Electric and Magnetic Field Characteristics of the Re5 Brain Stimulation System

Dear Editor,

Several animal studies have shown that low-intensity (milli-Tesla scale) repetitive (0.1-3 kHz pulse center frequency) transcranial magnetic stimulation of the brain (low-intensity rTMS) can exert significant neurobiological effects, including modulation of neuronal excitability [1], fostering neuroplasticity [2], neuronal survival [3], and axonal growth [4]. In the most important human clinical research, low intensity rTMS – sometimes referred to as transcranial Pulsating ElectroMagnetic Field (t-PEMF) – has demonstrated promising therapeutic potential across several conditions, such as severe neurological and psychiatric disorders such as Parkinson’s disease [5] and, most notably, major depressive disorder (MDD) [6],[7],[8]. The treatment potential of low-intensity rTMS in MDD is particularly compelling given the need for novel, accessible, and reconfigurable treatment options. This technology is portable, easy to administer, and associated with minimal side effects.

A quantitative framework for interpreting low-intensity rTMS exposure levels in the brain – with respect to the resulting electric and magnetic field distributions in patients – is currently lacking. To address this gap, the present letter investigates cortical fields generated by the Re5-NTS (Neuro Treatment System, Denmark) shown in Fig. 1a,b,c. This system, to the best of our knowledge, is currently the most widely used low-intensity rTMS device for MDD in research and clinical practice [6],[7],[8]. Re5-NTS delivers ~4.5 ms long biphasic sub-threshold magnetic pulses at 50 Hz from seven scalp-mounted coils positioned over temporal, parietal and occipital regions, resulting in diffuse, multifocal stimulation [6].

Fig. 1.

a) Positioning of the Re5-NTS array system with seven coils – sagittal view. b) Battery-powered, activated by pre-programmed ID card access stimulator (pulse generator) and its physical dimensions. c) View of the complete Re5-NTS system. d,e) Volumetric plots - cross-section views – of the magnetic and electric field magnitudes in the head for subject #1; maximum field values just outside white matter surface are reported in the same figure. The Re5-NTS system is operating at standard conditions. f) Surface plot of the electric field magnitude just outside white matter surface for subject #1. The field is normalized by its maximum value reported in the same figure. The Re5-NTS system is operating at standard conditions; coil current directions are shown in the figure. g) Mean E-field magnitude just outside the white matter interface, projected onto the white matter surface and averaged across all vertices within each brain lobe (Section S5, Supplement), then averaged across all 16 participants. h) Mean B-field magnitude on the white matter interface (the B-field is continuous across the interface) averaged across all vertices within each brain lobe, then averaged across all 16 participants Section S5, Supplement). i) Ratio of vector norm ‖B‖ (mT) to vector norm ‖E‖ (V/m) within each brain lobe from Fig. 1g,h, then averaged across all 16 participants. j) Typical electric, magnetic fields, and magnetic to electric field ratios in the cortex generated by t-PEMF Re5-NTS (present study), a comparable low intensity rTMS device used in [4], standard suprathreshold rTMS applied to subject #1 given a comparable CB-60 coil setup described in Section S6, Supplement, and typical tES setups [12],[13].

The device can be self-administered and is approved for the treatment of MDD in adults under the EU Medical Device Regulation (EU MDR 2017/745). It has been incorporated into treatment protocols at several public and private psychiatric hospitals in Denmark, where the most common practice includes 56 daily 30-minute sessions, with optional adjustments based on clinical judgment. Several studies have shown clinically significant response and remission rates, strong patient compliance, and favorable safety profiles. These include a randomized, sham-controlled trial [6] and cohort studies [7],[8] for treatment-resistant depression.

An authentic seven-coil array was modeled that is comprised of two pairs of serially connected coils above the temporal lobes, one pair of serially connected coil above the parietal lobe, and one coil above the occipital lobe. (The wiring diagram is shown in Fig. S1, Supplement). The coil assembly has total R_DC = 72.5Ω and L = 110 mH. The measured (Fig. S2, Supplement) $\frac{dI}{dt}=\text{937A}/\text{s}$ and I_peak = 0.53A.

The array tightly attached to the scalp was used to simulate the electric field E and magnetic flux density B just outside the white-matter interface or just inside gray matter interface of structural MRIs for sixteen participants with MDD (aged 55–80 years; seven women) from a recent study [9], using a boundary-element method accelerated by the fast multipole method [10]. SimNIBS headreco segmentation was used. Fig. 1d,e shows typical volumetric electric and magnetic field, $\Vert \mathit{E}\Vert$ and $\Vert \mathit{B}\Vert$, distribution in the head while Fig. 1f is the typical surface $\Vert \mathit{E}\Vert$ just outside the white matter interface.

For all sixteen subjects, the average $\Vert \mathit{E}\Vert$ and $\Vert \mathit{B}\Vert$ were computed for each of 74×2 regions of the Destrieux parcellation map [11]. Next, averaging for major brain lobes of all subjects has been made which is reported in Fig.1g,h,i. Finally, Fig. 1j summarizes the Re5-NTS field data of the present study (first row), relevant experimental study [4] (second row), conventional rTMS data for subject #1 given a comparable CB-60 coil setup described in Section S6, Supplement (third row), and typical tES field intensities [12],[13] (last row). The average electric field over the entire cortex is 0.01 V/m (Fig. 1g); the average magnetic field over the entire cortex is 0.3 mT (Fig. 1h). Further, more detailed comparison with the conventional rTMS setups is given in Section S6, Supplement.

Our results show that: (i) Re5-NTS system generates cortical electric fields which are at least 500 times lower than the suprathreshold rTMS and at the lower end of the conventional tES; (ii) generates magnetic fields which are ~30 times lower than the conventional rTMS (cf. also Section S6, Supplement) and; (iii) generates unusually high magnetic-to-electric field ratios, which is explained by a different coil design (Sections S1, S6, S7, Supplement).

Despite these low field values, some clinical effects of the Re5-NTS are evident [6],[7],[8]. We note that a similar device [4] used in a 14-day rodent study and listed in the fourth row of Fig. 1j produced the magnetic field of roughly the same magnitude and an even lower electric field. It has been shown in [4] that the corresponding pulsating magnetic (not electric!) field can promote neural circuit repair by inducing axon outgrowth and synaptogenesis [4]. We therefore hypothesize that a similar effect may be induced by the Re5-NTS system operating daily for approximately two months. Given this, additional increase in the magnetic field strength may be desirable. Further, more detailed discussion of possibly physical mechanisms of action is given in Sections S8, S9, and S10 of the Supplement.

In conclusion, we also note that the Re5-NTS system, which consists of seven coils driven in phase, effectively forms a single stimulation channel. Given its low power, the corresponding multichannel architecture becomes feasible, potentially enabling spatially distributed and dynamically steerable stimulation and whole-head scanning.