Personalizing TMS therapy for the individual patient

rTMS is a locally acting, non-drug therapy directed to a specific neuronal region of the cortex, the left dorsolateral prefrontal cortex (DLPFC). Research has shown that the DLPFC is strongly interconnected with other brain circuits involved with mood and closely involved with the limbic system of the brain. The initial direct effects of rTMS are to excite the underlying neuronal circuits but it is believed that modulating the excitability of the DLPFC can have wide-ranging effects on brain activity. (Bench et al 1992, Fox et al 2012, Drysdale et al 2017).

Repetitive TMS (rTMS) therapy offers an attractive alternative treatment profile for patients with major depressive disorder (MDD) who have not responded to medication or those who find the side-effects of medication intolerable.

rTMS treatment is generally well-tolerated with only minor side-effects following treatment (such as headache). rTMS has no known negative effects on cognition and there are normally no restrictions on driving a car to and from a treatment center, for example. After a treatment session, patients can return to their daily routine. No long-term side-effects from rTMS have been reported. Please see the complete list of possible risks and side effects either in the user manual or on Nexstim website nexstim.com/healthcare-professionals/depression-disorder/

rTMS has been shown to be effective in treating MDD in patients who have not benefitted from anti-depressant medication. A large number of both independently conducted as well as company-sponsored studies have evaluated the efficacy of rTMS in the treatment of MDD. These studies have been summarized in multiple meta-analyses that have consistently supported the antidepressant efficacy of rTMS.

Studies in depression commonly use the Montgomery-Asberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating Scale (HAMD) to measure outcomes.

In a well- conducted multisite study, the patient-reported remission rates were 26.5-28.7% and response rates were 41.5-56.4%. (Carpenter L. et al)

rTMS has been evaluated in a number of large multi-site, double-blinded sham-controlled trials. In these trials, patients have been received either daily rTMS to the left DLPFC or sham for between 3 and 6 weeks. A landmark trial was the NIMH (a US Government Agency)-funded study of 190 patients who had been diagnosed with MDD and a moderate level of resistance to medication. Using HAMD24 scoring, the trial showed that at week 6 active rTMS produced a clinically meaningful remission rate in depression that was approximately twofold higher than when the sham coil was used [George M. et. al 2010]

The first large trial of rTMS in Depression was a company-sponsored double-blind, multi-site study of 301 patients with MDD who had not benefited from prior treatment. The patients were randomized to receive either active or sham rTMS. Active rTMS was found to be significantly superior to sham rTMS on the MADRS at week 4 (with a post hoc correction for inequality in symptom severity between groups at baseline), as well as on the HAMD17 and HAMD24 scales at weeks 4 and 6. Response rates were significantly higher with active rTMS on all three scales at weeks 4 and 6. Remission rates were approximately two-fold higher with active rTMS at week 6 and significant on the MADRS and HAMD24 scales (but not the HAMD17 scale). There was a benefit shown for individuals who had previously failed just one depression medication regimen.[Reardon J. et al, 2007]

Nexstim nTMS technology uses advanced algorithms based on mathematically modelling to allow you to not only see where you are stimulating but also calculate the stimulation intensity received by your target, giving you confidence that you are treating the intended location with a personalized dose, every time.  The accuracy and precision that are based on this have been validated in neurosurgery (Takashashi et al.)  The exact same technology is used in depression therapy.

There are also initial, but promising results on the use of Nexstim nTMS technology in depression therapy. Clinical treatment outcomes of the 403 patients who have completed Nexstim navigated rTMS treatment with Nexstim NBT® system for major depressive disorder (MDD) were good: 49.6% were in remission at end of treatment and 76.2 % obtained a clinical response. (Read the report). While only a small sample, these outcomes are higher than what is usually reported for MDD patients treated with TMS: In a well- conducted multisite study, the patient-reported remission rates were 26.5-28.7% and response rates were 41.5-56.4%. (Carpenter L. et al)

The use of a navigated TMS enables reliable, knowledge-based identification of an individual patient’s DLPFC. Once the DLPFC is identified, the system can automatically identify the optimal target prior to any repeat session with a high degree of precision. Without neuronavigation, a rule-of-thumb, like the 5 cm rule needs to be employed. However, this results in identifying the DLPFC correctly in only approximately 30% of patients (Herwig et al, 2001). Although the motor cortex location corresponding to the thumb muscle twitch offers starting point for estimation, there is an additional error from locating the motor cortex manually.

Systems using the scalp 5 cm-rule ignore individual cortical anatomy, have an intrinsic error in locating the motor cortex for the starting point and offer no verification or documentation for intra-session or session-session targeting or dosing.

Targeting the DLPFC in depression is supported by more than 30 years of research. Lower metabolism and perfusion hemodynamics in the DLPFC, in patients vs. healthy controls, has been shown in hundreds of published research and clinical studies. See, e.g. Drevets et. al, Bench et al 1992.

Research has convincingly shown that the DLPFC is a valid target for intervention in mood-related disorders like MDD (Bench et al, 1992). The location of the DLPFC cannot be reliably determined in the individual patient by textbook-derived average distance from a scalp landmark or another functional target in the cortex. Given that stimulation might have undesirable effects off-target, it is important that the therapy provider is able to locate the DLPFC in the individual patient.

Having the individual patient’s own MRI head scan is the only way to reliably locate a central target to stimulate. Once an MRI is available, a navigated rTMS system can use the data to consistently target the same area of the patient’s brain with the same intensity for every treatment session.

Safety and efficacy has not been established for use of rTMS in pregnancy or nursing, precautions should be taken.

RTMS therapy is only indicated for use in adults. Safety and efficacy has not been established for concurrent use of medication in patients younger than 22, precautions should be taken.

Safety and efficacy have not been established for concurrent use of medication with rTMS, precautions should be taken. However, in routine clinical practice patients are often on medication.

rTMS devices are contraindicated for use in patients who have conductive, ferromagnetic or other magnetic-sensitive metals implanted in their head or within 30 cm of the treatment coil. Examples include cochlear implants, implanted electrodes/stimulators, aneurysm clips or coils, stents, bullet fragments or jewelry. rTMS devices are also contraindicated for use in patients who have active or inactive implants, including deep brain stimulators, cochlear implants, vagus nerve stimulators or implanted device leads. Contraindicated use could result in serious injury or death.

An rTMS system should not be used by operators who are pregnant, have any electrical implants, or metallic implants anywhere in the upper body.

The FDA guideline is that a candidate for rTMS therapy needs to have failed at least one antidepressant medication.

The total duration of the stimulation sequence in a treatment session is ~3-37.5 min depending on the decided treatment protocol. Nexstim NBS 6 with SmartFocus^® nTMS technology is FDA cleared and CE marked for 3 min theta burst 50 Hz and 19 – 37,5 min 10 Hz protocols

Some additional time (minutes) is also required to co-register the patient with their MRI dataset. Treatment is normally applied daily for 4-6 weeks. In order to benefit from navigated rTMS with accurate targeting and dose calculation and delivery, there is a one-time set-up procedure of around 20 min, prior to the actual rTMS therapy.