasticity6,30,39 and should be a target for recovery trials, with some uncertainty about how early and how intensively to start training.37,40 Importantly, we strongly recommend that in all recovery and rehabilitation research, the time from stroke onset is gathered and reported. The start and end of any intervention(s), experimental or standard of care, as well as timing of outcome and follow-up assessment should also be reported. Using this framework, the SRRR groups provide recommendations, e.g. the measurement group recommend core measures to be included in every trial of stroke recovery and rehabilitation;4 the biomarker group provide recommendations about the timing and type of data acquisition.3
The way forward
- Improved understanding of the natural history of recovery and stratification in trials. Applying repeated measurements at set time points (Figure 1) that start early and continue well into the chronic phase in larger cohorts of patients will help to establish the natural history of recovery in specific functional domains. We need better prognostic models of long-term outcome after stroke that are informed by behavioral, neurophysiological and neuroimaging data. Crucially, we need to better stratify patients in clinical trials that target restitution based on recovery potential.41 Most proof-of-concept trials to date that have started early after stroke are heavily underpowered by lack of proper stratification; leading often to prognostically unbalanced groups at baseline.42 Neurophysiology or neuroimaging approaches for stratification are only just emerging43; areas where there is sufficient evidence to support their use in recovery research are outlined in our biomarkers paper.3 Informed by such data, trials of promising new treatments would have a higher likelihood of identifying a true treatment effect if there is one.
- Better understanding of the neurobiology of spontaneous and treatment-induced recovery in human subjects. Animal studies have provided insights into the cellular and molecular events that underlie stroke recovery; this must continue; however, a pressing need exists to achieve this level of understanding in human subjects. Such an understanding will require an overhaul of many current approaches and the development of biomarkers that best reflect important stroke plasticity mechanisms. The resulting insights can be expected to identify a series of biological targets that could translate into improved application of post-stroke therapies in humans and provide a biological basis for testing novel stroke recovery interventions.44
- Characterizing different stroke recovery phenotypes. In clinical trials, we consistently identify the presence of responder and non-responder groups to a given treatment, but little is known regarding the underlying biological group differences. We need pre-clinical and clinical researchers to consistently measure neural injury and function and apply outcome measures that can distinguish behavioral restitution from compensation. This distinction will help us characterize and ultimately predict those most likely from those least likely to respond to a given intervention. An effort to understand recovery phenotypes will help target efficacious treatments towards responders and create renewed focus to develop better treatments for non-responders.
- Training new researchers. Given these priorities, an emphasis on cross-disciplinary training of new researchers will build capacity and linkages, while concurrently breaking down the silos that have historically divided basic and clinical researchers. This training should also include standardized training in core outcome assessment and biomarker acquisition for use in stroke recovery research in both animals and humans.
- Development of a network of clinical centers of excellence in stroke recovery. These centers would represent a place where clinicians understand, advocate and importantly, apply treatments at the right time and the right dose according to current best knowledge. Research would also be embedded in these centers.
- A radical new aim. We believe a new dialogue and a collective collaborative investment are needed to work towards a radical new goal of restitution and brain repair. Much of the thinking in this field is currently pragmatic, investigating interventions that could be delivered in existing health care settings. However, we urgently need to know what is possible in terms of recovery and restitution of function after stroke. This knowledge will only come about through aspirational research which seeks to achieve the largest effect size for the benefit of stroke survivors.45,46 We need to look no further than the first thrombolysis trials for inspiration, as they had little or no chance of implementation on a wide scale within acute stroke services as they were then set up. The early thrombolysis trials drove changes in the way acute (and hyperacute) services were delivered around the world. The field of restorative therapy after stroke requires the same sense of purpose and resolve.