Mechanisms of stroke recovery and restorative stroke therapeutics

Transcription

1 25th European Stroke Conference, Venice 13-15th April 2016 Mechanisms of stroke recovery and restorative stroke therapeutics NICK WARD, UCL INSTITUTE OF NEUROLOGY,

2 Disclosure. Patient choice

3 Overview Summary points 1. Recovery after stroke - we need to give more therapy 2. Why do some patients fail to recover - anatomy? 3. Why do some patients fail to recover - plasticity? 4. Progressing to clinical trials in humans too early

4 Recovery after stroke is proportional 1 predicted change 2 Winters et al., NNR (2015) observed change severe mild 1. How to turn non-recoverers into (proportional) recoverers? 2. How to improve on regaining 70% of what is lost?

5 Promoting Recovery After Stroke Upper limb treatment The dose of UL treatment after stroke is unacceptably low... Patients engaged in activity for only 13% of the day (Bernhardt et al, 2004) Patients were alone for over 60% of the day (Bernhardt et al, 2004) Practice of task-specific, functional UL movements in only 51% of UL sessions (Lang et al, 2009)

6 Promoting Recovery After Stroke Upper limb treatment increasing the dose Is there evidence to support increased dose repetitions? In animals, changes in primary motor cortex synaptic density occur after 400 (but not 60) reaches (Remple et al, 2001) In human stroke patients, typical number of repetitions in a session is 30 (Lang et al, 2009) Ability to perform repetitions related to function might be a threshold above which UL use improves and below which it decreases (Schweighofer et al, 2009)

7 Upper limb treatment increasing the dose Is there evidence to support increased dose - time on task? Increased dose studies have high variability in design extra = 2 hrs/week to 3 hrs/day some initiated early, some late Strong evidence for higher dose of practice high intensity repetitive task-oriented training

8 Rehabilitation Promoting of Recovery hand function After after Stroke stroke Upper limb Upper treatment limb treatment increasing the dose JAMA. 2016;315(6): hours over 10 weeks

9 Rehabilitation Promoting of Recovery hand function After after Stroke stroke Upper limb Upper treatment limb treatment increasing the dose Tx started within 14 days post-stroke CIMT (60 mins therapy plus 3 hrs mitt) Continue with mitt for extra 5 weeks Control = 30 mins day for 3 weeks CIMT = 6-7 FM points advantage

10 Upper limb treatment increasing the dose 36 hours over 12 weeks 127 patients (36 x 60 mins) robot vs matched = -0.1 on UL-FM* robot vs usual = on UL-FM* 18 hours over 8 weeks 73 patients (24 x 45 mins) robot vs matched = +0.8 on UL-FM MIT-Manus *not significant ARMin Clinically meaningful change in FM-UL = approx 7 points

11 Upper limb treatment increasing the dose 300 hours of upper limb therapy over 5 weeks = 8-11 points on UL-FM

12 Upper limb treatment increasing the dose 10 McCABE ΔFM-UL 5 EXPLICIT* clinically meaningful change MIT-MANUS ARMIN ICARE Therapy dose (hours)

13 Upper limb treatment increasing the dose PART 1 - SUMMARY More is generally better AVERT little and often better Dose response emerging from clinical trials ARMEO Spring

14 Why do only some stroke survivors recover? 1. Does recovery depend on anatomy? 2. Does recovery depend on plas5city? r 2 = 0 poten$al for plas$city increased plasticity decreased plasticity $me post-stroke

15 Does recovery depend on anatomy? Structural MRI Lesion likelihood map 50 patients single subject MACHINE LEARNING classification accuracy (whole brain) = 80% Red = good outcome Green = poor outcome

16 Does recovery depend on anatomy? Nat Rev Neurol Apr;6(4): Speech production score Speech production score Months since stroke Months since stroke Hope et al., Neuroimage Clinical, 2013

17 Does recovery depend on anatomy? PART 2 - SUMMARY Best predictor of UL recovery is initial impairment Anatomical damage does carry independently useful information Note causes of initial impairment not the same as factors important for recovery

18 Does recovery depend on plasticity?? 1. Does recovery depend on anatomy? 2. Does recovery depend on plas5city? r 2 = 0 poten$al for plas$city increased plasticity decreased plasticity $me post-stroke

19 Enhancing plasticity after stroke B critical period 2 nd stroke reinitiated critical period during which training can lead to full recovery

20 Does recovery depend on structural plasticity? Dendritic growth in vivo LIII pyramidal cell Axon arborisation in vivo Niell et al., Nat Neurosci 2004; 7: Hua et al., Nature 2005; 434: Kolb B et al., Neurosci Biobehav Rev 1998; 22:

21 Does recovery depend on structural plasticity? Wahl & Schwab, Front Hum Neurosci 2014 Newly sprouting fibres either locally (perininfarct) or crossing the midline A number of approaches have been used e.g. anti-nogo, inosine, GDF10 Also stem cells, granulocyte-colony stimulating factor (G- CSF)

22 Does recovery depend on functional plasticity? In the cortex GABA is inhibitory, glutamate is excitatory Reduced activity at GABAergic interneurons allows plasticity in adults Enhanced glutamatergic signalling leads to LTP So altering the balance of inhibition/excitation is important in reopening new periods of plasticity in adult cortex

23 Structural and functional plasticity Reduced GABA A -ergic and increased glutamatergic signalling expanded and less specific receptive fields (Winship et al, J Neurosci 2008) enhanced long-term potentiation (Hagemann et al., Ann Neurol. 1998;44:255 8) facilitation of downstream changes in neuronal structure (Chen et al., Nat Neurosci. 2011;14:587 94) remapping of sensorimotor functions to surviving cortex (Takatsuru et al., J Neurosci 2009;29: )

24 Enhancing use-dependent plasticity with drugs α5ia Increased tonic inhibition via extrasynaptic GABA A receptor alpha-5 subunit dominates in perilesional cortex Alpha-5 subunit blockade improved motor recovery in rodent model Does hyper- or hypo-excitability predominate in human stroke patients? Human trials?

25 Enhancing use-dependent plasticity with drugs less disability more disability SSRIs (e.g. FLAME, FOCUS in UK) Acetylcholinesterase inhibitors amphetamine

26 Enhancing use-dependent plasticity with drugs Recovery with: training from day 1 (in critical period) Recovery with: fluoxetine from day 1 training from day 7 (keeps critical period open) No recovery with: training from day 7 (outside critical period) No recovery with: fluoxetine from day 7 training from day 7 (can t re-open critical period) Fluoxetine administration after stroke decreased inhibitory interneuron expression in a medial premotor area

27 Enhancing use-dependent plasticity with NIBS Transcranial Direct Current Stimulation Facilitates Motor Learning Post Stroke: A Systematic Review and Meta-Analysis Kang et al, JNNP 2015

28 Enhancing use-dependent plasticity PART 3 - SUMMARY Stroke induces critical period plasticity Window does not shut! Structural and functional plasticity play a role Drugs available to manipulate excitation/ inhibtion in humans now!

29 Therapeutic targets in humans? Animal studies suggest that spontaneous biological recovery is (i) augmented by a homeostatic restitution of cortical activity secondary to reduced (phasic) GABA-ergic inhibition, or (ii) blocked by excessive (tonic) GABAergic inhibition Furthermore, both are amenable to pharmacological (or other) manipulation.

30 Therapeutic targets in humans? A biomarker.. is an indicator of disease state that is useful clinically as a substitute measure, reflecting underlying molecular/cellular events that are difficult to measure directly (in humans)

31 Biomarkers of potential for use-dependent plasticity Neuronal oscillations as biomarkers of plasticity mechanisms? Stroke patients with poorer outcomes have increased low-frequency oscillations Laaksonen K, et al. PloS One. 2013;8:e61146 similar to those caused by BZD and tiagabine suggesting predominant inhibitory mechanisms in peri-lesional cortex? In a single stroke patient, zolpidem reversed increased peri-lesional theta (4-10Hz) and beta oscillations leading to clinical improvement. Hall SD, et al. Clin Neurophys 2010;121: Zolpidem works at α-1 subunit containing GABA A receptors Increased early post-stroke sensorimotor excitability (less beta-rebound in response to tactile finger stimulation) Laaksonen K, et al.. Clin Neurophys 2012;123: and sensory map size predict good recovery Roiha K, et al. Clin Neurophys 2011;122: Less inhibition, more excitation = better outcome (might allow sprouting )

32 Biomarkers of potential for use-dependent plasticity A mechanistic approach to studying recovery requires an appropriate level of description Inhibitory interneuron SUPERFICIAL DEEP Pyramidal cell Bhatt et al Neuroimage 2016 Intracortical networks Task related networks Large scale networks MESOSCOPIC MACROSCOPIC NS Ward Curr Opin Neurol. 2015; 28: NS Ward Brain. 2015; 38:

33 New knowledge A mechanistic to change approach clinical prac2ce Mechanism Predic5on Therapy fluoxe5ne?? brain structure? brain func5on? α5ia? Mechanis)c understanding of early recovery in humans New models to predict upper limb outcome Biomarkers for iden$fying who and when to treat

34 Summary 1. More is better. We don t give enough physical or behavioural interventions to drive recovery. 2. Anatomy of damage in whole brain can help predict outcome and therefore stratification in restorative trials 3. There are clear lesion induced changes in structure that can support recovery anti NoGo, inosine, GDF10 4. Pushing inhibitory/excitatory balance away from inhibition opens door to structural plasticity 5. Need biomarkers of these processes in humans so we know what to target - drugs available now! 6. Too early for phase III trials - Understanding the mechanisms involved first (or at least in parallel) is crucial (funders please note!)

35 Acknowledgements FIL: Karl Friston Rosalyn Moran Gareth Barnes Richard Frackowiak Will Penny Jennie Newton ABIU/NRU: Fran Brander Kate Kelly Diane Playford Alan Thompson SOBELL DEPARTMENT : Holly Rossiter Muddy Bhatt Stephanie Bowen Ella Clark Svenja Espenhahn Chang-hyun Park Sven Bestman John Rothwell Penny Talelli Slides at FUNDING:

36 Why do only some stroke survivors recover? 1. Murphy TH, Corbett D. Plasticity during stroke recovery: from synapse to behaviour. Nat Rev Neurosci 2009;10: Carmichael ST. Targets for neural repair therapies after stroke. Stroke 2010;41(10 Suppl):S Philips JP, Devier DJ, Feeney DM. Rehabilitation pharmacology: bridging laboratory work to clinical application. J Head Trauma Rehabil 2003 Jul-Aug;18(4): Stagg CJ, Nitsche MA. Physiological basis of transcranial direct current stimulation. Neuroscientist 2011;17: Stinear CM, Ward NS. How useful is imaging in predicting outcomes in stroke rehabilitation? Int J Stroke. 2013;8(1): Ward NS. Assessment of cortical reorganisation for hand function after stroke. J Physiol. 2011;589(Pt 23):