Understanding Stroke Recovery
NICK WARD, CATHY PRICE, ALEX LEFF
All slides at:
www.ucl.ac.uk/ion/departments/sobell/Research/NWard/studentprofile/tsrn
………. or google ‘dr nick ward’ ………..
Modern approaches in motor
neurorehabilitation
NICK WARD, UCL INSTITUTE OF NEUROLOGY, QUEEN SQUARE
n.ward@ucl.ac.uk
Follow us on twitter @Wardlab
Understanding Stroke Recovery, Thames SRN AGM, London, 7th March 2013
Recovery After Stroke: Neurorehabilitation
I.
The problem – framework for approaches to upper limb
treatment after stroke
II.  Neuroplasticity as the key to recovery?
III.  Taking advantage of plasticity - driving motor recovery through
practice
IV.  Enhancing plasticity – pharmacotherapy
V.  Enhancing plasticity – cortical stimulation
VI.  Understanding variability through neuroimaging
VII.  Predicting outcome with neuroimaging
Recovery after stroke: Neurorehabilitation
I. The problem
Recovery after stroke: Neurorehabilitation
I. How do we treat people after stroke?
1.
2.
3.
4.
5.
Preserva)on of )ssue Avoid complica)ons Enhancement of plas)city Task specific training Compensa)on Rehabilita)on Recovery Recovery after stroke: Neurorehabilitation
I. When should we treat people after stroke?
1. EARLY – helps avoid complications
2. Natural history of recovery may be misleading
3. Can late treatment change impairment?
This patient made 90%
improvement 20 years after stroke
Recovery
What doafter
we mean
stroke:
byNeurorehabilitation
reorganisation?
II. What is brain plasticity?
Brain plasticity! Hold on ….. the cortex is not capable
of plasticity but is hardwired and immutable. Once
damage occurs, cortical neurons either die or at best
do not change their projection patterns…..”
Recovery after stroke: Neurorehabilitation
II. What is brain plasticity - structure?
Axon arborisation in vivo
Hua et al., Nature 2005; 434: 1022-1026
Niell et al., Nat Neurosci 2004; 7: 254-260
Dendritic growth in vivo
dendrites
axon
Recovery after stroke: Neurorehabilitation
II. What is brain plasticity - excitability?
•  In general - reduced activity at
GABAergic interneurons allows
plasticity e.g. reopening critical
period in adults
affected side
•  In general - enhanced
glutamatergic signalling leads to
LTP of connections
•  In general - altering the balance of
inhibition/excitation away from
inhibition is important in allowing
new periods of plasticity in adult
cortex
10 days post
stroke
affected side
Recovery after stroke: Neurorehabilitation
II. What is brain plasticity - excitability?
•  In general - reduced activity at
GABAergic interneurons allows
plasticity e.g. reopening critical
period in adults
•  In general - enhanced
glutamatergic signalling leads to
LTP of connections
•  In general - altering the balance of
inhibition/excitation away from
inhibition is important in allowing
new periods of plasticity in adult
cortex
Recovery after stroke: Neurorehabilitation
II. What is brain plasticity?
Activity takes advantage
of plastic changes, but
also enhances them
These are therefore
therapeutic targets for
the promotion of
recovery after stroke
activity
lesion induced
changes
inactivity
Recovery after stroke: Neurorehabilitation
III. How do we treat people after stroke?
Rehabilitation is 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
Treatments aimed at reducing impairments
Task-specific training
cortical
stimulation
other
drugs
Recovery
after stroke:
Neurorehabilitation
Does
it work
- Dose
III. Task specific practice (makes perfect)
Problem: average amount of out-­‐pa)ent speech therapy ~ 12 hours Recovery after stroke: Neurorehabilitation
III. Task specific practice (makes perfect)
Dose is important
Motor – 1000’s of repetitions
Language – 100 hours
Recovery after stroke: Neurorehabilitation
III. How to increase the dose?
•  multi-site single blind randomized controlled trial
•  4-week self-administered graded repetitive upper limb program in 103 stroke patients
approx 3 weeks post stroke
•  3 grades (mild, moderate, severe)
•  Provided with exercise book with instructions
•  Repetitions, inexpensive equipment
•  strength, range of motion, gross and fine motor skills
•  GRASP group showed greater improvement in upper limb function
•  GRASP group maintained this significant gain at 5 months post-stroke
Recovery after stroke: Neurorehabilitation
III. How to increase the dose?
Robotic treadmill training
Home video arm/hand training
Robotic arm training
Recovery after stroke: Neurorehabilitation
III. How to increase the dose – specialist clinics
www.camden.nhs.uk/gps/upper-limb-rehabilitation-clinic
www.ucl.ac.uk/ion/departments/sobell/Research/NWard/patientsprofile/infoforpatients/upperlimbclinic
Recovery after stroke: Neurorehabilitation
III. How to increase the dose – specialist clinics
www.ucl.ac.uk/jennycrinion/
Referral form: www.ucl.ac.uk/jennycrinion/
therapists
Recovery after stroke: Neurorehabilitation
III. How to increase the dose – specialist clinics
www.ucl.ac.uk/aphasialab/alex/c_cognitive.html
Recovery after stroke: Neurorehabilitation
III. How to increase the dose – specialist clinics
www.ucl.ac.uk/aphasialab/alex/c_hemianopia.html
Recovery after stroke: Neurorehabilitation
III. How to increase the dose?
http://www.arni.uk.com/
Recovery after stroke: Neurorehabilitation
III. How to increase the dose?
https://www.eyesearch.ucl.ac.uk/
http://www.readright.ucl.ac.uk/index.php
Recovery after stroke: Neurorehabilitation
III. How do we treat people after stroke?
Rehabilitation is 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
Treatments aimed at reducing impairments
Task-specific training
cortical
stimulation
other
drugs
Recovery after stroke: Neurorehabilitation
IV. Pharmacotherapy after stroke
Recovery after stroke: Neurorehabilitation
IV. Pharmacotherapy after stroke
Several agents considered:
•
Acetylcholinesterase inhibitors
•
Amphetamine
•
DA agonists (e.g. DARS in UK)
•
SSRIs (e.g. fluoxetine)
Recovery after stroke: Neurorehabilitation
IV. Pharmacotherapy after stroke
Lancet Neurol 2011;10:123-30
Recovery after stroke: Neurorehabilitation
IV. Pharmacotherapy after stroke
Lancet Neurol 2011;10:123-30
•  118 patients with ischemic stroke and hemiparesis (Fugl-Meyer scores ≤55)
•  fluoxetine (n=59; 20 mg once per day, orally) or placebo (n=59)
•  3 months starting 5 to 10 days after the onset of stroke
•  All patients had physiotherapy as delivered in local unit
•  The primary outcome measure was change in the FM score between day 0 and 90
Recovery after stroke: Neurorehabilitation
IV. Pharmacotherapy after stroke
Lancet Neurol 2011;10:123-30
less disability
Improved FM score at 90 days
more disability
Improved mRS score at 90 days
Recovery after stroke: Neurorehabilitation
IV. Pharmacotherapy after stroke
Lancet Neurol 2011;10:123-30
Enhanced
plasticity
Reduced GABAergic inhibition?
Increased glutamatergic/BDNF mediated LTP?
Recovery after stroke: Neurorehabilitation
V. Cortical Stimulation after stroke
Transcranial Magnetic Stimulation
Transcranial DC Stimulation
Enhancing ipsilesional excitability or
decreasing contralesional excitability of
motor cortex might enhance motor learning
by altering balance of excitation/inhibition
Ward & Cohen, 2004
Recovery after stroke: Neurorehabilitation
V. Cortical Stimulation after stroke - rTMS
Recovery after stroke: Neurorehabilitation
V. Cortical Stimulation after stroke - TDCS
Butler AJ et al, J Hand Ther 2012 Sep 7 (epub ahead of print)
Recovery after stroke: Neurorehabilitation
VI. Barriers to translation
None have entered into routine
clinical practice – why?
Recovery after stroke: Neurorehabilitation
VI. Understanding variability
input
input
input
input
Ward and Cohen, Arch Neurol 2004
Recovery after stroke: Neurorehabilitation
VI. Understanding variability
So, what is the brain
imaging for?
1.  How much will he recover?
2.  What is best treatment for him?
Ward and Cohen, Arch Neurol 2004
Recovery after stroke: Neurorehabilitation
BOLD SIGNAL
GRIP FORCE
VI. Understanding variability through fMRI
30%
GRIP
40%
20%
GRIP
GRIP
40 secs
GRIP
REST
40 secs
TIME
Recovery after stroke: Neurorehabilitation
VI. Overactivity in motor networks after stroke
Recovery after stroke: Neurorehabilitation
VI. Changing motor networks after stroke
affected
side
A
10 days
post stroke
infarct
B
17 days
post stroke
24 days
post stroke
31 days
post stroke
3 months
post stroke
affected
side
OUTCOMES
Barthel
ARAT
GRIP
NHPT
Patient A
20/20
57/57
98.7%
78.9%
Patient B
20/20
57/57
64.2%
14.9%
Recovery after stroke: Neurorehabilitation
VI. Understanding variability through fMRI
CSS Integrity
CSS Integrity
CSS Integrity
Ward et al., Brain 2006
Increasing ‘main effect’ of left hand grip
affected hemisphere
more CS damage
less CS damage
Recovery after stroke: Neurorehabilitation
VI. Understanding variability
Disruption to CST leads to a shift of
activity away from primary to secondary
motor areas
Longitudinally there is reorganization, but
only within networks that have survived
These areas can take on new and
functionally relevant roles
Their role in supporting recovered
function depends on the anatomy of
surviving brain networks
Ward et al 2003a, 2003b, 2004, 2006, 2007
affected hemisphere
Recovery after stroke: Neurorehabilitation
Predictive variables
VII. Predicting outcome after stroke
•  Infarct Size
•  Infarct Location
•  Pre-stroke medical co-morbidities
•  Pre-stroke experience, education, age
•  Severity of initial stroke deficits
•  Breadth of stroke deficits
•  Acute stroke interventions
•  Medications during stroke recovery period
•  Amount of post stroke therapy
•  Types of post stroke therapy
•  Medical complications after stroke
•  Socioeconomic status
•  Depression
•  Caregiver status
•  Genotype
30-50% of
variance in
outcomes
Recovery after stroke: Neurorehabilitation
VII. Predicting outcome after stroke
3 months post-stroke / 60% grip strength / fatigue or not
Referral to: a.kuppuswamy@ucl.ac.uk
https://www.ucl.ac.uk/ion/departments/sobell/Research/NWard/researchprofile/ourresearch/neurofast
Recovery after stroke: Neurorehabilitation
VII. Predicting outcome of upper limb recovery
Recovery after stroke: Neurorehabilitation
VII. Predicting outcome with DTI
Track from fMRI-defined hand
areas in 4 different cortical
motor areas
Shultz et al, Stroke 2012
Corrrelation with poststroke hand grip strength
!
Recovery after stroke: Neurorehabilitation
VII. Predicting outcome with structural MRI
•  Database of (i) hi-res structural MRI, (ii)
language scores and (iii) time since stroke
•  MRI converted to 3D image with index of degree
of damage at each 2mm3 voxel
•  This lesion image compared to others in
database and similar patients identified
•  Different ‘recovery’ curves can then be
estimated for different behavioural measures
Recovery after stroke: Neurorehabilitation
VII. Predicting response with DTI
Riley et al., Stroke 2011; 42: 421-6
Damage to M1 pathway limits response to robot assisted therapy
Recovery after stroke: Neurorehabilitation
VII. Predicting response with fMRI
Cramer et al., Stroke 2007; 38: 2108-14
Less activity in M1 limits response to robot assisted therapy
Recovery after stroke: Neurorehabilitation
VII. Predicting response to TMS/TDCS
unaffected
+
affected
-
unaffected
+
affected
-
Will the same treatment strategy work in these patients?
Recovery after stroke: Neurorehabilitation
VII. Stratification through multimodal assessment
Stinear, C. M. et al. Brain 2007 130:170-180
Copyright restrictions may apply.
Recovery after stroke: Neurorehabilitation
VII. Stratification through multimodal assessment
1.  SAFE = shoulder abduction + finger extension
(MRC scale) 72 h after stroke (range 0–10)
2.  TMS at 2 weeks
Stinear, C. M. et al. Brain 2012 Aug;135:2527-35
Copyright restrictions may apply.
3.  MRI/DTI at 2 weeks
Recovery after stroke: Neurorehabilitation
VII. Stratification through multimodal assessment
1.  SAFE = shoulder abduction + finger extension
(MRC scale) 72 h after stroke (range 0–10)
2.  TMS at 2 weeks
Stinear, C. M. et al. Brain 2012 Aug;135:2527-35
3.  MRI/DTI at 2 weeks
Recovery after stroke: Neurorehabilitation
Summary
•  Advances in neurorehabilitation are coming about through
advances in neuroscience
•  The dose of treatment is critical - more is generally better
•  Enhancement of plasticity is possible
•  Neuroimaging should help in stratification
•  Understanding the mechanisms of recovery and treatment
might allow targeted or individualized therapy after stroke in
future
Recovery after stroke: Neurorehabilitation
Additional References
1.  Murphy TH, Corbett D. Plasticity during stroke recovery: from synapse to behaviour.
Nat Rev Neurosci 2009;10:861-72.
2.  Carmichael ST. Targets for neural repair therapies after stroke. Stroke 2010;41(10
Suppl):S124-6
3.  Philips JP, Devier DJ, Feeney DM. Rehabilitation pharmacology: bridging laboratory
work to clinical application. J Head Trauma Rehabil 2003 Jul-Aug;18(4):342-56.
4.  Stagg CJ, Nitsche MA. Physiological basis of transcranial direct current stimulation.
Neuroscientist 2011;17:37-53
5.  Stinear CM, Ward NS. How useful is imaging in predicting outcomes in stroke
rehabilitation? Int J Stroke. 2013;8(1):33-7.
6.  Ward NS. Assessment of cortical reorganisation for hand function after stroke. J
Physiol. 2011;589(Pt 23):5625-32.
Recovery after stroke - Neurorehabilitation
Acknowledgements
FIL:
ABIU/NRU:
SOBELL DEPARTMENT :
Richard Frackowiak
Diane Playford
Chang-hyun Park
Karl Friston
Richard Greenwood
Holly Rossiter
Will Penny
Alan Thompson
Marie-Helen Boudrias
Alex Leff
Martin Brown
Karine Gazarian
Cathy Price
All nurses, physios, OTs, SLTs
Ella Clark
Jennie Newton
Stephanie Bowen
Peter Aston
Sven Bestmann
Eric Featherstone
John Rothwell
Penny Talelli
Some more slides at www.ucl.ac.uk/ion/departments/sobell/Research/NWard
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FUNDING:
Ward Lab at UCL or @WardLab