NICK WARD, UCL INSTITUTE OF NEUROLOGY, QUEEN SQUARE n.ward@ucl.ac.uk
Follow us on twitter @Wardlab
Royal Society of Medicine,
London, 29 th January 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

Recovery after stroke: Neurorehabilitation
I. The problem

Recovery after stroke: Neurorehabilitation
I. Thomas Twitchell, Brain, 1954
“Unless the first two or three weeks witness material change for the better, prognosis should be expressed in guarded terms”
Wilson, 1941

Recovery after stroke: Neurorehabilitation
I. Compensation vs Recovery
“…it is useful to divide neurorehabilitation into
(1) measures primarily aimed at assisting adaptation to (or compensating for) impairment, and
(2) those primarily aimed at reducing impairments.
The latter address underlying neurological deficits more directly but are relatively poorly understood”

Recovery after stroke: Neurorehabilitation
I. How do we treat people after stroke?
1. Preservation of tissue
2. Avoid complications
3. Enhancement of plasticity
4. Task specific training
5. Compensation
Rehabilitation 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

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?
Dendritic growth in vivo Axon arborisation in vivo dendrites axon

Recovery after stroke: Neurorehabilitation
II. What is brain plasticity - excitability?
• Reduced activity at GABAergic interneurons allows plasticity e.g. reopening critical period in adults
• Enhanced glutamatergic signalling leads to LTP of connections
• 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 cortical stimulation
Task-specific training other drugs

III. Task specific practice (makes perfect)
Problem: average amount of out-patient 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?
Robotic treadmill training
Home video arm/hand training
Robotic arm training

Recovery after stroke: Neurorehabilitation
III. How to increase the dose?

Recovery after stroke: Neurorehabilitation
IV. Pharmacotherapy after stroke

Recovery after stroke: Neurorehabilitation
IV. Pharmacotherapy after stroke
• chronic administration of SSRI fluoxetine reinstates ocular dominance plasticity in adulthood i.e. reopens critical period for plasticity
• …reverses amblyopia
• ...reduces intracortical inhibition
• ...blocked by diazepam (GABA
A
agonist)
• ...increases expression of BDNF
In humans (healthy and stroke), a single dose
• increases simple motor performance
• increases motor cortex activity (fMRI)
• increases motor cortex excitability (TMS)

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 more disability
Improved FM score at 90 days Improved mRS score at 90 days

Recovery after stroke: Neurorehabilitation
IV. Pharmacotherapy after stroke
Several agents considered:
• Acetylcholinesterase inhibitors
• Amphetamine
• DA agonists (e.g. DARS in UK)
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

Recovery after stroke: Neurorehabilitation
V. Cortical Stimulation after stroke

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
Ward and Cohen , Arch Neurol 2004 input

A
Recovery after stroke: Neurorehabilitation
VI. Changing motor networks after stroke affected side
B infarct affected side
10 days post stroke
17 days post stroke
24 days post stroke
31 days post stroke
3 months post stroke
OUTCOMES
Patient A
Patient B
Barthel
20/20
20/20
ARAT
57/57
57/57
GRIP
98.7%
64.2%
NHPT
78.9%
14.9%

Recovery after stroke: Neurorehabilitation
VI. Predicting treatment response unaffected
+ affected
- unaffected
+ affected
-
Will the same treatment strategy work in these patients?

Recovery after stroke: Neurorehabilitation
VI. Predicting outcome by measuring structural damage
• 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 2mm 3 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
VI. Multimodal stratification after stroke
Stinear, C. M. et al. Brain 2007 130:170-180
Copyright restrictions may apply.

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 individualised therapy after stroke in future

Recovery after stroke - Neurorehabilitation
Acknowledgements
FIL: ABIU/NRU: SOBELL DEPARTMENT
Richard Frackowiak
Rosalyn Moran
Karl Friston
Diane Playford
Richard Greenwood
Alan Thompson
Marie-Helen Boudrias
Holly Rossiter
Chang-hyun Park
Will Penny
Jennie Newton
Martin Brown
All nurses, physios, OTs, SLTs
Karine Gazarian
Emma Davis
Stephanie Bowen Peter Aston
Eric Featherstone Sven Bestmann
John Rothwell
Penny Talelli
Some more slides at www.ucl.ac.uk/ion/departments/sobell/Research/NWard
:
Follow us on
FUNDING:
Ward Lab at UCL or @WardLab