The disclosure relates to a system for stimulation of biological tissue and to a computer program product.
Non-invasive brain stimulation (NIBS) devices are valuable tools that can potentially be used to modulate neural activity and investigate the causal role that different brain regions and oscillations play in behavior, or to treat various psychiatric disorders. The two most widely-applied NIBS techniques are transcranial magnetic stimulation (TMS) and transcranial electric stimulation (TES). In TMS, an electromagnetic coil is placed on the scalp and e.g. driven with high-current pulses. The pulses induce a strong time-varying magnetic field in the vicinity of the coil which in turn induces an electric field in the brain regions under the coil. Furthermore, the article by M. Zaeimbashi et al., “Magnetic Temporal Interference for Noninvasive, High-resolution, and Localized Deep Brain Stimulation: Concept Validation”, bioRxiv, doi: https://doi.org/10.1101/2020.07.20.212845 describes using interfering high frequency magnetic fields of slightly different frequencies, wherein peripheral regions of the brain are affected by the high frequency magnetic fields, while in the interference region a magnetic field having a low frequency envelope is formed which can stimulate the corresponding brain region. However, the shape of the envelope is unchangeable such that the stimulation pattern is restricted.
It is an object underlying the proposed solution to provide a system permitting a less restricted stimulation pattern.
According to the proposed solution, a system for (in particular magnetic) stimulation of biological tissue is provided, comprising
The time-varying magnetic fields generated by the magnetic field generating devices and emitted into the biological tissue (e.g. neural tissue) and/or the electric fields induced in the tissue by the magnetic fields will interfere with one another in the region of the tissue where the fields overlap. The resulting magnetic and/or induced electric field in the overlap region will be amplitude-modulated at a frequency that equals or at least depends on the modulation frequency. The frequency of the amplitude modulation in any case will be lower than the frequency of the time-varying magnetic fields emitted into the tissue such that the tissue (in particular neural tissue) may not respond to the time-varying magnetic and/or induced electric fields, but only to the amplitude-modulated resulting fields. The effect on the tissue thus may be confined to the overlap region of the time-varying magnetic and/or induced electric fields. For example, the frequency of the modulation is lower than a third or a fifth of the frequency of the time-varying magnetic field (i.e. the carrier frequency). The carrier frequency of the time-varying magnetic fields may be in the kHz range (e.g. at least 1 KHz), while the modulation frequency may be below 500 Hz, below 300 or below 200 Hz. For example, the carrier frequency of at least one of the time-varying magnetic fields (e.g. of the one that is phase modulated) is at least 1 kHz.
Further, the carrier frequency of at least one of the time-varying magnetic fields (e.g. the one whose carrier frequency is at least 1 kHz) may be below 1 MHz, below 900 kHz, below 500 kHz, below 200 kHz, below 100 kHz, below 50 kHz or below 10 kHz. Further, the strength of time-varying magnetic field (the magnetic flux density) may be at least 0.1 T, at least 1 T, at least 2 T, at least 3 T, or at least 5 T. For example, the strength of time-varying magnetic field is between 2 and 3 T.
The modulation imposed on the time-varying magnetic field generated by at least one of the two magnetic field generating devices may be a phase or frequency modulation. If the time-varying magnetic field is phase (frequency) modulated, the phase (frequency) of the magnetic field varies over time (e.g. periodically). However, the solution is not restricted to a particular modulation scheme such that e.g. also an amplitude modulation scheme might be used. According to another embodiment of the solution, the carrier frequencies of the time-varying magnetic fields generated by the magnetic field generating devices are identical. It is noted that the term “carrier frequency” relates to the frequency of the (unmodulated) time-varying magnetic field (the “carrier magnetic field”). The carrier magnetic field may be continuous over time (e.g. non-pulsed), i.e. the time-varying magnetic field varies continuously (e.g. sinusoidally). The carrier magnetic field is modulated, e.g. phase or frequency modulated, wherein at least one of the time-varying magnetic fields is phase modulated. In case the magnetic and/or the induced electric field is not modulated (which may be the case for one of the magnetic fields), the carrier frequency is the (only) frequency of the time varying field.
The controlling arrangement may be configured to control the at least two magnetic field generating devices in such a way that the time-varying magnetic field generated by one of the magnetic field generating devices is phase modulated, while the time-varying magnetic field generated by the other magnetic field generating device is unmodulated.
Furthermore, the controlling arrangement may be configured to adjust the ratio of the amplitudes of the time-varying magnetic fields generated by the two magnetic field generating devices. The extent of amplitude modulation in particular depends on the vector sum of the two magnetic and/or induced electric fields at each location in the tissue. The modulation may be maximal when the two fields have equal magnitudes, and minimal near each magnetic field generating device, where one of the two fields may dominate the other. The locus of maximum amplitude modulation and thus the locus of maximum stimulation may be steered by adjusting the relative amplitudes (i.e. the amplitude ratio) of the generated time-varying magnetic fields.
The modulation in particular is generated by applying a time-varying modulation function to the carrier magnetic field, wherein the modulation function, in principle, may be chosen arbitrarily to create an amplitude modulated resulting field whose envelope may be designed e.g. dependent on the desired effect on the tissue. The solution thus allows a high flexibility in the generation of stimulation waveforms. For example, the modulation (the modulation function) may be simply sinusoidal. However, more temporally complex resulting fields may be created. For example, short stimulation “pulses” may be emulated. For this, the modulation may be a phase modulation comprising a switch from a first state in which the time-varying magnetic fields have opposite phases to a second state in which the time-varying magnetic fields are in phase. At the location where the two magnetic and/or induced electric fields have equal magnitudes, the two fields will thus normally cancel out, and only transiently add up when they are brought in-phase, resulting in a stimulation pulse.
According to an embodiment of the solution, at least one of the magnetic field generating devices comprises or consists of at least one electromagnetic coil. However, the solution is of course not restricted to a particular embodiment of the two magnetic field generating devices. For example, at least one of the magnetic field generating devices may comprise or consists of at least one rotatable permanent magnet to generate the time-varying magnetic field.
In case the magnetic field generating devices are realized by means of electromagnetic coils, each magnetic field generating device may comprise at least one capacitor that combines with the coil to form a resonant circuit. The capacitance may be chosen so that the resonant frequency of the resonant circuit matches the required stimulation carrier frequency. The resulting circuit may have very low impedance at the resonant frequency and may be easily driven with low-voltage electronics. Other embodiments that do away with the capacitor and drive the coil directly using high-voltage electronics are also conceivable.
To overcome potential overheating issues of the stimulation coils, the coils may be actively cooled by a system that circulates water, oil or cooling liquid around them. If necessary, the stimulation could be performed in an intermittent manner, where the coils are turned off when no stimulation is required, and only turned on around the time points when stimulation pulses are required. However, sudden onsets and offset of electric fields are known to affect neural firing. To prevent this, currents may be slowly ramped up and down to and from their maximum values over a small time period (tens to hundreds of milliseconds) at the onset and offset of a stimulation pulse.
According to another embodiment of the solution, the two magnetic field generating devices belong to a first group and the system comprises a second group of magnetic field generating devices that contains at least two magnetic field generating devices for generating time-varying magnetic fields, wherein the controlling arrangement is configured to control at least one of the two magnetic field generating devices of the second group in such a way that the time-varying magnetic field generated by the device is modulated. Of course, more than two groups of at least two magnetic field generating devices each may be provided.
The magnetic fields generated by the devices of the first group may have the same carrier frequency and the magnetic fields generated by the magnetic field generating devices of the second group may have the same carrier frequency, wherein, however, the carrier frequency of the first group may be different from the carrier frequency of the second group. In order to e.g. ensure that low frequency amplitude modulation occurs only at the location where the fields from all the magnetic field generating devices are essentially equal, i.e. to prevent “extra” low frequency amplitude-modulated spots caused by interference of fields originating from magnetic field generating devices of different (two or more) groups, each group may operate at a different carrier frequency. The carrier frequencies are e.g. chosen so that the difference between any two of them is larger than a frequency that a neural tissue can respond to (e.g. at least 0.2 kHz, at least 0.5 kHz or at least 1 kHz). Then, at the location where all the fields add up equally, the envelope of the combined field will consist of a low frequency component at the modulation frequency, and some higher frequency components due to the beating between the different carrier frequencies. Since e.g. neural tissue only responds to low frequencies, it will react to the component at the modulation frequency and not to the higher frequency components.
The controlling arrangement of the system according to the solution may comprise a programmable unit, e.g. a microcontroller. The programmable unit may generate at least one control signal (driving signal) for controlling the time-varying magnetic fields generated by the two magnetic field generating devices. For example, the controlling arrangement comprises an amplifier circuit that receives the control signal and supplies the amplified control signal to the magnetic field generating devices. The control signal may determine both the time-varying magnetic field generated by the magnetic field generating device, i.e. the carrier magnetic signal, and the modulation of the time-varying magnetic field. In particular, the control signals set the waveform (including the frequency, amplitude and/or phase) of the modulated or unmodulated time-varying magnetic field. The corresponding control signal instead of being provided by the programmable unit may also be generated by analogue circuitry.
In case that the magnetic field generating devices each comprise an electromagnetic coil, the control signals generated by the programmable unit may determine the current supplied to the coils. In this embodiment, a Hall effect current sensor may be used to monitor the current in each coil (e.g. in real-time). Other types of current sensors may also be utilized. The current may be read by the programmable unit (e.g. the microcontroller mentioned above) which may implement a controller (e.g. a PID controller) that sets the frequency, amplitude and/or phase of the control signal for each coil in order to maintain the current frequency, amplitude and/or phase at the desired values and counteract any changes, e.g. due to temperature rises, phase modulation and/or inductive coupling between the coils. The controller could alternatively be implemented using analog electronics. The programmable unit may also monitor a coil temperature (e.g. in real-time) using a temperature sensor placed e.g. at the surface of each coil to ensure that the coil temperature remains within an admissible range. It is noted that the controlling arrangement of the system according to the solution does not necessarily have to realize a feedback loop, i.e. it does not have to be configured as a controller (such as the PID controller mentioned above), but only for steering the magnetic field generating devices for generating the time-varying magnetic fields.
According to a further embodiment of the solution, the system is battery-powered, wherein DC-DC converters (e.g. buck converters) may convert the battery voltage to a suitable level for powering components of the system such as the magnetic field generating devices for generating the time-varying magnetic fields and/or the programmable unit mentioned above. Furthermore, communication with external devices (e.g. electroencephalography amplifiers) may be supported through optically isolated digital I/O interfaces and/or Bluetooth. This may completely isolate the system from a power grid and external devices to reduce noise and ensure subject safety. Moreover, an over-current protection fuse and/or an emergency disconnect button may be integrated for safety in case of any failure in the system.
The solution also relates to a computer program product comprising program code having instructions which—when executed by a programmable unit of the controlling arrangement of the system of any of the preceding claims—will cause the controlling arrangement to control the two magnetic field generating devices of the system in such a way that each of them generates a time-varying magnetic field, wherein the time-varying magnetic field of at least one of the devices is modulated.
Embodiments of the solution will be described hereinafter with reference to the drawings.
The two coils are to be placed on the scalp. Each coil may consist of multiple windings of copper wire with either an air core or a ferromagnetic core. The two coils may be manufactured in such a way to be as similar as possible. The coils can be made of litz wire to minimize skin and proximity effects. Each coil has been driven with a high-frequency (e.g. in the kHz range) sinusoidal current (having e.g. several to tens of amps). The two coils have been driven at the same frequency, but the phase of the current in the one of coils that causes the second electric field E2 is modulated at a low frequency (e.g. 100 Hz). When the two induced electric fields E1, E2 combine in a region (overlap region) of the brain, the resulting field is amplitude-modulated at the phase modulation frequency.
The extent of amplitude-modulation depends on the vector sum of the two electric fields E1, E2 at each location in the brain. The modulation is maximal when the two fields have equal magnitudes, and minimal near each coil, where one field dominates the other. As already set forth above, since neural tissue does not respond to unmodulated high-frequency electric fields, but responds to amplitude-modulated fields, neural modulation would be constrained to regions where the combined electric field exhibits large amplitude modulation. The locus of maximal amplitude-modulation can be steered by adjusting the relative magnitudes of the coil currents.
The phase modulation does not have be sinusoidal. Rather, in principle, any modulation waveform could be imposed on the magnetic field.
Further, short stimulation pulses can be emulated by having the two magnetic and electric fields be normally anti-phasic and briefly reversing the phase of one of the coils to bring the coils transiently in-phase. This embodiment is reflected by
According to
In order to target a deep site of the brain, the magnetic field generating devices D1, D2 may be placed with a larger distance from the midline (
The embodiment illustrated in
The coils 11, 12 can be actively cooled by a system that circulates water or oil around them. If necessary, the stimulation could be performed in an intermittent manner, where the coils are turned off when no stimulation is required, and only turned on around the time points when stimulation pulses are required. For example, as already mentioned above, the currents supplied to the coils may be slowly ramped up and down to and from their maximum values over a small time period (e.g. tens to hundreds of milliseconds) at the onset and offset of a stimulation pulse.
Further, a current sensor 15 (e.g. a Hall effect sensor) is used to monitor the current in each coil 11, 12 in real-time. The measured current value is transmitted to the microcontroller 14. The microcontroller 14 implements a PID controller that sets the amplitude and phase of a control signal transmitted from the microcontroller 14 to the amplifier circuit 13 for each coil 11, 12 in order to maintain the amplitude and phase of the current supplied to the coils 11, 12 at the desired values and counteract any changes due to temperature rises, phase modulation (other than the desired phase modulation), and/or inductive coupling between the coils 11, 12.
As already mentioned above, the PID controller could alternatively be implemented using analog electronics. The microcontroller 14 also monitors coil temperature in real-time using a temperature sensor 16 placed at the surface of each coil 11, 12 to ensure that the coil temperature remains within an admissible range.
The system 100 is battery-powered by means of at least one battery 2, wherein a buck converter 3 converts the battery voltage to a suitable level for powering the microcontroller 14. Further, the system 100 comprises optically isolated digital I/O and Bluetooth interfaces 4, 5 for permitting communication with external devices (e.g. electroencephalography amplifiers). The system may thus be isolated from a power grid and external devices to reduce noise and ensure subject safety. Furthermore, an over-current protection fuse 6 and emergency disconnect button 7 may be provided to respond to a failure in the device.
In order to increase stimulation strength and spatial resolution, the system 100 according to the solution may comprise more than two coils (or any other type of a magnetic field generating device) as shown in
As already discussed above, in order to ensure that low frequency amplitude modulation occurs only at the location where the fields from all the coils 11, 12, 21, 22 are equal and to prevent undesired low frequency amplitude-modulated region between the coils of different groups 10, 20, the coils 11, 12, 21, 22 of each group 10, 20 operate at different carrier frequencies, i.e. the coils 11, 12 of the first group operate at a first carrier frequency and the coils 21, 22 of the second group 20 operate at a second carrier frequency different from the first carrier frequency. Therefore, the overlap region is the region S of maximum stimulation. The carrier frequencies of the groups 10, 20 are chosen in such a way that the difference between them is much larger than a frequency that a neural tissue can respond to (e.g. larger than 1 kHz). Accordingly, at a location where the fields generated and/or induced by the coils 11, 12, 21, 22 interfere, the envelope of the resulting field will have a low frequency component at the modulation frequency and some higher frequency components due to the different carrier frequencies of the two groups 10, 20. Of course, more than two groups may be used. Also, at least one of the groups may comprise more than two coils.
Number | Date | Country | Kind |
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20206444.0 | Nov 2020 | EP | regional |
This application is a National Phase Patent Application of International Patent Application Number PCT/EP2021/080940, filed on Nov. 8, 2021, which claims priority of European Patent Application Number 20 206 444.0, filed on Nov. 9, 2020.
Filing Document | Filing Date | Country | Kind |
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PCT/EP2021/080940 | 11/8/2021 | WO |