Neural stimulation for alleviating nausea

Abstract

A signal generator is provided that is configured to generate a signal adapted to be delivered to the brain of a subject to alleviate nausea in the subject. The stimulation signal is defined by a waveform having a frequency and a phase. The stimulation signal is characterized by one or more instantaneous disruptions of the phase of the waveform. A system (100) for alleviating nausea is provided. The system (100) comprises: the signal generator (102) configured to generate the stimulation signal; and one or more electrodes (104, 106a-c) configured to deliver the stimulation signal to the brain of a subject.

Description

[0001] NEURAL STIMULATION FOR ALLEVIATING NAUSEA

[0002] Field of the Invention

[0003] The present invention relates to stimulation signals and systems for alleviating nausea in a subject and particularly, although not exclusively, to stimulation signals and systems adapted fortranscranial stimulation to alleviate nausea.

[0004] Background

[0005] Nausea is an unpleasant sensation for a person and can reduce their ability to concentrate on a task they are carrying out, making it more difficult for the person to carry out their task.

[0006] In some contexts, nausea can be particularly pronounced and problematic. For example, motion sickness is a common condition affecting huge numbers of people. With the advent of virtual reality (VR) and augmented reality (AR), motion sickness is becoming more prevalent in a wider variety of contexts.

[0007] According to Griffin’s model of motion sickness (M. Griffin, 1996), motion sickness can be classified into three categories. Type-I motion sickness corresponds to nausea caused by motion that is felt but not seen. For example, motion caused by reading in a moving vehicle and off-vertical axis rotation in darkness are classified as type-l motion sickness. Type-I I motion sickness corresponds to nausea caused by motion that is seen but not felt. For example, VR motion sickness and cybersickness (nausea caused by the prolonged use of digital screen devices) are classified as type-ll motion sickness. Finally, type-ill motion sickness corresponds to nausea caused when the inputs received by all motion sensory organs from the visual, vestibular and somatosensory systems are uncorrelated with each other. For example, Coriolis rotation is classified as type-ill motion sickness.

[0008] Current approaches for alleviating nausea include galvanic vestibular stimulation (GVS) and bone- conducted vibration (BCV).

[0009] However, both GVS and BCV are indirect nausea mitigation methods that act on the peripheral sensory organs of the nausea / vomiting control centre of the brain such as the sensory organs in the inner ears. For example, a small device / actuator may be attached behind the mastoids. Therefore, the alleviation of nausea using these methods can take a long time to be achieved and the positive effects (i.e., alleviated nausea) are relatively short-lived. For example, Weech et al. (Weech et al., 2020) found that GVS can take ~30 minutes to begin alleviating the effects of nausea.

[0010] Additionally, GVS is known to be an uncomfortable process for a subject to be subjected to and BCV can cause an unpleasant vibration to be felt on the skin. Moreover, the presence of a device attached to the mastoids for applying GVS or BCV can be uncomfortable for users.

[0011] The present invention has been devised in light of the above considerations. Summary of the Invention

[0012] In a general sense, the present invention provides a signal whose waveform is adapted to provide a subject with alleviation of their motion sickness (indexed by a nausea rating) on shorter timescales than is observed with other approaches (such as GVS or BCV), and alleviation that lasts longer, whilst subjecting the subject to less discomfort than other approaches.

[0013] In a first aspect, there is provided a signal generator configured to generate a signal adapted to be delivered to the brain of a subject to alleviate nausea in the subject. The stimulation signal is defined by a waveform having a frequency and a phase. The stimulation signal is characterized by one or more instantaneous disruptions of the phase of the waveform.

[0014] In another aspect, there is provided a delivery unit configured to receive a stimulation. The delivery unit comprises one or more electrodes configure to deliver the stimulation signal to the brain of a subject. The stimulation signal is defined by a waveform having a frequency and a phase. The stimulation signal is characterized by one or more instantaneous disruptions of the phase of the waveform.

[0015] In some examples, the one or more electrodes may be adapted to deliver electroencephalogram (EEG) signals to the brain.

[0016] In some embodiments, the delivery unit may further comprise a wearable cap. The one or more electrodes may be mounted on or in the wearable cap.

[0017] In some examples, the wearable cap may be an EEG cap with electrodes mounted thereon.

[0018] In some embodiments, the one or more electrodes may be positioned such that they are configured to deliver stimulation to the left parietal cortex of the subject.

[0019] In this way, it may be possible to deliver the stimulation signal directly to that part of the brain (the left parietal cortex) that generates the neural oscillations that induce nausea in the subject.

[0020] In some examples, a stimulation electrode may be positioned at the P3 EEG position on the subject. The P3 position is a known coordinate in the International 10-20 system and the Modified Combinatorial Nomenclature.

[0021] The P3 position may be understood as being a position on the scalp at which an electrode is placeable. The P3 position is a position on the scalp that overlays the left parietal lobe. The P3 position is displaced to the left from the midline sagittal plane of the skull of the subject by a distance approximately equal to 20% of the length of the preauricular-to-preauricular line along the surface of the skull of the subject. The P3 position is displaced back from the preauricular-to-preauricular line of the subject by a distance approximately equal to 20% of the length of the line along the surface of the skull between the nasion and the inion of the subject.

[0022] In some embodiments, the one or more electrodes may include one or more stimulation electrodes configured to deliver the stimulation signal to the brain of the subject, and one or more return electrodes configured to remove current from the brain of the subject after delivery of the stimulation signal by the one or more stimulation electrodes.

[0023] By providing one or more return electrodes, the risk of causing current-induced burn in the subject is reduced, thereby making the system safer for use.

[0024] In some examples, there may be more return electrodes than stimulation electrodes to ensure that all of the delivered current is returned through the one or more return electrodes without exceeding their current-bearing capacity.

[0025] In some examples, the one or more return electrodes may be positioned at positions on the skull around the stimulation electrode to ensure that the return current is collected by at least one of the return electrodes.

[0026] In some embodiments, the one or more electrodes may include one stimulation electrode and a plurality of return electrodes.

[0027] In this way, it can be ensured that all the delivered current is returned through the one or more return electrodes without exceeding their current-bearing capacity.

[0028] In some examples, the one or more electrodes may include a single stimulation electrode positioned at the P3 position, as described above.

[0029] In such examples, the one or more electrodes may include three return electrodes positioned around the P3 position.

[0030] For example, the three return electrodes may be positioned at the CP1 , TP7 and O1 positions respectively.

[0031] The CP1 position may be understood as being a position on the scalp at which an electrode is placeable. The CP1 position is a position on the scalp that overlays the left parietal lobe. The CP1 position is displaced to the left from the midline sagittal plane of the skull of the subject by a distance approximately equal to 10% of the length of the preauricular-to-preauricular line along the surface of the skull of the subject. The CP1 position is displaced back from the preauricular-to-preauricular line of the subject by a distance approximately equal to 10% of the length of the line along the surface of the skull between the nasion and the inion of the subject.

[0032] The TP7 position may be understood as being a position on the scalp at which an electrode is placeable. The TP7 position is a position on the scalp that overlays the left parietal lobe and the left temporal lobe. The TP7 position is displaced to the left from the midline sagittal plane of the skull of the subject by a distance approximately equal to 40% of the length of the preauricular-to-preauricular line along the surface of the skull of the subject. The TP7 position is displaced back from the preauricular-to- preauricular line of the subject by a distance approximately equal to 10% of the length of the line along the surface of the skull between the nasion and the inion of the subject. The O1 position may be understood as being a position on the scalp at which an electrode is placeable. The O1 position is a position on the scalp that overlays the left occipital lobe. The O1 position is at a height just above the left ear and is displaced left from the occipital point of the skull of the subject by a distance approximately equal to 5% of the circumference of the skull where the circumference of the skull is measured as the perimeter of the circle passing through points just above the ears, just above the bridge of the nose, and just above the occipital point.

[0033] In some embodiments, the system may be integrated with a virtual reality headset.

[0034] In some embodiments, the system may be integrated with an augmented reality headset.

[0035] It may be particularly advantageous to integrate such nausea-alleviating systems in VR and / or AR headsets as approximately 40-70% of VR headset users are known to experience type-ll motion sickness - i.e., VR motion sickness.

[0036] In some examples, the system described herein may be useable to alleviate nausea, to alleviate type-l motion sickness (e.g., motion-induced motion sickness), to alleviate type-ll motion sickness (e.g., VR- induced motion sickness or cybersickness when the subject is not themselves moving), and / or type-ill motion sickness (e.g., VR-induced motion sickness or cybersickness when the subject is also moving, thereby causing a sensory mismatch between the visual, vestibular and somatosensory systems).

[0037] In another aspect, there is provided a stimulation signal adapted to be delivered to the brain of a subject to alleviate nausea in the subject. The stimulation signal is defined by a waveform having a frequency and a phase. The stimulation signal is characterized by one or more instantaneous disruptions of the phase of the waveform.

[0038] Each of the instantaneous disruptions of the phase of the waveform may be understood as being an instantaneous discontinuity in the phase of the waveform. In other words, there is a discontinuity in the temporal derivative of the stimulation - i.e., a kink in the temporal profile of the waveform.

[0039] Previous work carried out by the inventors (Li et al., 2022) has demonstrated that EEG-based phase biomarkers (such as phase-locking values, PLV, of the left parietal inter-trial coherence, ITC, at 18Hz) are positively corelated with type-ll motion sickness (such as VR motion sickness, VRMS) with a correlation strength of r = 0.496 and a p-value of p=0.026.

[0040] By applying a signal having one or more instantaneous phase disruptions as part of its waveform to a subject’s brain, endogenous phase information of neural oscillations that are symptomatic of nausea (e.g., type-ll motion sickness) may be disrupted. This, in turn, rapidly disrupts nausea-linked brain activity patterns (e.g., the PLV of the left parietal ITC at 18 Hz), thereby alleviating the symptoms of nausea experienced by the subject.

[0041] As is set out below, the application of the stimulation signal described herein alleviates nausea in a subject, and provides benefits over both BCV and GVS. Firstly, the stimulation signal is able to induce an alleviation in nausea quicker than GVS and BCV, and the alleviation is longer-lasting than in BCV cases. Secondly, the subject experiences less discomfort than they would if they were subjected to GVS and BCV, for example, because GVS and BCV rely on attaching a device behind the mastoids while the stimulation signal may be applied using a cap.

[0042] In some examples, one or more (or each) of the one or more instantaneous phase disruptions may be an instantaneous phase inversion of the waveform. In other words, one or more (or each) of the one or more discontinuous phase disruptions may be an instantaneous change in phase of the waveform by 180 degrees.

[0043] In other examples, one or more (or each) of the one or more instantaneous phase disruptions may be an instantaneous change in phase of the waveform by 30 degrees or more, 45 degrees or more, 60 degrees or more, 90 degrees or more, 120 degrees or more, or 135 degrees or more.

[0044] In some examples, one or more (or each) of the one or more instantaneous phase disruptions may be an instantaneous change in phase of the waveform by 180 degrees or less, 135 degrees or less, 120 degrees or less, 90 degrees or less, 60 degrees or less, or 45 degrees or less.

[0045] In some examples, one or more (or each) of the one or more instantaneous phase disruptions may be an instantaneous change in phase of the waveform by between 30 degrees and 180 degrees, between 30 degrees and 135 degrees, between 30 degrees and 120 degrees, between 30 degrees and 90 degrees, between 30 degrees and 60 degrees, between 30 degrees and 45 degrees, between 45 degrees and 180 degrees, between 45 degrees and 135 degrees, between 45 degrees and 120 degrees, between 45 degrees and 90 degrees, between 45 degrees and 60 degrees, between 60 degrees and 180 degrees, between 60 degrees and135 degrees, between 60 degrees and 120 degrees, between 60 degrees and 90 degrees, between 90 degrees and 180 degrees, between 90 degrees and 135 degrees, between 90 degrees and 120 degrees, between 120 degrees and 180 degrees, between 120 degrees and 135 degrees, or between 135 degrees and 180 degrees.

[0046] In some examples, one or more (or each) of the instantaneous phase disruptions may be a forwardchange in the phase (i.e., a discontinuous advance in the phase of the waveform).

[0047] In some examples, one or more (or each) of the instantaneous phase disruptions may be a backwardchange in the phase (i.e., a discontinuous reversal in the phase of the waveform).

[0048] In some examples there may be a plurality of instantaneous phase disruptions. In such examples, at least one of the instantaneous phase disruptions may be a forward-change in the phase of the waveform. Additionally or alternatively, at least one of the instantaneous phase disruptions may be a backwardchange in the phase of the waveform. Alternatively, all of the instantaneous phase disruptions may be a forward-change in the phase of the waveform. Alternatively, all of the instantaneous phase disruptions may be a backward-change in in the phase of the waveform. In some embodiments, the stimulation signal may be characterized by a plurality of instantaneous disruptions of the phase of the waveform, having a respective number of complete cycles of the waveform, between each instantaneous disruption of the phase.

[0049] A complete cycle of the waveform may be understood to be a complete revolution of the phase (i.e., a 360 degree revolution in the phase of the waveform). This may also be understood to be a complete time period of the waveform (i.e., the inverse of the frequency of the waveform, T = 1 / v).

[0050] In some embodiments, the respective number of complete cycles of the waveform between each instantaneous disruption of the phase may vary between each successive pair of instantaneous disruptions of the phase.

[0051] In other words, the plurality of instantaneous disruptions of the phase may be non-uniformly distributed throughout the waveform. That is, the temporal separation between each instantaneous disruption of the phase may vary between successive pairs of phase disruptions.

[0052] By varying the temporal distribution of the plurality of instantaneous disruptions of the phase throughout the waveform, the risk of a low-frequency carrier wave (i.e., a low-frequency component of the stimulation signal that dictates the timing of the instantaneous phase disruptions) coupling into the neural oscillations is eliminated, thereby preventing the stimulation signal from inadvertently inducing nausea in the subject.

[0053] In some embodiments, the waveform may be defined by a cyclically repeating waveform section. The waveform section may be characterized by one or more instantaneous disruptions of the phase and a respective number of complete cycles of the repeating waveform section between each of the instantaneous disruptions of the phase.

[0054] In other words, the overall profile of the waveform may comprise a plurality of repeating waveform sections appended to one another to form a larger waveform profile. In this way, the computational burden associated with encoding the signal for generation by a signal generator may be reduced as the same set of operations may be repeatedly applied to generate multiple iterations of the repeating waveform section one after another to define the overall waveform.

[0055] In some embodiments, the respective number of complete cycles of the repeating waveform section between each of the instantaneous disruptions of the phase may be different between each pair of instantaneous disruptions of the phase.

[0056] In other words, the plurality of instantaneous disruptions of the phase within each of the repeating waveform sections may be non-uniformly distributed within that waveform section. That is, the temporal separation between each instantaneous disruption of the phase may vary between successive pairs of phase disruptions within a single repeating waveform section.

[0057] By varying the temporal distribution of the plurality of instantaneous disruptions of the phase throughout the waveform, the risk of a low-frequency carrier wave (i.e., a low-frequency component of the stimulation signal that dictates the timing of the instantaneous phase disruptions arising from the regular repetition of the repeating waveform section) coupling into the neural oscillations is significantly reduced, thereby mitigating any potential inducement of nausea in the subject by the stimulation signal.

[0058] In some embodiments, each cyclically repeating waveform section may include three or more instantaneous disruptions of the phase.

[0059] Three or more instantaneous disruptions of the phase within the repeating waveform section may be advantageous as it may reduce the likelihood of a low-frequency carrier wave (as discussed above) from coupling into the neural oscillation of the subject.

[0060] In some examples, each of the repeating waveform sections may include three or more, five or more, eight or more, or ten or more instantaneous disruptions of the phase.

[0061] In some examples, each of the repeating waveform sections may include ten or fewer, eight or fewer, or five or fewer instantaneous disruptions of the phase.

[0062] In some examples, each of the repeating waveform sections may include between three and ten, three and eight, three and five, five and ten, five and eight, or eight and ten instantaneous disruptions of the phase.

[0063] In a particular example, each of the repeating waveform sections may include three instantaneous disruptions of the phase of the waveform.

[0064] In some examples, the number of complete cycles between each successive pair of the instantaneous disruptions of the phase may be predetermined or may be determined by a processor.

[0065] For example, in a particular example where each of the repeating waveform sections includes three instantaneous disruptions of the phase of the waveform, the first instantaneous disruption of the phase may occur after three complete cycles of the waveform, the second instantaneous disruption of the phase may occur after a further four complete cycles of the waveform, and the third instantaneous disruption of the phase may occur after a further seven complete cycles of the waveform. Such a distribution of the instantaneous disruptions of the phase may be particularly effective for mitigating nausea in the subject.

[0066] In some embodiments, the respective number of complete cycles between each successive pair of the instantaneous disruptions of the phase may be randomly determined.

[0067] For example, a random number generator may be used, or a random number generation function may be executed to determine each respective number of complete cycles before the next instantaneous disruption of the phase.

[0068] By randomly distributing the instantaneous disruptions of the phase throughout the waveform, the risk of a low-carrier frequency wave coupling into the neural oscillations of the subject may be entirely (or almost entirely) eliminated, thereby preventing the stimulation signal itself from inducing nausea in the subject.

[0069] In some embodiments, the frequency of the waveform may be 25 Hz or less. In some examples, the frequency of the waveform may be 60 Hz or less, 50 Hz or less, 30 Hz or less, 20 Hz or less, or 10 Hz or less.

[0070] In some embodiments, the frequency of the waveform may be 10 Hz or more.

[0071] In some examples, the frequency of the waveform may be 20 Hz or more, 25 Hz or more, 30 Hz or more, 50 Hz or more, or 60 Hz or more.

[0072] In some examples, the frequency of the waveform may be between 10 and 60 Hz, 10 and 50 Hz, 10 and 30 Hz, 10 and 25 Hz, 10 and 20 Hz, 20 and 60 Hz, 20 and 50 Hz, 20 and 30 Hz, 20 and 25 Hz, 25 and 60 Hz, 25 and 50 Hz, 25 and 30 Hz, 30 and 60 Hz, 30 and 50 Hz, or 50 and 60 Hz.

[0073] In some embodiments, the frequency of the waveform may be fixed.

[0074] In other words, the frequency of the waveform may not change overtime.

[0075] In a particular example, the frequency of the waveform may be fixed at 18 Hz. As mentioned above, the inventors have observed that the PLV of the left parietal ITC at 18Hz exhibits a positive correlation with a subject experiencing the symptoms of nausea (e.g., in the form of type-ll motion sickness - specifically VR motion sickness).

[0076] By providing a stimulation signal with the same frequency as nausea-inducing neural oscillations of the subject, the stimulation signal is able to more effectively disrupt the phase of the neural oscillations, thereby preventing the onset of nausea or alleviating nausea in the subject.

[0077] In some examples, the stimulation signal described herein may be useable to alleviate nausea, to alleviate type-l motion sickness (e.g., motion-induced motion sickness), to alleviate type-ll motion sickness (e.g., VR-induced motion sickness or cybersickness when the subject is not themselves moving), and / or type-ill motion sickness (e.g., VR-induced motion sickness or cybersickness when the subject is also moving, thereby causing a sensory mismatch between the visual, vestibular and somatosensory systems).

[0078] In some embodiments, the signal generator described herein may be configured to generate the stimulation signal described herein.

[0079] In some embodiments, the delivery unit described herein may be configured to receive the stimulation signal described herein. The one or more electrodes may be configured to deliver said stimulation signal to the brain of a subject.

[0080] In another aspect, there is provided a system for alleviating nausea. The system comprises the signal generator described herein and the delivery unit described herein.

[0081] In other words, the system comprises a signal generator configured to generate the stimulation signal, as described herein; and one or more electrodes configured to deliver the stimulation signal to the brain of a subject. In some examples, the one or more electrodes may be adapted to deliver electroencephalogram (EEG) signals to the brain.

[0082] In another aspect, there is provided a computer-readable medium comprising instructions that, when executed by a computer comprising a signal generator, cause the signal generator to generate the stimulation signal as described herein.

[0083] In another aspect, there is provided a computer program product comprising logic that, when executed by a computer comprising a signal generator, causes the signal generator to generate the stimulation signal as described herein.

[0084] In another aspect, there is provided a method of alleviating nausea. The method comprises: generating the stimulation signal as described herein; and delivering the stimulation signal to the brain of a subject via one or more electrodes to alleviate nausea in the subject.

[0085] In some embodiments, generating the stimulation signal comprises generating the stimulation signal by the signal generator described herein.

[0086] In some embodiments, delivering the stimulation signal to the brain of the subject comprises delivering the stimulation signal by the delivery unit described herein.

[0087] The invention includes the combination of the aspects and preferred features described except where such a combination is clearly impermissible or expressly avoided.

[0088] Summary of the Figures

[0089] Embodiments and experiments illustrating the principles of the invention will now be discussed with reference to the accompanying figures in which:

[0090] Figure 1 shows an example of a stimulation signal adapted to alleviate nausea in a subject upon application to the subject’s brain.

[0091] Figure 2 shows a block diagram schematic of a system configured to generate a stimulation signal for alleviating nausea.

[0092] Figure 3 shows a photograph of a system for alleviating nausea comprising a wearable cap with electrodes positioned at the P3, CP1 , TP7 and O1 positions, and integrated with a VR headset.

[0093] Figure 4A shows a simulated electric field in a brain which is stimulated using the system of Figure 3.

[0094] Figures 4B-4C show examples of a simulated electric field in a brain for different stimulating signals.

[0095] Figure 5 shows an example of a tunnel travel task used to test the system shown in Figure 3.

[0096] Figure 6 shows experimental results demonstrating the efficacy of the system described herein at alleviating nausea. Figure 7 shows experimental results plotting indications of different forms of discomfort experienced by test subjects in procedures implemented to test the system shown in Figure 3.

[0097] Detailed Description of the Invention

[0098] Aspects and embodiments of the present invention will now be discussed with reference to the accompanying figures. Further aspects and embodiments will be apparent to those skilled in the art. All documents mentioned in this text are incorporated herein by reference.

[0099] Figure 1 shows an example of a stimulation signal adapted to alleviate nausea in a subject upon application to the subject’s brain.

[0100] The stimulation signal of Figure 1 is defined by a series of repeating waveform sections. One repeating waveform section is shown in detail in Figure 1 . The stimulation signal may be understood to comprise a series of consecutive identical repeating waveform sections entrained one after another.

[0101] The stimulation signal of Figure 1 has a fixed frequency of 18 Hz. After three complete cycles of the waveform (corresponding to 166.7 ms) the waveform profile exhibits an instantaneous disruption of the phase of the waveform. The instantaneous disruption is an instantaneous inversion - i.e., an instantaneous change in the phase of the waveform of 180 degrees. After a further four complete cycles of the waveform (corresponding to 222.2 ms) the waveform exhibits another instantaneous disruption of the phase of the waveform. This second instantaneous disruption is also an instantaneous inversion of the phase - i.e., an instantaneous change in the phase of the waveform of 180 degrees. After a further seven complete cycles of the waveform (corresponding to 388.9 ms), the waveform exhibits another instantaneous disruption of the phase of the waveform. This third instantaneous disruption is also an instantaneous inversion of the phase - i.e., an instantaneous change in the phase of the waveform of 180 degrees.

[0102] The instantaneous phase disruptions (or inversions in the case of the stimulation signal of Figure 1) disrupt phase-locking in neural oscillations in the left parietal lobe that induce symptoms of nausea (such as type-l, -II, or -III motion sickness) thereby mitigating these neural oscillations and consequently preventing or alleviating nausea in a subject.

[0103] The skilled person will understand that the stimulation signal described herein is not limited to the “3-4-7” configuration depicted in Figure 1 , and that other numbers of complete cycles between successive instantaneous disruptions to the phase are possible.

[0104] In some examples, each of the repeating waveform sections may include three or more, five or more, eight or more, or ten or more instantaneous disruptions of the phase.

[0105] In some examples, each of the repeating waveform sections may include ten or fewer, eight or fewer, or five or fewer instantaneous disruptions of the phase. In some cases, the number of complete cycles between each successive pair of the instantaneous phase disruptions may be randomly determined (e.g., by a random number generator).

[0106] In some examples, each of the repeating waveform sections may include between three and ten, three and eight, three and five, five and ten, five and eight, or eight and ten instantaneous disruptions of the phase.

[0107] As discussed above, the extent of the disruption of the phase of the waveform need not be a complete 180 degree inversion. In some examples, each of the instantaneous disruptions of the phase may be an instantaneous change in the phase of the waveform by 30 degrees or more, 45 degrees or more, 60 degrees or more, 90 degrees or more, 120 degrees or more, or 135 degrees or more.

[0108] Alternatively, each of the instantaneous phase disruptions may be an instantaneous change in the phase of the waveform by 180 degrees or less, 135 degrees or less, 120 degrees or less, 90 degrees or less, 60 degrees or less, or 45 degrees or less.

[0109] Alternatively, each of the instantaneous phase disruptions may be an instantaneous change in the phase of the waveform by between 30 degrees and 180 degrees, between 30 degrees and 135 degrees, between 30 degrees and 120 degrees, between 30 degrees and 90 degrees, between 30 degrees and 60 degrees, between 30 degrees and 45 degrees, between 45 degrees and 180 degrees, between 45 degrees and 135 degrees, between 45 degrees and 120 degrees, between 45 degrees and 90 degrees, between 45 degrees and 60 degrees, between 60 degrees and 180 degrees, between 60 degrees and 135 degrees, between 60 degrees and 120 degrees, between 60 degrees and 90 degrees, between 90 degrees and 180 degrees, between 90 degrees and 135 degrees, between 90 degrees and 120 degrees, between 120 degrees and 180 degrees, between 120 degrees and 135 degrees, or between 135 degrees and 180 degrees.

[0110] In some examples, each of the instantaneous phase disruptions may be a forward-change in the phase (i.e., a discontinuous advance in the phase of the waveform).

[0111] In some examples, each of the instantaneous phase disruptions may be a backward-change in the phase (i.e., a discontinuous reversal in the phase of the waveform).

[0112] In some examples, at least one of the instantaneous phase disruptions may be a forward-change in the phase of the waveform. Additionally or alternatively, at least one of the instantaneous phase disruptions may be a backward-change in the phase of the waveform. Alternatively, all of the instantaneous phase disruptions may be a forward-change in the phase of the waveform. Alternatively, all of the instantaneous phase disruptions may be a backward-change in in the phase of the waveform.

[0113] While the stimulation signal of Figure 1 has a frequency of 18 Hz, other frequencies for the stimulation signal may be possible. For example, the frequency of the waveform may be 60 Hz or less, 50 Hz or less, 30 Hz or less, 20 Hz or less, or 10 Hz or less. Alternatively, the frequency of the waveform may be 20 Hz or more, 25 Hz or more, 30 Hz or more, 50 Hz or more, or 60 Hz or more. Alternatively, the frequency of the waveform may be between 10 and 60 Hz, 10 and 50 Hz, 10 and 30 Hz, 10 and 25 Hz, 10 and 20 Hz, 20 and 60 Hz, 20 and 50 Hz, 20 and 30 Hz, 20 and 25 Hz, 25 and 60 Hz, 25 and 50 Hz, 25 and 30 Hz, 30 and 60 Hz, 30 and 50 Hz, or 50 and 60 Hz.

[0114] Figure 2 shows a block diagram schematic of a system 100 configured to generate a stimulation signal, such as shown in Figure 1 , for alleviating nausea. The system 100 comprises a signal generator 102 configured to generate the stimulation signal. The signal generator 102 may, in some examples, comprise a random number generator (not shown) for use in randomly determining the number of complete cycles of the waveform between successive instantaneous disruptions to the phase.

[0115] The system 100 further comprises a stimulation electrode 104 and three return electrodes 106a-c mounted on a wearable cap 108. The stimulation electrode 104 is configured to deliver the stimulation signal to the brain of the subject. The return electrodes 106a-c are configured to collect return current from the brain of the subject after successful delivery of the stimulation signal to prevent current-induced burn. In other examples, other numbers of stimulation electrodes 104 and return electrodes 106 may be implemented.

[0116] The stimulation electrode 104 is preferably positioned to overlay the left parietal lobe, for example, at the P3 position as described above. The return electrodes 106a-c are preferably positioned around the stimulation electrode to collect return current after successfully delivery of the stimulation signal. For example, the first return electrode 106a may be positioned at the CP1 position as described above. Additionally or alternatively, the second return electrode 106b may be positioned at the TP7 position as described above. Additionally or alternatively, the third return electrode 106c may be positioned at the O1 position as described above.

[0117] Figure 3 shows a photograph of a system for alleviating nausea comprising a wearable cap with electrodes positioned at the P3, CP1 , TP7 and O1 positions, and integrated with a VR headset. As discussed above in relation to Figure 2, the electrode at P3 is a stimulation electrode 104 configured to deliver the stimulation signal to the left parietal lobe of the subject, while the electrodes at CP1 , TP7 and O1 are each return electrodes 106a-c for collecting return current after successful delivery of the stimulation signal.

[0118] The system of Figure 3 is integrated with a VR headset and is configured to alleviate VR motion sickness in the user (regardless of whether the user is static and therefore experiencing type-ll motion sickness, or moving and therefore experiencing type-ill motion sickness).

[0119] Figure 4A shows a simulation of the electric field in a brain which has been stimulated using a stimulation signal characterised by a random-phase waveform (e.g., using the system of Fig. 3).

[0120] Figure 4B shows how the polarity of the simulated electric field changes with the polarity of a control signal characterised by a regular simulated waveform. In contrast, Figure 4C shows the electric field in the brain which is stimulated by an active stimulation with a random-phase waveform where the phase of the stimulation signal waveform was randomly instantaneously disrupted (inverted). As shown in Figure 4C, the phase shift of the stimulation signal waveform causes the electrode current, and hence the electric field in the brain, to maintain substantially the same polarity for longer (i.e., for two half-cycles of the sinusoidal waveform) than if a regular sinusoid was used to stimulate the brain. As discussed above, this disruption in the polarity of the electric field can usefully disrupt phase-locking in neural oscillations in the left parietal lobe that induce symptoms of nausea.

[0121] EXPERIMENTAL RESULTS

[0122] An experimental procedure to test the system was implemented as a single-blinded, sham-controlled, counter-balanced, within-subject, multi-visit study. The within-subject factor was the stimulation type which had three levels that were counterbalanced across lab visits with at least a one-week time interval between each visit.

[0123] The three levels were: (i) active stimulation with a random-phase waveform where the phase of the stimulation signal waveform was randomly instantaneously disrupted (inverted) between 3 and 9 complete cycles of the waveform; (ii) a sham simulation with a random phase waveform applied for 20 seconds (a 10-second ramp up followed by a 10-second ramp down), and (iii) a control stimulation characterised by a regular sinusoidal waveform having a frequency of 18 Hz. The waveform of the control simulation was chosen because it was suitable for inducing nausea (as opposed to alleviating nausea) in the subject.

[0124] Eighteen adults between the ages of 20 and 30 years old were recruited for the test procedure. Each participant was tested with all three of the levels set out above. The order of the three tests was counterbalanced for each subject. The inclusion criteria for the test were: (i) a moderate VRMS susceptibility, as defined by Li, Varela, et al., 2020 through the assessments of self-reported motion sickness susceptibility questionnaire scores having resultant scores between 10 and 36; (ii) no transcranial alternating current contraindications; and (iii) no more than two hours per month of the user of VR and / or first-person PC shooting games.

[0125] Each subject visited the test lab three times for all three levels of stimulation set out above. Each subject, on each visit, completed a 2-back working memory task using the PC-based PsyToolkit platform both before and after the stimulation session. The duration of the 2-back task before the session was 3 minutes. The duration of the 2-back task after the session was 9 minutes. The duration of each session was 28 minutes, during which the subject was exposed to a VR motion sickness-inducing environment, as depicted in Figure 5. In each test, the subject was stationary in an office chair, and therefore experience type-ll motion sickness. While being exposed to the nausea-inducing environment, the subject performed a multitasking cognitive task. The procedure was approved by the ethics panel of the University of Glasgow, College of Medical Veterinary and Life Sciences. During the experiment, the metrics shown in Table 1 below were extracted respectively for further statistical analysis (as discussed below in relation to Figures 6 and 7). Specifically self-assessed reports of the standard fast motion sickness scale (FMS) were collected every four minutes during stimulation to assess whether the stimulation signal of Figure 1 reduced VR motion sickness in the subject. Selfassessed reports on the perception of stimulation were also collected every four minutes during stimulation to assess whether the stimulation signal caused discomfort in the subject.

[0126] Table 1: Summary of Metrics used to assess system performance

[0127] The VR motion sickness stimulus used in this study was adapted from the NeuroRacer proposed by Anguera et al. (Anguera et al., 2013). NeuroRacer was originally designed as a 2D first-person perspective racing game to train and assess participants’ multitasking cognitive control abilities through challenging their visual discrimination ability in the context of visuomotor tracking ability. In the context of this study, a simplified VR version of NeuroRacer was used, as shown in Figure 5. NeuroRacer was simplified to provide a fixed game difficulty (as opposed to the standard adaptive difficulty) as the main goal of the use of the VR version of NeuroRacer in this context was to induce VR motion sickness, as opposed to providing the subject with cognitive training. This VR version of NeuroRacer induced VR motion sickness by causing a sensory mismatch between the visual and vestibular sensory inputs - i.e., a sensory mismatch was induced between the forward-moving visual motion of a virtual tunnel and the still physical body of the subject on a normal chair. The VR version of NeuroRacer shown in Figure 6 and used in this study is more effective at inducing VR motion sickness because the inducement of motion sickness is much stronger in VR settings than in 2D displays (which may induce cybersickness).

[0128] The route within the tunnel shown in Figure 5 was configured to enact normal VR locomotion, including curves, uphill and downhill paths, but without upside down and / or off-axis paths. While exposed to this passive locomotion, subjects required to perform two cognitive tasks. The first task was a visuomotor tracking task that as part of the tunnel environment (they had to track and control a black-and-white game object to hit the centre of cubes in the tunnel as accurately as possible by moving a joystick on a VR controller). The second task was a visual discrimination task presented on a virtual screen in the centre of the subject’s field of view (a stream of different coloured shapes - red, green and blue; circles, pentagons and squares - was presented with the target - a green circle - appearing every 2-3 seconds. The subject had to response to the target as quickly as possible by pressing a trigger while ignoring all non-target distractors).

[0129] Each subject underwent a training phase lasting four minutes to familiarise themselves with the controls and tasks. This was then followed by the main task - a tunnel travel task comprising the two cognitive tasks. The tunnel travel task lasted 28 minutes in total, divided into five runs lasting four minutes each. The movement speed of the tunnel was fixed in each run. After each four-minute run, there was a two- minute break where the tunnel stopped and subjects rated their experience of VR motion sickness on FMS, following the FMS rating, and completed a survey to scale their perception of stimulation (phosphene, headache, neck pain, scalp pain, tingling, itching, burning sensation, sleepiness, trouble concentrating, and acute mood change) from 0 (unnoticeable) to 10 (severe).

[0130] As discussed above, for each test of the system, the stimulation electrode 104 was placed at the P3 position. The return electrodes 106a-c were placed at the CP1 , TP7 and O1 positions respectively. The current intensity of the stimulation electrode 104 was set to 0.999 mA, while the current intensity of each of the return electrodes 106a-c was set to 0.333 mA. The impedance of each of the electrodes 104, 106a- c was held below 10 kQ, Each of the electrodes was a circular electrode having a radius of 1 cm, although other shapes and sizes of the electrodes may be used without limitation.

[0131] The active stimulation session involved applying a stimulation signal, such as shown in Figure 1 with a 10-second ramp up and 10-second ramp down either side of each stimulation signal delivery.

[0132] The sham stimulation session involved applying a 10-second ramp up period immediately followed by a 10-second ramp down period with no signal delivered between the ramp-up and ramp-down periods.

[0133] The control session involved applying a standard 18 Hz alternating current signal with a 10-second ramp- up and a 10-second ramp down either side of each signal delivery.

[0134] Figure 6 shows experimental results demonstrating the efficacy of the system described herein for alleviating nausea.

[0135] As can be seen from Figure 6, the sensation of experiencing VR motion sickness increases with time during each stimulation session but that, over the course of the first 16 minutes of stimulation, the stimulation signal (such as shown in Figure 1) effectively alleviates the sensation of nausea compared to the sham session (expected to and seen to induce a ‘standard’ level of VR motion sickness) and the control session (expected to and seen to induce an enhanced level of VR motion sickness). As such it can be seen that the stimulation signal described herein (and shown in exemplary form in Figure 1) is suitable for (and indeed adapted to) alleviate nausea in a subject.

[0136] Figure 7 shows experimental results plotting indications of different forms of discomfort experienced by subjects during application of the active, sham and control stimulations. As can be seen from Figure 7, it can be clearly seen that there is little to no perceptible side effect from application of the stimulation signal to the brain of the subject (the perception scores for each side effect being less than 2 and often less than 1).

[0137] For example, the application of the stimulation signal can be seen to have induced little to no perception of phosphenes.

[0138] With respect to the onset of headaches, it can be seen that the application of the stimulation signal caused a headache that increased in severity overtime but that the severity of the headache remained almost unnoticeable throughout the stimulation process.

[0139] It can also be seen that the application of the stimulation signal induced practically unnoticeable levels of neck pain with only a very slight increase in the perception of neck pain over the course of the stimulation period.

[0140] Similarly, almost entirely unnoticeable levels of scalp pain were reported.

[0141] Subjects reported a slight increase in sleepiness over the course of the stimulation period but this increase was broadly consistent across the active, sham, and control sessions and so is not attributable to the stimulation signal itself.

[0142] No increase in itching was reported by any subjects during the stimulation period, and the perception of itching was consistently almost completely unnoticeable by the subjects.

[0143] Subjects experienced little to no tingling sensation during the course of the stimulation period and, indeed the perception of tingling decreased over time during the active stimulation session.

[0144] Similarly, subjects experienced little to no burning sensation during the course of the stimulation period.

[0145] With respect to both tingling and burning sensations, it is noted that the control session (the non-phase- modulated 18 Hz stimulation) induced higher levels of tingling and burning sensations, while the phase- disrupted stimulation signal described herein, and shown in exemplary form in Figure 1 , induces unexpectedly lower levels of burning and tingling.

[0146] The application of the stimulated signal had little to no impact on the subject’s perception of their ability to concentrate during the stimulation session, and the application of any of the active, sham and control stimulation sessions did not result in any acute mood changes at all.

[0147] The application of the stimulated signal to the brain for mitigating nausea is compared to the application of GVS and BCV in Table 2. As summarized in Table 2, the application of the stimulated signal exhibited more fast-acting alleviation of nausea than GVS and BCV. For example, the stimulated signal exhibited nausea mitigation effects after 10 mins, which is 20 mins faster than GVS (Weech et al., 2020) and 15 minutes faster than BCV (determined experimentally).

[0148] Table 2: Comparison between the proposed method, GVS and BCV

[0149] The features disclosed in the foregoing description, or in the following claims, or in the accompanying drawings, expressed in their specific forms or in terms of a means for performing the disclosed function, or a method or process for obtaining the disclosed results, as appropriate, may, separately, or in any combination of such features, be utilised for realising the invention in diverse forms thereof.

[0150] While the invention has been described in conjunction with the exemplary embodiments described above, many equivalent modifications and variations will be apparent to those skilled in the art when given this disclosure. Accordingly, the exemplary embodiments of the invention set forth above are considered to be illustrative and not limiting. Various changes to the described embodiments may be made without departing from the spirit and scope of the invention.

[0151] For the avoidance of any doubt, any theoretical explanations provided herein are provided for the purposes of improving the understanding of a reader. The inventors do not wish to be bound by any of these theoretical explanations.

[0152] Any section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0153] Throughout this specification, including the claims which follow, unless the context requires otherwise, the word “comprise” and “include”, and variations such as “comprises”, “comprising”, and “including” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

[0154] It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent “about,” it will be understood that the particular value forms another embodiment. The term “about” in relation to a numerical value is optional and means for example + / - 10%.

[0155] References

[0156] A number of publications are cited above in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Full citations for these references are provided below. The entirety of each of these references is incorporated herein.

[0157] Weech, S., Wall, T., & Barnett-Cowan, M. (2020). Reduction of cybersickness during and immediately following noisy galvanic vestibular stimulation. Experimental Brain Research, 238(2), 427-437. https: / / doi.Org / 10.1007 / S00221 -019-05718-5

[0158] Griffin, M. (1996, October 17). Handbook of Human Vibration, https: / / shop.elsevier.com / books / handbook- of-human-vibration / griffin / 978-0-12-303041 -2

[0159] Li, G., McGill, M., Brewster, S., Chen, C. P., Anguera, J. A., Gazzaley, A., & Rollick, F. (2022) Datasets for multimodal biosensing for vestibular network-based cybersickness detection [Data set], Zenodo. https: / / doi.org / 10.5281 / zenodo.6373681

[0160] Li, G., Varela, F. M., Habib, A., Zhang, Q., McGill, M., Brewster, S., & Rollick, F. (2020). Exploring the feasibility of mitigating VR-HMD induced cybersickness using cathodal transcranial direct current stimulation. 2020 IEEE International Conference on Artificial Intelligence and Virtual Reality (AIVR), 123-

[0161] 129. https: / / doi.Org / 10.1109 / AIVR50618.2020.00030

[0162] Anguera, J. A., Boccanfuso, J., Rintoul, J. L., Al-Hashimi, O., Faraji, F., Janowich, J., Kong, E., Larraburo, Y., Rolle, C., Johnston, E., & Gazzaley, A. (2013). Video game training enhances cognitive control in older adults. Nature, 501 (7465), Article 7465. https: / / doi.org / 10.1038 / nature12486

[0163] Reference Numerals

[0164] 100 Neural stimulation system

[0165] 102 Signal generator

[0166] 104 Stimulation electrode

[0167] 106a-c Return electrodes

[0168] 108 Wearable cap

Claims

Claims:1 . A signal generator configured to generate a signal adapted to be delivered to the brain of a subject to alleviate nausea in the subject, wherein the stimulation signal is defined by a waveform having a frequency and a phase, and wherein the stimulation signal is characterized by one or more instantaneous disruptions of the phase of the waveform.

2. A delivery unit configured to receive a stimulation signal, wherein the delivery unit comprises one or more electrodes configured to deliver the stimulation signal to the brain of a subject, wherein the stimulation signal is defined by a waveform having a frequency and a phase, and wherein the stimulation signal is characterized by one or more instantaneous disruptions of the phase of the waveform.

3. The delivery unit according to claim 2, further comprising: a wearable cap, wherein the one or more electrodes are mounted on or in the wearable cap.

4. The delivery unit according to claim 2 or 3, wherein the one or more electrodes are positioned such that they are configured to deliver the stimulation signal to the left parietal cortex of the subject.

5. The delivery unit according to any of claims 2 to 4, wherein the one or more electrodes include one or more stimulation electrodes configured to deliver the stimulation signal to the brain of the subject, and one or more return electrodes configured to remove current from the brain of the subject after delivery of the stimulation signal by the one or more stimulation electrodes.

6. The delivery unit according to any of claims 2 to 5, wherein the one or more electrodes include one stimulation electrode and a plurality of return electrodes.

7. The delivery unit according to any of claims 2 to 6, wherein the delivery unit is integrated with a virtual reality headset or an augmented reality headset.

8. A stimulation signal adapted to be delivered to the brain of a subject to alleviate nausea in the subject, wherein the stimulation signal is defined by a waveform having a frequency and a phase, and wherein the stimulation signal is characterized by one or more instantaneous disruptions of phase of the waveform.

9. The stimulation signal according to claim 8, wherein the stimulation signal is characterized by a plurality of instantaneous disruptions of the phase of the waveform, and having a respective number of complete cycles of the waveform between each instantaneous disruption of the phase.

10. The stimulation signal according to claim 9, wherein the respective number of complete cycles of the waveform between each instantaneous disruption of the phase varies between each successive pair of instantaneous disruptions of the phase.11 . The stimulation signal according to claim 9 or 10, wherein the waveform is defined by a cyclically repeating waveform section, the waveform section being characterized by one or more instantaneous disruptions of the phase and a respective number of complete cycles of the repeating waveform section between each of the instantaneous disruptions of the phase.

12. The stimulation signal according to claim 11 , wherein the respective number of complete cycles of the repeating waveform section between each of the instantaneous disruptions of the phase is different between each pair of instantaneous disruptions of the phase.

13. The stimulation signal according to claim 11 or 12, wherein each cyclically repeating waveform section includes three or more instantaneous disruptions of the phase.

14. The stimulation signal according to any of claims 9 to 13, wherein the respective number of complete cycles between each successive pair of the instantaneous disruptions of the phase is randomly determined.

15. The stimulation signal according to any of claims 8 to 14, wherein the frequency of the waveform is 25 Hz or less.

16. The stimulation signal according to any of claims 8 to 15, wherein the frequency of the waveform is 10 Hz or more.

17. The stimulation signal according to any of claims 8 to 16, wherein the frequency of the waveform is fixed.

18. The signal generator according to claim 1 , wherein the signal generator is configured to generate the stimulation signal according to any of claims 8 to 17.

19. The delivery unit according to any of claims 2 to 7, wherein the delivery unit is configured to receive the stimulation signal according to any of claims 8 to 17, and wherein the one or more electrodes are configured to deliver said stimulation signal to the brain of a subject.

20. A system for alleviating nausea, the system comprising: a signal generator according to claim 1 or 18; and the delivery unit according to any of claims 2 to 7 or 19.21 . A computer-readable medium comprising instructions that, when executed by a computer comprising a signal generator, cause the signal generator to generate the stimulation signal of any of claims 8 to 17.

22. A computer program product comprising logic that, when executed by a computer comprising a signal generator, causes the signal generator to generate the stimulation signal of any of claims 8 to 17.

23. A method of alleviating nausea, the method comprising: generating the stimulation signal according to any of claims 8 to 17; and delivering the stimulation signal to the brain of a subject via one or more electrodes to alleviate nausea in the subject.

24. The method of alleviating nausea according to claim 23, wherein generating the stimulation signal comprises generating the stimulation signal by the signal generator of claim 1 or 18.

25. The method of alleviating nausea according to claim 23 or 24, wherein delivering the stimulation signal to the brain of a subject comprises delivering the stimulation signal by the delivery unit of any of claims 2 to 7 or 19.

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