What is TMS? 9-45 - The Use of Transcranial Magnetic... · • 4 large, multisite, randomized controlled trials demonstrated clinically significant antidepressant effect of TMS (2

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tmshealthsolutions.com

Transcranial Magnetic Stimulation for Treatment-Resistant OCD

Ryan Vidrine, MD Director of TM SHS OCD Program

UCSF Asst Professor of Psychiatryrvidrine@ tm shealthsolutions.com

IOCDF Conference July 2019Austin, Tx


• What is TMS?

• TMS for Depression (in brief)

• Formulation & Neurobiology of OCD

• Proposed TMS Targets of Stimulation, TMS Protocol, & Mechanism of Action

• Efficacy from FDA Clearance Study

• TMS Health Solutions –Private Practice Data/Outcomes

• Selecting OCD Patients for TMS & Insurance Coverage

• Patient Testimonials & Q&A

What to Expect from this talk:


What is TMS? Transcranial Magnetic Stimulation

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Based on Faraday Principle

• Rapidly fluxing magnetic field

• Induces electric current in underlying cortex

• Electric field --> depolarization of neurons

• Allows focal manipulation of cortical activity

• Excitatory or Inhibitory



rTMS: Figure 8 coil

Focused Magnetic Field

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Deep TMS: H shaped CoilBrainsway

Diffuse Magnetic Field


What does a course of TMS look like for patients?

Intake

Daily TMS Treatments plus Weekly Check-ins

End TMS

Start of TMS

Post TMS Check-ins

Week One

Week Two Week Three-Eight Week

Nine

TIME

• Adm inistered in sessions lasting approxim ately 20-40 m inutes, five tim es a w eek, over a period of 4-6 w eeks

• No anesthesia or sedation is required and patients can resum e their usual activities (including w ork) im m ediately

• M ost responders show signs of response by the 2nd or 3rd w eek


TMS: Contraindications

• Non-removable metallic objects in or around the head

• Conductive, ferromagnetic or other magnetic sensitive metals that are implanted or are non-

removable within 30 cm of treatment coil

• Implanted electrodes/ stimulators

• Deep Brain Stimulator

• Aneurysm clips or coils

• Cochlear implants

• Stents

• Bullet or other metal fragments

• Metallic tattoos

N euroS ta r T M S T herapy S ys tem U ser M anua l. N eurone tics , Inc : M a lve rn , P A .

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TMS: Side Effects

• Headache

• Scalp sensitivity

• Syncope

• Seizure• < 1%• No development of seizure disorders• No medical complications


FDA Approved Target for Depression


Overall Summary of Effectiveness in Major Depression

• 4 large, multisite, randomized controlled trials demonstrated clinically significant antidepressant effect of TMS

(2 industry, 1 by NIH, 1 European augmentation study)

• Prospective, naturalistic RCT confirms these results in real-world practice settings

• Efficacy in private practice data

• Remission rates from 15%-30% in the double-blind phase, and 30% or more in open-label

• Overall, 1 in 2 patients respond and 1 in 3 patients achieve remission

• TMS is, generally, associated with a high level of treatment adherence, >80% of patients completed acute treatment in

both research setting and in clinical practice

George MS, Lisanby SH, Avery D, et al. Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: a sham-controlled randomized trial. Archives of General Psychiatry 67, 507-516, 2010Herwig U, Fallgatter AJ, Hoppner J, et al. Antidepressant effects of augmentative transcranial magnetic stimulation: randomized multicentre trial. British Journal Psychiatry, 191, 441-448, 2007Levkovitz Y, Isserles M, Padberg F, et al. Efficacy and safety of deep transcranial magnetic stimulation for major depression: a prospective multicenter randomized controlled trial. World Psychiatry 14, 64-73, 2015O’Reardon JP, Solvason HB, Janicak PG, et al. Efficacy and safety of transcranial magnetic stimulation for the acute treatment of major depression: a multisite randomized controlled trial. Biological Psychiatry, 62, 1208-1216, 2008

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• Exposure and response prevention first line for non-comorbid/mild OCD

• Medications:

• Fluoxetine

• Paroxetine

• Sertraline

• Fluvoxamine

• Clomipramine

Above treatments result in ≥30% improvement for 40-60% of OCD patients

Current Approved Treatments for OCD


Cortico-Striato-Thalamo-Cortical (CSTC) loops

Orbitofrontal Cortex (OFC)Anterior Cingulate Cortex (ACC)Ventromedial Prefrontal Cortex (VMPFC)

Dorsomedial Prefontral Cortex (DMPFC)Supplementary Motor Area (SMA)Ventral Striatum (VS) (accumbens, caudate)

Thalamus

Amygdala & Bed Nucleus of Stria Terminalis (BNST)

Implicated Brain Targets


ACC acts as hub connected to 3 key networks (Salience, Reward, & Non-Reward) via CSTC loops

fMRI studies show pain, negative affect, and cognitive control all activate an overlapping region of the dACC, processing negative emotional and reinforcing information and then directing motivated behavior.

The estimator of “Expected Value of Control” (EVC)• control signals can indicate “identity” & “intensity”

• control signal passed to “regulatory centers” (DLPFC & others)

ACC control signals are used to exert top-down control over downstream effectors of a chosen behavior:

• problem solving and correction

• assessing salience of stimuli & emotion• assessing motivational information

• role in conditioning, harm expectancy, extinction

ANTERIOR CINGULATE CORTEX (ACC)

Source: McGovern, 2017

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Mis-specified control signals - > persistent anxiety-producing sense of threat or unease generated by otherwise innocuous stimuli that cannot be extinguished.

Repetitive behaviors to reduce this distress signal are ineffective, but the individual persists with these maladaptive behaviors, unable to abandon them and switch to more useful strategies.

Ex. 1: Overestimating the threat of germs and exaggerating the importance of the act of cleaning lead to contamination obsessions and washing compulsions. Unable to quench the feeling of threat from the contaminant, the individual continues to perform the exaggerated cleansing rituals.

DORSAL ACC ABERRANT CONTROL SIGNAL HYPOTHESIS

Source: McGovern, 2017


• Impaired ability to inhibit intrusive thoughts, urges, feelings, and behaviors (motor control & response inhibition)

• decreased interneuron inhibitory behavior in striatum

• Decreased connectivity/activity in cognitive control/ Salience Network

• Inappropriate automatic & subconscious threat responses or inappropriately sustained threat responses• mis-specification of control signal identity & intensity

• exaggerated amygdala or BNST response to threat

• Decreased ability to effortfully correct behavior, learn, adapt, extinguish fear (affective & reward processing)

• dysregulation of medial & lateral OFC & mis-specification of control signal identity & intensity

• Get stuck in worsening re-entry loops of obsessions in search of reward• dysregulation of lateral OFC & its connection to amygdala & reward circuits

• Dysregulated evaluation of punishment over reward • dysfunction at ACC, Reward network, &/or Non-Reward network

IN SUMMARY, OCD PATIENTS DEMONSTRATE:


TMS for OCD

• Non-invasive, minimal side effects

• Standard depression protocols do not seem to consistently work in OCD

• Promising studies targeting SMA, DMPFC/ACC, and OFC

• Deeper TMS could allow greater variety of brain structures to be targeted

• Recent FDA Clearance for Brainsway H7 dTMS device in Aug 2018

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Supplementary Motor Area (SMA)

https://neuroscientificallychallenged.com/glossary/supplementary-motor-area


Dorsomedial Prefrontal Cortex (DMPFC) &Anterior Cingulate Cortex (ACC)

Daskalakis et al (2016). Zangen et al (2016).

*Only FDA cleared target for OCD.


Lateral Orbitofrontal Cortex (OFC)

Ruffini et al., 2009; Nauczyciel et al.,2014

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• Effects of TMS may be more pronounced when the targeted circuit is active. (addiction, PTSD, smoking)

• Items that are stored in long-term memory become prone to change (stimulation) upon retrieval (following provocation)

• Personal provocations/hierarchy designed by treating clinician &/or therapist prior to Tx

• OCD symptoms provoked for each subject using internal or external stimuli to induce the typical OCD sx and distress in that individual

• Provocation/exposure done at beginning or just prior to treatment

• Provocations should aim to achieve score of 4-7 on 10 point Visual analog scale (VAS) before proceeding with stimulation

Carmi, 2017; Dinur-Klein, 2014; Isserles, 2013

PROVOCATION OF OCD SYMPTOMS


MULTICENTER OCD STUDY

USA-Mt. Sinai Medical Center-Neuropharmacology Services -University of California, Los Angeles-University of California, San Diego-University of Florida-University of Chicago-Advanced Mental Health Care -Linder Center of Hope-TMS Hope Center Long Island

CANADA- Center for Addiction and Mental Health

ISRAEL-Tel Hashomer Hospital

11 sites from North America and Europe

PI: Joseph Zohar MD, Abraham Zangen PhD

A Prospective Double Blind Randomized Controlled Study to Evaluate the Safety and Efficacy of H7

Deep Transcranial Magnetic Stimulation (dTMS) in Obsessive-Compulsive Subjects who Failed SSRIs

Led to FDA Clearance of Brainsway H7 device to treat OCD in Aug 2018

Carmi et al. (2019)


BrainsWay H7 Coil Targets the DMPFC and ACC

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FDA Target for Depression

Standard depression protocols do not seem to work for OCD based on current evidence

FDA Target for OCD

Dorsomedial Prefrontal cortex

Anterior Cingulate Cortex (ACC)


INCLUSION CRITERIA DEMOGRAPHICS

• 94 patients met inclusion criteria

• 58% Male, 75% Caucasian

• Prior meds 98% (19% took 5 SSRI’s), Prior CBT 69%

• Family hx OCD 55%

• Outpatients, men and women 22-68 years of age

• Subjects with at least moderate OCD (Y-BOCS score of ≥ 20)

• Maintained on SSRI’s at a therapeutic dosage for at least 2 months prior to study entry and for the duration of the trial

• and/or maintained on psychotherapeutic behavioral interventions in the maintenance stage (i.e. not during the assessment or skills acquisition or training stages)

Primary Objective: Change in Y-BOCS between the active and sham treatments groups at 6 wks

• Response Rate –reduction of at least 30% in YBOCS score from baseline

• Partial Response Rate – reduction of at least 20% in YBOCS score from

• Remission Rate – defined as YBOCS score < 10

Carmi et al. (2019)


AVERAGE IMPROVEMENT IN YBOCS SCORES

Carmi et al. (2019)

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38%

11%

55%

27%

Full response (> 30%) Partial response (> 20%)

RESPONSE RATES IN ACTIVE VS SHAM DEEP TMS

Carmi et al. (2019)


MEAN CHANGE IN YBOCS FROM BASELINEMEDICATION TRIALS VS DEEP TMS TRIAL

Data on SSRI medications based on meta-analysis (Soomro et al., 2008)

4.47

5.57

7

5.55

6.7

1.4

3.123.64

1.68

3.6

∆=3.1

∆=3.87

∆=3.36

∆=2.45

∆=3.07

Dark = TreatmentLight = Sham

Carmi et al. (2019)


TMS HEALTH SOLUTIONS

Private Practice Outcomes

*Results to be shown during conference presentation

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WHO IS RIGHT FOR TREATMENT AND IS TMS COVERED BY INSURANCE?

FDA Indicated for Major Depressive Disorder in adult patients who have failed to receive satisfactory improvement from a prior antidepressant medication at or above the minimal effective dose and duration in the current episode. Insurance currently covers treatment but can vary in requirements by plan.

Brainsway H7 dTMS FDA cleared for OCD treatment but most insurance companies have not written their policies yet.

Patient Characteristics:

• In a recurrent or chronic episode

• Multiple medication attempts, yet still symptomatic

• Experiences frequent side effects from medication

• Obsessions/compulsions impede ability to use medications

• Inadequate response to exposure response prevention


SUMMARY & CONCLUSIONS:

• TMS is safe, non-invasive, & has been FDA approved for MDD for the last 10 years.

• 2018 - FDA clearance for OCD specifically for the Brainsway H7 system

• Multiple targets & protocols being explored: SMA, OFC, DMPFC/ACC, & low vs high freq

• Exposure/Provocation protocol is unique to OCD treatment and may enhance outcomes

• In treatment resistant OCD, TMS is a reasonable, low-risk, evidence-based option to prescribe

• Many clinicians already using TMS will likely be looking to provide this treatment, but may not have sufficient OCD experience to appropriately tailor treatment to individual patients. Having experienced OCD clinicians who also feel comfortable with TMS, or having TMS clinicians partner with experienced OCD clinicians, will be important in translating clinical trial results to actual real world results.


Questions ?

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Dougherty, D.D. & Ahmari, S.E. (2015). Dissecting OCD Circuits: From Animal Models to Targeted Treatments

Dougherty, D. D. et al. (2018). Neuroscientifically Informed Formulation and Treatment Planning for Patients With Obsessive-Compulsive Disorder: A Review.

Ting, J.T. & Feng, G. (2011). Neurobiology of Obsessive-Compulsive Disorder: Insights into Neural Circuitry Dysfunction through Mouse Genetics. Fettes, Schulze, Downar (2017). Cortico-Striatal-Thalamic Loop Circuits of the Orbitofrontal Cortex: Promising Therapeutic Targets in Psychiatric Illness

Berlim et al (2013). Repetitive transcranial magnetic stimulation (rTMS) for obsessive compulsive disorder (OCD): An exploratory meta-analysis of randomized and sham-controlled trials

Zhou et al (2017). An updated meta-analysis: Short-term therapeutic effects of repeated transcranial magnetic stimulation in treating Obsessive Compulsive Disorder

Rehn et al (2018). A Meta-Analysis of the Effectiveness of Different Cortical Targets Used in Repetitive Transcranial Magnetic Stimulation (rTMS) for the Treatment of Obsessive-Compulsive Disorder (OCD)

Downar (Dec 5, 2017 CTMSS Grand Rounds). Beyond One Size Fits All: Tailoring the rTMS Protocol to the patient.

Dunlop, Hanlon, Downar (2016) Noninvasive brain stimulation treatments for addiction and major depressionBloch et al (2010). Meta-Analysis of the Dose-Response Relationship of SSRI in Obsessive-Compulsive Disorder.

Pittenger, C., & Bloch, M. H. (2014). Pharmacological Treatment of Obsessive-Compulsive Disorder

Hollander et al. (2016). The cost and impact of compulsivity: A research perspective.

Soomro et al (2008). Selective serotonin re-uptake inhibitors (SSRIs) versus placebo for obsessive compulsive disorder (OCD).

References


Ruffini et al (2009). Augmentation Effect of Repetitive Transcranial Magnetic Stimulation Over the Orbitofrontal Cortex in Drug-Resistant Obsessive-Compulsive Disorder Patients: A Controlled Investigation

Nauczyciel (2014). Repetitive transcranial magnetic stimulation over the orbitofrontal cortex for obsessive-compulsive disorder: a double-blind, crossover study

Dunlop et al (2016). Reductions in Cortico-Striatal Hyperconnectivity Accompany Successful Treatment of Obsessive-Compulsive Disorder with Dorsomedial Prefrontal rTMS

Dunlop, Hanlon, Downar (2016) Noninvasive brain stimulation treatments for addiction and major depression

Carmi et al (2017). Clinical and electrophysiological outcomes of deep TMS over the medial prefrontal and anterior cingulate cortices in OCD patientsZangen et al (2016). Deep TMS of the Anterior Cingulate Cortex in OCD patients

Daskalakis et al (2016). Validation of a 25% Nasion–Inion Heuristic for Locating the Dorsomedial Prefrontal Cortex for Repetitive Transcranial Magnetic Stimulation

Holbert and Witter (2017) Positive clinical response to treatment of obsessive–compulsive disorder using dual-site transcranial magnetic stimulationDinur-Klein et al (2014). Smoking Cessation Induced by Deep Repetitive Transcranial Magnetic Stimulation of the Prefrontal and Insular Cortices: A Prospective, Randomized Controlled Trial. Isserles et al (2013). Effectiveness of Deep Transcranial Magnetic Stimulation Combined with a Brief Exposure Procedure in Post-Traumatic Stress Disorder – A Pilot Study. Tendler et al. (2018). O14. Deep TMS of the Medial Prefrontal and Anterior Cingulate Cortices for OCD: A Double-Blinded Multi-Center Study.

Carmi et al. (2019) Efficacy and Safety of Deep Transcranial Magnetic Stimulation for Obsessive-Compulsive Disorder: A Prospective multicenter double-blind placebo-controlled trial

References


Documents

What is TMS? 9-45 - The Use of Transcranial Magnetic... · • 4 large, multisite, randomized controlled trials demonstrated clinically significant antidepressant effect of TMS (2