NICK WARD UCL INSTITUTE OF NEUROLOGY

1. Neuroplasticity: does it occur in the older brain? NICK WARD UCL INSTITUTE OF NEUROLOGY British Geriatrics Society, BMA House, London 27th January 2011

2. What is different about the older brain? What do we mean by plasticity? Motor system changes with ageing Motor system changes after stroke

3. 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’

4. 1. ‘Neural changes in response to activity’ Dendritic growth in vivo (600:1 time lapse) Axon arborisation in vivo (600:1 time lapse) Niell et al., Nat Neurosci 2004; 7: 254-260 Hua et al., Nature 2005; 434: 1022-1026

5. 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 dendriticarbor. Nat Neurosci 2004; 7: 254-260

6. 1. ‘Neural changes in response to activity’ from Kolb 1995

7. 1. ‘Neural changes in response to activity’ 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) 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) System level plasticity = state- and history-dependent change in connection strength between areas.

8. 1. ‘Neural changes in response to activity’

9. 1. ‘Neural changes in response to activity’ scan 2 scan 3 scan1 Draganski B et al., Nature. 2004 ;427:311-2

10. Task: button press sequence Training related increases in grey matter 1. ‘Neural changes in response to activity’

11. “…..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…..” 1. ‘Neural changes in response to activity’ 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

12. | 2. Imaging cerebral reorganisation - Ageing

13. GRIP FORCE 40% 30% 20% GRIP GRIP GRIP 40 secs BOLD SIGNAL GRIP REST 40 secs TIME 2. Imaging cerebral reorganisation - Ageing

14. force time right hand 15 10 5 t-score fMRI – main effects

15. force time contralateral central sulcus ipsilateral cerebellum (lobule VI) contralateral superior cingulate sulcus fMRI – activity during force modulation

16. BF1 BG = average effect of all hand grips BF = increase in BOLD signal with increasing peak force fMRI – normal motor system activation

17. Ward et al., Neurobiol Aging 2007 Ipsilateral M1 activity related to increasing age 2. Imaging cerebral reorganisation - Ageing Main effect of hand grip

18. right iPMv cPMv cPMd iPMd left IHI cM1 iM1 2. Imaging cerebral reorganisation - Ageing

19. Increasing response to force modulation in inferior frontal gyrus / BA44 with advancing age fig 5 2. Imaging cerebral reorganisation - Ageing Ward et al., Neurobiol Aging 2007

20. excitability 2. Imaging cerebral reorganisation - Ageing right iPMv cPMv cPMd iPMd left cM1 iM1

21. SMA SMA PMv PMv PMd PMd M1 2. Imaging cerebral reorganisation - Ageing M1

22. SMA PMv PMd 2. Imaging cerebral reorganisation - Ageing SMA PMv PMd M1 M1

23. SMA PMv PMd 2. Imaging cerebral reorganisation - Ageing SMA PMv PMd M1 M1

24. For other tasks there may be different cognitive or ‘network’ solutions 2. Imaging cerebral reorganisation - Ageing ISO NONISO Heuninckx et al. 2005

25. 2. Imaging cerebral reorganisation - Ageing 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 Wu & Hallett 2005

26. 3. Imaging cerebral reorganisation - Stroke

27. affected hemisphere 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

28. CSS Integrity CSS Integrity CSS Integrity Ward et al., Brain 2006 affected hemisphere more CS damage less CS damage 3. Imaging cerebral reorganisation - Stroke Increasing ‘main effect’ of left hand grip

29. affected side A 10 days post stroke 17 days post stroke 24 days post stroke 31 days post stroke 3 months post stroke infarct B affected side 3. Imaging cerebral reorganisation - Stroke

30. 4. Implications for neurorehabilitation: Increase ‘practice’?

31. 4. Implications for neurorehabilitation: Modify plasticity • 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

32. input input input input 4. Implications for neurorehabilitation: Stratify? Ward and Cohen, Arch Neurol 2004

33. unaffected unaffected affected affected - - + + 4. Implications for neurorehabilitation: Stratify? a measurable change (in the brain) which characterises the ability to benefit from a particular treatment

34. Greater gains predicted by: 1. Less impairment at baseline 2. Lower M1 activity at baseline 4. Implications for neurorehabilitation: Stratify?

35. Brain reorganisation – is there a limit? • Age related changes and stroke related changes in motor system organisation are qualitatively similar • ‘Reorganising’ treatments will work differently • If stroke related changes are adaptive, does this mean older patents have less reserve? • Or does it mean that there is ‘reserve’ elsewhere? • Older brains are ‘changeable’ but with more effort • Is this a dose problem or a strategy problem? • Chronological age is not the same as biological age

36. Neuroplasticity: does it occur in the older brain? Acknowledgements FUNDING: ABIU/NRU: Richard Greenwood Alan Thompson Martin Brown Diane Playford Katie Sutton All nurses, physios, OTs, SLTs SOBELL DEPARTMENT : John Rothwell Penny Talelli Sven Bestmann Orlando Swayne Hartwig Siebner FIL: Richard Frackowiak Jennie Newton Peter Aston Eric Featherstone Will Penny