Plasticity after stroke: implications for motor and non-motor functions. Annapoorna Kuppuswamy Institute of Neurology Queen Square

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1 Plasticity after stroke: implications for motor and non-motor functions Annapoorna Kuppuswamy Institute of Neurology Queen Square

2 Talk structure Plasticity What is plasticity? Importance of plasticity for learning and recovery (re-learning) Plasticity after stroke Harnessing plasticity for stroke recovery Fatigue Defining post stroke fatigue (PSF) Causes and misconceptions Is fatigue a result of maladaptive plasticity? Summary and future directions

after stroke Harnessing plasticity for stroke recovery Fatigue Defining post

3 What is plasticity? The brain's ability to change and reorganize in response to some change in input from internal or external Brain slice sources. Cortex Pyramidal cell Plasticity takes place in the cortex changing strength of existing connections new connections getting rid of unused connections

input from internal or external Brain slice sources.

4 What is plasticity? Developmental Experience independent (Hebbian) Experience expectant Developmental? Birth Experience dependant Injury

5 Why is plasticity important? Role of plasticity in learning Zatorre et. al., Nature Neuroscience 2012, review

6 Why is plasticity important? Role of plasticity in learning Zatorre et. al., Nature Neuroscience 2012, review

7 Stroke and plasticity time window Murphy & Corbett, Nat Rev Neuroscience, 2009

8 Harnessing plasticity enriched environments Yu et al., J Neuroscience 2014

9 Harnessing plasticity enriched environments Robotic treadmill training Home video arm/hand training Robotic arm training

10 Enhancing plasticity - drugs Chollet et. al., Lancet Neurology 2011

11 Enhancing plasticity - NIBS Site: ipsi/contra/combined Stimulation: High/low/combination Hz Number: pulses/sessions/ duration Time: during/after/before therapy Stroke: location/type Le et. al., Am J Phys Med Rehab 2014

pulses/sessions/ duration Time: during/after/before

12 Plasticity: the good and bad Plasticity: an opportunity to improve motor function Maladaptive plasticity: fatigue?

13 Defining post stroke fatigue (PSF) Overwhelming tiredness Chronic, Comes on without warning, Normally not relieved by rest Impacts physical activities, mental activities, feeling of loss of control Barbour and Mead, 2012; Eilertsen et al., 2013; Flinn and Stube, 2010; Kirkevold et al., 2012; White et al., 2012; Young et al., 2013 Fatigue is a feeling arising from difficulty in initiation of or sustaining voluntary effort Chaudhuri & Behan Lancet 2004

2012; Eilertsen et al., 2013; Flinn and Stube, 2010; Kirkevold et al., 2012; White et al., 2012; Young et al.

14 Origins of fatigue: neuropsychiatric? Mood Sleep Fatigue

15 Origins of fatigue: maladaptive plasticity in cortico-motor system? Early exposure to cytokines Ormstad et. al., 2012 Non-reversal of altered cortical neurophysiology i.e. failure of homeostatic mechanisms Alterations in cortical neurophysiology and behaviour Kuppuswamy et. al., 2015 Fatigue

16 Post-stroke fatigue: a deficit in corticomotor excitability? A cross-sectional observational study Secondary Motor Areas Inputs to M1 VA (TMS) Dependent variable - Self reported fatigue (FSS-7) N = 70 First time stroke Chronic (>3 months) Variables controlled 1- depression 2- motor function (grip strength) 3- cognitive ability (attention) M1 CST Motor output Intra-cortical interactions M1 SICI, LICI, I-O (TMS) Output pathways RMT, AMT (TMS)

reported fatigue (FSS-7) N = 70 First time stroke Chronic (>3 months) Variables controlled 1- depression 2-

17 RMT and PSF RMT Spearman CC = 0.3 Spearman p = 0.01 Backward stepwise regression R 2 = p = (variables eliminated ICI and VA) FSS score

01 Backward stepwise regression R 2 = 0.

18 PSF: is it a deficit in cortico-motor control? Behavioural correlate Unilateral Motor and not cognitive N = 42 First time stroke Chronic (>3 months) Kuppuswamy et. al., JNNP 2015

19 Limb heaviness a manifestation of PSF? FSS-7 Common symptom of stroke Not related to motor weakness Related to fatigue N = 69 First time stroke Chronic (>3 months) Motor Impairment Score (z-value) Kuppuswamy et. al., NNR 2015 (in press)

20 Summary - fatigue PSF is a disorder of the sensorimotor system Low M1 excitability Prolonged movement times (affected limb only) Limb heaviness

21 Summary & future directions Plasticity after stroke underpins recovery of function We can enhance recovery by using enriched environments We can enhance plasticity by using drugs or NIBS Plasticity can also have negative effects : e.g. fatigue Dose and timing of interventions for enhancing plasticity Identify mechanisms of fatigue for developing interventions

22 Acknowledgements Dr Nick Ward, Miss Ella Clark Prof John Rothwell Research students Mr Kurren Sandhu Mrs Isobel Turner Dr Anna Kuppuswamy funded by Senior Research Training Fellowship

STROKE CARE NOW NETWORK CONFERENCE MAY 22, 2014

STROKE CARE NOW NETWORK CONFERENCE MAY 22, 2014 Rehabilitation Innovations in Post- Stroke Recovery Madhav Bhat, MD Fort Wayne Neurological Center DISCLOSURE Paid speaker for TEVA Neuroscience Program.