Repetitive Transcranial Magnetic Stimulation (rTMS)

Primer

Repetitive Transcranial Magnetic Stimulation (rTMS) is a form of brain stimulation that uses focused magnetic field pulses to induce electrical currents in neural tissue non-invasively, via an inductor coil positioned against the scalp.

Mechanism of Action

  • rTMs is thought to work by altering neurotransmitter transmission, neuronal electrophysiology, blood flow, brain activity in a frequency-dependent manner.[1]

Delivery Parameters

  • rTMS parameters include adjusting the stimulation intensity, frequency, pattern, and site
  • Conventional figure-8 or circular rTMS coils can target brain regions 1 to 4 cm deep to the scalp, while helmet-shaped “deep” rTMS coils can stimulate slightly deeper structures.
  • For determining coil placement, magnetic resonance imaging (MRI) guidance is the most precise method. But in clinical reality, scalp-based navigation is most common.
  • The stimulus intensity is based on individually determined resting motor threshold (RMT), which is the minimum intensity needed to elicit muscle twitches at relaxed upper or lower extremities, by visual inspection or electromyography (EMG) assessment
    • The most common intensity in all trials to date is between 110% to 120% RMT.[2]
      • Stimulation above these levels are outside conventional safety guidelines.
    • Newer theta-burst stimulation (TBS) protocols are more commonly delivered at lower intensities (e.g. - 70%-80% active motor threshold).[3]
      • TBS protocols require only 1 to 3 minutes of stimulation and may achieve comparable or stronger effects.
      • Intermittent TBS (iTBS) is considered excitatory and continuous TBS (cTBS) inhibitory.
  • Different stimulation frequency and patterns also exert different effects
    • Conventionally, high-frequency rTMS (5 to 20 Hz) is considered excitatory, while low-frequency stimulation (1 to 5 Hz) is inhibitory.
    • Conventional stimulation is delivered in 2 to 10-second trains at 10- to 60-second intervals, in 15 to 45-minute sessions.

rTMS Treatment Parameters

Milev, R. V. et al. (2016). Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 4. Neurostimulation treatments. The Canadian Journal of Psychiatry, 61(9), 561-575.
Intensity, frequency, and site • Stimulate at 110%-120% of resting motor threshold (70%-80% for theta-burst stimulation)
• Select stimulation frequency and site
Treatment course • Perform stimulation 5 times weekly (Level 1)
• Deliver initial course until symptom remission is achieved, up to 20 sessions (4 weeks) (Level 1)
• Extend course to 30 sessions (6 weeks) in responders who have not achieved symptom remission (Level 3)
Maintenance course • Use rTMS as needed to maintain response (Level 3)

Recommendation for rTMS Stimulation Protocols

Milev, R. V. et al. (2016). Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 4. Neurostimulation treatments. The Canadian Journal of Psychiatry, 61(9), 561-575.
First line • High-frequency rTMS to left DLPFC
• Low-frequency rTMS to right DLPFC
Second line • Bilateral rTMS to DLPFC (left high-frequency and right low-frequency) (Level 1)
• Low-frequency rTMS to right DLPFC (in non-responders to high-frequency left DLPFC-rTMS), OR high-frequency rTMS to left DLPFC (in non-responders to low-frequency right DLPFC-rTMS) (Level 1)

TBS protocols (Level 3):
• Intermittent TBS to left DLPFC
• Left intermittent and right continuous TBS to DLPFC
• Intermittent TBS to bilateral DMPFC
Third line • High-frequency rTMS to bilateral DMPFC (Level 3)
DLPFC = dorsolateral prefrontal cortex; DMPFC = dorsomedial prefrontal cortex; rTMS = repetitive transcranial magnetic stimulation; TBS = theta-burst stimulation.

Number of Treatments

  • Standard protocols deliver rTMS once daily, for 5 days of the week
  • 3-times-per-week rTMS has also been reported as similarly effective, but with slower improvement and a similar number of sessions required overall.
  • Studies have found peak effects at 26 to 28 sessions of rTMS.[4]
    • Thus, at least 20 sessions (i.e. - 4 weeks) should be attempted before declaring treatment failure, with extension to 25 to 30 sessions if improvements occur.

Effectiveness

  • Repeated rTMS sessions can exert therapeutic effects that last several months.
  • Most rTMS studies are on patients with some degree of treatment resistant depression (i.e. - failed at least 1 or 2 antidepressant trials)
    • One study showed that in moderately treatment-resistant depression, rTMS was more effective in reducing depressive symptoms than an antidepressant medication switch.[5]
  • rTMS is considered a first-line treatment for MDD for patients who have failed at least 1 antidepressant treatment
  • Unfortunately, without maintenance treatment, relapse is common following successful rTMS treatment.[6]
    • One study had a median relapse by 120 days (and relapse rates of 25%, 40%, 57%, and 77% at 2, 3, 4, and 6 months).[7]
    • There remains insufficient evidence to support any one schedule of rTMS maintenance sessions over another.
  • rTMS is remains less effective than electroconvulsive therapy (ECT), especially for patients with symptoms of psychosis.
    • Additionally, rTMS response rates are worse in patients who have also failed ECT.[8]

Contraindications

Absolute

  • The only contraindication to rTMS is if an individual has metallic hardware (e.g. - cochlear implants, brain stimulators or electrodes, aneurysm clips) anywhere in their head, except the mouth.

Relative

  • Cardiac pacemaker, implantable defibrillator, a history of epilepsy, or the presence of a brain lesion (vascular, traumatic, neoplastic, infectious, or metabolic).
  • A history of seizures or epilepsy are a relative contraindication to rTMS[9]
    • To date, less than 25 cases of rTMS-induced seizure have been reported worldwide (in terms of numbers, rTMS has a ∼0.01% to 0.1% incidence, versus 0.1% to 0.6% on antidepressant medications, and 0.07% to 0.09% incidence in the general population)
    • High-frequency rTMS is contraindicated in patients with a history of seizures, but low-frequency rTMS has been demonstrated to be safe in patients with epilepsy.

Adverse Events

  • The most common adverse effects for rTMS are scalp pain during stimulation (∼40%) and transient headache post-stimulation (∼30%). Both diminish over the course of treatment and usually respond to over-the-counter analgesia.[10]
  • rTMS does not appear to worsen cognition and also has little evidence of improving cognition.

Pearls

  • Most rTMS studies use rTMS as an add on treatment to individuals already on antidepressant medications.

Comparison with Other Brain Stimulation Therapies

Depression

Neurostimulation in the Treatment of Major Depressive Disorder

Milev, R. V. et al. (2016). Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 4. Neurostimulation treatments. The Canadian Journal of Psychiatry, 61(9), 561-575.
Neurostimulation Overall Recommendation Acute Efficacy Maintenance Efficacy Safety and Tolerability
rTMS • First line (for patients who have failed at least 1 antidepressant) Level 1 Level 3 Level 1
ECT • Second line
• First line in some acute clinical situations 		Level 1 Level 1 Level 1
tDCS • Third line Level 2 Level 3 Level 2
Vagal Nerve Stimulation (VNS) • Third line Level 3 Level 2 Level 2
DBS • Investigational Level 3 Level 3 Level 3
MST • Investigational Level 3 Not known Level 3

References

1) Noda, Y., Silverstein, W. K., Barr, M. S., Vila-Rodriguez, F., Downar, J., Rajji, T. K., ... & Blumberger, D. M. (2015). Neurobiological mechanisms of repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex in depression: a systematic review. Psychological medicine, 45(16), 3411.
2) Milev, R. V., Giacobbe, P., Kennedy, S. H., Blumberger, D. M., Daskalakis, Z. J., Downar, J., ... & CANMAT Depression Work Group. (2016). Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 4. Neurostimulation treatments. The Canadian Journal of Psychiatry, 61(9), 561-575.
3) Milev, R. V., Giacobbe, P., Kennedy, S. H., Blumberger, D. M., Daskalakis, Z. J., Downar, J., ... & CANMAT Depression Work Group. (2016). Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 4. Neurostimulation treatments. The Canadian Journal of Psychiatry, 61(9), 561-575.
4) Milev, R. V., Giacobbe, P., Kennedy, S. H., Blumberger, D. M., Daskalakis, Z. J., Downar, J., ... & CANMAT Depression Work Group. (2016). Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 4. Neurostimulation treatments. The Canadian Journal of Psychiatry, 61(9), 561-575.
5) Dalhuisen, I., van Oostrom, I., Spijker, J., Wijnen, B., van Exel, E., van Mierlo, H., ... & van Eijndhoven, P. (2024). rTMS as a next step in antidepressant nonresponders: a randomized comparison with current antidepressant treatment approaches. American Journal of Psychiatry, 181(9), 806-814.
6) Milev, R. V., Giacobbe, P., Kennedy, S. H., Blumberger, D. M., Daskalakis, Z. J., Downar, J., ... & CANMAT Depression Work Group. (2016). Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 4. Neurostimulation treatments. The Canadian Journal of Psychiatry, 61(9), 561-575.
7) Milev, R. V., Giacobbe, P., Kennedy, S. H., Blumberger, D. M., Daskalakis, Z. J., Downar, J., ... & CANMAT Depression Work Group. (2016). Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 4. Neurostimulation treatments. The Canadian Journal of Psychiatry, 61(9), 561-575.
8) Downar, J., Geraci, J., Salomons, T. V., Dunlop, K., Wheeler, S., McAndrews, M. P., ... & Giacobbe, P. (2014). Anhedonia and reward-circuit connectivity distinguish nonresponders from responders to dorsomedial prefrontal repetitive transcranial magnetic stimulation in major depression. Biological psychiatry, 76(3), 176-185.
9) Dobek, C. E., Blumberger, D. M., Downar, J., Daskalakis, Z. J., & Vila-Rodriguez, F. (2015). Risk of seizures in transcranial magnetic stimulation: a clinical review to inform consent process focused on bupropion. Neuropsychiatric Disease and Treatment, 11, 2975.
10) Milev, R. V., Giacobbe, P., Kennedy, S. H., Blumberger, D. M., Daskalakis, Z. J., Downar, J., ... & CANMAT Depression Work Group. (2016). Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 4. Neurostimulation treatments. The Canadian Journal of Psychiatry, 61(9), 561-575.