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

2. 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?

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. 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’

5. 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’

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

7. 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’

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

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…..” 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’

12. | 2. Imaging cerebral reorganisation - Ageing

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

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

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

16. fMRI – normal motor system activation B F1 B G = average effect of all hand grips B F = increase in BOLD signal with increasing peak force

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

18. right left cM1iM1 cPMdiPMd cPMv iPMv IHI 2. Imaging cerebral reorganisation - Ageing

19. 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

20. right left cM1iM1 cPMdiPMd cPMv iPMv excitability 2. Imaging cerebral reorganisation - Ageing

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

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

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

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

25. 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 youngyoung v old 2. Imaging cerebral reorganisation - Ageing

26. 3. Imaging cerebral reorganisation - Stroke

27. 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

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

29. A B infarct 3 months post stroke 17 days post stroke 24 days post stroke 31 days post stroke OUTCOMESBarthelARATGRIPNHPT Patient A20/2057/5798.7%78.9% Patient B20/2057/5764.2%14.9% 10 days post stroke affected side 3. Imaging cerebral reorganisation - Stroke

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

31. 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

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

33. affectedunaffected + + - - affectedunaffected 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? 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

36. 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?