What’s new in transcranial magnetic stimulation Recent developments have enhanced the benefits of this treatment

Philip G. Janicak, MD herapeutic neuromodulation takes advantage of the brain’s elec- Adjunct Professor Department of and trochemical makeup. This allows for treatment devices that modu- Behavioral Sciences late neurocircuits relevant to behaviors disrupted in disorders such Northwestern University Feinberg School T as major depressive disorder (MDD) (eg, sleep quality, appetite, cognitive, of Medicine Chicago, Illinois and executive functions). The default mode network (comprised of struc- Member, Current Psychiatry Editorial Board tures such as the medial prefrontal cortex [MPFC], the posterior cingulate Disclosure cortex, the hippocampus, and their functional connectivity) serves as a Dr. Janicak is an unpaid consultant to Neuronetics, prime example of circuitry that can be targeted by this approach.1 Inc., and has a financial relationship with Otsuka Pharmaceuticals. For 80 years, electroconvulsive therapy (ECT) has been an important neuromodulation option for patients with more severe illness. Recently, additional neuromodulatory approaches have been FDA-cleared, includ- ing transcranial magnetic stimulation (TMS), vagus nerve stimulation (VNS), and deep brain stimulation (DBS). Another approach, transcra- nial direct current stimulation (tDCS), has been extensively studied for its potential clinical utility but is not FDA-cleared. The Table (page 12) pro- vides descriptions of these therapies. Since being cleared by the FDA in 2008, TMS has arguably made the greatest strides in providing an alternate neuromodulation treatment option for patients with MDD, with >1,000 centers nationally and 7 TMS devices FDA-cleared for treatment of depression. In this article, we review recent developments in TMS.

An evolving therapeutic option While primarily studied as a monotherapy for MDD, in clinical prac- tice TMS (Box, page 13) is typically used as an adjunct to medication and .2,3 In this context, it has demonstrated efficacy for

Current Psychiatry

BRIAN STAUFFER Vol. 18, No. 3 11 Table Therapeutic neuromodulation for psychiatric disorders Treatment Description Clinical application Deep brain stimulation Invasive “functional neurosurgical” Depression procedure that uses electrical current Dystoniaa to directly modulate specific areas of Obsessive-compulsive disordera the CNS What’s new Parkinson’s diseasea in TMS Magnetic seizure Intense, high-frequency magnetic Depression therapy pulses sufficient to induce a seizure Transcranial direct Sustained, low-intensity, constant Depressed mood current stimulation current flow usually passing from Anxiety anode to cathode electrodes placed Other symptoms (eg, attention/ on the scalp concentration problems) Transcranial magnetic Intense high- or low-frequency Depressiona stimulation magnetic pulses produce neuronal Migrainea excitation or inhibition Obsessive-compulsive disordera Clinical Point (DTMS) In clinical practice, Posttraumatic stress disorder TMS is typically Substance use disorders used as an adjunct Tinnitus to medication and Vagus nerve Intermittent mild electrical pulses Depressiona psychotherapy stimulation delivered to the left vagus nerve, Epilepsya whose afferent fibers affect structures such as the locus ceruleus and raphe nucleus aFDA-cleared indication DTMS: deep transcranial magnetic stimulation

more difficult-to-treat mood disorders with enhanced efficacy, shorter treatment ses- an excellent safety and tolerability profile sions, and/or improved tolerability. For whether used with or without medication.4-6 example, lower frequency right DLPFC To further improve the efficiency and stimulations (eg, 1 Hz) can decrease the efficacy of TMS while maintaining its safety risk of seizures and improve overall tol- and tolerability, researchers and clinicians erability. While this has not been studied have been exploring a few initiatives. as extensively as higher frequency left DLPFC stimulations (eg, 5 to 20 Hz), exist- ing evidence supports similar efficacy Altered treatment parameters between these 2 approaches.7 One initiative is assessing the feasibility of altering various treatment parameters, Theta burst stimulation. Some TMS devices such as the total number of treatment ses- can be adapted to deliver theta burst stimu- sions (30 to 60 sessions); the frequency lation (TBS). This produces trains of triple, of sessions (eg, more than once daily); 50 Hz, pulsed bursts (usually with 200 ms Discuss this article at the total number of magnetic pulses per inter-burst intervals occurring at a rate of www.facebook.com/ session (eg, >3,000); the stimulation coil 5 Hz; at 80% MT) to model naturally occur- MDedgePsychiatry localization (eg, left vs right dorsal lateral ring theta rhythms. These bursts can be prefrontal cortex [DLPFC]; MPFC; and administered in stimulation protocols using various methods to determine optimal intermittent TBS (iTBS) (eg, 10 bursts of coil placement (eg, EEG F3 coordinate or triplets over 2 seconds every 10 seconds; 30 MRI-guided neuro-navigational methods). pulses per burst; for approximately 3 min- Current Psychiatry 12 March 2019 Such refinements offer the potential for utes; totaling 600 pulses) or continuous TBS (cTBS) bursts given in an uninterrupted Box train (eg, 40 seconds, 600 pulses). Evidence Key points: Transcranial indicates these protocols facilitate long-term magnetic stimulation potentiation (ie, iTBS) and long-term depres- MDedge.com/psychiatry sion (ie, cTBS), which in turn can modulate • Transcranial magnetic stimulation (TMS) utilizes intense, localized magnetic fields to synaptic plasticity. alter activity in neural circuits implicated in While some clinicians are using TBS the pathophysiology of depression off-label, a recent non-inferiority trial • Randomized, sham-controlled acute trials (N = 395) reported similar efficacy and have demonstrated the efficacy of TMS for treatment-resistant depression safety comparing standard 10 Hz TMS to • Clinical availability of TMS has grown an iTBS protocol at 120% of resting motor steadily over the past 10 years as >1,000 threshold (both over the left DLPFC).8 This centers have been opened and additional has led to FDA clearance of the TMS device devices have been FDA-cleared adapted to provide iTBS in this trial.8 • TMS has the potential to avoid safety From a more practical perspective, TBS and tolerability concerns associated with antidepressant pharmacotherapy (eg, has the potential to reduce the number of weight gain, sexual dysfunction) and pulses (eg, 600 vs 3,000) and the total num- electroconvulsive therapy (eg, cognitive Clinical Point deficits) ber of sessions required, as well as the dura- Newer coil designs tion of treatment sessions (eg, 37.5 minutes • Greater sophistication in the choice of stimulation parameters, as well as other allow for shortening to <5 minutes). This can accelerate the ongoing efforts to optimize the benefits of time to response and decrease patient and TMS, are yielding better clinical outcomes the total session staff commitment, with resulting cost sav- duration by ings.9 Despite this recent progress, ongoing approximately 50% research still needs to clarify issues such as the risk/benefit profile, particularly in Increasing durability of effect younger and older populations, as well as Because high relapse and recurrence rates assessment of duration of initial benefit and compromise the initial benefit of any anti- appropriate maintenance strategies. depressant therapy, appropriate mainte- nance strategies are essential. Several studies have evaluated strategies to maintain the New devices acute benefit of TMS for treatment-resistant Another initiative is the development of depression. alternative TMS equipment. For example, One was a 6-month, open-label TMS newer coil designs with enhanced cooling durability of effect trial for acute responders ability allow for a substantial decrease in (n = 99) in the pivotal registration study.5 the required inter-train interval duration During this study, all participants were between stimulation trains, thus shortening given antidepressant medication mono- the total session duration by approximately therapy. In addition, with early indication 50% (eg, from 37.5 to 19 minutes). The use of relapse, patients received a reintroduc- of different coil arrays (eg, the H-coil capa- tion of TMS sessions (32/99 patients; mean ble of deeper vs surface stimulation) may number of sessions = 14.3). With this pro- allow for more direct stimulation of relevant tocol, approximately 84% re-achieved their neurocircuitry (eg, cingulate cortex), possi- response status. The overall relapse rate was bly improving efficacy and shortening time approximately 13%.5 to onset of benefit. However, in head-to- In a 1-year naturalistic study, 63% head comparisons with single-coil devices, of patients (75/120) who met response or enhanced efficacy for depression has not remission criteria after an acute course of TMS been clearly demonstrated. One caveat is that still met response criteria after 12 months. the increase in depth of magnetic field pen- These patients received clinician-determined etration results in a loss of focality, resulting maintenance treatment that included reintro- in the stimulation of larger brain areas. This duction of TMS when indicated.3 might increase the risk of adverse effects In a prospective, 12-month, multisite, Current Psychiatry such as seizures. randomized pilot study, 67 patients with Vol. 18, No. 3 13 treatment-resistant MDD underwent an • have depressive episodes of longer antidepressant medication washout and duration (eg, >3 years) then received 30 sessions of TMS mono- • have a high risk of suicide therapy.10 Those who met criteria for • have psychotic or catatonic features improvement (n = 49) were then random- associated with their depression ized to once-monthly TMS or observation • have difficulty maintaining their phys- only. All patients remained medication-free ical well-being What’s new but could receive TMS re-introduction if • have bipolar depression. in TMS they deteriorated. At the end of the study, Although existing evidence supports a pos- both groups demonstrated comparable out- sible benefit with TMS for bipolar depres- comes, with a trend to a longer time before sion (used in combination with a mood relapse among participants who received stabilizer), the lack of a definitive trial once-monthly TMS. Although these results (precluding FDA clearance for this indica- are preliminary, they suggest that some tion) and the lack of insurance coverage patients could be treated both acutely and both limit the routine use of TMS for this then maintained with TMS alone. indication.15 Clinical Point Re-introducing TMS in patients who One potential advantage of TMS over 13 TMS may achieve show early signs of relapse after having an ECT is a lower cost. Transcranial magnetic initial response achieves rates of sustained stimulation also may make it possible to similar efficacy as improvement that compare favorably with achieve similar efficacy as ECT with fewer ECT with fewer those of other strategies used to manage cognitive adverse effects when used in com- cognitive adverse patients with treatment-resistant depression. bination with ECT to reduce the number of effects acute ECT treatments required or as part of a maintenance strategy after a patient expe- TMS vs ECT riences an acute response to ECT.13 The question often arises as to whether TMS is a viable alternate treatment to ECT. I Magnetic seizure therapy (MST) vs ECT. believe the answer is unequivocally yes and An experimental treatment, MST uses a no. By this, I mean some patients who in TMS device capable of producing more the past only had ECT as their next option intense magnetic fields sufficient to induce when medications and psychotherapy were a seizure.16 The advantage of MST over insufficient may now consider TMS. In sup- ECT-induced seizures is better control of port, there is evidence of comparable effi- intra-cerebral current path and density, thus cacy between TMS and ECT in a subgroup avoiding deeper cortical areas associated of patients who were considered clinically with memory (eg, hippocampus) and mini- appropriate for ECT.11-13 mizing cognitive adverse effects. As with How to best identify this group remains ECT, however, anesthesia and muscle relax- unclear, but investigators are exploring ation are required. Presently, MST remains predictive biomarkers. For example, a large investigational. study (N = 1,188), with functional mag- netic resonance imaging (fMRI) reported that depressed patients could be divided Other potential indications into 4 neurophysiological “biotypes” In addition to MDD, TMS is also being based on different patterns of aberrant studied as a potential treatment for other connectivity in limbic and fronto-striatal neuropsychiatric disorders. networks.14 The authors further noted that such distinctions were helpful in predict- Obsessive-compulsive disorder (OCD). A ing response in a subgroup of patients recent double-blind study that evaluated (n = 154) who received TMS. a deep TMS (DTMS) device reported a sig- For now, experience indicates certain nificantly better outcome based on the Yale- clinical factors may provide some guidance. Brown Obsessive-Compulsive Scale score Patients are usually better served by ECT with active high-frequency (20 Hz) DTMS Current Psychiatry 14 March 2019 if they: (n = 18) vs a sham control (n = 15).17 The initial benefit persisted up to 1 month after the end of treatment. The authors specu- Related Resources lated that this benefit may be due to direct • Ziemann U. Thirty years of transcranial magnetic stimulation: where do we stand? Exp Brain Res. 2017;235(4):973-984. modulation of the anterior cingulate cortex. MDedge.com/psychiatry • Janicak PG, Sackett V, Kudrna K, et al. Transcranial magnetic These results led to the first FDA clearance stimulation for the treatment of major depression: an update of a deep TMS device for treating OCD. on recent advances. Current Psychiatry. 2016:15(6):49-56.

Cognition. Because TMS does not require a seizure to produce its antidepressant effect and does not require anesthesia, the risk of neurocognitive disruption is low. In fact, depression, other psychiatric indications evidence suggests TMS may have beneficial with promising data include schizophre- cognitive effects.18 nia (eg, refractory auditory hallucina- In an effort to take advantage of this tions, negative symptoms), posttraumatic benefit, researchers have explored provid- stress disorder, and various addictive disor- ing psychoeducation and psychotherapy ders.21 Because results have been mixed for sessions (eg, behavioral activation) during most of these disorders, definitive trials are Clinical Point 19,20 TMS treatments (“online”). The rationale needed to clearly characterize the potential TMS is being studied is that neurocircuitry subserving various role of TMS. cognitive functions may be in a heightened as a potential state of receptivity during a TMS treatment, treatment for which would allow patients to assimilate An ongoing evolution bipolar depression, and better utilize the therapeutic informa- Neuromodulation is undergoing a renais- schizophrenia, tion provided.19,20 sance spurred on by the need for more PTSD, and addictive Researchers are also looking at the use effective treatments to manage some of our of TMS to treat patients with mild cogni- most challenging illnesses. Transcranial disorders tive impairment or early dementia. These magnetic stimulation and other forms of patients often experience comorbid depres- therapeutic neuromodulation are welcome sion, and TMS could potentially improve additions for managing treatment-resistant memory via both its pro-cognitive and anti- depression, OCD, and possibly other dis- depressant effects.1 The lack of effective treat- orders. But perhaps their greatest value is ments for dementia supports pursuing TMS as a bellwether for what’s to come. In addi- as a therapeutic option for these patients. tion to the ongoing refinements to existing neuromodulation­ devices, newer modula- Other neuropsychiatric disorders. In addi- tion approaches (eg, temporal interference tion to early-onset cognitive problems, stimulation) and the search for reliable other neurologic indications with promis- biomarkers may dramatically expand and ing data for TMS include chronic pain syn- enhance our clinical options.14,22 dromes, Parkinson’s disease, tinnitus, and References migraine headaches (a hand-held FDA- 1. Koch G, Bonnì S, Pellicciari MC, et al. Transcranial magnetic cleared device is now available for treating stimulation of the precuneus enhances memory and neural activity in prodromal Alzheimer’s disease. Neuroimage. migraines). In addition to OCD and bipolar 2018;169: 302-310. continued

Bottom Line Transcranial magnetic stimulation (TMS) continues to evolve as a nonpharmacologic treatment for mood disorders, obsessive-compulsive disorder, and potentially for other indications. Recent developments, including altered treatment parameters, new devices, and strategies for increasing the durability of antidepressant effects, Current Psychiatry have enhanced the benefits of TMS. Vol. 18, No. 3 15 2. O’Reardon JP, Solvason B, Janicak PG, et al. Efficacy and Prop Neuropsychopharmacol Biol Psychiatry. 2014;51: safety of repetitive transcranial magnetic stimulation 181-189. (rTMS) in the acute treatment of major depression: results 12. Janicak PG, Dowd SM, Martis B, et al. Repetitive transcranial of a multicenter randomized controlled trial. Biol Psychiatry. magnetic stimulation versus electroconvulsive therapy for 2007;62(11):1208-1216. major depressive: preliminary results of a randomized trial. 3. Dunner DL, Aaronson ST, Sackheim HA, et al. A multisite, Biol Psychiatry. 2002;51(8):659-667. observational study of transcranial magnetic stimulation for 13. Lanocha K, Janicak PG. TMS for depression: relationship to patients with pharmacoresistant major depressive disorder: ECT and other therapeutic neuromodulation approaches. durability of benefit over a one-year follow-up period. J Clin In: Bermudes RA, Lanocha KI, Janicak PG (eds). Transcranial Psychiatry. 2014;75(12):1394-1401. magnetic stimulation: clinical applications for psychiatric 4. Janicak PG, O’Reardon JP, Sampson SM, et al. Transcranial practice. Washington, DC: American Psychiatric Association What’s new magnetic stimulation in the treatment of major depressive Publishing; 2018. disorder: a comprehensive summary of safety experience 14. Drysdale AT, Grosenick L, Downar J, et al. Resting-state in TMS from acute exposure, extended exposure, and during connectivity biomarkers define neurophysiological reintroduction treatment. J Clin Psychiatry. 2008;69: subtypes of depression. Nat Med. 2017;23(1):28-38. 222-232. 15. Aaronson ST, Croarkin PE. Transcranial magnetic 5. Janicak PG, Nahas Z, Lisanby SH, et al. Durability of clinical stimulation for the treatment of other mood disorders. In: benefit with transcranial magnetic stimulation (TMS) in Bermudes R, Lanocha K, Janicak PG (eds). Transcranial the treatment of pharmacoresistant major depression: magnetic stimulation: clinical applications for psychiatric assessment of relapse during a 6-month, multisite, open- practice. Washington, DC: American Psychiatric Association label study. Brain Stimul. 2010;3(4):187-199. Publishing; 2018. 6. Janicak PG. Risk management issues in transcranial 16. Cretaz E, Brunoni AR, Lafer B. Magnetic seizure magnetic stimulation for treatment of major depression. therapy for unipolar and bipolar depression: a In: Bermudes R, Lanocha K, Janicak PG (eds). Transcranial systematic review. Neural Plast. 2015;2015:521398. doi: magnetic stimulation: clinical applications for psychiatric 10.1155/2015/521398. Clinical Point practice. Washington, DC: American Psychiatric Association 17. Carmi L, Alyagon U, Barnea-Ygael N, et al. Clinical and Publishing; 2018. electrophysiological outcomes of deep TMS over the medial Newer modulation 7. Chen J, Zhou C, Wu B, et al. Left versus right repetitive prefrontal and anterior cingulate cortices in OCD patients. transcranial magnetic stimulation in treating major Brain Stimul. 2018;11(1):158-165. approaches and the depression: a meta-analysis of randomised controlled trials. 18. Martis B, Alam D, Dowd SM, et al. Neurocognitive effects of Psychiatry Res. 2013;210(3):1260-1264. repetitive transcranial magnetic stimulation in severe major search for reliable 8. Blumberger DM, Vila-Rodriguez F, Thorpe KE, et al. depression. Clin Neurophysiol. 2003;114:1125-1132. Effectiveness of theta burst versus high-frequency 19. Donse L, Padberg F, Sack AT, et al. Simultaneous rTMS biomarkers may repetitive transcranial magnetic stimulation in patients with and psychotherapy in major depressive disorder: Clinical depression (THREE-D): a randomised non-inferiority trial. outcomes and predictors from a large naturalistic study. expand our clinical Lancet. 2018;391(10131):1683-1692. Brain Stimul. 2018;11(2):337-345. 9. Chung SW, Hoy KE, Fitzgerald PB. Theta-burst stimulation: 20. Russo GB, Tirrell E, Busch A, et al. Behavioral activation options a new form of TMS treatment for depression? Depress therapy during transcranial magnetic stimulation for major Anxiety. 2015;32(3):182-192 depressive disorder. J Affect Disord. 2018;236:101-104. 10. Philip NS, Dunner DL, Dowd SM, et al. Can medication 21. Pannu J, DE Souza DD, Samara Z, et al. Transcranial free, treatment-resistant, depressed patients who initially magnetic stimulation for disorders other than depression. respond to TMS be maintained off medications? 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