Main Brain Stimulation Techniques (partial listing) A Review of the Science and Practical Applications of TMS. Impact of Persistent Depression

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1 Main Brain Stimulation Techniques (partial listing) A Review of the Science and Practical Applications of TMS Jon W. Draud, MS, MD Clinical Professor of Psychiatry University of Tennessee College of Medicine Memphis, Tennessee Medical Director of Psychiatry Pain Management Group Trust Point Psychiatric Hospital St. Thomas Rutherford Hospital Medical Director and Principal Draud Sudbury Psychiatric Solutions Private Practice, Adult and Adolescent Psychiatry Nashville, Tennessee FDA Approved Not FDA Approved ECT (electroconvulsive therapy) FEAST (focal electrically administered seizure therapy) rtms (repetitive TMS) Brainsway, Magstim, Neuronetics, Neuralieve, Neostim, Neosync DBS (deep brain stimulation) Parkinson s disease RST (responsive stimulation therapy) Epidural cortical stimulation VNS (vagus nerve stimulation) Epilepsy and Depression 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) Transcranial pulsed ultrasound Impact of Persistent Depression 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 health care 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) Katon WJ. Biol Psychiatry. 2003;54(3): Rugulies R. Am J Prev Med. 2002;23(1): Fawzy FI, et al. Arch Gen Psychiatry. 1993;50(9): Fawzy FI, et al. Arch Gen Psychiatry. 2003;60(1): Cook JM, et al. Am J Geriatr Psychiatry. 2002;10(4): Eaton WW, et al. Diabetes Care. 1996;19(10): American Foundation for Suicide Prevention. Major Depression is a Leading Health Risk in the Workplace Setting Top 10 health conditions by annual medical, drug, absenteeism, and presenteeism costs per 1000 FTEs 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 FTE = full time equivalent. employers. Loeppke R, et al. J Occup Environ Med. 2009;51(4): Cost Impact of Depression on Associated Illnesses STAR*D Study Demonstrates That Current Treatments Have Limited Effectiveness Collins RL, et al. Manag Care. 2006;15(10 Suppl 9):3-9. 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): Rush AJ, et al. Am J Psychiatry. 2006;163(11): Fava M, et al. Am J Psychiatry. 2006;163(7): McGrath PJ, et al. Am J Psychiatry. 2006;163(9):

2 Likelihood of Discontinuing Treatment Increases with Each New Medication Attempt Systemic Drug Side Effects Weight Gain Fatigue Constipation Headache/ Migraine Diarrhea Abnormal Nausea Ejaculation Drowsiness Impotence Relapse during Long-Term Follow-Up STAR*D Study Results The higher the level of treatment resistance prior to remission, the faster the relapse in long-term follow-up Insomnia Sweating Decreased Libido Tremor Nervous Anxiety Treatment Discontinuation Increased Appetite Side Effects Decreased Weakness Appetite Dry Mouth Dizziness Trivedi MH, et al. Am J Psychiatry. 2006;163(1): Rush AJ, et al. Am J Psychiatry. 2006;163(11): Fava M, et al. Am J Psychiatry. 2006;163(7): McGrath PJ, et al. Am J Psychiatry. 2006;163(9): Rush AJ, et al. Am J Psychiatry. 2006;163(11): TMS How Do ECT and TMS Differ? Application of electromagnetic induction described by Michael Faraday in 1839 Faraday s Law: a timevarying 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 Faraday M. Experimental Research in Electricity. Volume 1. London: Quaritch; 1839:1-15. Barker AT. J Clin Neurophysiol. 1991;8(1): Barker AT, et al. Lancet. 1985;11(8437): Herwig U, et al. Biol Psychiatry. 2001;50(1): Hz rtms 1 Hz TMS Speer AM, et al. Biol Psychiatry. 2000;48(12): Speer AM, et al. Biol Psychiatry. 2000;48(12):

3 ECT and rtms vastly differ Key Take-Aways High Frequency rtms (> 1 Hz) enhances cortical excitability Mechanism of Action for TMS Faraday s Law The Forgotten Half of the Truth C Electricity is the Currency of the Brain All of synaptic pharmacology simply serves to transmit electrical signals to the next neuron Michael Faraday ( ) 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 Brain is an Electrochemical Organ George MS, et al (Eds). Transcranial Magnetic Stimulation in Clinical Psychiatry. Arlington, VA: American Psychiatric Publishing, Inc.; TMS Mechanism of Effect TMS Increases Neurogenesis in Hippocampal Dentate Gyrus 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 Sack AT, et al. Brain Res Brain Res Rev. 2003;43(1): Ueyama E, et al. Psychiatry Clin Neurosci. 2011;65(1):77-81.

4 Treating the Brain as an Electrochemical Target Brain activity can be altered: Chemically (eg, via drugs) or Electrically (eg, via TMS) Drug action is anatomically diffuse and systemic TMS is focused, noninvasive and non-systemic Prefrontal Cortex Ventromedial Prefrontal Cortex Amygdala Major brain regions known to be involved in mood regulation Biological Effects of TMS 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 synaptically connected cortical and subcortical regions Pizzagalli DA. Neuropsychopharmacology. 2011;36(1): Li X, et al. Biol Psychiatry. 2004;55(9): Teneback CC, et al. J Neuropsychiatry Clin Neurosci. 1999;11(4): Biological Changes with rtms in Human Studies 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 DST = dexamethasone suppression test; DLPFC = dorsolateral prefrontal cortex; PFC = prefrontal cortex; TSH = thyroid-stimulating hormone. Biological Effects of TMS (cont d) 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 BDNF = brain-derived neurotrophic factor; LTD = long-term depression; LTP = long-term potentiation; GABA = gamma-aminobutyric acid. Lisanby SH, et al. Depress Anxiety. 2000;12(3): Kim EJ, et al. Neurosci Lett. 2006;405(1-2): Shajahan PM, et al. Prog Neuropsychopharmacol Biol Psychiatry. 2002;26(5): Teneback CC, et al. J Neuropsychiatry Clin Neurosci. 1999;11(4): Epstein CM, et al. Neurology. 1990;40(4): George MS, et al. Neuroreport. 1995;6(14): Post A, et al. J Psychiatr Res. 2001;35(4): Pooled effects of 1 Hz prefrontal TMS in 5 healthy adults, 120% MT, BOLD fmri, P <.001, cluster P <.05 for display Prefrontal TMS Effects Limbic Blood Flow Different Left DLPFC TMS Targets Show Variability in Resting State Functional Connectivity Nahas Z, et al. Biol Psychiatry. 2001;50(9): Fox MD, et al. Biol Psychiatry. 2012;72(7):

5 Differences in Resting State Functional Connectivity between More Effective vs Less Effective DLPFC Stimulation Sites Prefrontal TMS Induces Dopamine Release in Ipsilateral Caudate pulse 1s Hz, total 450 Fox MD, et al. Biol Psychiatry. 2012;72(7): Strafella AP, et al. J Neurosci. 2001;21(15):RC157. Declining Amygdala and Prefrontal Activity with Worsening Depression Cortical Governance over Limbic Activity Could we wake this up with TMS? Post A, et al. J Psychiatr Res. 2001;35(4): Alexander GE, et al. Annu Rev Neurosci. 1986;9: Clinical Safety and Tolerability Considerations 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 Post A, et al. J Psychiatr Res. 2001;35(4):

6 Initial TMS Antidepressant Studies Clinical Trial Data Past and Present 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.; Comparative Analysis of Effect Size: TMS Therapy vs Medications TMS Therapy Week 4 (HAM-D-17) Critique of Early Studies 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? 0.0 Overall Population 1 AD Failure Subgroup O Reardon JP, et al. Biol Psychiatry. 2007;62(11): Janicak PG, et al. J Clin Psychiatry. 2008;69(2): Khan A, et al. Arch Gen Psychiatry. 2000;57(4): Kozel FA, et al. J Psychiatr Pract. 2002;8(5): Meta-Analysis of Left DLPFC rtms Included 12 controlled trials (n = 230) Mean effect size 0.53 (CI ) Comparable effect to antidepressants Would need at a minimum 20 negative studies to override this result TMS Therapy Demonstrates a Clear Separation between Active and Sham Treatment RCT Key Outcome Measure MADRS Change Score > 3 Reduction in Depressive Symptoms at Week 4 P =.0018 P =.0006 P =.0063 Kozel FA, et al. J Psychiatr Pract. 2002;8(5): LOCF analysis of intent-to-treat population. Demitrack MA, et al. Psychopharmacol Bull. 2009;42(2):5-38.

7 Independent Study Reinforces Efficacy for TMS Consistent Response and Remission Rates across a Broad Range of Treatment Resistance 1 in 2 Patients Respond, 1 in 3 Patients Achieve Remission Naturalistic, Open Label Treatment Utilization and Outcomes Study 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-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 George MS, et al. Arch Gen Psychiatry. 2010;67(5): Patient reported outcomes (PHQ-9) were consistent with physician-rated outcomes 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): TMS Represents a Cost Saving over Treatment-As-Usual TMS Therapy in the Care Continuum TMS represents a cost savings per patient per year compared 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) Simpson KN, et al. Adv Ther. 2009;26(3): SSRI = selective serotonin reuptake inhibitor; SNRI = serotonin-norepinephrine reuptake inhibitor; NDRI = norepinephrine-dopamine reuptake inhibitor; MAOI = monoamine oxidase inhibitor; TCA = tricyclic antidepressant. Antidepressant Effect of dtms in Relation to the Number of Failed Pharmacotherapy Trials TMS Therapy Modulates Discrete Deep Brain Regions Treatment with TMS reduces hyperconnectivity within the default mode network (ventromedial prefrontal cortex, pregenual anterior cingulate cortex, thalamus, and precuneus) Levkovitz Y, et al. World Psychiatry. 2015;14(1): Liston C, et al. Biol Psychiatry. 2014;76(7):

8 TMS Modulates EEG Gamma Frequency in Distributed Brain Regions 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 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 reintroduction of TMS at some point during the 52-week follow up. Average number of TMS days was 16.2 days EEG = electroencephalogram. Kito S, et al. Brain Stimul. 2014;7(1): Dunner DL, et al. J Clin Psychiatry. 2014;75(12): Need for Maintenance rtms 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 TMS Maintenance as a Substitute for Maintenance ECT A Case Study TMS is an efficacious, well-tolerated, non-invasive brain stimulation treatment for MDD ECT is an effective maintenance treatment for depression, but is not tolerated by some patients and declined by others ADM = antidepressant medication. Li X, et al. Depress Anxiety. 2004;20(2): Benadhira R, et al. Am J Psychiatry. 2005;162(1):193. Abraham G, et al. Can J Psychiatry. 2002;47(4):386. Cristancho MA, et al. J ECT. 2013;29(2): Change in BDI Scores from Initial Observation (baseline prior to first TMS session) to 3 months, 6 months, and Last Observation No Efficacy/Effectiveness Gap 307 real-world US patients, on medication, 58% response, 37% remission, average 28 sessions 100 patients, U Penn practice model, 50% response, 25% remission BDI = Beck Depression Inventory. Cristancho MA, et al. J ECT. 2013;29(2): Carpenter LL, et al. Depress Anxiety. 2012;29(7): Connolly KR, et al. J Clin Psychiatry. 2012;73(4):e567-e573.

9 TMS Improves Evoked-fMRI Cortical Responses after TBI Future Applications TBI = traumatic brain injury. Lu H, et al. Sci Rep. 2015;5: TMS Restores Cortical Excitability after TBI A Summary of Our Current Understanding of Factors That Contribute to Post-Stroke Impairment LFP = local field potential; MUA = multi-unit activity. Lu H, et al. Sci Rep. 2015;5: Auriat AM, et al. Front Neurol. 2015;6:226. Performance on Measures of Discourse Productivity before and 2 Months after Receiving Real rtms Finding the Right Words: TMS Improves Discourse Productivity in Non-Fluent Aphasia after Stroke N = 10. Medina J, et al. Aphasiology. 2012;26(9): Medina J, et al. Aphasiology. 2012;26(9):

10 TMS-Induced Global Propagation of Transient Phase Resetting Associated with Directional Information Flow stms Has Been Shown to be Effective for the Acute Treatment of Migraine Kawasaki M, et al. Front Hum Neurosci. 2014;8:173. CSD = cortical spreading depression; TMS = single pulse transcranial magnetic stimulation. Andreou AP, et al. Brain. 2016;139(Pt 7): The Impact of TMS on Mechanically and Chemically Induced CSD rtms Could be a Safe and Effective Treatment Option for Patients with Chronic Low Back Pain Resulting in Depression and Insomnia Andreou AP, et al. Brain. 2016;139(Pt 7): ISI = Insomnia Severity Index; NRS = Pain Numerical Rating Scale; PDI = Pain Disability Index. Park EJ, et al. Korean J Pain. 2014;27(3): TMS for the Treatment of Pharmacoresistant Nondelusional Auditory Verbal Hallucinations in Dementia AVHs are known as a core symptom of schizophrenia, but also occur in a number of other conditions, not least in neurodegenerative disorders such as dementia In the last decades, TMS emerged as a valuable therapeutic approach towards several neurological and psychiatric diseases, including AVHs The study authors reported a case of a 76-year-old woman with vascular-degenerative brain disease, complaining of threatening AVHs The patient was treated with a high-frequency temporoparietal (T3P3) rtms protocol for 15 days A considerable reduction of AVHs in frequency and content (no more threatening) was observed. Although further research is needed, this seems an encouraging result AVH = auditory verbal hallucination. Marras A, et al. Case Rep Psychiatry. 2013;2013: Assessing and Stabilizing Aberrant Neuroplasticity in Autism Spectrum Disorder: The Potential Role of TMS TMS has rapidly evolved to become a widely used, safe, and non-invasive neuroscientific tool to investigate a variety of neurophysiological processes, including neuroplasticity The diagnostic and therapeutic potential of TMS in ASD is beginning to be realized ASD = autism spectrum disorder. Desarkar P, et al. Front Psychiatry. 2015;6:124.

11 Irritability, Lethargy, and Hyperactivity Rating Scores Decreased Significantly Post-TMS Stereotype Behavior, Ritualistic Behavior, and Total RBS Scores Decreased Significantly Casanova MF, et al. Front Hum Neurosci. 2014;8:851. RBS = Repetitive Behavior Scale. Casanova MF, et al. Front Hum Neurosci. 2014;8:851. Forest Plot of Comparison of Auditory Hallucination Scales in Active rtms vs Sham Stimulation Forest Plot of Comparison of Response Rate in Active rtms vs Sham Stimulation (Auditory Hallucination of Patients with Schizophrenia Spectrum Disorders) Zhang Y, et al. Neural Regen Res. 2013;8(28): Zhang Y, et al. Neural Regen Res. 2013;8(28): The ERP Waveforms and Brain Topographic Maps of Tinnitus Patients before rtms The ERP Waveforms and Brain Topographic Maps of Tinnitus Patients after rtms ERP = event-related potential. Yang H, et al. PLoS One. 2013;8(8):e Yang H, et al. PLoS One. 2013;8(8):e70831.

12 TMS and Postoperative Pain One rtms Session Cuts Cumulative Morphine Use by 40% TMS half-life? RCT, 20 Gastric Bypass Patients, L DLPFC, 20 minutes, 10 Hz, 100% rmt The use of TMS for postoperative pain off-label. rmt = resting motor threshold. Borckardt JJ, et al. Anesthesiology. 2006;105(3): Borckardt JJ, et al. Anesthesiology. 2006;105(3): TMS Anti-Suicide Study 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 Beck Suicide Scale Visual Analog Scale I am currently bothered by thoughts of suicide George MS, et al. Brain Stimul. 2014;7(3): SSI = Scale of Suicidal Ideation. George MS, et al. Brain Stimul. 2014;7(3): Future Applications Key Take-Aways Psychiatry Schizophrenia Bipolar depression PTSD OCD Preliminary human data suggest the potential application of TMS in these conditions Neurology Stroke rehab Chronic pain Trigeminal neuralgia Headache ADHD Tinnitus Epilepsy Parkinson s disease 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 PTSD = posttraumatic stress disorder; OCD = obsessive-compulsive disorder; ADHD = attentiondeficit/hyperactivity disorder. Serafini G, et al. Neuropsychobiology. 2015;71(3):

13 Further Reading Recommended Clinical Practice Essentials Training Roles and responsibilities Establishing a treatment plan Informed consent Safety considerations Outcome evaluation Post-treatment planning George MS, Belmaker RH. Transcranial Magnetic Stimulation in Clinical Psychiatry. Arlington, VA: American Psychiatric Publishing, Inc.; Higgins ES, George MS. The Neuroscience of Clinical Psychiatry: The Pathophysiology of Behavior and Mental Illness. Philadelphia, PA: Lippincott; Higgins ES, George MS. Brain Stimulation Therapies for Clinicians. Washington, DC: American Psychiatric Publishing; Perera T, et al. The Clinical TMS Society Consensus Review and Treatment Recommendations for TMS Therapy for Major Depressive Disorder. Brain Stimul. 2016;9(3): Clinical Recommendations Indicated Patient Population: The labeled indication for use for the TMS therapy states that, TMS therapy is indicated for the treatment of Major Depressive Disorder in adult patients who have failed to receive satisfactory improvement from prior antidepressant medication in the current episode. Recommendation 1: TMS therapy is recommended as an acute treatment for symptomatic relief of depression in the indicated patient population. [Strength of the recommendation: A, consistent evidence from Level 1 studies] Recommendation 2: TMS therapy is recommended for use as a subsequent option in patients who previously benefited from an acute treatment course and are experiencing a recurrence of their illness (continuation or maintenance). [Strength of the recommendation: A, consistent evidence from Level 1 studies] Perera T, et al. The Clinical TMS Society Consensus Review and Treatment Recommendations for TMS Therapy for Major Depressive Disorder. Brain Stimul. 2016;9(3): Clinical Recommendations (cont d) Recommendation 3: TMS therapy can be administered with or without the concomitant administration of antidepressant or other psychotropic medications. [Strength of the recommendation: B, Extrapolation from Level 2 Studies] Recommendation 4: TMS therapy can be used as a continuation or maintenance treatment for patients who benefit from an acute course. [Strength of the recommendation: A, consistent evidence from Level 1 studies] Recommendation 5: TMS therapy can be reintroduced in patients who are relapsing into depression after initially responding to TMS treatment. [Strength of the recommendation: B, Extrapolation from Level 2 studies] Perera T, et al. The Clinical TMS Society Consensus Review and Treatment Recommendations for TMS Therapy for Major Depressive Disorder. Brain Stimul. 2016;9(3): CPT I Codes for Therapeutic TMS Should I start my own TMS practice? Code Description Therapeutic Repetitive Transcranial Magnetic stimulation (TMS) treatment; initial, including cortical mapping, motor threshold determination, delivery and management (Report only once per course of treatment) (Do not report in conjunction with 95928, 95929, 90868, 90869) Subsequent delivery and management, per session Subsequent motor threshold redetermination with delivery and management 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 Perera T, et al. The Clinical TMS Society Consensus Review and Treatment Recommendations for TMS Therapy for Major Depressive Disorder. Brain Stimul. 2016;9(3):