NICK WARD

UCL INSTITUTE OF NEUROLOGY

Neuroplasticity: does it occur in the older brain?

British Geriatrics Society, BMA House, London 27th January 2011

1. What do we mean by plasticity?

2. Motor system changes with ageing

3. Motor system changes after stroke

What is different about the older brain?

Plasticity! Hold on ….. the cortex is not capable of change but is hardwired and immutable. Once damage occurs, cortical neurons either die or at best do not change their projection patterns…..”

1. ‘Neural changes in response to activity’

Dendritic growth in vivo (600:1 time lapse)

Niell et al., Nat Neurosci 2004; 7: 254-260

Axon arborisation in vivo (600:1 time lapse)

Hua et al., Nature 2005; 434: 1022-1026

1. ‘Neural changes in response to activity’

Dendritic growth in vivo (600:1 time lapse)

Niell et al., In vivo imaging of synapse formation on a growing dendritic arbor. Nat Neurosci 2004; 7: 254-260

1. ‘Neural changes in response to activity’

from Kolb 1995

1. ‘Neural changes in response to activity’

In humans it will not be the synapses per se but the neural circuits in which they participate which will be the appropriate explanatory level to understand plasticity

Continuous change in structure and ultimately function throughout a lifetime (Bryan Kolb, 1995)

Increments in synaptic efficacy occur when firing of one neuron repeatedly produces firing in another neuron to which it is connected (Hebb’s postulate, 1947)

System level plasticity = state- and history-dependent change in connection strength between areas.

1. ‘Neural changes in response to activity’

1. ‘Neural changes in response to activity’

scan1 scan 2 scan 3

Draganski B et al., Nature. 2004 ;427:311-2

1. ‘Neural changes in response to activity’

Task: button press sequence

Training related increases in grey matter

1. ‘Neural changes in response to activity’

“…..the cortex is not capable of plasticity but is hardwired and immutable. Once damage occurred, cortical neurons either died or at best did not change their projection patterns…..”

The structure of the brain is constantly changing – this is the basis of learning both in health and disease

However, it requires ‘activity’ to take advantage of these processes and create new connections and networks

1. ‘Neural changes in response to activity’

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2. Imaging cerebral reorganisation - Ageing

GRIP

REST

BO

LD S

IGN

AL

TIME

40 secs

GR

IP F

OR

CE

GRIP GRIP GRIP

30%20%

40%

40 secs

2. Imaging cerebral reorganisation - Ageing

fMRI – main effects

right hand15

10

5

t-score

forc

e

time

ipsilateral cerebellum (lobule VI) contralateral superior cingulate sulcuscontralateral central sulcus

fMRI – activity during force modulationfo

rce

time

fMRI – normal motor system activation

BF1

BG = average effect of all hand grips

BF = increase in BOLD signal with increasing peak force

Ipsilateral M1 activity related to increasing age

Ward et al., Neurobiol Aging 2007

Main effect of hand grip

2. Imaging cerebral reorganisation - Ageing

right

leftcM1 iM1

cPMd iPMd

cPMv iPMv

IHI

2. Imaging cerebral reorganisation - Ageing

fig 5

Ward et al., Neurobiol Aging 2007

Increasing response to force modulation in inferior frontal gyrus /

BA44 with advancing age

2. Imaging cerebral reorganisation - Ageing

right

leftcM1 iM1

cPMd iPMd

cPMv iPMv

excitability

2. Imaging cerebral reorganisation - Ageing

M1

PMv

SMA

PMd

M1

PMv

SMA

PMd

2. Imaging cerebral reorganisation - Ageing

M1

PMv

SMA

PMd

M1

PMv

SMA

PMd

2. Imaging cerebral reorganisation - Ageing

M1

PMv

SMA

PMd

M1

PMv

SMA

PMd

2. Imaging cerebral reorganisation - Ageing

Heuninckx et al. 2005

ISO

NONISO

For other tasks there may be different cognitive or ‘network’

solutions

2. Imaging cerebral reorganisation - Ageing

Wu & Hallett 2005

Subjects learned a sequence of button presses

Older took longer than younger to become automatic

‘Equal’ performance by time of scanning

old v young young v old

2. Imaging cerebral reorganisation - Ageing

3. Imaging cerebral reorganisation - Stroke

Disruption to CST leads to a shift of activity away from primary to secondary motor areas

These areas can take on new and functionally relevant roles

They are important in supporting recovered function

affected hemisphere

3. Imaging cerebral reorganisation - Stroke

less CS damagemore CS damage

Increasing ‘main effect’ of left hand gripaffected hemisphere

Ward et al., Brain 2006 CSS Integrity CSS Integrity

CSS Integrity

3. Imaging cerebral reorganisation - Stroke

A

B

infarct3 months

post stroke17 days

post stroke24 days

post stroke31 days

post stroke

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%

10 days post stroke

affected side

affected side

3. Imaging cerebral reorganisation - Stroke

4. Implications for neurorehabilitation: Increase ‘practice’?

• Cortical stimulation with task oriented training e.g. rTMS or TCDC strimulation

• Motor imagery, action observation

• Pharmacotherapy e.g. amphetamine, DA agonists, FLAME

• Pharmacotherapy e.g. plasticity modifying drugs

4. Implications for neurorehabilitation: Modify plasticity

Ward and Cohen, Arch Neurol 2004

input

input

input

input

4. Implications for neurorehabilitation: Stratify?

affected unaffected

+ +- -

affected unaffected

4. Implications for neurorehabilitation: Stratify?

a measurable change (in the brain) which characterises the ability to benefit from a particular treatment

Greater gains predicted by:

1. Less impairment at baseline

2. Lower M1 activity at baseline

4. Implications for neurorehabilitation: Stratify?

Brain reorganisation – is there a limit?

1. Age related changes and stroke related changes in motor system organisation are qualitatively similar

2. ‘Reorganising’ treatments will work differently

3. If stroke related changes are adaptive, does this mean older patents have less reserve?

4. Or does it mean that there is ‘reserve’ elsewhere?

5. Older brains are ‘changeable’ but with more effort

6. Is this a dose problem or a strategy problem?

7. Chronological age is not the same as biological age

FIL:

Richard Frackowiak

Jennie Newton

Peter Aston

Eric Featherstone

Will Penny

SOBELL DEPARTMENT :

John Rothwell

Penny Talelli

Sven Bestmann

Orlando Swayne

Hartwig Siebner

Acknowledgements

ABIU/NRU:

Richard Greenwood

Alan Thompson

Martin Brown

Diane Playford

Katie Sutton

All nurses, physios, OTs, SLTs

FUNDING:

Neuroplasticity: does it occur in the older brain?