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The Evolution of ECT: from Cerletti & Bini to the BRAIN

Initiative

Sarah Hollingsworth Lisanby, MDDirector, Translational Research Division, National Institute of Mental Health

Director, Noninvasive Neuromodulation Unit, Experimental Therapeutics and

Pathophysiology Branch, Intramural Research Program, NIMH

NIH BRAIN Initiative: Neural Recording and Modulation Technologies (Team B)

Mag

netic

TMS MST

TranscranialMagnetic

Stimulation

Magnetic Seizure Therapy

Ele

ctric

al

Electroconvulsive Therapy

TDCS/TACSTranscranial Direct or

Alternating Current

ECT

Oth

er

Low Intensity Focused UltraSound

Optical, RF and THz Stimulation – Low Level Light, Near InfraRed, Millimeter waves, TeraHz

LIFUS

Electroconvulsive Therapy

ECT

Watch This Space

BRAIN Initiativemapping brain activity at the speed of

thought

http://braininitiative.nih.gov/

THE BRAIN INITIATIVE®

“Giving scientists the tools they need to get a dynamic picture of the brain in action and better understand how we think and how we learn and how we remember. And that knowledge could be – will be – transformative.” --

POTUS, April 2, 2013

United States White House announced the

“Next Great American Project”


• New directions in science are launched by new tools more often than new concepts

• Concept-driven revolution explains old things in new ways

• Tool-driven revolution discovers new things that have to be explainedFreeman Dyson

Imagined Worlds, 1997


• Large-scale recording & modulation

– at or near cellular resolution

Modular nanophotonic probes for dense, large-scale neural recording with single-cell resolutionRoukes (PI, Caltech), Shepard, Siapas, Tolias

NIH U01NS090596

What’s the role of ECT in the BRAIN Initiative Era?

ECT

• Dosing: One size fits all• Used primarily for schizophrenia• Limited knowledge of mechanism• Excessive memory side effects

Electroconvulsive Therapy Circa 1938

Modern ECTElectroconvulsive Therapy Circa 2018

• Dosing: Individualized• Used primarily for depression• Emerging knowledge of mechanism• Reduced memory side effects

Evolution of ECT: 8 Decades of Progress

Evolution of ECT: 8 Decades of Progress?

ECT: Some Things Don’t Change

• Highly Effective in– Reducing all cause mortality

Philibert 1995; O’Conner 2001; Kobeissi 2011


• Highly Effective in– Reducing all cause mortality – Inducing remission from severe

depression• Prolonging Remission in Depressed

Elders (PRIDE) NIMH sponsored study– N=222 depressed seniors – 83% remission rate among completers

0.0

5.0

10.0

15.0

20.0

25.0

30.0

35.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

HR

SD

VISIT

U01 MH084241 [Kellner…Lisanby. Am J Psych 2016]



depression– Rapid onset of action


Per

cent

of P

atie

nts

ECT Treatment Visit



depression– Rapid onset of action– Rapidly resolves suicidal ideation

0

10

20

30

40

50

60

70

80

90

0 1 2 3 4

Pe

rce

nt

HRSD Item #3 Score

Baseline

Last Observed

0=Absent1 life is empty/not worth living2 Recurrent thoughts/wishes about death of self3=Active suicidal thoughts, threats, gestures4=Serious suicide attempt



• Anesthesia– Protects body from motor convulsion and improves cardiovascular

stabilityECT Circa 1938 ECT Circa 2018

ECT: Some Things Do Change

• Anesthesia• Electrode Placement

Personal0

10

20

30

40

50

60

70

80

Am

nesi

a S

core

(%)

UnilateralBilateral

ImpersonalLisanby et al. Arch Gen Psych 2000

BilateralUnilateral


s

• Anesthesia• Electrode Placements

Personal0

10

20

30

40

50

60

70

80

Am

nesi

a S

core

(%)

UnilateralBilateral

Impersonal

BilateralUnilateral

Lee et al. Neuroimage 2012

BilateralUnilateral


Lisanby et al. Arch Gen Psych 2000

Sackeim et al. Brain Stimulation 2008;1:71-83

0.3 0.3

ms

1.5

ms

1.5

ms

• Anesthesia• Electrode Placements• Pulse Shape

Sine Wave

Brief Pulse

1-2 ms

Ultra-Brief Pulse

0.25-0.3ms


• Anesthesia• Electrode Placements• Pulse Shape

Brief Pulse

1-2 ms

Ultra-Brief Pulse

0.25-0.3ms 0

5

10

15

20

25

0 .1 .2 .3 .4 .5

Cur

rent

, I

Pulse DurationAgnew & McCreery, 1990

PW

Cu

rre

nt


Effic

acy

(%)

50%RUL

150%RUL

500%RUL

150%BL

0

10

20

30

40

50

60

70

80

90

0

10

20

30

40

50

60

EfficacyAmnesia

Am

nesi

a (%

)

Sackeim et al., 2000

• Anesthesia• Electrode Placements• Pulse Shape• Individualizing dosage

– From “one size fits all”, to– Age-based dosing, to – Seizure threshold

titration


• For efficacy• For safety

Sackeim et al. Arch Gen Psych 20001

Dose above seizure threshold

RUL 1.5 ms PW

Lessons Learned: Dosage Matters

Dose above seizure thresholdMcCall et al. Arch Gen Psych 2000

RUL 1.5 ms PW



Sackeim et al., 2000; Nobler et al. 1994; Luber et al. 2000

Effic

acy

(%)

50%RUL

150%RUL

500%RUL

150%BL

0

10

20

30

40

50

60

70

80

90

0

10

20

30

40

50

60

EfficacyAmnesia

Am

nesi

a (%

)

Delta Theta

Lessons Learned: Dosage is Complicated

• Electrode Placement– Spatial distribution

Lee et al., EMBC14

• Electrode Placement– Spatial distribution– Novel electrode

placements

Lee et al., ISEN 2012; Rosa et al JECT 2011

Fronto-MedialFEAST

E/Eth

0

≥ 2

1


Current Density Distributions

Stimulation Strength Relative to Neural Activation Threshold

Lee

et a

l., E

MBC

14

Stimulation Strength & Focality with ECT & MST

• ECT E-field exceeds neural activation threshold by >2 times and stimulates > 94% of brain volume, much higher than necessary for seizure induction

• FEAST and FM more focal and closer to threshold stimulation • MST induces weakest, most superficial E-field, stimulating only 4% of brain volume

Lee et al., EMBC14

MST: 0.11 × Threshold

ECT: 0.8-3.4 × Threshold

4%

47%

• Electrode Placement– Spatial distribution– Novel electrode

placements possible– Multi-electrode arrays

for E-field shaping

Conventional


High Def RUL

• Electrode Placement• Pulse Shape

– Pulse Width

1-2 ms

Brief Pulse

0.25-0.3ms

Ultra-Brief Pulse



– Pulse Width


Shortening the pulse width undoes the efficacy of

bilateral electrode placement


– Pulse Width– Waveform

Conventional

Biphasic

Charge balancedPre-polarization

Multiphasic

Charge balanced, but predominantly monophasic



– Pulse Width– Waveform– Amplitude


Conventional Amplitude

0.8 – 0.9 A

BL RUL

Reduced Amplitude

0.1-0.4 A

Peterchev et al. JECT. 2010


– Pulse Width– Waveform– Amplitude


R01 MH091083; MPI: Lisanby / PeterchevPeterchev et al. Neuropsychopharmacology 2015

Lowering amplitude improves focality

E field relative to neural activation threshold

ECT

MST

Opportunity to dissociate efficacy from side effects

• Electrode Placement• Pulse Shape• Total Delivered Charge

– milliCoulombs (mC)




Same Charge (mC)Different Cognitive outcomes

Sackeim et al. 2008




Same Charge (mC)Different Cognitive outcomes


Sackeim et al. 2008




Pre-ECT 6th ECT Post-ECT1 Wk Post0

5

10

15

20

25

30

35

HAM

D S

core

RUL 6xSTRUL 2.5xSTRUL 1.5xST

BL 2.5xST

• RUL less effective than BL when given at low dose

• 6x threshold RUL as effective as BL

• Electrode Placement• Pulse Shape• Total Delivered Charge• Individual Parameters

– Matter



– Matter– Should be individually

optimized




optimized, eg.• Frequency


R01 MH091083; MPI: Lisanby / Peterchev



optimized, eg.• Frequency• Directionality


Spe

llman

, Pet

erch

ev, L

isan

by 2

009

Unidirectional

Bidirectional



optimized– Interactions among

parameters should be examined


J ECT 2010

Device Design

Con

vent

iona

l App

roac

hR

atio

nal A

ppro

ach Computational

Models

Stimulation

Device

Parameters

Clinical Trials

Revise stimulation

paradigm

Open Label

Randomized Trials

Clinically test each stimulation paradigm

Animal &Healthy Human Studies

Revise

R01 MH091083; MPI: Lisanby / Peterchev

Lessons Learned: Relapse Prevention

• Prolonging Remission in Depressed Elders (PRIDE)– NIMH-funded U01 (PIs: Lisanby and Kellner)– 8 centers across the United States– 1,326 patients screened, 240 enrolled– Mean age 70 ± 8 yrs, 58% female

Kellner …. Lisanby. Am J Psych 2016a,b

HobokenPRIDE Investigators’ Meeting – Nov 5-6, 2011

PRIDE Study Sites



• Prolonging Remission in Depressed Elders (PRIDE)• Aims: To compare efficacy and tolerability of 2 post-ECT

continuation treatment strategies:– PHARM - venlafaxine (VLF) + Li– STABLE - Symptom titrated algorithm based longitudinal ECT

Phase 2 (6 mo)

C-ECT (STABLE)+VLF+Li

VLF+Li

CR, F/T

(Bsl Ph 2)

CR, F/T at specified time points

(see Table 3)

CR=clinical ratings

Fig 5. PRIDE Trial Design F/T=functional and tolerability ratings

Phase 1

ECT+VLF

CR, F/T

(Bsl Ph1)

Remitters

Nonremitters

Prolonging Remission post ECT

Pharm

STABLE

Pro

babi

lity

of M

aint

aini

ng R

emis

sion

20.3% relapsed

Odds of relapse 1.7x higher than STABLE

13.1% relapsed

Kellner …. Lisanby. Am J Psych 2016a,b

• Emerging biomarkers of response show regional specificity

Lessons Learned: Emerging Evidence of Mechanism

Abbott et al 2014

• Emerging biomarkers of response show regional specificity

• ECT modalities differ in their regional effects

Lee et al Neuroimage 2011

BL

BF

RUL


• Unknown if hippocampal stimulation may also contribute to side effects, or efficacy, or both

• ECT Induces and saturates LTP• Hypothesized role in ECT-induced

amnesia

Stewart & Reid 1993; SteCasarotto et al 2013

pre- post-tetanus


• Stigma

ECT: Some Things Still Need To Change

What will the future of ECT look like?

• Safer• Faster• Longer-lasting• Less need for

anesthesia?– Weaker or no

motor convulsion Old Dog – New Trick

• Target Discovery – Understanding mechanisms of therapeutic action and adverse

cognitive side effects• Advanced Tools

– Advances in seizure induction technique to optimize spatial and temporal resolution

• Experimental Trials– Testing that reaching and engaging specific targets will result in

improved clinical outcomes for depression

Roadmap for Getting There

Know where you are going

Have a way to get there

Make an impact upon arrival

NIMH Noninvasive Neuromodulation Unit

* Special Volunteer

Luber

Lisanby

RadmanOberman*

Jones

Deng

Akhlaghi

Velez-Afanador

Thomas

Altekruse

ETPB Shared Staff: Shora, YuNIAAA Collaborator: Ted GeorgeSummer Student: Michael DibComing Sept 2018: Michele Noh (Deng NARSAD YIA)

Special Thanks to ETPB Medical and Nursing staff,

George Dold, Bruce Pritchard, and the Section on

Instrumentation

Rationale for UltraBrief Pulse

• Closer to chronaxie• More efficient stimulus means

seizure induced with lower total E-field exposure

• Different time constants between soma and axon

• Briefer pulse widths less stimulation of cell bodies

Peterchev & Lisanby, unpublished

Standard Pulse Width

Ultra Brief Pulse

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