FORSKNING INDENFOR NEUROREHABILITERING PÅ INSTITUT FOR MEDICIN OG SUNDHEDSTEKNOLOGI, AAU KIM DREMSTRUP AND NATALIE MRACHACZ-KERSTING

FORSKNING INDENFOR NEUROREHABILITERING PÅ INSTITUT FOR MEDICIN OG SUNDHEDSTEKNOLOGI, AAU KIM DREMSTRUP AND NATALIE MRACHACZ-KERSTING

Brain activity to control external devices and activities Brain-Computer-Interface

Brain activity to control external devices and activities Brain-Computer-Interface We associate the users intent (imagination OR attempt of a movement) & the artificial production of the imagined OR attempted movement.

Neuroplasticity and associative LTP Neuroplasticity: the ability of the brain to reorganize neural pathways based on e.g. learning new skills, recovery from injury Mechanisms of motor cortex plasticity? - persistent changes in synaptic efficacy? proposed by Hebb, 1949; review refer to Sanes & Donoghue, 2000; Cook & Bliss, 2006 D.O. Hebb and synaptic plasticity: Synaptic terminals strengthened by correlated activity will be retained or sprout new branches. Synaptic terminals that are persistently weakened by non-correlated activity will eventually loose their hold on the postsynaptic cell.

Paired Associative Stimulation tibialis anterior Pre-measures TMS alone 16 Intervention Peripheral nerve stimulus + TMS Review of PAS protocols: Suppa et al., 2017 ISI 360 TMS alone Post-measures 16 Mrachacz-Kersting et al. J Neurophysiol (2007)

Paired Associative Stimulation tibialis anterior Pre-measures TMS alone 16 Peripheral nerve stimulus + TMS Intervention ISI 360 TMS alone Post-measures 16 Mrachacz-Kersting et al. J Neurophysiol (2007)

Paired Associative Stimulation tibialis anterior Pre-measures TMS alone 16 Peripheral nerve stimulus + TMS Intervention How long should the ISI be for optimal plasticity induction? ISI 360 TMS alone Post-measures 16 100 HV Mrachacz-Kersting 50 et msal. J Neurophysiol (2007)

The correlated activation! TMS alone Pre-measures 16 Peripheral nerve stimulus + TMS Intervention n=6 7 sessions/subject spaced at least 2 days apart where ISI s were varied non - discriminately common peroneal nerve stimulus intensity: 1 MT ISI 360 TMS intensity: 120% RTh TMS alone Post-measures 16 Mrachacz-Kersting et al. J Neurophysiol (2007)

The correlated activation! conti Optimal ISI s for induction of LTP and LTD Resting TA MEPamplitude [% Baseline] 900 800 700 600 500 400 300 200 100 0 * * 20 30 40 45 50 55 60 ISI [ms] * * Bi-directional modulation of cortical plasticity induced by PAS protocol depending on ISI ISI of 55 ms appears optimal HOWEVER: large standard deviations Roy et al. J Neurophysiol (2007) Mrachacz-Kersting et al. J Neurophysiol (2007)

Determination of the optimal inter-stimulus interval 5 4 3 N39 peak [latency: N39 peak 42ms] [latency: 42 ms] TA SEP [µv] 2 1 0-1 -2-3 -4-50 0 50 100 150 200 250 Time [ms] Mrachacz-Kersting et al. J Neurophysiol (2007)

Optimized ISI PAS @ rest The 6 ms central processing delay 400 Change in TA MEP [% Pre-intervention] 350 300 250 200 150 100 50 n = 4 0 SEP+0 Sep+1 SEP+2 SEP+3 SEP+4 SEP+5 SEP+6 SEP+7 SEP+8 SEP+9 SEP+10 Inter-stimulus interval [SEP + ms] Mrachacz-Kersting et al. J Neurophysiol (2007)

Voluntary activation of the target muscle a possible solution? Three interventions: PAS at rest PAS + DF DF alone Optimal ISI for each participant (SEP latency + CPD of 6 ms) Mrachacz-Kersting et al. J Neurophysiol (2007)

Voluntary activation of the target muscle a possible solution? A Pre-Intervention Post-Intervention PAS + DF effective across all participants PAS only B DF only C PAS + DF 200µV 50ms Resting TA MEP amplitude [% baseline] 300 250 200 150 100 50 0 PAS only DF only PAS + DF 15 min into intervention Post intervention * Mrachacz-Kersting et al. J Neurophysiol (2007)

Voluntary activation of the target muscle a possible solution? A Pre-Intervention Post-Intervention PAS + DF effective across all participants PAS only B DF only C PAS + DF 200µV 50ms Resting TA MEP amplitude [% baseline] 350 300 250 200 150 100 50 0 Pre-intervention * Postintervention * 30 min postintervention Mrachacz-Kersting et al. J Neurophysiol (2007)

Effects of PAS athletes SEP = 45 ± 2 ms ISI = 51 ± 2 ms 150 * MEP amplitude change [% pre-intervention] 100 50 0 TA SOL * n = 8-50 PAS DF PAS+DF

Paired Associative Stimulation tibialis anterior Pre-measures TMS alone 16 Peripheral nerve stimulus + TMS Intervention ISI 360 TMS alone Post-measures 16 100 HV Mrachacz-Kersting 50 ms et al. J Neurophysiol (2007)

Paired Associative Stimulation tibialis anterior TMS alone Pre-measures 16 Peripheral nerve stimulus + TMS Intervention Optimal ISI necessary Optimal results when combined with voluntary activation of the target muscle Non-responders remain! (e.g. athletes) 360 ISI TMS alone Post-measures 16 Mrachacz-Kersting et al. J Neurophysiol (2007)

PAS requires two artificial stimuli: TMS and ES

An associative Brain-Compute-Interface tibialis anterior TMS alone Pre-measures 5 12 Peripheral nerve nerve stimulation stimulus + + MRCP TMS # Intervention 50 Post-measures ISI TMS alone 5 12 100 HV Mrachacz-Kersting 50 ms et al. J Physiol (2012)

The movement related cortical potential as part of PAS England Canada Denmark Professor Dario Farina Dr. Ning Jiang Dr. Kim Dremstrup

The movement-related cortical potential 15 10 5 MMP MRCP (μv) 0-5 -10 RP MP -15-3 -2-1 0 1 Time (s) Movement start A negative EEG deflection preceding and accompanying voluntary real and imaginary movements. MRCP amplitude is related to force and speed.

Baseline session Identify timing of individual peak-negativity in MRCPs in relation to the visual cue. This time is used for the subsequent intervention to ensure the afferent feedback generated artificially arrives during the maximal activation of M1 [Mrachacz-Kersting et al. 2012]

BCI associative Intervention The associativity: stimulate the deep branch of the common peroneal nerve so that the afferent flow arrives during the peak negativity of the MRCP [Mrachacz-Kersting et al. 2012]

For our BCI intervention to work, we need to have a stable MRCP

-2-1.5-1 -0.5 0 0.5 1 1.5 2 time [s]

-2-1.5-1 -0.5 0 0.5 1 1.5 2 time [s]

-2-1.5-1 -0.5 0 0.5 1 1.5 2 time [s]

-2-1.5-1 -0.5 0 0.5 1 1.5 2 time [s]

-2-1.5-1 -0.5 0 0.5 1 1.5 2 time [s] -2-1.5-1 -0.5 0 0.5 1 1.5 2 time [s]

The MRCP PN is stable within a session and across sessions for healthy participants.

What about in chronic stroke patients???

5 µv Onset of attempted dorsiflexion task B 500 ms 150 Session 1 Session 2 Session 3 5 µv Peak negativity [ms in relation to task onset at 0 ms] 100 50 0-50 -100-150 -200 500 ms -250 1 2 3 4 5 6 7 Patient

The MRCP PN is stable within a session and across sessions for chronic stroke patients. BUT timing differs from patient to patient.

What about acute stroke patients???

200 Patient 5 200 Patient 19 PN Time [ms] 100 0-100 PN Time [ms] 100 0-100 -200 1 2 3 4 5 6 7 8 9 10 11 12 Session Number -200 1 2 3 4 5 6 7 8 9 10 11 12 Session Number 100 PN Time [ms] 0-100 -200 1 2 3 4 5 6 7 8 9 Patient Number

-2-1.5-1 -0.5 0 0.5 1 1.5 2 time [s]

-2-1.5-1 -0.5 0 0.5 1 1.5 2 time [s]

-2-1.5-1 -0.5 0 0.5 1 1.5 2 time [s]

-2-1.5-1 -0.5 0 0.5 1 1.5 2 time [s]

An example of a single trial when the ES timing is off. Possible reasons: Patient fatigue? movement quality affected Patient inattentive? timing in relation to the cue affected -2-1.5-1 -0.5 0 0.5 1 1.5 2 time [s]

Another example of a single trial when the ES timing is off. Possible reasons: Patient fatigue? movement quality affected Patient inattentive? timing in relation to the cue affected -2-1.5-1 -0.5 0 0.5 1 1.5 2 time [s]

The MRCP PN is stable within a session but NOT across sessions for acute stroke patients. Timing of the electrical stimulus does not have to be perfect every time. But then is it like PAS????

Paired Associative Stimulation tibialis anterior Pre-measures TMS alone 16 Peripheral nerve stimulus + TMS Intervention How long should the ISI be for optimal plasticity induction? ISI 360 TMS alone Post-measures 16 100 HV Mrachacz-Kersting et al. J Neurophysiol (2007) 50 ms

An associative Brain-Compute-Interface tibialis anterior TMS alone Pre-measures 5 12 Peripheral nerve nerve stimulation stimulus + + MRCP TMS # Intervention 50 Post-measures ISI TMS alone 5 12 100 HV Mrachacz-Kersting 50 ms et al. J Physiol (2012)

An associative Brain-Computer-Interface (BCI) in chronic stroke Visual display on computer screen during the intervention (B) FOCUS REST 2 3 s 2 2 4 5 s s s Mrachacz-Kersting et al. J Neurophysiol (2016)

Chronic stroke patients BCI associative intervention 1200 TA p-p MEP amplitude [µv] 1000 800 600 400 pre-intervetion post-intervention 30 min post-intervention MRCP 200 0 45 50 55 60 65 70 TMS intensity [%S.O.] Mrachacz-Kersting et al. (2016) J Neurophysiol

Chronic stroke patients - BCI associative intervention TA p-p MEP amplitude [µv] 1200 1000 800 600 400 200 pre-intervetion post-intervention 30 min post-intervention 10 m walk test: Pre: 15.5 s Post 10.5 s Foot Tap Frequ: Pre: 2.31 Hz Post: 3.42 Hz Finger Tap Frequ: Pre: 3.17 Hz Post: 3.18 Hz 0 45 50 55 60 65 70 TMS intensity [%S.O.] Mrachacz-Kersting et al. (2016) J Neurophysiol

Chronic stroke patients BCI non-associative intervention 1600 1400 MRCP TA p-p MEP amplitude [µv] 1200 1000 800 600 400 200 0 40 45 50 55 60 65 70 75 TMS intensity [%S.O.] Mrachacz-Kersting et al. (2016) J Neurophysiol

Chronic stroke patients - BCI non-associative intervention TA p-p MEP amplitude [µv] 1600 1400 1200 1000 800 600 400 200 10 m walk test: Pre: 8.03 s Post 8.05 s Foot Tap Frequ: Pre: 4.03 Hz Post: 3.8 Hz Finger Tap Frequ: Pre: 0.53 Hz Post: 0.53 Hz 0 40 45 50 55 60 65 70 75 TMS intensity [%S.O.] Mrachacz-Kersting et al. (2016) J Neurophysiol

Chronic stroke patients TA p-p MEP amplitude [fraction of pre MEPmax] 3,0 2,5 2,0 1,5 1,0 0,5 BCIassociative A Day 1 0,0 80 90 100 110 120 130 140 TMS intensity [% RMT] TA p-p MEP amplitude [fraction of pre MEPmax] 3,0 2,5 2,0 1,5 1,0 0,5 D BCI non- associative Day 1 pre-intervention post-intervention 30 min post-intervention 0,0 80 90 100 110 120 130 140 TMS intensity [% RMT] TA p-p MEP amplitude [fraction of pre MEPmax] C Day 3 3,0 2,5 2,0 1,5 1,0 0,5 0,0 80 90 100 110 120 130 140 TA p-p MEP amplitude [fraction of pre MEPmax] F Day 3 3,0 2,5 2,0 1,5 1,0 0,5 0,0 80 90 100 110 120 130 140 Mrachacz-Kersting et al. (2016) J Neurophysiol TMS intensity [% RMT] TMS intensity [% RMT]

Acute stroke patients 1000 Day 1 TA p-p MEP amplitude [µv] 800 600 400 200 pre-intervetion post-intervention 30 min post-intervention MRCP 0 40 45 50 55 60 65 70 TMS intensity [%S.O.]

Acute stroke patients 1000 Day 6 TA p-p MEP amplitude [µv] 800 600 400 200 pre-intervetion post-intervention 30 min post-intervention MRCP 0 35 40 45 50 55 60 65 TMS intensity [%S.O.]

Acute stroke patients 1000 Day 12 TA p-p MEP amplitude [µv] 800 600 400 200 pre-intervetion post-intervention 30 min post-intervention MRCP 0 35 40 45 50 55 60 65 TMS intensity [%S.O.]

Acute stroke patients TA p-p MEP amplitude [µv] 1000 800 600 400 200 Day 12 10 m walk test: Pre: 8.47 s Post 5.52 s LE-FM: Pre: 24/34 Post: 33/34 0 35 40 45 50 55 60 65 TMS intensity [%S.O.]

Acute stroke patients TA p-p MEP amplitude [µv] 1000 800 600 400 200 pre-intervetion post-intervention 30 min post-intervention TA p-p MEP amplitude [µv] 300 250 200 150 100 50 pre-intervetion post-intervention 30 min post-intervention 0 0 30 35 40 45 50 55 84 60 86 88 90 92 94 96 98 100 TMS intensity [%S.O.] TMS intensity [%S.O.]

Special Thanks! The Chronic study team, especially: Aleksandra Pavlovic Dario Farina Kim Dremstrup Ning Jiang Sasa Radovanovic Vladimir Kostic The patients The Acute study team, especially: Andrew JT Stevenson Dario Farina Helle Jørgensen Kim Dremstrup Kåre E Severinsen Margherita Castronovo Ning Jiang Susan Aliakbaryhosseinabadi The patients The afferent feedback team: Andrew JT Stevenson Anna C Lundgaard Dario Farina Michael Voigt Ning Jiang The participants The upper limb team: Donatella Mattia Margherita Castronovo Fabiano Landi The participants The funders: EU SEP-210192113 Lundbeck Fonden Otto Mønsted Fonden The Obels Family Foundation The Kong Christian den Tiendes Fond

REMAP - Amyotrophic lateral sclerosis (ALS) patients

MRCP opening vs closing the hand

ALS-FRSr = 2

ALS-FRSr = 11

ALS-FRSr = 34