TMS: An Update with Practical Implications for the Clinician

Jon W. Draud, MD, MSClinical Professor of PsychiatryUniversity of Tennessee College of MedicineMemphis, Tennessee

Medical Director of PsychiatryTrust Point Psychiatric Hospital and St. Thomas Rutherford HospitalNashville, Tennessee

Co-Owner and Co-Founder Draud Sudbury Psychiatric Solutions

Co-Owner and Co-Founder South East TMS AllianceNashville, Tennessee

TMS Background and Treatment-Resistant Depression

Main Brain Stimulation Techniques(partial listing)

ECT = electroconvulsive therapy; FEAST = focal electrically administered seizure therapy; rTMS = repetitive TMS; DBS = deep brain stimulation; RST = responsive stimulation therapy; VNS = vagus nerve stimulation; MST = magnetic seizure therapy; tDCS = transcranial direct-current stimulation; TENS = transcutaneous electrical nerve stimulation; CES = cranial electrical stimulation; EPI-fMRI = echo planar functional magnetic resonance imaging.

• ECT– FEAST

• rTMS– Brainsway, Magstim, Neuronetics, Neuralieve, Neostim, Neosync

• DBS – Parkinson’s disease– RST – Epidural cortical stimulation

• VNS – Epilepsy and Depression

• MST • tDCS• TENS

– CES

• EPI-fMRI • Transcranial pulsed ultrasound

FDA Approved

Not FDAApproved

Impact of Persistent Depression

Katon WJ. Biol Psychiatry. 2003;54(3):216-226. Rugulies R. Am J Prev Med. 2002;23(1):51-61. FawzyFI, et al. Arch Gen Psychiatry. 1993;50(9):681-689. Fawzy FI, et al. Arch Gen Psychiatry. 2003;60(1):100-103. Cook JM, et al. Am J Geriatr Psychiatry. 2002;10(4):437-446. Eaton WW, et al. Diabetes Care. 1996;19(10):1097-1102. American Foundation for Suicide Prevention.

• The impact on health resource use is profound– Excess health care visits are for medical evaluation of

untreated depression symptoms (eg, chest pain, backache, chronic pain)

– Excess utilization of healthcare resources overall– Increases are evident on both direct and indirect costs

• 30% of depressed patients attempt suicide– Nearly half of these complete (> 19,000 suicides/year

in the United States)

Major Depression is a Leading Health Risk in the Workplace Setting

FTE = full time equivalent. Loeppke R, et al. J Occup Environ Med. 2009;51(4):411-428.

“Even without disability costs being included … the combined medical, pharmacy, absenteeism and presenteeism costs of … depression, and fatigue are far more costly than … previously realized …”

“… the cost ranking of health conditions … [including productivity loss] … is significantly different from the more traditional cost ranking of medical or pharmacy costs alone.”

“…an integrated approach of combining medical or pharmacy costs [with lost productivity] provides a more complete and actionable financial assessment for employers.”

Top 10 health conditions by annual medical, drug, absenteeism, and presenteeism costs per 1000 FTEs

Cost Impact of Depression on Associated Illnesses

Collins RL, et al. Manag Care. 2006;15(10 Suppl 9):3-9.

ConditionAnnual Medical Costs

per Patient without Depression (USD$)

Annual Medical Costs per Patient with

Depression (USD$)

Heart failure 2.56 6.74

Allergic rhinitis 3.27 8.46

Asthma 3.73 10.56

Migraine 3.82 15.47

Back pain 11.61 33.25

Diabetes 13.06 27.28

Hypertension 13.38 27.16

Ischemic heart disease

62.40 110.94

STAR*D Study Demonstrates That Current Treatments Have Limited Effectiveness

STAR*D = Sequenced Treatment Alternatives to Relieve Depression; HAM-D = Hamilton Rating Scale for Depression. Trivedi MH, et al. Am J Psychiatry. 2006;163(1):28-40. Rush AJ, et al. Am J Psychiatry. 2006;163(11):1905-1917. Fava M, et al. Am J Psychiatry. 2006;163(7):1161-1172. McGrath PJ, et al. Am J Psychiatry. 2006;163(9):1531-1541.

Likelihood of Discontinuing Treatment Increases with Each New Medication Attempt

Trivedi MH, et al. Am J Psychiatry. 2006;163(1):28-40. Rush AJ, et al. Am J Psychiatry. 2006;163(11):1905-1917. Fava M, et al. Am J Psychiatry. 2006;163(7):1161-1172. McGrath PJ, et al. Am J Psychiatry. 2006;163(9):1531-1541.

Systemic Drug Side Effects Weight Gain

Constipation

Diarrhea

Nausea

Drowsiness

Insomnia

Decreased Libido

Nervous Anxiety

Increased Appetite

Decreased Appetite

Fatigue

Headache/Migraine

Abnormal Ejaculation

Impotence

Sweating

Tremor

Treatment Discontinuation Side Effects

Weakness

Dry Mouth

Dizziness

Relapse during Long-Term Follow-UpSTAR*D Study Results

Rush AJ, et al. Am J Psychiatry. 2006;163(11):1905-1917.

The higher the level of treatment resistance prior to remission, the faster the relapse in long-term follow-up

Level 1 (non-resistant)

Level 2 (1 prior Tx failure)

Level 3 (2 prior Tx failures)

Level 4 (3 prior Tx failures)

MDD

MDD = major depressive disorder.Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. Third Edition. New York, NY: Cambridge University Press; 2008. Pizzagalli DA. Neuropsychopharmacology. 2011;36(1):183-206.

PrefrontalCortex

In MDD, some areas of the

brain are hypoactive and

others are hyperactive

Amygdala

Brainstem Neurotransmitter Centers

Thalamus

Striatum

Anterior Cingulate

Cortex

Hippocampus

Hypothalamus

LOW

HIGH

Neural Activity

TMS

Faraday M. Experimental Research in Electricity. Volume 1. London: Quaritch; 1839:1-15. Barker AT. J Clin Neurophysiol. 1991;8(1):26-37. Barker AT, et al. Lancet. 1985;11(8437):1106-1107.

• Application of electromagnetic induction described by Michael Faraday in 1839– Faraday’s Law: a time-varying magnetic field induces

an electric current that runs perpendicular to the time-varying motion of the magnetic field

• Clinical application: pulsed magnetic fields can induce electrical currents in brain tissues and neurons

How Do ECT and TMS Differ?

Herwig U, et al. Biol Psychiatry. 2001;50(1):58-61.

ECT TMS

Direction of induced current Radial Tangential

Current reaches deep structures

Yes No

Anesthesia required Yes No

Seizure induced Yes No

20 Hz rTMS

Speer AM, et al. Biol Psychiatry. 2000;48(12):1133-1141.

1 Hz TMS

Speer AM, et al. Biol Psychiatry. 2000;48(12):1133-1141.

Key Take-Aways

• ECT and rTMS vastly differ

• High Frequency rTMS (> 1 Hz) enhances cortical excitability

Mechanism of Action for TMS

Faraday’s Law

Michael Faraday (1797–1867)

C

Cortex TMS Coil

“The induced electromotive force in any closed circuit is equal to the time rate of change of the magnetic flux through the circuit”

The Forgotten Half of the Truth

George MS, et al (Eds). Transcranial Magnetic Stimulation in Clinical Psychiatry. Arlington, VA: American Psychiatric Publishing, Inc.; 2007.

The Brain is an Electrochemical Organ

Electricity is the Currency of the Brain

All of synaptic pharmacology simply serves to transmit electrical signals to the next neuron

TMS Mechanism of Effect

Sack AT, et al. Brain Res Brain Res Rev. 2003;43(1):41-46.

Acute effects of pulsed magnetic fields in the brain:• Induction of localized electric current• Depolarization of neurons in superficial cerebral cortex• Alteration in cerebral blood flow and metabolic activity; neurotransmitter

release• Distant action on connected circuits

TMS Increases Neurogenesis in Hippocampal Dentate Gyrus

Ueyama E, et al. Psychiatry Clin Neurosci. 2011;65(1):77-81.

Treating the Brain as an Electrochemical Target

Pizzagalli DA. Neuropsychopharmacology. 2011;36(1):183-206.

• Brain activity can be altered:

– Chemically (eg, via drugs) or

– Electrically (eg, via TMS)

• Drug action is anatomically diffuse and systemic

• TMS is focused, non-invasive and non-systemic Major brain regions known to be

involved in mood regulation

Anterior Cingulate Gyrus

PrefrontalCortex

Amygdala

VentromedialPrefrontal Cortex

How Can TMS Affect the Brain?

TSH = thyroid stimulating hormone.George MS, et al (Eds). Transcranial Magnetic Stimulation in Clinical Psychiatry. Arlington, VA: American Psychiatric Publishing, Inc.; 2007.

• Physical property of TMS– Pain, noise, placebo

• Electrical fields effects – most likely mechanism• Magnetic field effects (not electrical)?

– Highly unlikely but not impossible• Change in blood brain barrier?

– Possible – checking with diffusion scanning – assume effects are due to neuronal (glial) excitation and cascade of effects thereafter

• Clinical effects might be neurohormonally mediated (eg, TSH, prefrontal)

• Short-term effects (eg, speech arrest) are likely circuit mediated

Biological Effects of TMS

Li X, et al. Biol Psychiatry. 2004;55(9):882-890. Teneback CC, et al. J Neuropsychiatry Clin Neurosci. 1999;11(4):426-435.

Acute Effects• Induces electric current• Depolarizes neurons in superficial cortex• Leads to local and trans-synaptic changes in brain

activity Example

• Left prefrontal TMS

• 22 depressed individuals

• Activation demonstrated at site of stimulation and also at synapticallyconnected cortical and subcortical regions

Biological Changes with rTMS in Human Studies

PFC = prefrontal cortex; DLPFC = dorsolateral PFC; DST = dexamethasone suppression test.Teneback CC, et al. J Neuropsychiatry Clin Neurosci. 1999;11(4):426-435. Szuba MP, et al. BiolPsychiatry. 2001;50(1):22-27. Pridmore S. Psychiatry Clin Neurosci. 1999;53(1):33-37.

• rTMS produces changes in PFC and paralimbic blood flow with DLPFC stimulation

• Increased output of TSH in association with acute mood change in depression

• Normalization of the DST with rTMS

Biological Effects of TMS (continued)

BDNF = brain-derived neurotrophic factor; LTD = long-term depression; LTP = long-term potentiation; GABA = γ-aminobutyric acid. Lisanby SH, et al. Depress Anxiety. 2000;12(3):178-187. Kim EJ, et al. Neurosci Lett. 2006;405(1-2):79-83. Shajahan PM, et al. Prog Neuropsychopharmacol Biol Psychiatry. 2002;26(5):945-954. TenebackCC, et al. J Neuropsychiatry Clin Neurosci. 1999;11(4):426-435. Epstein CM, et al. Neurology. 1990;40(4):666-670. George MS, et al. Neuroreport. 1995;6(14):1853-1856. Post A, et al. J PsychiatrRes. 2001;35(4):193-215.

• Chronic Effects– Specific outcome is dependent upon stimulation

parameters– Alteration of monoamine concentrations– β-receptor, serotonin-receptor modulation– Induction of neurogenesis genes (eg, BDNF)– Plasticity, LTD/LTP effects– Local GABA, glutamate effects – Stimulation of the DLPFC alters functional activity of

the anterior cingulate and deeper limbic regions

How Does TMS Correct the Neurophysiologic Defect in MDD?

Leuchter AF, et al. Front Hum Neurosci. 2013;7:37.

• The brain is a distributed network system whose connections aremaintained by rhythmic oscillations. Alpha rhythms are responsible forregulating functional connectivity over long distances in the brain

• In MDD, the brain is locked into a state marked by highly resonantlow-frequency rhythmic oscillations– Normal oscillations:synchronous and asynchronous rhythm

– Oscillations in MDD:monotonous synchrony

• Goal of TMS is to reset cortical and thalamocortical oscillators,leading to increased flexibility in network formation

• Successful treatment is marked by increased variability in oscillatoryactivity

Prefrontal TMS Effects Limbic Blood Flow

Nahas Z, et al. Biol Psychiatry. 2001;50(9):712-720.

Pooled effects of 1 Hz prefrontal TMS in 5 healthy adults, 120% MT, BOLD fMRI,P < .001, cluster P < .05 for display

TMS Coil Location

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100

150

200

250

Frontalcortex

Striatum Hippo

B m

ax (

fmo

l/m

g)

β-adrenergic receptors

TMS Control

TMS Affects β-adrenergic and Serotonergic Transmission in Animal Models

Fleischmann A, et al. J Neural Transm. 1996;103(11):1361-1366. Ben-Shachar D, et al. Brain Res. 1999;816(1):78-83.

Chronic rTMS modulates β-adrenergic receptors in cortex

(Fleischmann et al [1996] found down regulation; Ben-Sachar et al [1999] found up-regulation in cortex)

TMS Affects β-adrenergic and Serotonergic Transmission in Animal Models (continued)

Ben-Shachar D, et al. Brain Res. 1999;816(1):78-83.

Chronic rTMS(15 Hz, 3.5 s, 10 d, 7 cm coil)

reduced 5-HT2receptors in cortex

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50

100

150

200

250

300

350

Frontal cortex Striatum Hippo

B m

ax (

fmo

l/m

g p

rote

in)

5-HT2 Receptors

TMS

Control

Prefrontal TMS Induces Dopamine Release in Ipsilateral Caudate

Strafella AP, et al. J Neurosci. 2001;21(15):RC157.

15 10 pulse 1s trains @10 Hz, total 450

Declining Amygdala and Prefrontal Activity with Worsening Depression

Post A, et al. J Psychiatr Res. 2001;35(4):193-215.

Could we wake this up with TMS?

Cortical Governance over Limbic Activity

Alexander GE, et al. Annu Rev Neurosci. 1986;9:357-381.

Clinical Safety and Tolerability Considerations

Post A, et al. J Psychiatr Res. 2001;35(4):193-215.

• What’s common, what’s not…• No evidence of cognitive sequelae• Common adverse events

– Self-limited headache after treatment (~ 1 in 4)– Cutaneous discomfort during stimulation (~ 1 in 6)– Pain during stimulation (~ 3–5%)

• Risk of seizure– 9 cases reported in the world literature with rTMS– Self-limited– No reported sequelae or progression to seizure

disorder– No additional cases since inception of 1998 guidelines

Key Take-Aways

• Synaptic pharmacology serves to transmit electrical signals to the next neuron; In clinical practice, rTMS uses pulsed magnetic fields to induce electrical current in brain tissue and neurons

• One goal of rTMS is to reset cortical and thalamocortical oscillators, leading to increased flexibility in network formations

• rTMS modulates monoamines, glutamate, GABA, as well as intracellular plasticity cascades

Clinical Trial Data

Past and Present

Initial TMS Antidepressant Studies

1,2 = randomized, controlled, remainder of studies were open.George MS, et al (Eds). Transcranial Magnetic Stimulation in Clinical Psychiatry. Arlington, VA: American Psychiatric Publishing, Inc.; 2007.

Study NFreqHz

MT % Pulses/S#

SessTotal Pulses

% changeHDSR ES

Hoflich et al, 1993 2 .3 105-130 250 10 2500 10.3 0.71

Kolbinger et al, 1995 15 .25 90 250 5 1250 15 ----

George et al, 1995 6 20 80 800 5 4000 26 1.35

1Pascual-Leone, 1996 17 10 90 2000 5 10,000 45 1.76

2George et al, 1997 12 20 80 800 10 800 17 1.36

Epstein et al, 1998 32 10 110 250 5 1250 52 1.12

Figiel et al, 1998 56 10 110 500 5 2500 44.4 1.78

Comparative Analysis of Effect Size:TMS Therapy vs Medications

O’Reardon JP, et al. Biol Psychiatry. 2007;62(11):1208-1216. Janicak PG, et al. J Clin Psychiatry. 2008;69(2):222-232. Khan A, et al. Arch Gen Psychiatry. 2000;57(4):311-317.

TMS Therapy Week 4 (HAM-D-17)

0.0

0.2

0.4

0.6

0.8

1.0

OverallPopulation

1 AD FailureSubgroup

Pharmaceutical Antidepressants(HAM-D-17)

0.0

0.2

0.4

0.6

0.8

1.0

Pharmaceuticals(Khan)

0.49

0.55

0.83

(N = 301) (N = 164)

Critique of Early Studies

Kozel FA, et al. J Psychiatr Pract. 2002;8(5):270-275.

• Sample sizes generally small

• Study design: single blinded

• Some subsets of robust responders but generally reduction in baseline scores < 50%

• Questions as to adequacy of sham in terms of blind and block of magnetic stimulus

• Does TMS have antidepressant effects that are not meaningful clinically?

Meta-Analysis of Left DLPFC rTMS

Kozel FA, et al. J Psychiatr Pract. 2002;8(5):270-275.

• Included 12 controlled trials (n = 230)

• Mean effect size 0.53 (CI 0.24-0.82)

• Comparable effect to antidepressants

• Would need—at a minimum—20 negative studies to override this result

Cochrane Meta-Analysis

RCT = randomized controlled trial.Martin JL, et al. Cochrane Database Syst Rev. 2002;(2):CD003493.

• Included 14 RCTs of rTMS but critiqued the small sample size of rTMS studies generally (Median n = 19, range 6–40 participants) if Klein et al is excluded

• Found benefit for rTMS of the left DLPFC at 2 weeks and for right DLPFC at 1 Hz but…

• Concluded – “there is no strong evidence for benefit from using transcranial magnetic stimulation to treat depression”

Learning to Optimize TMS or Why Cochrane is Definitely Not the Last Word

MADRS = Montgomery-Asberg Depression Rating Scale; TRD = treatment-resistant depression.

Fitzgerald PB, et al. Am J Psychiatry. 2006;163(1)-88-94.

RCT of bilateral TMS in TRD

Sequential slow TMS on the Rand fast TMS on the L

6-week trial, daily TMS added onto existing medications, N = 50

Response rate of 44% andremission of 36% observed onMADRS, 52% and 40%respectively on HAM-D-17

Significantly greater response toactive than sham stimulation at 2weeks and across the fullduration of the study

Better results than citalopramover 12-weeks in the STAR*Doutcomes in the same issue ofAJP (47% and 30% on MADRS)

Summary of TMS Acute Unipolar Depression Trials

George MS, et al. Arch Gen Psychiatry. 2010;67(5):507-516.

• 3 large prospective RCTs support TMS for treating acute moderately TRD

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

• Safe, tolerable, but inefficient

• Good clinical adoption

– 500 Neuronetics machines sold in United States alone

– App 12 remitters/day in United States alone

• Durability appears good: 90% retention of response at 12 months

Clinical Benefit Varies by Prior Treatment Failure in STAR*D and TMS Therapy

Avery DH, et al. J Clin Psychiatry. 2008;69(3):441-451.

% R

em

iss

ion

(H

AM

-D-1

7)

27.5%

21.2%

16.2%

6.9%

25.6%

17.9% 18.2%

0%

10%

20%

30%

40%

Comparison of Monotherapy Outcomes:Pharmacotherapy vs TMS Therapy

STAR-D Study Outcome TMS Therapy Outcome

No or Limited Prior Rx 1 Prior Failure 2 Prior Failures 3 Prior Failures

Sample Size (N): 2876 727 221 5843 28 11

Treatment Resistance[Low] [High]

TMS Therapy Demonstrates a Clear Separation between Active and Sham Treatment

LOCF analysis of intent-to-treat populationDemitrack MA, et al. Psychopharmacol Bull. 2009;42(2):5-38.

P = .0018

P = .0006P = .0063

RCT Key Outcome Measure – MADRS Change Score

> 3 × Reduction in Depressive Symptoms at Week 4

Independent Study Reinforces Efficacy for TMS

George MS, et al. Arch Gen Psychiatry. 2010;67(5):507-516.

• NIMH-sponsored Optimization of TMS (OPT-TMS) Study– Independent of industry– Rigorous RCT; active sham-controlled (1:1 randomization), duration-adaptive

design with 3 weeks of daily weekday treatment (fixed-dose phase) followed by continued blinded treatment for up to another 3 weeks in improvers

– 190 patients treated at 4 premier academic sites• Primary outcome measure: Percent Remission at 3 weeks

‒ 4 × greater likelihood of achieving remission with active treatment vs sham treatment

Mark S. George, MD; Sarah H. Lisanby, MD; David Avery, MD; William M. McDonald, MD; Valerie Durkalski, PhD;Martina Pavlicova, Phd; Berry Anderson, Phd, RN; Ziad Nahas, MD; Peter Bulow, MD; Paul Zarkowski, MD;Paul E. Holtzheimer III, MD; Theresa Schwartz, MS; Harold A. Sackeim, PHD

NIMH Multi-Site OPT-TMS Studywith Active Sham Control

George MS, et al. Arch Gen Psychiatry. 2010;67(5):507-516

14%

5%

0%

2%

4%

6%

8%

10%

12%

14%

16%

Remission

TMS

Sham

P < .015N = 190; Odds ratio is 4.2

Consistent Response and Remission Rates across a Broad Range of Treatment Resistance

LOCF analysis of intent-to-treat population. CGI-S outcomes in acute phase.*0–1 adequate antidepressant medications; **≥ 2 adequate antidepressant medications.PHQ-9 = 9-item Patient Health Questionnaire. Carpenter LL, et al. Depress Anxiety. 2012;29(7):587-596.

1 in 2 Patients Respond, 1 in 3 Patients Achieve Remission

Naturalistic, Open Label Treatment Utilization and Outcomes Study

Patient reported outcomes (PHQ-9) were consistent with physician-rated outcomes

TMS Therapy is Cost Effective When Compared to Antidepressant Medication Use-As-Usual

Simpson KN, et al. Adv Ther. 2009;26(3):346-368.

Model Assumptions for Comparison of Treatments over One Year of Care:

• TMS: Total utilization, 60 sessions/yr

• Reimbursement Cost Assumption: US $300/treatment

• Follow Up: Medication –monotherapy maintenance

• Lost time to attend TMS treatment sessions included in the model

• Efficacy as described in STAR*D study outcomes (Levels 2 and 3)

• Costs for Medications (avg. wholesale price, including generics)

• Includes cost of physician visits for medication management

TMS TherapyAntidepressant Medication

Management As-Usual

TMS Represents a Cost Saving over Treatment-As-Usual

Simpson KN, et al. Adv Ther. 2009;26(3):346-368.

• TMS represents a cost savings per patient per yearcompared to current standard of care:– US $1123

– Without productivity and work loss costs included in the model (Payer Perspective)

– US $7621– With productivity and work loss costs included in

the model (Employer Perspective)

Annual Estimated Cost Savings with TMS as a Covered Benefit for a Mid-Sized Payer

Milliman, Inc. An Actuarial Analysis of Treatment Resistance in Patients with Major Depressive Disorder in a Commercially Insured Population. December 4, 2012. http://us.milliman.com/uploadedFiles/insight/health-published/pdfs/actuarial-analysis-depressive-disorders.pdf. Accessed June 27, 2016.

0

50

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200

250

300

Payer Perspective Employer Perspective

Annual Cost Savings in Millions ($)

TMS Therapy in the Care Continuum

SSRI = selective serotonin reuptake inhibitor; SNRI = serotonin-norepinephrine reuptake inhibitor; NDRI = norepinephrine-dopamine reuptake inhibitor; MAOI = monoamine oxidase inhibitor; TCA = tricyclic antidepressant.

Change in HAM-D Measured Weekly

Levkovitz Y, et al. World Psychiatry. 2015;14(1):64-73.

Response and Remission Rates for dTMS and Sham Groups at the End of Week 5 and Week 16

Levkovitz Y, et al. World Psychiatry. 2015;14(1):64-73.

Antidepressant Effect of dTMS in Relation to the Number of Failed Pharmacotherapy Trials

Levkovitz Y, et al. World Psychiatry. 2015;14(1):64-73.

Percentage of Patients Achieving Response or Remission for 0%, 0% to 30%, and > 30% of the

Total Time in the Study of dTMS and Sham Groups

Levkovitz Y, et al. World Psychiatry. 2015;14(1):64-73.

Mean HAM-D-17 Scores for the 80% rTMS, 110% rTMS, and Sham Groups at Timepoints throughout the Study

Bakim B, et al. Bulletin of Clinical Psychopharmacology. 2012;22(3):244-253.

Mean MADRS Scores for the 80% rTMS, 110% rTMS, and Sham Groups at Timepoints throughout the Study

Bakim B, et al. Bulletin of Clinical Psychopharmacology. 2012;22(3):244-253.

TMS Therapy Modulates Discrete Deep Brain Regions

Liston C, et al. Biol Psychiatry. 2014;76(7):517-526.

• Treatment with TMS reduces hyperconnectivitywithin the default mode network (ventromedial prefrontal cortex, pregenualanterior cingulate cortex, thalamus, and precuneus)

TMS Modulates EEG Gamma Frequency in Distributed Brain Regions

EEG = electroencephalogram.Kito S, et al. Brain Stimul. 2014;7(1):145-146.

Treatment with TMS Therapy is associated with an enhancement of  gamma band activity in DLPFC and anticorrelated reduction of activity in the precuneus

Precuneus

Long-Term Treatment Outcomes of TMS in Naturalistic Setting

Dunner DL, et al. J Clin Psychiatry. 2014;75(12):1394-1401.

• 257 patients with medication-resistant unipolar depression received TMS and followed post-treatment for 52 weeks

• At the end of acute treatment 120 patients met criteria for either response or remission. Of those, 75 (62.5%) met response criteria throughout the follow-up period

• Of the entire cohort, 93 patients (36.2%) received re-introduction of TMS at some point during the 52-week follow up. Average number of TMS days was 16.2 days

Need for Maintenance rTMS

ADM = antidepressant medication.Li X, et al. Depress Anxiety. 2004;20(2):98-100. Benadhira R, et al. Am J Psychiatry. 2005;162(1):193. 2005. Abraham G, et al. Can J Psychiatry. 2002;47(4):386.

In principle, the best way to maintain benefit would be rTMS sessions

Options include transition back to ADM or rTMS sessions at reduced frequency

Maintenance ECT may be a model in this regard

Very small amount of data with maintenance rTMS

No Efficacy/Effectiveness Gap

Carpenter LL, et al. Depress Anxiety. 2012;29(7):587-596. Connolly KR, et al. J Clin Psychiatry. 2012;73(4):e567-e573.

• 307 real-world US patients, on medication, 58% response, 37% remission, average 28 sessions

• 100 patients, U Penn practice model, 50% response, 25% remission

Failure!

George MS, et al (Eds). Transcranial Magnetic Stimulation in Clinical Psychiatry. Arlington, VA: American Psychiatric Publishing, Inc.; 2007.

Despite 2 decades of research

• We still largely use the initial approximations (marginally refined)

• We have not achieved the same remission rates as ECT

• We do not understand the LD50 or upper safety limit of dose

• We do not understand, fully, the translational neurobiology (neural mechanisms) of how TMS acts to get patients undepressed

TMS and Postoperative Pain

The use of TMS for postoperative pain off-label. rMT = resting motor threshold. Borckardt JJ, et al. Anesthesiology. 2006;105(3):557-562.

RCT, 20 Gastric Bypass Patients, L DLPFC, 20 minutes, 10 Hz, 100% rMT

One rTMS Session Cuts Cumulative Morphine Use by 40%

Borckardt JJ, et al. Anesthesiology. 2006;105(3):557-562.

TMS half-life ?

TMS Anti-Suicide Study

George MS, et al. Brain Stimul. 2014;7(3):421-431.

• High dose, 3-day adjunctive TMS study on inpatients admitted for suicidal ideation

• Randomized, sham-controlled

• N = 45, 2 sites – Ralph H. Johnson VA Medical Center, Walter Reed National Military Medical Center

• 2 years

• 18,000 stimuli/day, 54,000 total

Active TMS Significantly Reduced Suicidal Ideation

SSI = Scale of Suicidal Ideation.George MS, et al. Brain Stimul. 2014;7(3):421-431.

Beck Suicide Scale Visual Analog ScaleI am currently bothered by thoughts of suicide

Future Applications

PTSD = posttraumatic stress disorder; OCD = obsessive-compulsive disorder; ADHD = attention-deficit/hyperactivity disorder.Serafini G, et al. Neuropsychobiology. 2015;71(3):125-139.

• Stroke rehab

• Chronic pain– Trigeminal neuralgia

– Headache

• ADHD

• Tinnitus

• Epilepsy

• Parkinson’s disease

• Schizophrenia

• Bipolar depression

• PTSD

• OCD

Psychiatry Neurology

Preliminary human data suggest the potential application of TMS in

these conditions

Key Take-Aways

• Early rTMS trials were flawed in that they were inconsistent in the frequency and number of treatments given

• More recent studies have shown that rTMS is equal to, if not superior to pharmacotherapy for TRD

• A very recent study has demonstrated that high dose, 3-day adjunctive rTMS reduces suicidal ideation

Further Reading

George MS, Belmaker RH. Transcranial Magnetic Stimulation in Clinical Psychiatry. Arlington, VA:American Psychiatric Publishing, Inc.; 2007.

Higgins ES, George MS. The Neuroscience of Clinical Psychiatry: The Pathophysiology of Behavior andMental Illness. Philadelphia, PA: Lippincott; 2007.

Higgins ES, George MS. Brain Stimulation Therapies for Clinicians. Washington, DC: AmericanPsychiatric Publishing; 2009.

Practical Discussion & Conclusions #1

1. Which patients are most likely to benefit from TMS in clinical practice?

– Per FDA guidelines, adults patients who have failed 1 antidepressant medication at or above the minimal effective dose and duration in the current episode

– Patients must be free of seizure disorders and metallic implants on or near the head (Examples include cochlear implants, electrodes/stimulators, aneurysm clips and coils, bullet fragments, jewelry, and hair barrettes)

• On the market and what makes them different? What about the economic differences and what about reimbursement?

Practical Discussion & Conclusions #1 (Continued)

– Per insurance guidelines, adult patients with moderate or severe MDD diagnosis who have failed 2 antidepressants and 2 medication augmentation therapies (TRD)

– Patients must be free of seizure disorders and metallic implants on or near the head (Examples include cochlear implants, electrodes/stimulators, aneurysm clips and coils, bullet fragments, jewelry, and hair barrettes)

Practical Discussion & Conclusions #2

2. Should I start my own TMS practice?

– A good estimate of startup cost for equipment and space requirements ranges between $100,000 to $150,000

– Additional monies for staff cost must be considered as well (TMS coordinator, TMS treater, billing specialist)

– Insurance coverage varies state to state, as do reimbursement rates

– Medicare is the only carrier that covers nationally

Practical Discussion & Conclusions #3

3. What are the approved rTMS devices and how do I find them?

– NeuroStar TMS Therapy – www.neurostar.com

or call 1-877-600-7555

– Brainsway – www.brainsway.com/us

or call 1-844-386-7001

– Magstim – http://magstim.com

or call +44-1994-240-798