The consequences of the new European reclassification of non-invasive brain stimulation devices and the medical device regulations pose an existential threat to research and treatment: An invited opinion paper.

A significant amount of European basic and clinical neuroscience research includes the use of transcranial magnetic stimulation (TMS) and low intensity transcranial electrical stimulation (tES), mainly transcranial direct current stimulation (tDCS). Two recent changes in the EU regulations, the introduction of the Medical Device Regulation (MDR) (2017/745) and the Annex XVI have caused significant problems and confusions in the brain stimulation field. The negative consequences of the MDR for non-invasive brain stimulation (NIBS) have been largely overlooked and until today, have not been consequently addressed by National Competent Authorities, local ethical committees, politicians and by the scientific communities. In addition, a rushed bureaucratic decision led to seemingly wrong classification of NIBS products without an intended medical purpose into the same risk group III as invasive stimulators. Overregulation is detrimental for any research and for future developments, therefore researchers, clinicians, industry, patient representatives and an ethicist were invited to contribute to this document with the aim of starting a constructive dialogue and enacting positive changes in the regulatory environment.

The effect of pulse shape in theta-burst stimulation: Monophasic vs biphasic TMS.

BACKGROUND: Intermittent theta-burst stimulation (i) (TBS) is a transcranial magnetic stimulation (TMS) plasticity protocol. Conventionally, TBS is applied using biphasic pulses due to hardware limitations. However, monophasic pulses are hypothesised to recruit cortical neurons more selectively than biphasic pulses, predicting stronger plasticity effects. Monophasic and biphasic TBS can be generated using a custom-made pulse-width modulation-based TMS device (pTMS). OBJECTIVE: Using pTMS, we tested the hypothesis that monophasic iTBS would induce a stronger plasticity effect than biphasic, measured as induced increases in motor corticospinal excitability. METHODS: In a repeated-measures design, thirty healthy volunteers participated in three separate sessions, where monophasic and biphasic iTBS was applied to the primary motor cortex (M1 condition) or the vertex (control condition). Plasticity was quantified as increases in motor corticospinal excitability after versus before iTBS, by comparing peak-to-peak amplitudes of motor evoked potentials (MEP) measured at baseline and over 60 min after iTBS. RESULTS: Both monophasic and biphasic M1 iTBS led to significant increases in MEP amplitude. As predicted, linear mixed effects (LME) models showed that the iTBS condition had a significant effect on the MEP amplitude (χ2 (1) = 27.615, p < 0.001) with monophasic iTBS leading to significantly stronger plasticity than biphasic iTBS (t (693) = 2.311, p = 0.021). Control vertex iTBS had no effect. CONCLUSIONS: In this study, monophasic iTBS induced a stronger motor corticospinal excitability increase than biphasic within participants. This greater physiological effect suggests that monophasic iTBS may also have potential for greater functional impact, of interest for future fundamental and clinical applications of TBS.

xTMS: A Pulse Generator for Exploring Transcranial Magnetic Stimulation Therapies.

A cascaded H-bridge based pulse generator for transcranial magnetic stimulation is introduced. The system demonstrates complete flexibility for producing different shape, duration, direction, and rate of repetition of stimulus pulses within its electrical limits, and can emulate all commercial and research systems available to-date in this application space. An offline model predictive control algorithm, used to generate pulses and sequences, shows superior performance compared to conventional carrier-based pulse width modulation. A fully functioning laboratory prototype delivers up to 1.5 kV, 6 kA pulses, and is ready to be used as a research tool for the exploration of transcranial magnetic stimulation therapies by leveraging the many degrees-of-freedom offered by the design.

Relative Comparison of Non-Invasive Brain Stimulation Methods for Modulating Deep Brain Targets.

This study models and investigates whether temporally interfering electric fields (TI EFs) could function as an effective non-invasive brain stimulation (NIBS) method for deep brain structure targeting in humans, relevant for psychiatric applications. Here, electric fields off- and on-target are modelled and compared with other common NIBS modalities (tACS, TMS). Additionally, local effects of the field strength are modelled on single-compartment neuronal models. While TI EFs are able to effectively reach deep brain targets, the ratio of off- to on-target stimulation remains high and comparable to other NIBS and may result in off-target neural blocks. Clinical Relevance- This study builds on earlier work and demonstrates some of the challenges -such as off-target conduction blocks- of applying TI EFs for targeting deep brain structures important in understanding the potential of treating neuropsychiatric conditions in the future.

Comparison between the modelled response of primary motor cortex neurons to pulse-width modulated and conventional TMS stimuli.

In this study, the neural response to pulse-width modulated (PWM) transcranial magnetic stimulation (TMS) is estimated using a computational neural model which simulates the response of cortical neurons to TMS. The recently introduced programmable TMS uses PWM to approximate conventional resonance-based TMS pulses by fast switching between voltage levels. The effect of such stimulation on the six cortical layers is modelled by estimating the activation threshold of the neurons. Modelling results are compared between the novel device and that of conventional TMS stimuli generated by Magstim stimulators. The neural responses to the PWM pulses and the conventional stimuli show a high correlation, which validates the use of pulse-width modulated pulses in TMS.Clinical Relevance- This computational modelling study demonstrates an equivalent effect of PWM and conventional TMS pulses on the nervous system which paves the way to more flexibility in exploring and choosing stimulation parameters for TMS treatment.

Design Analysis and Circuit Topology Optimization for Programmable Magnetic Neurostimulator.

Transcranial magnetic stimulation (TMS) is a form of non-invasive brain stimulation commonly used to modulate neural activity. Despite three decades of examination, the generation of flexible magnetic pulses is still a challenging technical question. It has been revealed that the characteristics of pulses influence the bio-physiology of neuromodulation. In this study, a second-generation programmable TMS (xTMS) equipment with advanced stimulus shaping is introduced that uses cascaded H-bridge inverters and a phase-shifted pulse-width modulation (PWM). A low-pass RC filter model is used to estimate stimulated neural behavior, which helps to design the magnetic pulse generator, according to neural dynamics. The proposed device can generate highly adjustable magnetic pulses, in terms of waveform, polarity and pattern. We present experimental measurements of different stimuli waveforms, such as monophasic, biphasic and polyphasic shapes with peak coil current and the delivered energy of up to 6 kA and 250 J, respectively. The modular and scalable design idea presented here is a potential solution for generating arbitrary and highly customizable magnetic pulses and transferring repetitive paradigms.

Programmable Transcranial Magnetic Stimulation: A Modulation Approach for the Generation of Controllable Magnetic Stimuli.

OBJECTIVE: A transcranial magnetic stimulation system with programmable stimulus pulses and patterns is presented. The stimulus pulses of the implemented system expand beyond conventional damped cosine or near-rectangular pulses and approach an arbitrary waveform. METHODS: The desired stimulus waveform shape is defined as a reference signal. This signal controls the semiconductor switches of an H-bridge inverter to generate a high-power imitation of the reference. The design uses a new paradigm for TMS, applying pulse-width modulation with a non-resonant, high-frequency switching architecture to synthesize waveforms that leverages the low-pass filtering properties of neuronal cells. The modulation technique enables control of the waveform, frequency, pattern, and intensity of the stimulus. RESULTS: A system prototype was developed to demonstrate the technique. The experimental measurements demonstrate that the system is capable of generating stimuli up to 4 kHz with peak voltage and current values of ±1000 V and ±3600 A, respectively. The maximum transferred energy measured in the experimental validation was 100.4 Joules. To characterize repetitive TMS modalities, the efficiency of generating consecutive pulse triplets and quadruplets with interstimulus intervals of 1 ms was tested and verified. CONCLUSION: The implemented TMS device can generate consecutive rectangular pulses with a predetermined time interval, widths and polarities, enables the synthesis of a wide range of magnetic stimuli. SIGNIFICANCE: New waveforms promise functional advantages over the waveforms generated by current-generation TMS systems for clinical neuroscience research.

Temporally Interfering TMS: Focal and Dynamic Stimulation Location.

In this study, we present a temporal interference (TI) concept to achieve focal and steerable stimulation in the targeted brain area through transcranial magnetic stimulation (TMS). This method works by inducing two high-frequency electric fields with a slight frequency difference via two independent coils. The intrinsic nonlinear nature of the nerve membrane, which acts as a low-pass filter, does not allow the nerve to engage at high frequencies. Instead, neurons at the intersection of two electric fields can follow the frequency difference of the two fields. For 3D MRI-derived head models, the finite element method is used to compute the electric field induced by the time-varying magnetic field along with the electric field penetration depth and the activated volume for the specific coil parameters. A deeper stimulation with an acceptable spatial spread can be obtained by controlling the intersection of the fields by finding the optimal position and orientation of the two coils. Moreover, by changing the voltage ratio of the coils, and not their mechanical orientation, the intended area can be dynamically driven. The computational results show that the TI technique is an efficient approach to resolve the electric field depth-focality trade-off, which can be a reasonable alternative to complex coil designs. The system proposed in this paper shows a great promise for a more dynamic and focused magnetic stimulation.

Physiological Artifacts and the Implications for Brain-Machine-Interface Design.

The accurate measurement of brain activity by Brain-Machine-Interfaces (BMI) and closed-loop Deep Brain Stimulators (DBS) is one of the most important steps in communicating between the brain and subsequent processing blocks. In conventional chest-mounted systems, frequently used in DBS, a significant amount of artifact can be induced in the sensing interface, often as a common-mode signal applied between the case and the sensing electrodes. Attenuating this common-mode signal can be a serious challenge in these systems due to finite common-mode-rejection-ratio (CMRR) capability in the interface. Emerging BMI and DBS devices are being developed which can mount on the skull. Mounting the system on the cranial region can potentially suppress these induced physiological signals by limiting the artifact amplitude. In this study, we model the effect of artifacts by focusing on cardiac activity, using a current- source dipole model in a torso-shaped volume conductor. Performing finite element simulation with the different DBS architectures, we estimate the ECG common mode artifacts for several device architectures. Using this model helps define the overall requirements for the total system CMRR to maintain resolution of brain activity. The results of the simulations estimate that the cardiac artifacts for skull-mounted systems will have a significantly lower effect than non-cranial systems that include the pectoral region. It is expected that with a pectoral mounted device, a minimum of 60-80 dB CMRR is required to suppress the ECG artifact, depending on device placement relative to the cardiac dipole, while in cranially mounted devices, a 0 dB CMRR is sufficient, in the worst-case scenario. In addition, the model suggests existing commercial devices could optimize performance with a right-hand side placement. The methods used for estimating cardiac artifacts can be extended to other sources such as motion/muscle sources. The susceptibility of the device to artifacts has significant implications for the practical translation of closed-loop DBS and BMI, including the choice of biomarkers, the system design requirements, and the surgical placement of the device relative to artifact sources.