Y 3% Pain 1% Drug abuse 23% Non-Invasive Brain Stimulation and - - 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, Laboratory for NIBS and Robotics Burke Neurological Institute Associate Professor of Clinical Neurophysiology, Weill Cornell Medicine Professor of Neuroscience, ECU Australia Lecturer in Neurology, Harvard Medical School TMS

23% Other <1% Orthopedic conditions 1% Cancer 8% Cognitive impairments 3% Pain 1% Drug abuse 18% Sensorimotor disorders 30% Psychiatric disorders 1% Speech/language 17% Brain damage 2% Pediatrics <1% Eating disorders

Listings for; “TMS” Source: www.clinicaltrials.gov Berenson-Allen Center for Noninvasive Brain Stimulation Beth Israel Deaconess Medical Center Harvard Medical School

rTMS combined with behavioral therapy?

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

Tsagaris et al , 2016 Burke Neurological Institute, New York

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….?

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

Focality / Specificity

Smaller Coil Network activation

How does repetitive behavior affect motor cortex?

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

How does NIBS affect motor cortex?

TMS Demonstration

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

Physiology of TMS

Hallett, 2000

) ( α ) ( α Magstim EMG Instrument Stimulating coil Magstim EMG Instrument Magstim Magstim EMG Instrument EMG Instrument Stimulating coil

Ramón y Cajal

ADULT M1 Di Lazzaro et al. (1998)

Muscle Spinal recordings

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)

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.

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

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)

Yozbatiran et al, 2009 Malcom et al, 2007 Hummel et al, 2007 Talelli et al., 2007 Kim et al., 2006 Hummel et al, 2006 Khedr et al., 2005 Hummel et al, 2005 Takeuchi, et al, 2008 Boggio et al, 2007 Fregni et al., 2006 Fregni et al., 2005 Mansur et al., 2005 Takeuchi et al., 2005 Boggio, et al., 2006 Werhahn, et al., 2003

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

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

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 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

tDCS 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

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

Robotics for assessment of performance kinematics

Pre – training Post - training

Upper limb robotics at Burke-Cornell, New York

Robotics with brain stimulation in patients with motor dysfunction

Edwards PI: R01 HD069776 Method' Author' Priming'Method' PROTOCOL' Effect' Dura:on' rTMS' Iyer' rTMS%% rTMS% increased%inhibitory%effect% >60%min% % % Daskalakis'' rTMS%% rTMS% no%change% % % Siebner' tDCS% rTMS% no%change% 20%min% % % Siebner' tDCS% rTMS% reversed%results%in%MEP% 20%min% TBS' Iezzi' voluntary%% (finger%abduct'n)%*% cTBS% reversed%results%in%MEP% >30%min% % % lezzi' voluntary%% (finger%abduct'n)%*% iTBS% %reversed%results%in%MEP% >30%min% PAS' Muller' N20H5ms% N20+2ms% priming%produced%increase%in%MEP% >30%min% % % Muller' N20+2ms% N20+2ms% priming%had%no%effect%on%MEP% change% >30%min% % % Zienman' voluntary%*% N20H5% enhanced%inhibiLon% % % Zienman' voluntary%*% N20+2ms% no%change% *%presumed%excitaLon% Inhibitory% ExciLtory%%

TMS

Prelim data for Nexstim NICHE Trial

Nexstim NICHE Trial 2014-16

Clinicaltrials.gov # NCT02089464

PI: Richard Harvey RIC

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

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

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 Environment

Nexstim NICHE Trial 2014-16

Clinicaltrials.gov # NCT02089464

Mean change across both groups (n ~150): UEFM was 8.2 points *no difference between sham and real groups

International Stroke Conference Feb 2017 Announcement

Source: www.nexstim.com/news-and-events/press-releases/2017/

Ac#ve&coil& Sham&Coil&

How does unaffected M1 excitability relate to hemiparesis?

!

Figure'4.'Sample'data'for'pa3ent'with'cor3cal/subcor3cal'stroke'(A)'axial'T1'MRI'with'leE'cor3cal/subcor3cal'

C A D B

Mike Fox MD PhD BIDMC/MGH/Harvard Aaron Boes MD PhD BIDMC/MGH/UIOWA Amy Kuceyeski, Ph.D. Radiology and Neuroscience, Weill Cornell

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

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)

Post-stroke aphasia?

How is the network disrupted? Is NIBS useful? Can it be effectively combined with SL therapy?

Elsner B, Kugler J, Pohl M, Mehrholz J (2013) Transcranial direct current stimulation (tDCS) for improving aphasia in patients after stroke (Review). Cochrane Database Syst Rev 6:CD009760. Evidence / Rationale

No evidence for tDCS as useful adjunct some merit in cathodal stimulation?

Thiel et al (2013). Evidence of NIBS on language networks and recovery in early post-stroke aphasia.

R hem1 Hz rTMS + SL therapy improves language recovery and favors L hem language network activation

+

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

Repetitive transmagnetic stimulation (rTMS)

CIHR: MOP-286185

+ Subject 1

Infarct

Pars triangularis

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

rTMS combined with behavioral therapy?

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

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

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

rTMS% Concurrent)) rTMS% BT% BT% BT% BT%%

Secs.,%Mins.% Hours,%Days%%

rTMS% BT% BT% rTMS% rTMS%

Conceptual)Guide)for)Timing)of)rTMS)and)Behavioral)Therapy)

Interleaved)

WITHIN)SESSION)) BETWEEN)SESSION))

SequenAal)) rTMS%

Tsagaris et al , 2016

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

rTMS & Psychotherapy in Major Depressive Disorder

Donse, L., Padberg, F., Sack, A. T., Rush, A. J., & Arns, M. (2018). Simultaneous rTMS and psychotherapy in major depressive disorder: Clinical outcomes and predictors from a large naturalistic study. Brain Stimulation, 11(2), 337-345.

• Feasibility & clinical outcome of simultaneous rTMS + PT in MDD
• n = 196 patients, non-psychotic MDD or dysthymia
• Treatment regimen: Min. 2-3 days per week; Max 2x per day, # of sessions varied

TMS Intervention (20 Min) High, low, or both sequentially High frequency (HF): 10 Hz left DLPFC, 110-120% RMT, 30 trains of 5 s duration, inter-train interval 30s, 1500 pulses per session Low frequency (LF): 1 Hz right DLPFC, 110-120% MT, 120 trains of 10s duration, ITI 1s, 1200 pulses per session LF + HF: Low frequency (1000 pulses per session) then HF protocol at full length Psychotherapy Intervention Primarily CBT, specific approach individualized based on clinical needs

• f individual

Duration: 45 minutes Decision to continue treatment were based on

• 1. Response to treatment
• 2. Clinical evaluation of symptom

severity

• 3. Patient request

rTMS & Psychotherapy in Major Depressive Disorder

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

Donse et al (2018)

BDI change over the course of treatment for the total group (N=196) and the follow-up group (n=73). Error bars, SEM

Resonders VS. Nonresponders High VS. Low Frequency Results

• Mean BDI scores significantly reduced after

rTMS + PT (55.9% reduction)

• No differences in overall BDI score found

between HF & LF protocol groups

• Remission rate of 56% (<37 monotherapy)
• Response rate of 66% (29-58 monotherapy)

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

Donse et al (2018)

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

Thank you

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