Repairing the brain after stroke: towards personalised rehabilitation Valerie Pomeroy Professor of Neurorehabilitation University of East Anglia First some background

Stroke: the important facts  Admission to a stroke unit improves outcome by 28%  Stroke is the leading cause of severe adult disability  150,000 people in UK have a stroke each year  Third of those left with permanent severe disability  Stroke costs the NHS £2.8 billion a year in direct care costs – more than the cost of treating coronary heart disease  Each year the total cost of stroke is £9 billion  Rehabilitation therapies drive brain recovery

Rehabilitation drives brain recovery People who received usual rehabilitation in a stroke unit. Self-paced thumb-index tapping Acute = 4-7 days after stroke Chronic = 3 months later Askim et al 2009 Specific intervention One session of physical therapy to improve dexterity Size of cortical output map Abductor Pollicis Brevis 9HPT scores Liepert et al 2000

Recovery expectations and uncertainty Stroke survivors “ My hope is to recover to my previous level, to be able to walk as well as before and to use the arm, to get as close as possible to where I was before, preferably all the way there. I’m not sure its going to be possible” “I haven’t got to the point when I say ‘right, that’s it, I’ve got to live with it’. I still feel that I can definitely improve, that is my aim, to improve” Wiles et al 2002, Wottrich et al 2012 Physiotherapists “everybody’s different, nobody can predict ……. nobody can tell you how fast you are going to get there, you know, take it one step at a time” “ I do think her expectations are quite high …. I think I’ve got to keep reinforcing every time she comes …. that she may never feel as good as she did and she may not achieve absolutely everything that she wants to”.

Repairing the brain after stroke: towards personalised rehabilitation Valerie Pomeroy Professor of Neurorehabilitation University of East Anglia Provision of therapy tailored to individual stroke survivors guided by the use of biological, behavioural and environmental information

Training the motor execution system after stroke (DIS) ORGANISATION (DEFICIT OF) MOVEMENT SENSORY FEEDBACK PRACTICE PRIME Patients UNABLE to produce sufficient voluntary activation of muscle for repetitive activity Patients ABLE to produce sufficient voluntary activation of muscle for repetitive activity AUGMENT Patients ABLE to produce SOME voluntary activation of muscle for repetitive activity

Prime, Augment, Practice Framework Substantial paresis Mild paresis Pomeroy et al 2011

Prime, Augment, Practice Framework Substantial paresis Mild paresis

Stroke rehabilitation is an active participatory process through which people learn to move again Motor Learning

Motor learning process Reviewed by Dayan & Cohen. Neuron 2011:72: No skill Full skill

Motor learning process Reviewed by Dayan & Cohen. Neuron 2011:72: No skill Full skill

Motor learning process Reviewed by Dayan & Cohen. Neuron 2011:72: No skill Full skill Practice Time Sleep

Motor learning for skilled functional activity

Profile of upper limb recovery Verheyden et al 2008 % maximum score (Fugl-Meyer)

Profile of upper limb recovery Verheyden et al 2008 % maximum score (Fugl-Meyer)

Profile of upper limb recovery Verheyden et al 2008 % maximum score (Fugl-Meyer)

Crux of the stroke rehabilitation challenge How to provide the therapeutic environment to enhance motor learning in individual stroke survivors

Pictures - Google Images Observational learning Action Observation and Observation-to-Imitate  Hypothesis = observational learning might enhance motor recovery in people with substantial paresis [ Pomeroy et al 2005 ]  Early phase trials suggest benefit in moderate-mild stroke survivors [ Ertelt 2007, Franceschini 2012 ] Comparison of OTI + usual care & usual care alone in people with substantial paresis within 1 month of stroke Change in Motricity score Cowles et al 2013

Stimulation over damaged brain area to strengthen connection to weak muscles rTMS induces excitability changes in corticospinal pathways. Has been investigated as a means to enhance the effects of physical practice 27 participants, MCA infarct, mean days after stroke Pomeroy et al 2007 Mean changes (SE) from baseline

Stimulation over damaged brain area to strengthen connection to weak muscles rTMS induces excitability changes in corticospinal pathways. Has been investigated as a means to enhance the effects of physical practice 27 participants, MCA infarct, mean days after stroke Pomeroy et al 2007 Mean changes (SE) from baseline

Mean [95% CIs] within-group changes: baseline to outcome Hammett et al 2011 Mobilisation and Tactile Stimulation (MTS)

Mean [95% CIs] within-group changes: baseline to outcome Hammett et al 2011 Mobilisation and Tactile Stimulation (MTS)

Personalised rehabilitation Which therapies for which stroke survivors? Worse outcome Made no difference Improved but adverse events Best outcome

Can we predict who is likely to respond to what and/or what likely recovery will be? At

Targeting therapies for motor recovery “Initial degree of motor impairment is the best predictor of motor recovery following a stroke” Canadian Stroke Network

Mean [95% CIs] within-group changes: baseline to outcome Hammett et al 2011 Mobilisation and Tactile Stimulation (MTS) Who is likely to benefit? r = 0.8; p<0.001

Mean [95% CIs] within-group changes: baseline to outcome Hammett et al 2011 Mobilisation and Tactile Stimulation (MTS) Who is likely to benefit? r = 0.8; p<0.001

Moving forward: Validation and development of prognostic models in larger groups of stroke survivors receiving well-characterised physical therapies in pragmatic clinical trials

Clinical efficacy of Functional Strength Training for upper limb motor recovery early after stroke: neural correlates and prognostic indicators The FAST-Indicate Trial Questions for this 2-group randomised controlled trial 1. If providing FST early after stroke can enhance upper limb recovery more than Movement Performance Therapy (MPT); 2. Which particular patients might benefit from FST and from MPT; 3. How the brain recovers when people participate in FST and MPT. Problem 6 months after stroke many people still have a non-functional upper limb Recruitment started Oct 2012 Key measures Ability to use upper limb + neurophysiology+ fMRI + DTI + VLSM += Comprehensive investigation of the mechanisms of brain recovery and prognostic indicators for rehabilitation

Clinical efficacy of the Soft-Scotch Walking Initial FooT (SWIFT) Cast on walking recovery early after stroke and the neural-biomechanical correlates of response Questions for this 2-group randomized controlled trial 1. If using a SWIFT Cast early after stroke enhances walking recovery 2. Which particular people might benefit from the SWIFT Cast 3. How the SWIFT Cast influences recovery of movement Problem 6 months after stroke many people cannot cross the road before lights turn red Recruitment ended Dec 2012 Key measures Ability to walk + Biomechanics (move quality + Voxel Lesion Statistical Mapping + = Neuro-biomechanics Novel investigation of the mechanisms of brain recovery and prognostic indicators for rehabilitation

Therapy outcome Patient & Therapist Patient & Therapist Therapy outcome 2000

M1 descending tract intact Lesion inferior parietal lobe 10 reps reach & grasp Ye s Therapy A No Therapy B 40 reps reach & grasp Ye s No Therapy C 80 reps reach & grasp Ye s No Therapy D Therapy outcome Patient & Therapist Patient & Therapist Therapy outcome From “Art” to Science

Some upper limb activities Balance Self-care Unilateral activity Bilateral activity Locomotion

ICF & Bio-psycho-social frameworks Pathology Impairment Activity Participation Bio Psycho Social Disease process Physiological, psychological consequences Functional consequences Social consequences Molecules Cells Organs Body systems Person experience Two people relationships Family effects Immediate and wider community Environmental factors Biological factors