Y P Non-Invasive Brain Stimulation and Behavioral Therapy O Dylan - - PDF document

Berenson-Allen Center for Noninvasive Brain Stimulation Beth Israel Deaconess Medical Center Harvard Medical School

Non-Invasive Brain Stimulation and Behavioral Therapy

Dylan J. Edwards PhD

Director, Moss Rehabilitation Research Institute, Philadelphia Professor of Neuroscience, ECU Australia !"#$%&'()*+,-%.*/0%),012*'!13%/0,!1456

Berenson-Allen Center for Noninvasive Brain Stimulation Beth Israel Deaconess Medical Center Harvard Medical School

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Plasticity

Adaptive Maladaptive

Berenson-Allen Center for Noninvasive Brain Stimulation Beth Israel Deaconess Medical Center Harvard Medical School

Pharmacology Behavioral Intervention Brain Stimulation Limitations and advantages of restorative methods!.?

Focality / Specificity

Smaller Coil Network activation

How does repetitive behavior affect motor cortex?

P L E A S E D O N O T C O P Y

Simple repetitive finger movements increase excitability Motor map changes with skilled practice

How does NIBS affect motor cortex?

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) ( ! ) ( ! Magstim EMG Instrument Stimulating coil Magstim EMG Instrument Magstim Magstim EMG Instrument EMG Instrument Stimulating coil

*"+,-'.'/"0"#'

789:!'5.

Di Lazzaro et al. (1998)

5;"<*(' 6=&>#*'%(<3%?&>$"

SICF

300 250 200 150 100 50

Amplitude

(% control) 2 1 3 4 5 2.5 1.5 3.5 4.5

Inter-stimulus Interval (ms)

1.5 msec.

Ziemann et al, 1998 Periodicity ~ 1.5ms I-waves

TMS

Berenson-Allen Center for Noninvasive Brain Stimulation Beth Israel Deaconess Medical Center Harvard Medical School

D Edwards

williamcalvin.com

Donald Hebb

“An excited neuron tends to decrease its discharge to inactive neurons, and increase this discharge to any active neuron, and therefore to form a route to it, whether there are intervening neurons between the two or not. With repetition, this tendency is prepotent in the formation of neural routes”. (Hebb, 1932, p.13).

The Organisation of Behaviour: A Neuropsychological Theory. D.O. HEBB (1949)

P L E A S E D O N O T C O P Y

Rate-dependent TMS protocols

Low-frequency ~1Hz High-frequency ~10Hz Inhibitory Excitatory

REPETITIVE

Intermittent

2 sec 8 sec

50Hz 5Hz

Continuous Excitatory Inhibitory

THETA BURST

Glu

Ca++ Na+ AMPA Post-synaptic Dendritic spine Pre-synaptic NMDA AMPA Na+ Mg++ EPSP Long-term potentiation Thickbroom (2007) Ex Brain Res.

Glu

AMPA Post-synaptic Dendritic spine Pre-synaptic NMDA Na+ Mg++ Ca++

CaM CaMKII

AMPA Ca++ Na+ EPSP

!

Long-term potentiation Thickbroom (2007) Ex Brain Res.

Glu

AMPA NMDA Mg++ Ca++

CaM

Ca++

LTP/ LTD

CaMKII PP2B

C N Long-term depression Thickbroom (2007) Ex Brain Res. Webster et al (2006) Berenson-Allen Center for Noninvasive Brain Stimulation Beth Israel Deaconess Medical Center Harvard Medical School

Clinical application - rTMS, Stroke Motor Recovery

Webster et al (2006)

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IMPROVED CORTICOMOTOR OUTPUT FROM IPSI-LESIONAL M1 & IMPROVED MOTOR BEHAVIOUR

P L E A S E D O N O T C O P Y

Webster et al (2006) Webster et al (2006)

Functional Improvements sRT/cRT Pinch force acceleration fingers/thumb AROM Movement accuracy Purdue Pegboard JTT TMS correlates Resting MT Transcallosal Inhibition MEP Amplitude

IMPROVED CORTICOMOTOR OUTPUT FROM IPSI-LESIONAL M1 & IMPROVED MOTOR BEHAVIOUR

How does combined intervention affect motor cortex?

Altering cortical excitability before repetitive synaptic activity

Lang et al (2004)

• 1mA 10mins tDCS
• rTMS at 5Hz 100stim train at AMT – decreases SICI, but not lasting change in

excitability as tested by single pulse TMS

• Result= after effects of tDCS can generate opposite effects of rTMS or

conversely can alter the after effects of tDCS

Berenson-Allen Center for Noninvasive Brain Stimulation Beth Israel Deaconess Medical Center Harvard Medical School Buch et al 2011, J Neurosci

Is coupling NIBS with therapy good?

If!

Motor Training NIBS

= improvement in function ‘X’ = improvement in function ‘X’

does! and!

Motor Training NIBS

+

= improvement in function

2X, X2, or 0??

Motor systems example

P L E A S E D O N O T C O P Y

%1/2 SICF

Berenson-Allen Center for Noninvasive Brain Stimulation Beth Israel Deaconess Medical Center Harvard Medical School Berenson-Allen Center for Noninvasive Brain Stimulation Beth Israel Deaconess Medical Center Harvard Medical School

1mV Pre-tDCS Post-tDCS Post-Robot

Anodal tDCS combined with robotic motor training

Edwards et al (2009)

Group SICI Index

Conditioned / uncond MEP amplitude

0.5 1

p < 0.05

* *

Pre tDCS Post tDCS Post Robot

Edwards et al (2009)

Anodal tDCS combined with robotic motor training

Robotics for assessment of performance kinematics

Pre – training Post - training

9==(%'*&@A'%3A3)&<"'#)'B;%C(DE3%>(**+'F(G'H3%C

Robotics with brain stimulation in patients with motor dysfunction

Edwards PI: R01 HD069776

P L E A S E D O N O T C O P Y

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TMS

Prelim data for Nexstim NICHE Trial

Nexstim NICHE Trial 2014-16

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Repetitive Transcranial Magnetic Stimulation (rTMS)

Electrical field display Aiming tool: centering, rotation, tilting

Parameters:

• 900 pulses
• 1 Hz rTMS (inhibitory) to M1 of

non-lesioned hemisphere

• 110% of motor threshold for

Extensor Digitorum Communis (m.EDC)

Patient set up

Task Oriented Rehabilitation

Patient Goals:

• Cut food with knife & fork
• Cook
• Reach for items above

shoulder height

• Fasten clothing (buttons,

zippers, laces)

• Hold grandchild
• Hold tools in affected hand
• Driving
• Golf

Collaborative process between therapist and patient

Person Occupation Occupation Environment

Nexstim NICHE Trial 2014-16

Improvement ! 5 UEFM points 6 mths post (Primary) Experimental group: 67% (95% CI, 58%–75%) n=117 Control Group: 65% (95% CI, 52%–76%) n=52

Mean change UEFM points 6 mths Experimental: 8.2 ±7pts Control: 8.5 ±8pts P=0.87

Harvey et al, 2018 Stroke

P =0.76

P L E A S E D O N O T C O P Y

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How does unaffected M1 excitability relate to hemiparesis?

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J = M F

Courtesy A .Boes MD March 2017

VLSM in 3-12month Post-Stroke (hemiparesis)

Hot colour = maximum overlap for unaffected hemisphere hyper-excitability

n=103

Berenson-Allen Center for Noninvasive Brain Stimulation Beth Israel Deaconess Medical Center Harvard Medical School

Other cortical areas?

Webster et al (2006) Webster et al (2006)

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+

Electrical field display Aiming tool: centering, rotation, tilting Parameters:

• 900 pulses
• 1 Hz rTMS (inhibitory) to pars

triangularis of non-lesioned hemisphere

• Motor threshold determination

with First dorsal interosseus muscle

• Real - 90% RMT
• Sham – 10% RMT

Patient set up

rTMS plus speech therapy, inpatient stroke

CIHR: MOP-286185

+ Subject 1

Infarct

Pars triangularis

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Berenson-Allen Center for Noninvasive Brain Stimulation Beth Israel Deaconess Medical Center Harvard Medical School

Neuronix Ltd.[1]

NICETM System Neuronix Ltd., Israel [3]!

! ! Electric stimulator with maximum power ! ! Connected to stereotactic system with controller and user graphical display

TMS for Alzheimer’s disease - Neuronix

• Combines TMS to enhance

plasticity with cognitive exercises

• TMS to a brain network

followed by cognitive tasks that activate that network

• Daily sessions lasting 1 hour

for 6 weeks

TMS for Alzheimer’s disease-Neuronix

Courtesy Dr D. Press

P L E A S E D O N O T C O P Y

TMS for Alzheimer’s disease-Neuronix Stimulation Sites

Courtesy Dr D. Press

Results of Initial NeuroAD trials

• Neuronix has completed a phase III trial of

TMS+Cognitive therapy in mild-moderate AD

• Prospective, double-blind trial of 130

patients

• Initial results presented at meetings

showing efficacy in the mild AD patients but not in overall group

Courtesy Dr D. Press

Berenson-Allen Center for Noninvasive Brain Stimulation Beth Israel Deaconess Medical Center Harvard Medical School Harvard Medical School

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Berenson-Allen Center for Noninvasive Brain Stimulation Beth Israel Deaconess Medical Center Harvard Medical School

Donse et al (2018)

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Berenson-Allen Center for Noninvasive Brain Stimulation Beth Israel Deaconess Medical Center Harvard Medical School

Donse et al (2018)

P L E A S E D O N O T C O P Y

Berenson-Allen Center for Noninvasive Brain Stimulation Beth Israel Deaconess Medical Center Harvard Medical School D J Edwards Berenson-Allen Center for Noninvasive Brain Stimulation Beth Israel Deaconess Medical Center Harvard Medical School D J Edwards

Wilkinson et al (2019)

Berenson-Allen Center for Noninvasive Brain Stimulation Beth Israel Deaconess Medical Center Harvard Medical School D J Edwards

Wilkinson et al (2019)

Conclusions

• Brain state influences the response to

neuromodulation

• Homeostatic mechanisms may oppose further

enhancement when interventions are combined

• Combined neuromodulation & behavioral therapy

can be effective

• The optimal circumstances require further

investigation

Berenson-Allen Center for Noninvasive Brain Stimulation Beth Israel Deaconess Medical Center Harvard Medical School D J Edwards

P L E A S E D O N O T C O P Y