Y P O Berenson-Allen Center for Noninvasive Brain Stimulation - - PDF document

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Linda L. Carpenter, MD

Professor, Brown University Department of Psychiatry Chief, Butler Hospital Mood Disorders Program Providence, Rhode Island

Berenson-Allen Center for Noninvasive Brain Stimulation Beth Israel Deaconess Medical Center October, 2019

Disclosure of Financial Relationships

• NeoSync – Research Support
• Neuronetics – Research Support
• Affect Neuro- Research Support,

Consulting

• Janssen - Research Support,

Consulting

Off-label use of TMS devices will be discussed

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Unresolved Symptoms Following Adequate Trial (Dose and Duration) of Antidepressant Medication

STAR*D = Sequenced Treatment Alternatives to Relieve Depression Trivedi MH et al. (2006), Am J Psychiatry 163(1):28-40

Percent

67% Mild symptoms ~28% Moderate symptoms ~23% Severe symptoms ~12% Very severe symptoms ~4%

Depressive Symptoms (QID-SR Score) After Up to 12 Weeks Antidepressant Treatment STAR*D Study (N=2,876)

Remission ~33% 4

YLD=Years Lost Due to Disability

Depression is the #1 GLOBAL CAUSE OF DISABILITY

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1896: D’Arsonval - demonstrates electromagnetic stimulation 1910: Sylvanus Thompson- retina stimulation magneto-phosphenes 1985: Jalinous, Freeston, Barker

• First TMS Device

1982: Polson – Sheffield UK Peripheral Nerve Stimulation 1985: Barker & Cain - publish TMS to cortex

Tony Barker, unpublished data, February 2019

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What is TMS?

• Pulsed electricity through

a coil of wires

• MRI-strength magnetic

fields penetrate scalp skull and meninges

• Faraday’s Law – current

induced in perpendicular plane

• Neurons – Depolarize +

Fire Action Potential

• Effect circuits beneath coil

and in remote brain regions A single TMS pulse induces current in neurons which project from superficial to deeper cortex

How it Works: TMS Energy Transfer

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Randomized Controlled Clinical Trials FDA Clearance for TMS Devices to treat Major Depressive Disorder

O’Reardon J et al 2007, George M et al, 2010

Levkovitz Y et al 2015 “Figure-8” Shaped Coil “H-Coil” (Hersed) October 2008 October 2013 Magstim Neuronetics Brainsway Nexstim MagVenture NeuroSoft Mag & More H-Coil

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MDD Brain Target for TMS Therapy: Why Target Dorsolateral Prefrontal Cortex? Baseline subgenual cingulate connectivity predicts rTMS treatment response

Liston C et al, 2014

rTMS normalized depression- related subgenual hyperconnectivity to DMN

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TREAT:

Prefrontal Cortex Single Pulse

TMS Abductor Pollicis Brevis (thumb) Muscle or First Dorsal Interosseous (first finger)

Peripheral Motor Nerve Efferent Vertebral column

CALIBRATE: Motor Cortex

MEP Monitor

Ground

APB muscle

Methods for TMS Coil Targeting (DLPFC)

5 cm

EEG 10/20 Site for F3 “5 Cm Rule”

Neuronavigation to Anatomic Target Where is DLPFC? Border between the anterior 1/3 and middle 2/3 of the middle frontal gyrus (F2) and between the superior and inferior frontal sulci (Brodmann areas 46 and 9).

ABP

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Outcomes: RCTs Leading to FDA Clearance of TMS Devices for MDD

• Week 6 MADRS
• 24% v. 13% Response
• Subset w/ 1 med failure:

50% Resp, 33% Remit

• Replicated by OPT TMS
• ALL FIGURE 8 DEVICES

O’Reardon J et al 2007

MADRS (p=.057) HAMD17 (p=.006)

TMS Response and Remission Rates in Neuronetics’ Controlled Acute Study

O’Reardon J et al, 2007

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Extended TMS Acute Course for Nonresponders (n=71) Open Cross Over Trial (n=85, former sham)

Avery DH et al, 2008

FDA Approval based on Subset (n=164) from Overall Study Sample (n=301)

Demitrack, MA & Thase, ME, 2009

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10 Highly Significant Outcomes in Subset (n=164) who failed ONE Adequate Antidepressant Trial

** P<.01.; LOCF analysis of evaluable study population.

Demitrack, MA & Thase, ME, 2009

23 37 54 10 20 30 40 50 60 Week 2 Week 4 Week 6 Rate (%)

TMS Response and Remission Rates in FDA-Indicated Population

7 19 33 10 20 30 40 50 60 Week 2 Week 4 Week 6 Rate (%)

HAMD-24 Response Rates

(>50% Improvement from Baseline)

HAMD-24 Remission Rates

(HAMD-24 Total Score <11)

Demitrack, MA & Thase, ME, 2009

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TMS Side Effects in Neuronetics TMS Trial

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O’Reardon J et al, 2007

NIH Optimization of TMS for Depression Study (OPT-TMS)

4 University Hospital TMS Clinics Novel Sham (more effective blind) Same device and stim parameters as Neuronetics clinical trial but no Industry sponsorship MRI-guided coil placement Large Sample N=190 (ITT)

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OPT-TMS “Active Sham” Condition

• Mimicked the somatosensory experience of TMS
• Masked the TMS administrators and patients to TMS acoustic signals
• Serial Assessment of Potential unblinding

George MS et al, 2010

OPT- TMS Primary Efficacy Outcome

(Remission)

Replicated Neuronetics’ Trial Results

George MS et al, 2010

b Adjusted odds ratio - adjusted for site, age duration of current depressive episode, and medication resistance

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OPT- TMS Continuous Outcomes

Confirmed efficacy as reported by Neuronetics’ Sponsored Trial George MS et al, 2010

Naturalistic Outcomes Study 58% Responders, 37% Remitters

• Clinical results matched those reported in

controlled research trials.

• Confirmed that TMS therapy is safe and

well tolerated in a nonresearch population.

• 54% of the patients had ATR>1 but,

resistance level NOT a predictor of response Carpenter LL et al, 2012

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Long-Term Durability of TMS?

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For Comparison with Relapse Following TMS: Relapse During Follow-Up in STAR*D

The greater the level of treatment resistance (prior to remission), the more quickly a patients with TRD will relapse

Rush et al, 2006

Level 1 (non-resistant) Level 2 (1 prior Tx failure) Level 3 (2 prior Tx failures) Level 4 (3 prior Tx failures)

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Durability of Response

(n=99 followed 24 weeks) Time to Relapse

(recurrence of full DSM-IV criteria for MDD for 2 weeks OR no improvement despite 6 week course of TMS reintroduction)

Time to Reintroduction of TMS

(CGI Severity change of 1 point over two successive weeks)

• 10% Relapsed

(Kaplan-Meier survival estimate=12.9%)

• 38% had “symptom

worsening”

• TMS re-introduction “rescue”
• 2 session/week x 2 weeks, then

daily

• 84.2% who got “booster”

TMS re-achieved response

Janicak PG et al, 2010

Naturalistic Long-Term Outcomes

63% Acute TMS Responders Remained Responders Throughout Follow up 36% Required Additional TMS Treatments Mean Number of Additional Treatments=16

Dunner D et al, 2014

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Maintenance TMS – Prospective RCT

6-site study Med-Free Responders to Acute Course of TMS N=49 randomized: “SCHEDULED” (1 TMS/month) OR ”OBSERVED” (assess/month) BOTH get ‘RESCUE TMS’ when indicated Is RESPONSE TO TMS maintained longer with

• nce/month maintenance

TMS?

Philip N et al, 2015 Deng Z et al, 2012

TMS Coil Size/Shape Impacts Shape and Depth of Stimulation Field

Spread

• Electric Field Tradeoff:

Depth vs. Focality Depth

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Outcomes: RCT Leading to FDA Clearance of Brainsway Device

• Week 5 HAMD
• 38% v. 21%

Response

• 33% v. 15%

Remission

• Unique Coil Design
• L>R DLPFC

Levkovitz Y, et al 2015 (ITT) Change in HDRS- 21 from BL to Week5 p=.06 Significantly Higher Remission In Less Resistant Depression

H-Coil Continuation Phase Treatment (2 sessions/week)

Yip AG, et al 2017

33 Nonresponders to Active TMS during Acute Phase Of Blinded RCT (20 sessions/4 weeks) Continued Blinded TMS 2/week for 12 more weeks 61% Achieved RESPONSE Status with the additional sessions

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FDA-Cleared Stimulation Protocols for MDD

High-Frequency Stimulation demonstrated efficacy for TRD (Large RCTs)

Figure-8 coils: Left DLPFC 3000 pulses daily 10 Hz Four-second trains 75 trains of 40 pulses 26 sec interval* 5 days/wk x 6 weeks= 30 Taper (3/wk=>2/wk=>1/last week) 9 wks of care (36 sessions)

(O’Reardon et al. 2007)

H-coil: L>R DLPFC 1980 pulses daily 18 Hz Two-second trains 55 trains of 36 pulses 20 sec interval 5 days/wk x 4 weeks Taper: 2 days/wk x 12 wks 16 wks of care (44 sessions)

(Levkovitz et al. 2015) RCT Patient Characteristics:

• Outpatients, not acute suicidality
• Unipolar, Nonpsychotic MDD (recurrent or single episode)
• Treatment Resistant to Adequate Medication trials (1-4) or
• Treatment Intolerant to multiple med trials
• Medication-Free during participation

Speer et al. 2000

rTMS over Left DLPFC (100% MT) x 2 weeks

20 Hz increased rCBF

• prefrontal cortex (L>R)
• cingulate gyrus (L >>R)
• left amygdala
• bilateral insula, basal ganglia, uncus,

hippocampus\

• bilateral parahippocampus, thalamus, and

cerebellum 1-Hz decreased rCBF (in small areas)

• right prefrontal cortex
• left medial temporal cortex
• left basal ganglia
• left amygdala

rCBF not related to degree of clinical change

TMS Parameters: Effect of Pulse Frequency: “Fast” vs. “Slow”

PET scans @ baseline vs. after TMS #10 n=10 Depressed Patients

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Berlim et al, Neuropsychopharmacology, 2013

Low Frequency rTMS Stimulation (≤ 1 Hz)

Meta-Analysis of LF-rTMS vs. Sham rTMS for MDD (8 RCTs, n=263) Response

Mean # treatment sessions= 12.6 ± 3.9 Response: 38.2% v. 15.1% (OR = 3.35; 95% CI = 1.4 – 8.02; p = 0.007). Remission: 34.6% v 9.7% p < 0.0001) Better Response èprotocols delivering >1200 pulses/session

TMS Therapy: Areas of Differentiation and Development

• Coil Geometry/ Targeted Cortical Tissue

– Neuronavigate to stimulate specific/personalized circuitry – fMRI response to task in scanner

• Stimulation Parameters

– Pulse Frequency (Hz) or Pattern (Theta Burst) – Shortened inter-train intervals – Multiple sessions per day

• Cognitive Inputs: What the brain is doing during

stimulation

– Symptom Provocation (OCD) – Cognitive Enhancement (Dementia and Other Disorders) – Combination TMS with psychotherapy

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TMS Coil Placement: Neuronavigation

• Visualization of TMS coil in relation to brain in

real time on a screen

• Anatomic landmarks “co-register” the head and

the coil in the coordinate system of the brain MRI

• P. Fitzgerald et al. 2009

Neuronavigation-Guided Coil Placement

“5 cm-Rule “vs. “MRI-Neuronavigated “ to Left DLPFC

n=51 with MDD 4 weeks daily TMS 100% MT 1500 pulses/session

• Numerically Greater Improvement
• 42% vs. 18% Responders (p=.07)

Not Statistically Superior to “5-cm Rule”

• P. Fitzgerald et al. 2009

n=51 with MDD 4 weeks daily TMS 100% MT 1500 pulses/session

?

Where is the best spot to stimulate?

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Downar J et al, 2013

New Stimulation Target for MDD

Cortical Nodes and Networks : DMPFC

• Network of prefrontal

regions –PET studies show resting metabolic activity is reduced for MDD

• DORSOMEDIAL PFC is a

NEXUS for neural networks relevant to MDD

• Target used for MDD

treatment in Canadian Clinics

• Under investigation in US

Magventure Fig-8: Left DLPFC 1

• MDD Indication (2018)
• 600 pulses daily (3 min, 9 sec)
• Pulses are “bursts”= 50 Hz triplets
• 5 Hz “carrier frequency”
• 120% RMT (hand)
• 2-second trains (“intermittent”)
• 8-sec rest interval
• 20 sessions over 4 weeks

1Blumberger et al. 2018;

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Effect of Different Pulse Patterns

• n Synaptic Efficiency (Plasticity)

Intermittent Theta-Burst Stimulation has demonstrated enhancement of neuroplasticit

Shorter Treatments with Same Outcomes? Intermittent Theta Burst TMS (iTBS) for MDD:

Blumberger et al 2018

N=205 randomized 10 Hz standard (37.5 min) iTBS (3 min , 600 pulses) Both 120% over Left DLPFC MRI-guided coil placement Continue stable meds

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iTBS for MDD: Noninferiority Trial

Blumberger et al 2018

iTBS slightly better on some outcomes, but not enough to reach the Non-Inferiority margin

• Open-Label Naturalistic Treatment in Several Different Protocols
• Daily rTMS to bilat DMPFC: 1 Session (n=65) or 2 Sessions (n=65)
• 1 Session/Day= 10 Hz, 3000 pulse/hemisphere
• 2 Sessions/Day= 20 H, 1500 pulse/hemisphere for each session
• 80 minutes break between sessions
• Both groups got total 6000 pulses/day
• All patients got 30 sessions

Optimization of Treatment: More Sessions Per Day To Get MDD Better Faster

Schulze L. et al. 2017 No significant group effect on pace of improvement from session to session Significant group effect on pace of improvement over time

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TMS Enhancement of Cognitive Performance

• Over 60 studies in 2013 review
• Improved speed, accuracy, or performance on tasks

involving perceptual, motor, executive processing

• Mechanisms:

– Nonspecific: clicking sound, vibrations (somatosensory) – Direct modulation of a network or region leads to more efficient processing – Disruption of processes that compete with or distract from task performance

Reviewed by Luber & Lisanby, 2014

Hebbian-like Learning

• “Neurons that fire together wire together”

– Donald Hebb, a Canadian neuropsychologist (1949)

• A synapse between two neurons is strengthened

when the neurons on either side of the synapse (input and output) have highly correlated outputs.

• Long-Term Potentiation (LTP):

long-lasting signal transmission increase between 2 neurons (increased “plasticity”)

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Concept of State-Dependency

• “…the state of the targeted cortical region during the

application of stimulation greatly influences the effects…”

• Think of TMS as an “interaction between external stimulus

and the underlying state of the stimulated region or network.”

• GOAL: Control ongoing neural

activity in the targeted region and associated networks to improve outcomes

Review by Sathappan et al 2019

Engagement of Specific Brain Functions During TMS Behavioral Activation Psychotherapy

Protocol Development in Open Pilot Trial Behavioral Activation to promote Hedonic Drive Technician Training by Psychologist Set /Monitor Daily BA Goals Russo et al 2018

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New Therapeutic Areas for TMS Therapy: Active Areas of Clinical Research

Autism Bipolar Depression Anxiety Disorders OCD* PTSD Schizophrenia Substance Use Disorders Smoking Cessation Executive Function Deficits/Dementia Parkinson’s Disease Stroke (Rehab) Migraine* Tinnitus Multiple Sclerosis Traumatic Brain Injury

Portable, single pulse TMS for MIGRAINE FDA-Approved “Cerena” by eNeura

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Brainsway OCD RCT Outcomes (n=99)

Carmi et al 2019

H-7 Coil

Tavares et al. 2018

Randomized, Sham-Controlled Trial (n=50)

* * *p<.05

20 sessions in 4 weeks; 18 Hz, 120% MT, 55 trains 2 sec each TRD patients OFF antidepressants Tavares et al. 2018

New Therapeutic Areas for TMS Therapy H1-Coil TMS for Bipolar I or II Depression

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1 Hz rTMS for Depression During Pregnancy

Kim et al 2019

Active (n=11)vs. Sham (n=11 2nd and 3rd Trimester Response 82% v 46% Remission 27% v 19%

Significant difference in HAMD score change No change in estradiol of progesterone Late term pre-term birth in n=3 who got active stimulation 1 Hz, 900 pulses at 100% RT

• Changes in blood flow and metabolism at the

stimulation site

• Brain-derived neurotrophic factor upregulation
• Reductions in GABA/glutamate concentrations
• Enhancements in synaptic plasticity
• Change in neural oscillations
• Changes in the connectivity/activity of neural

circuitry, e.g., DLPFC-anterior cingulate cortex

Probably not one single mechanism for rTMS therapeutic action

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Summary of Imaging Literature: TMS for MDD

Early findings:

• Inhibitory or excitatory consequences of stimulation
• TMS modulated brain activity under the stimulation site, BUT

also effects at deeper regions (sgACC) associated with clinical improvement. Functional connectivity studies:

• Clinical improvements related to changes distal (rather than

proximal) to the stim site

• TMS modulates (normalizes?) functional relationships between

neural networks.

• Similar connectivity changes across studies, regardless of TMS

parameters.

• Modest sample sizes; minimal statistical validation.

Philip et al 2018

TMS Therapy: Summary

• TMS for is safe and effective for MDD
• Generally covered only for TRD Patients (1-4 Meds)
• Figure 8 coil and H-coil devices - equivalent
• Acute Course generally takes 6-9 weeks
• Maintenance TMS Not Approved/Covered
• We can target different areas of brain to treat MDD
• Primarily Left DLPFC (high frequency stim)
• Also Right DLPFC (low frequency stim)
• Not FDA Approved/Covered for Bipolar Depression
• Recent FDA Clearance of H-Coil for OCD
• Recent FDA Clearance Theta-Burst (Quicker!)

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Future TMS Therapy

• Data TMS for many neuropsychiatric disorders
• Ongoing RTCs for PTSD, Smoking Cessation, others
• Functional connections involving DMN and sgACC are

important – maybe guide targeting?

• MRI: Imaging Biomarkers and Endophenotypes
• EEG: Individual Oscillatory Signatures
• Symptom Provocation and Cognitive Training Designs
• Enhance Targeting: Brain Functions and Circuits
• More Understanding of Mechanisms of Action
• Ability to sustain benefits and prevent relapse
• Greater Access: Take-Home Stimulation Devices

Thank You!

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