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WO2025097075A1 - Méthodes et appareils pour le traitement non invasif de troubles du système nerveux - Google Patents

Méthodes et appareils pour le traitement non invasif de troubles du système nerveux Download PDF

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Publication number
WO2025097075A1
WO2025097075A1 PCT/US2024/054294 US2024054294W WO2025097075A1 WO 2025097075 A1 WO2025097075 A1 WO 2025097075A1 US 2024054294 W US2024054294 W US 2024054294W WO 2025097075 A1 WO2025097075 A1 WO 2025097075A1
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WIPO (PCT)
Prior art keywords
stimulation
stimuli
vibratory
electrotactile
vibrotactile
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Pending
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PCT/US2024/054294
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English (en)
Inventor
Peter A. Tass
Eric Aldenbrook
Gary BARBADILLO
Sean BRINKERHOFF
Mark Brinkerhoff
John Dring
Greg GENGARELLY
Justus A. KROMER
Eric WURTZ
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Leland Stanford Junior University
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Leland Stanford Junior University
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Publication of WO2025097075A1 publication Critical patent/WO2025097075A1/fr
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61H—PHYSICAL THERAPY APPARATUS, e.g. DEVICES FOR LOCATING OR STIMULATING REFLEX POINTS IN THE BODY; ARTIFICIAL RESPIRATION; MASSAGE; BATHING DEVICES FOR SPECIAL THERAPEUTIC OR HYGIENIC PURPOSES OR SPECIFIC PARTS OF THE BODY
    • A61H23/00—Percussion or vibration massage, e.g. using supersonic vibration; Suction-vibration massage; Massage with moving diaphragms
    • A61H23/02—Percussion or vibration massage, e.g. using supersonic vibration; Suction-vibration massage; Massage with moving diaphragms with electric or magnetic drive
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61H—PHYSICAL THERAPY APPARATUS, e.g. DEVICES FOR LOCATING OR STIMULATING REFLEX POINTS IN THE BODY; ARTIFICIAL RESPIRATION; MASSAGE; BATHING DEVICES FOR SPECIAL THERAPEUTIC OR HYGIENIC PURPOSES OR SPECIFIC PARTS OF THE BODY
    • A61H23/00—Percussion or vibration massage, e.g. using supersonic vibration; Suction-vibration massage; Massage with moving diaphragms
    • A61H23/02—Percussion or vibration massage, e.g. using supersonic vibration; Suction-vibration massage; Massage with moving diaphragms with electric or magnetic drive
    • A61H23/0245—Percussion or vibration massage, e.g. using supersonic vibration; Suction-vibration massage; Massage with moving diaphragms with electric or magnetic drive with ultrasonic transducers, e.g. piezoelectric
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/0404—Electrodes for external use
    • A61N1/0408—Use-related aspects
    • A61N1/0456—Specially adapted for transcutaneous electrical nerve stimulation [TENS]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/36014—External stimulators, e.g. with patch electrodes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61H—PHYSICAL THERAPY APPARATUS, e.g. DEVICES FOR LOCATING OR STIMULATING REFLEX POINTS IN THE BODY; ARTIFICIAL RESPIRATION; MASSAGE; BATHING DEVICES FOR SPECIAL THERAPEUTIC OR HYGIENIC PURPOSES OR SPECIFIC PARTS OF THE BODY
    • A61H2201/00—Characteristics of apparatus not provided for in the preceding codes
    • A61H2201/50—Control means thereof
    • A61H2201/5058—Sensors or detectors
    • A61H2201/5071—Pressure sensors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61H—PHYSICAL THERAPY APPARATUS, e.g. DEVICES FOR LOCATING OR STIMULATING REFLEX POINTS IN THE BODY; ARTIFICIAL RESPIRATION; MASSAGE; BATHING DEVICES FOR SPECIAL THERAPEUTIC OR HYGIENIC PURPOSES OR SPECIFIC PARTS OF THE BODY
    • A61H2205/00—Devices for specific parts of the body
    • A61H2205/06—Arms
    • A61H2205/065—Hands
    • A61H2205/067—Fingers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/36014—External stimulators, e.g. with patch electrodes
    • A61N1/36025—External stimulators, e.g. with patch electrodes for treating a mental or cerebral condition

Definitions

  • TECHNICAL FIELD [0002] The present embodiments relate generally to therapeutic techniques and more particularly to effective treatment of neurological disorders using noninvasive methods and apparatuses.
  • BACKGROUND [0003] Pharmacological and surgical treatments of Parkinsons disease (PD) may be limited because of side effects and reduced therapeutic efficacy.
  • Vibrotactile Coordinated Reset (vCR) stimulation was designed as an alternative or additional treatment for PD and other brain disorders characterized by abnormally synchronized neuronal activity. Specifically, vCR delivered to the patients fingertips was developed to provide a non-invasive alternative to deep brain stimulation (DBS) for PD therapy.
  • DBS deep brain stimulation
  • skin thickness, skin elasticity, skin viscosity, characteristics of the subcutaneous tissue are individual characteristics of every single patient that may vary with, e.g., age, gender, skin type, pigmentation, and smoking habits.
  • PD patients do not only suffer from motor impairments, but also from sensory impairments as well as an impairment of sensorimotor integration (i.e., the matching of motor and sensory commands in the brain).
  • sensorimotor integration i.e., the matching of motor and sensory commands in the brain.
  • receptive field sizes are enlarged in PD patients, impairing the proprioceptive input form the skin and rendering it significantly more coarse-grained than in healthy controls [Conte A, Khan N, Defazio G, Rothwell JC, Berardelli A.: Pathophysiology of somatosensory abnormalities in Parkinsons disease.
  • the present embodiments relate generally to therapeutic techniques and more particularly to effective treatment of neurological and psychiatric disorders using noninvasive methods and apparatuses.
  • Some embodiments relate to more effective vibrotactile stimulation, i.e., stronger physiological effects with less vibration power/amplitude, by means of a vibrotactile mechanical stimulator (tactor), comprising a combination of one or more elements among: (i) Shock absorber: The oscillating mass is coupled to the housing by a spring serving as shock absorber to effectively reduce the vibration of the tactor housing.
  • Nondisc contactor To increase the physiological/medical effects of vibrotactile stimuli, a physiologically more effective contactor shape.
  • Wavebreaking hole As additional feature (in one possible embodiment), a wavebreaker type (non-annular) perimeter around the hole further reduces the spread of surface waves in the free surround of the contactor.
  • a tactor of some embodiments enables physiologically more effective vibratory stimulation at considerably lower vibration amplitudes and, hence, significantly reduced noise levels.
  • vibrations of the housing of the tactor are considerably reduced so that, in turn, the propagation of skin vibration waves is significantly reduced.
  • the wave-breaking hole additionally reduces the wave propagation.
  • Some embodiments relate to enabling more effective non-invasive stimulation, by realizing a 3-(physiological) channel electrotactile stimulation of just one part of the skin, for example, one fingertip. Stimulation can easily be applied, e.g., at night in a convenient manner.
  • a 3-channel electrotactile stimulation of embodiments achieves physiologically more effective non-invasive stimulation with considerably lower battery requirements and no noise.
  • Stimulation can be delivered through only one stimulation site, e.g., one fingertip.
  • Other embodiments can use more than one stimulation sites, e.g., two or more fingertips. This can be done in early stages of the therapy, whereas later on single-site therapy can be used as maintenance therapy.
  • Some embodiments relate to enabling more effective non-invasive stimulation using vibrotactile and electrotactile fingertip stimulation. According to certain general aspects, the present embodiments effectively reduce unwanted mechanical and proprioceptive stimulation while securely mounting controller and battery for a fingertip stimulation array.
  • the present embodiments allow for vibrotactile and/or electrotactile and/or electrical and/or infrared fingertip stimulation with minimal amount of artificial hand stimulation. Furthermore, the present embodiments enable reduction of moisture buildup, discomfort, e.g., caused by friction. In addition, embodiments enable a safe connection between a low weight controller and the fingertip stimulators. Continuous physiological input to the non-covered skin of the hand enables sensory input that enhances favorable plasticity mechanisms and, hence, therapeutic effects. [0017] Some embodiments relate to enabling more effective non-invasive stimulation, by combining vibrotactile and electrotactile stimulation. On the one hand, the combination 5 S23-357-PCT P. Tass et al. Atty.
  • Dkt.102354-0785 enables to achieve a sufficient electrode-skin contact.
  • the combined stimulation enables using different physiological channels (per stimulation site), utilizing different mechanoreceptor channels, to achieve significantly stronger and more effective stimulation at lower amplitudes of the vibrotactile stimulation.
  • the hybrid stimulation of embodiments achieves physiologically more effective non-invasive stimulation at considerably lower vibration amplitudes and, hence, significantly reduced noise levels.
  • the combination of vibrotactile and electrotactile stimulation modalities realizes a considerably larger inventory of effective stimuli. This increases therapeutic efficacy and counteracts habituation effects.
  • Some embodiments relate to methods and apparatuses that use compound pulses and/or continuous stimulation with modulated amplitudes.
  • various embodiments include a device that delivers continuous stimulation with specifically modulated vibration amplitudes.
  • One compound pulse can contain more than only one supra-threshold part. These stimuli enable spatially more focal and/or shorter activation. In addition, shorter stimuli enable greater temporal jitter of stimulus onsets (as explained below). This is one aspect of embodiments, in addition to the remarkably precise Bluetooth connection between both controllers.
  • Some embodiments relate to or include personalization/calibration.
  • pedestals are adapted to the patient’s vibratory threshold and, hence, reflect a fundamental parameter of the patient’s sensory information processing. The vibratory threshold varies between patients. They may also vary within patients in the course of the treatment.
  • Some embodiments employ temporal jitter of stimulus onsets and/or temporal jitter of suprathreshold vibration amplitudes and/or temporal jitter of vibratory burst durations and/or subthreshold vibration amplitude and/or vibration frequency.
  • the compound pulses enable shorter vibratory pulse and, in turn, greater temporal jitter of stimulus onsets.
  • this may cause a further increase of the stimulation efficacy.
  • variation/jitter/randomization of more than one quantity may increase the stimulation 6 S23-357-PCT P. Tass et al.
  • Atty. Dkt.102354-0785 effect In one embodiment, the variations of the different quantities are not correlated. In another embodiment, the variation of two or more quantities may be correlated. [0021] Another embodiment uses methods to prevent in-channel masking effects. For example, to avoid mutual masking effects and habituation, the interval between any two subsequent vibrotactile stimuli, specifically vibratory bursts, delivered to the same stimulation channel (i.e., “in-channel”) should optimally amount to 3-5 times the vibrotactile stimulus’ duration. Compound stimuli enable to increase the temporal jitter of the stimulus onsets. However, to further increase the extent of temporal jitters not inducing in-channel masking effects, embodiments use specific methods to adapt stimulus parameters and stimulation patterns.
  • Some embodiments relate to specific hard- and firmware apparatuses as well as stimulation methods to overcome the limitations mentioned above, among others.
  • Embodiments enable considerably more precise vibrotactile and/or electrotactile stimulation, i.e., stronger physiological effects with less vibration power/amplitude, by avoiding interhemispheric inhibition by delivering wireless multisite stimulation to remote and/or bilateral stimulation sites at highest temporal precision.
  • Some embodiments provide for specific pairing of stimulus activations (i.e., varying and/or nonmirror-pairing) in case of bilateral stimulation.
  • a wireless synchronization mechanism of embodiments can be applied to a large class of applications, including but not limited to, e.g., noninvasive stimulation in a general sense, e.g., vibrotactile and/or electrotactile stimulation of different body parts together with visual and/or auditory and/or olfactory stimulation, with all or at least some of these devices being wirelessly connected.
  • embodiments enable connection of such devices with invasive devices such as deep brain stimulators and/or spinal cord stimulators and/or epicortical stimulators etc.
  • Some embodiments relate to a method and device that delivers non-invasive, in particular, sensory stimulation treatment in a way that counteracts habituation, e.g., by increasing and rewarding patients’ attention, alertness, curiosity level and activating additional brain areas besides primary sensory brain areas.
  • the present embodiments counteract habituation and increases the therapeutic effects, e.g., by boosting the propagation of desynchronizing effects through disease-related brain circuits. 7 S23-357-PCT P. Tass et al. Atty.
  • Dkt.102354-0785 Some embodiments relate to methods and apparatuses for automatically/autonomously calibrating relevant stimulation parameters for non-invasive and invasive multichannel CR stimulation and related stimulation techniques, random reset stimulation as well as combinations thereof. Several embodiments use vibrotactile and/or electrotactile stimulation. [0025] The present embodiments can potentially be applied to a wide range of disorders.
  • Abnormal neuronal synchronization and abnormal synaptic connectivity patterns are not only found in Parkinsons disease, but are also characteristic of a larger number of disorders of the central and peripheral nervous system, for instance, movement disorders, essential tremor, tic disorders, Tourette’s syndrome, tremor in multiple sclerosis, dystonia, chronic stroke, epilepsy, depression, migraine, tension headache, spasticity, incomplete spinal cord injury, obsessive/compulsive disorder, attention deficit hyperactivity disorder (ADHD), irritable bowel syndrome, chronic pain syndromes, e.g., complex regional pain syndrome, neuropathic pain and trigeminal neuralgia, pelvic health disorders, e.g., pelvic pain or overactive bladder, tinnitus, dissociation in borderline personality disorder and post-traumatic stress disorder.
  • ADHD attention deficit hyperactivity disorder
  • FIGs.1A and 1B illustrate an example tapper assembly according to embodiments in unexploded and exploded format, respectively.
  • FIG.2 illustrates one potential version of a vibration motion generating device according to embodiments.
  • FIG.3 is an exploded view of an example motor assembly according to embodiments.
  • FIG.4 illustrates aspects of how a contactor according to embodiments is allowed to touch the finger surface very consistently no matter what skin profile is presented from the tapper housing.
  • FIG.5 provides an overall view of an example tapper assembly view showing the device and the connecting cable.
  • FIG.6 shows an example Large Finger insertion according to embodiments. 8 S23-357-PCT P.
  • FIGs.7A to 7C illustrate an example of how a large finger is inserted, and the strap ends are tightened and latched in place with the star levers according to embodiments.
  • FIGs.8A and 8B illustrate an example Small Finger insertion according to embodiments.
  • FIGs.9A to 9C further illustrate an example Small Finger Insertion of embodiments.
  • FIGs.10A and 10B show an example of star Levers in open position, and latched in closed position, respectively.
  • FIG.11 illustrates an example Octaberry Contactor according to embodiments.
  • FIG.12 illustrates many possible shapes of contactors and surround shapes according to embodiments.
  • FIG.13 illustrates an example of different contactor and surround shapes according to embodiments.
  • FIG.14 illustrates another example of different contactor and surround shapes according to embodiments.
  • FIG.15 illustrates an example embodiment with two different pairs of contactors.
  • FIG.16 illustrates an example of a pressure sensor according to embodiments.
  • FIG.17 is a contactor ground view of an octaberry according to embodiments.
  • FIG.18 is a graph which shows vs. , where . denotes the radius of the hole, and is the length of of the octagon to embodiments.
  • FIG.26 is a schematic showing the cross section of upper (‘1’) and lower (‘2’) part of an example pulse oximeter-type housing of a 3-channel electrotactile single-finger stimulator according to embodiments.
  • FIG. 27 is a schematic illustrating an example zero-baseline monophasic pulse form with non-vanishing net dc current with amplitude I E and duration T E according to embodiments.
  • FIG. 28 is a schematic illustrating an example monophasic pulse form with non- vanishing baseline and zero average current as used in an embodiment.
  • FIG. 29 is a schematic illustrating an example monophasic pulse form with non- vanishing baseline and zero average current as used in an embodiment.
  • FIG.30 is a schematic illustrating an example balanced biphasic pulse form with vanishing baseline and zero average current as used in an embodiment.
  • FIG.31 is a schematic illustrating an example balanced biphasic pulse form with vanishing baseline and zero average current as used in an embodiment.
  • FIG.32 is a schematic illustrating an example asymmetric balanced biphasic waveform with vanishing baseline and zero average current as used in an embodiment.
  • FIG.33 is a schematic illustration of an example 3:2 ON-OFF CR RVS (rapidly varying sequences) stimulation with electrotactile stimulation according to embodiments.
  • FIG.34 is a top view of an example controller with fixation band according to embodiments.
  • FIG.35 is a top view of another example controller with fixation band according to embodiments.
  • FIG.36 is a top view of another example controller with fixation band according to embodiments.
  • FIG.37 is a bottom view of an example fixation band according to embodiments.
  • FIG.38 is a bottom view of another example fixation band according to embodiments.
  • FIG.39 is a side view of an example fixation band according to embodiments.
  • FIG.40 is a side view of another example fixation band according to embodiments. 10 S23-357-PCT P. Tass et al. Atty. Dkt.102354-0785
  • FIG.41 illustrates another example embodiment.
  • FIG.42 is a schematic showing an example base of one embodiment of a circular hybrid contactor.
  • FIG.43 is a schematic showing an example base of one embodiment of a stretched octaberry.
  • FIG.44 is a schematic illustrating an example 100 ms vibratory pulse starting at 0.1 s, around constant indentation 0.5 mm, according to embodiments.
  • FIG.45 is a schematic of an example steplike stimulus starting at t 1 and ending at t2, with vanishing indentation baseline according to embodiments.
  • FIG.46 is a schematic of an example smooth steplike stimulus starting at t1 and ending at t 2 , with vanishing indentation baseline according to embodiments.
  • FIG.47 is a schematic of an example steplike stimulus starting at t1 and ending at t2, with non-vanishing indentation baseline according to embodiments.
  • FIG.48 Schematic illustrating a zero-baseline monophasic pulse form with non- vanishing net dc current with amplitude I E and duration T E according to embodiments.
  • FIG.49 is a schematic illustrating an example monophasic pulse form with non- vanishing baseline and zero average current as used in another embodiment.
  • FIG.50 is a schematic illustrating an example monophasic pulse form with non- vanishing baseline and zero average current as used in another embodiment.
  • FIG.51 is a schematic illustrating an example balanced biphasic pulse form with vanishing baseline and zero average current as used in another embodiment.
  • FIG.52 is a schematic illustrating an example balanced biphasic pulse form with vanishing baseline and zero average current as used in another embodiment.
  • FIG.53 is a schematic illustrating an example asymmetric balanced biphasic waveform with vanishing baseline and zero average current as used in another embodiment.
  • FIG.54 is a schematic illustrating an example steplike mechanical stimulus and the corresponding electrotactile stimulus train according to embodiments.
  • FIG.55 is a schematic illustrating an example 1:1 phase locked hybrid (i.e., combined vibratory and electrotactile) stimulation with zero phase shift according to embodiments. 11 S23-357-PCT P. Tass et al. Atty. Dkt.102354-0785
  • FIG.56 is a schematic illustrating an example 1:1 phase locked hybrid (i.e., combined vibratory and electrotactile) stimulation with non-zero phase shift according to embodiments.
  • FIG.57 is a schematic illustrating an example hybrid (i.e., combined vibratory and electrotactile) stimulation with increasing 1:n cycle ratio between vibratory and electrotactile (e.g., with n increasing from 1 to 3 in the course of the vibratory burst according to embodiments.
  • FIG.58 is a schematic illustrating an example 2:1 phase locked bimodal (i.e., combined vibratory and electrotactile) stimulation with zero phase shift, where one electrotactile stimulus is delivered per 2 vibratory cycles according to embodiments.
  • FIG.59 is a schematic illustrating an example 1:2 phase locked bimodal (i.e., combined vibratory and electrotactile) stimulation with zero phase shift, where two electrotactile stimuli are delivered per vibratory cycle according to embodiments.
  • FIG.60 is a schematic illustrating an example 1:3 phase locked bimodal (i.e., combined vibratory and electrotactile) stimulation with zero phase shift, where three electrotactile stimuli are delivered per vibratory cycle according to embodiments.
  • FIG.61 is a schematic illustrating an example 1:1 phase locked hybrid (i.e., combined vibratory and electrotactile) stimulation with zero phase shift according to embodiments.
  • FIG.62 is a schematic illustrating an example 1:1 phase locked hybrid (i.e., combined vibratory and electrotactile) stimulation with zero phase shift, with different vibratory and electrotactile stimulus duration according to embodiments.
  • FIG.63 is a schematic illustrating an example phase locked hybrid (i.e., combined vibratory and electrotactile) stimulation with zero phase shift, with temporally patterned electrotactile stimulus and more complex cycle ratio between vibratory and electrotactile stimulation according to embodiments.
  • FIG.64 is a schematic illustrating an example phase locked hybrid (i.e., combined vibratory and electrotactile) stimulation with zero phase shift, with temporally patterned electrotactile stimulus and more complex cycle ratio between vibratory and 12 S23-357-PCT P. Tass et al. Atty. Dkt.102354-0785 electrotactile stimulation, where the m:1 cycle ratio changes during a vibratory burst, with m decreasing from 3 to 1 according to embodiments.
  • phase locked hybrid i.e., combined vibratory and electrotactile
  • FIG.65 is a schematic illustrating an example phase locked hybrid (i.e., combined vibratory and electrotactile) stimulation with zero phase shift, with temporally patterned electrotactile stimulus and more complex cycle ratio between vibratory and electrotactile stimulation, where the final 4 electrotactile stimuli are delivered phase locked to the pedestal according to embodiments.
  • FIG.66 is a schematic illustrating an example 2:1 phase locked hybrid (i.e., combined vibratory and electrotactile) stimulation with zero phase shift, with phase locked electrotactile stimuli coinciding with half of the maxima of the vibratory burst according to embodiments.
  • FIG.67 is a schematic illustrating an example 4:1 phase locked hybrid (i.e., combined vibratory and electrotactile) stimulation with zero phase shift, with phase locked electrotactile stimuli coinciding with a fourth of the maxima of the vibratory burst according to embodiments.
  • FIG.68 is a schematic illustrating an example hybrid stimulation with temporal jitter between vibrotactile and electrotactile stimuli according to embodiments.
  • FIG.69 is a diagram illustrating an example of a standard vibration signal with high (250 Hz) intra-burst frequency with constant 0.5 mm indentation.
  • FIG.70 is a diagram illustrating an example of a novel vCR vibration signal with high (250 Hz) intra-burst frequency with constant 0.5 mm indentation and sub-threshold pedestal, circumscribed in time, according to embodiments.
  • FIG.71 is a diagram illustrating an example of a vibratory signal with high (250 Hz) intra-burst frequency with constant 0.5 mm indentation and continuous sub-threshold pedestal.
  • FIG.72 is an example schematic illustration of 3:2 ON-OFF CR RVS (rapidly varying sequences) stimulation without pedestals according to embodiments.
  • FIG.73 illustrates the corresponding vCR stimulation pattern with pedestals according to embodiments.
  • FIG.74 is a diagram illustrating an example of the first period of a jitter-free CR sequence (blue hatched stimuli) with jitter intervals (blue rectangles) and final stimuli (solid blue stimuli) (following an OFF period) according to embodiments.
  • FIG.75 is a schematic illustration of an example vibrotactile 3:2 ON-OFF CR RVS pattern with pedestals and uniform randomization of the vibration amplitude according to embodiments.
  • FIG.76 is a schematic illustration of an example vibrotactile 3:2 ON-OFF CR RVS pattern with pedestals and uniform randomization of the vibratory burst durations according to embodiments.
  • FIG.77 is a schematic illustrating an example slow random variation of the pedestal in channel 1 according to embodiments.
  • FIG.78 is a schematic illustrating an example combination of a slow variation of the carrier-type frequency , a slow random variation of the pedestal and a variation of the burst amplitude in channel 2 according to embodiments.
  • FIG.79 is an example illustration of an in-channel masking prevention (IMP) pause (illustrated by shaded rectangle) of three times the duration of the vibratory burst according to embodiments.
  • IMP in-channel masking prevention
  • FIG.80 is an example illustration of an in-channel masking prevention (IMP) pause (illustrated by shaded rectangle) of three times the duration of the vibratory burst according to embodiments.
  • FIG.81 is an example illustration of a jitter-free CR sequence with in-channel masking prevention pauses (red bars) according to embodiments.
  • FIG.82 is an example illustration of the period between vibratory bursts and in the j-th channel according to embodiments.
  • FIG.83 is an example illustration of stimulus trains with different mean period according to embodiments.
  • FIG.84 is an example illustration of a (jitter-free) CR sequence with different percentage of skipped (i.e., inactivated) stimuli according to embodiments.
  • FIG.85 is a schematic illustrating an example interaction between master session timer and local session timer according to embodiments. 14 S23-357-PCT P. Tass et al. Atty. Dkt.102354-0785
  • FIG.86 is a functional block diagram illustrating example aspects of embodiments.
  • FIG.87 illustrates an example of the intermingled administration of main stimulation mode (“main mode”) and rare stimulation mode (“rare mode”) according to embodiments.
  • FIG.88 illustrates an example of the intermingled administration of the main stimulation mode (“main mode”) and two rare stimulation modes (“rare mode 1” and “rare mode 2”) according to embodiments.
  • FIG.89 illustrates another example of the intermingled administration of the main stimulation mode (“main mode”) and two rare stimulation modes (“rare mode 1” and “rare mode 2”) according to embodiments.
  • FIG.90 illustrates an example of the intermingled administration of the main stimulation mode (“main mode”) and three rare stimulation modes (“rare mode 1”, “rare mode 2” and “rare mode 3”) according to embodiments.
  • FIG.91 illustrates an example regular 3:2 ON-OFF CR RVS (rapidly varying sequences) pattern according to embodiments.
  • FIG.92 illustrates an example of an embodiment #1 rare mode cycle C r interspersed in the main mode vCR pattern from Figure 5 according to embodiments.
  • FIG.93 illustrates an example of two embodiment #1 rare mode cycles Cr interspersed in the main mode vCR pattern from Figure 5 according to embodiments.
  • FIG.94 illustrates another example of two embodiment #1 rare mode cycles C r interspersed in the main mode vCR pattern from Figure 5 according to embodiments.
  • FIG.95 illustrates an example of an embodiment #2 rare mode cycle Cr interspersed in the main mode vCR pattern from Figure 5 according to embodiments.
  • FIG.96 illustrates an example of an embodiment #4 rare mode cycle Cr interspersed in the main mode vCR pattern from Figure 5 according to embodiments.
  • FIG.97 illustrates an example of an embodiment #4 rare mode cycle C r interspersed in the main mode vCR pattern from Figure 5 according to embodiments.
  • FIG.99 is a diagram illustrating an example where random jitter was added to the stimulus onset times according to embodiments.
  • FIG.105B shows how the CR sequence pools are named.
  • FIG.106 illustrates mean synaptic weight after stimulation onset averaged over different network and sequence realizations according to embodiments.
  • FIG.107 illustrates trajectories of the Kuramoto order parameter (top) and the mean synaptic weight (bottom) during a session with stimulation epochs according to embodiments.
  • FIG.108 illustrates total reward after each session for subsequent sessions achieved by the RL algorithm according to embodiments.
  • FIG.109 illustrates traces of the simulated patient’s condition, the Kuramoto order parameter, , and the mean synaptic weight, , during the indicated sessions for the two cases in FIG.108 according to embodiments.
  • FIG.110 is a schematic of a setup to adjust the probability at which CR sequences are drawn during shuffled CR according to embodiments. 16 S23-357-PCT P. Tass et al. Atty.
  • FIG.111 provides simulated traces of the simulated patient’s condition, the Kuramoto order parameter, and the mean synaptic weight according to embodiments.
  • FIGs.112A-112D illustrates simulations for each network type and different initial mean synaptic weights according to embodiments.
  • FIGs.113A-113D provide statistical analysis of mean synaptic weight before, during, and after stimulation for inhomogeneous networks (A,B) and homogeneous networks (C,D) according to embodiments.
  • Embodiments described as being implemented in software should not be limited thereto, but can include embodiments implemented in hardware, or combinations of software and hardware, and vice-versa, as will be apparent to those skilled in the art, unless otherwise specified herein.
  • an embodiment showing a singular component should not be considered limiting; rather, the present disclosure is intended to encompass other embodiments including a plurality of the same component, and vice-versa, unless explicitly stated otherwise herein.
  • the present embodiments encompass present and future known equivalents to the known components referred to herein by way of illustration. 17 S23-357-PCT P. Tass et al.
  • Atty. Dkt.102354-0785 [00138] Among other things, the present Applicant recognizes that ideally, therapeutic stimulation of the skin of the fingertips should be performed with constant pressure, irrespective of the position of the hand and fingers.
  • the present Applicant recognizes that ideally, therapeutic stimulation of the skin of the fingertips should be performed with constant pressure, irrespective of the position of the hand and fingers.
  • vCR pilot studies performed so far [K.J. Pfeifer, J.A. Kromer, A.J. Cook, T. Hornbeck, E.A. Lim, B.J.P. Mortimer, A.S. Fogarty, S.S. Han, R. Dhall, C.H. Halpern, P.A. Tass: Coordinated Reset Vibrotactile Stimulation Induces Sustained Cumulative Benefits in Parkinson’s Disease.
  • embodiments use a custom plastic and rubber enclosure that has an elastomeric band. This band can be tightened or loosened by both clinicians and patients to create a suitable pressure interface between contactor and the skin surface.
  • the device is designed to fit all primary finger sizes from a 5% Asian female size to a 95% Caucasian male size.
  • the device of some embodiments has two primary modes of fitment.
  • the first is for larger diameter fingers and has a rubber pad pressing against the fingernail with a wraparound elastic strap providing the necessary skin contact pressure.
  • the arrangement is too large for small fingers so it has a second mode of fitment.
  • the second mode includes the shifting of the rubber pad to a more constrained position which creates a smaller opening for finger compression. Both of these modes use the elastomeric strapping and are adjustable to suit the actual needs of the patient.
  • the present embodiments describe fingertips, but the new mechanical stimulator and, in particular, the non-disc-contactor can also be mounted to other parts of the body, e.g., the back of the fingers, the back/palm of the hand, the forearm etc.
  • FIG.1A An example tapper assembly 100 according to embodiments is shown in unexploded and exploded format in FIGs.1A and 1B, respectively.
  • the assembly 100 comprises a finger top soft cover 102, a strap 104, a housing top cover 106, a bottom half 108 and a star lever 110.
  • FIG.1B illustrates how the strap 104 integrates with the finger top cover 102, which together connect with the housing top cover 106.
  • FIG.1B further 18 S23-357-PCT P.
  • Tass et al. Atty. Dkt.102354-0785 illustrates how the tapper 112 projects into the top cover 106, while housed in the bottom half 108.
  • FIG.2 illustrates one potential version of the vibration motion generating device 202.
  • the tapper is comprised of a linear motor 202 that vibrates linearly toward and away from the fingerprint skin surface at a vibration frequency. It is intended to operate at various forces / frequencies.
  • this motor 202 has a central post and other mating components that fasten and align with each other to provide a suspension system that directs and constrains the majority of the vertical motion in a single central axis.
  • the two flat spring elements provide a flexure and a spring return feature as the motor vibrates.
  • Each flat spring is bonded to the moving element/mass 206 in the center area and to the housing 204 on the outer surfaces.
  • This layout provides motor compliance to the user’s finger surface and can maintain intermittent contact during motor operation (tapper feature).
  • different amounts of indentation will be accomplished during motor operation.
  • the tapper mounted to the fingertip in the absence of motor action (i.e., without vibration being delivered), the skin indentation is substantially constant, but varies across the contactor surface.
  • an example contactor enables two advantageous features of stimulation: [00145] (i) The skin indentation of the contactor is spatially varying in the absence of vibration. This can be particularly effective for the stimulation of the FA I and FA II mechanoreceptors. [00146] (ii) For adequately tuned length of the connection between contactor and motor, parts of the contactor have no skin contact during specific phases of the motor’s oscillation. These parts repetitively push into the skin and get retracted. Stimulation with revolving skin 19 S23-357-PCT P.
  • FIG.3 illustrates example aspects of a double flat spring architecture of embodiments.
  • embodiments significantly reduce motor- induced vibrations of the tapper’s housing. This is significant because ideally only the top contactor 302 should move, whereas the stationary, non-vibrating housing should block vibratory skin waves from propagating beyond the chosen area.
  • the tapper utilizing more than two flat springs and equivalent elements. However, all of these embodiments are characterized by reduced coupling between the motor elements and tapper housing 204. In particular, any stiff coupling between motor and housing is avoided. In this way, motor oscillations are not directly locked to the housing.
  • the driving vibration motor has a small embedded driving coil and a dedicated moving mass within it in a very small format (small diameter specifically).
  • embodiments mount an entire small motor assembly to the center area of parallel flat spring elements 304, 310 via a post 316 and bottom hub 314. These flat spring elements are specifically designed with embedded flexures (e.g.306, 308) to allow perpendicular linear motion.
  • the flat springs 304, 310 have cut outs that create flexures for the motor attachment in the center area. The arrangement is very much like a trampoline. This allows very focused linear driving forces/motion exactly where needed.
  • the configuration also provides a soft suspension system that complies with the position of the patient’s finger surface. It basically allows the contactor (e.g. implemented as an octaberry 402 in FIG.4) to touch the finger surface very consistently no matter what skin profile is presented from the tapper housing. 20 S23-357-PCT P. Tass et al.
  • FIG.4 illustrates aspects of how a contactor 402 according to embodiments is allowed to touch the finger surface very consistently no matter what skin profile is presented from the tapper housing.
  • FIG.5 provides an overall view of tapper assembly view showing the device and the connecting cable. This cable connects to the driver system that provides pulsed therapeutic signals. The connecting cable comes in various lengths to accommodate large to small finger lengths. Lengths are measured in centimeters between the back of the Tapper assembly wall and the midpoint of the connector jack.
  • Large Finger Mode The finger top soft cover is open to the full width of the housing (lower left to upper right in this view). This allows a large finger to be inserted into the 21 S23-357-PCT P.
  • FIG.6 illustrates an example showing a large finger insertion aspects. The large finger is inserted, and the strap ends are tightened and latched in place with the star levers, as further illustrated in FIGs.7A-7C.
  • Small Finger Mode The finger top part is narrowed within the side walls of the housing. This allows a small finger to be inserted into the tapper assembly, as further illustrated in FIGs.8A and 8B.
  • FIGs.9A to 9C further illustrate aspects of an example small finger insertion of embodiments.
  • FIGs.10A and 10B show an example of star levers 1002 in open position, and latched in closed position, respectively. They provide low profile latching with the elastic strap ends and can be operated (tightened and latched) with one hand.
  • An example octaberry contactor 1102 according to embodiments is shown from top view in FIG.11. This shape is specifically designed to maximize skin sensitivity to minimal vibration energy. Basically, it moves up and down to tap the fingerprint skin surface and create the desired sensation.
  • contactor 1102 shown in FIG.11 is just one of many possibilities as illustrated in FIG.12. Any of these or other shapes can be mounted within the vibration device.
  • the cross hatched portions of these are moving contactors that can protrude through any hole shape.
  • One purpose of the free surround area between contactor and tapper housing is to block or reduce the propagation of skin vibration waves. In the vCR pilot studies performed so far [K.J. Pfeifer, J.A. Kromer, A.J. Cook, T. Hornbeck, E.A. Lim, B.J.P. Mortimer, A.S. Fogarty, S.S. Han, R. Dhall, C.H. Halpern, P.A.
  • Tass Coordinated Reset Vibrotactile Stimulation Induces Sustained Cumulative Benefits in Parkinson’s Disease. Frontiers in Physiology 12:624317 (2021)], the contactor was moving within a simple circular hole of the tactor housing.
  • the hole in the tactor housing may attain more complex, e.g., non-circular and/or wave-breaking shapes. This is to reduce the energy of the skin vibration wave before it actually reaches the tactor housing, in this way strengthening the damping effect of the tactor housing. 22 S23-357-PCT P. Tass et al. Atty.
  • FIG.12 illustrates different breakwater-type of surrounds embracing the contactor.
  • the five illustrated examples all include a small disk-like contactor 1202.
  • the contactor is surrounded by a low-lying area 1204-1 to 1204-5.
  • the depth of this low- lying area can be chosen such that the skin is not able to touch the bottom of this low-laying area.
  • the skin touches (parts of) the low-lying area.
  • the low-lying area is embraced, e.g., by a circular surround (e.g.1204-1) or flower-shaped surround (e.g.1204-2, 1204-3, 1204-4).
  • the surround may attain more complex, breakwater-type shapes to contain vibratory skin waves by means of destructive interference.
  • the low-lying area there may be lifted areas.
  • the low-lying area with lifted areas 1206 can be embraced by a circular surround 1204-5 or by a surround of breakwater-type of shape.
  • the lifted areas can have different shapes, e.g., the height of the lifted areas may increase with increasing distance from the contactor. All these different elements and embodiments are used to break or reduce skin vibratory waves.
  • FIG.13 illustrates different contactor and surround shapes.
  • FIG.14 illustrates additional different examples of contactor and surround shapes.
  • FIG.15 illustrates example embodiments with two different pairs of contactors.
  • FIG.16 An example of a pressure sensor 1602 is shown in FIG.16. It is comprised of piezo based technology and can be added to a number of locations on the assembly (above fingernail, on fingerprint area, under controller, etc). This example sensor is very thin and is calibrated to suit the range of forces of interest. It, or one like it, can also measure vibration in a range of interest for vibrotactile stimulation. Data from this sensor can be transmitted to any number of control / feedback systems.
  • Sensors in embodiments can be used for local and remote monitoring.
  • sensors can be used for monitoring such things as patient compliance, quality of therapy, device location, proper use, body motion / associated exercise, closed loop feedback for vibration control, product maintenance, end of life, degradation tracking for service, and pulse oximetry for physiological responses to therapeutic inputs.
  • Sensors in some embodiments can also be used for cross finger vibration mitigation.
  • Principles of a non-disc contactor, such as an octaberry contactor according to embodiments will now be presented.
  • embodiments are directed to a contactor (i.e., the part of the mechanical stimulator that interacts with the patient’s skin and deeper layers) which causes stronger physiological/medical effects with the same amount of force/energy/vibration amplitude.
  • a contactor i.e., the part of the mechanical stimulator that interacts with the patient’s skin and deeper layers
  • the present Applicant recognizes that the following three characteristics of the contactor surface significantly increase the stimulation effect: increased outer circumference, inner circumference (hole) and non-flat contactor surface.
  • typical contactors are discs or disc-like.
  • the contactor used in the vCR pilot studies [K.J. Pfeifer, J.A. Kromer, A.J. Cook, T.
  • a contactor has a larger outer circumference compared to a simple circle/disc.
  • the contactor uses a so-called octaberry shape: an octagon with semi-circles attached to the octagon’s sides, giving rise to a berry-type shape.
  • inner circumference hole
  • the present Applicant recognizes that previous contactors used for vCR were typically solid discs that did not have a hole [K.J.
  • an example contactor of embodiments has a hole.
  • a contactor is an annular stretched octaberry with outer diameter and inner (hole) diameter .
  • FIG.17 is a contactor view of an octaberry to embodiments, which is an octagon with semi-circles attached to all sides, leading to a berry-type shape 1702 with increased outer circumference without sharp edges or angles that might compromise a subject’s skin when applied during longer stimulation sessions.
  • An annular octaberry has a hole 1704 which comes with an inner circumference and, hence, increased total circumference.
  • the span of the octagon is given by [00177]
  • the outer [00178]
  • the inner be sufficiently large, e.g., , but not too close to the span. 25 S23-357-PCT P. Tass et al. Atty.
  • octaberry (with identical area) with inner diameter mm has an outer diameter mm.
  • embodiments is a stretched annular octagon. Stretching serves the following purposes: it further increases the total circumference; and when mounted to fingertips, it works for a large range of fingertip sizes, in particular, for thin fingertips, too.
  • Stretched annular octaberry A stretched octagon provides the basis for a stretched octaberry.
  • An annular stretched octaberry has a hole, e.g., an elliptic hole.
  • FIGs.20- 22 show examples of the ground view of contactor embodiments. These ground views constitute annular stretched octaberries with identical semi-circles and, hence, identical height compared to a non-stretched octaberry.
  • FIG.20 illustrates an example annular octaberry with semi-circles 2002 on the stretched sides of the octagon.
  • FIG.21 illustrates an example annular stretched octaberry with semi-circles 2102 on the stretched sides of the octagon.
  • FIG.22 illustrates an example stretched octaberry with 27 S23-357-PCT P. Tass et al. Atty.
  • the area of the octagon reads [00211] and hence [00212] is of the octaberry: 28 S23-357-PCT P. Tass et al. Atty. Dkt.102354-0785 [00213] The area of t [00214] With [00215] The area of [00216] Accordingly, the area of the annular stretched octaberry is given by [00217] Example: identical area as a disk with 3mm diameter: [00218] The set of S23-357-PCT P. Tass et al.
  • the contactor for the example apparatus contains an inner and an outer electrode, with inner electrode diameter around 1 mm and inner diameter of the outer, surrounding (reference) electrode around 6 mm. These values can vary from 0.4-1.7 mm or 0.2- 2.5 mm (inner electrode diameter) and from 5.5 mm-6.5 mm or 4.5-7.5 mm (inner diameter of the outer electrode).
  • Another embodiment contains an inner electrode with 3 mm diameter and an outer electrode with 10 mm inner diameter.
  • the base of the example contactor 2301 contains both a smaller inner electrode 2307, surrounded by an insulating surface (white circle between 2307 and 2306), and smaller surrounding electrode 2304 for the delivery of Meissner and Merkel mode stimuli (described in more detail below) and a larger inner electrode (2307 and 2306 coactivated) and larger surrounding electrode 2302 for the administration of Pacinian mode stimuli (described in more detail below).
  • Insulating surfaces (2303, 2305 and white circle between 2306 and 2307) separate the different electrodes.
  • one or more insulating surfaces can be deepened (and, hence, in greater distance to the skin compared to the rest of the contactor surface).
  • FIG.24 illustrates an example contactor for double 3-channel electrotactile stimulation according to embodiments.
  • a pair of the example embodiment of a two electrode contactor 2301 as shown in FIG.23 is embedded in an octaberry-shaped contactor.
  • the contactor can attain other, e.g., oval or elliptic forms.
  • One advantage of certain of the present embodiments is that only one (anatomical) stimulation site is sufficient for treatment delivery. For example, one fingertip is sufficient as a stimulation target. Accordingly, the contactor for 3-channel stimulation can be mounted to the fingertip by means of devices using constant force springs and/or elastic bands 31 S23-357-PCT P. Tass et al.
  • FIG.25 illustrates an example fingertip pulse oximeter in which embodiments can be integrated
  • FIG.26 is a schematic showing the cross section of upper 2601 and lower 2602 part of the pulse oximeter-type housing of the 3-channel electrotactile single-finger stimulator.
  • the fingertip 2604 is mounted on the convex contactor 2603 containing circular and annular electrodes.
  • One of these annular electrodes is schematically illustrated by one white half ring.
  • Impedance changes are caused by mechanical as well as physiological changes. Mechanical changes are caused by varying contact area and/or pressure, whereas physiological changes are due to physiological alterations, e.g., sweating at the electrode site. Some of these changes can 32 S23-357-PCT P. Tass et al. Atty. Dkt.102354-0785 be at least partially counteracted by current controlled delivery of the stimulation current. However, relevant mechanical changes, e.g., caused by peeling back electrodes or strong changes of contact area and/or pressure, still remain a challenge.
  • some embodiments use hybrid stimulation, where the mechanical stimulation enables sufficiently constant contact area and pressure of the stimulation electrodes, as will be described in more detail below.
  • Other (simpler) embodiments use solely electrotactile stimulation with an constant force mounting, e.g., realized by means of one or more constant force springs and/or elastic bands and/or elastic fingerstall.
  • Different embodiments use different pulse forms (i.e., waveforms).
  • one embodiment can use more than one pulse forms. Pulse forms without current balancing (FIG.27) are not used in preferred embodiments since they may cause skin irritations.
  • Different types of current-balanced pulse forms can be used by different embodiments, for instance: monophasic pulse forms with non-vanishing baseline and zero average current of positive (FIG.28) or negative polarity (FIG.29), balanced biphasic pulse forms with vanishing baseline and zero average current (FIG.30 and FIG.31) or asymmetric balanced biphasic waveforms with vanishing baseline and zero average current (FIG.32).
  • balanced biphasic pulse forms with vanishing baseline and zero average current FIG.30 and FIG.31
  • asymmetric balanced biphasic waveforms with vanishing baseline and zero average current FIG.32
  • Other embodiments may use other current-balanced pulse forms.
  • typical parameter ranges are: pulse amplitude I E : up to 50 mA pulse width T E : 2-1000 s inter-pulse-pause P E : 0-1000 s, typical values are around 40-50 s Pulse rates, i.e., the rate at which the pulse forms mentioned above are delivered: 1 Hz-25 kHz Pulses can be delivered as bursts, i.e., groups of sequentially delivered pulses. Burst rate: 1 – 1000 Hz Time between bursts: 1-1000 ms [00249] Some embodiments may use values outside the parameter ranges above. 33 S23-357-PCT P. Tass et al. Atty.
  • FIG.27 is a waveform diagram illustrating a zero-baseline monophasic pulse form with non-vanishing net dc current with amplitude IE and duration TE. Some embodiments do not use such pulse forms for electrotactile stimulation since they can cause rapid skin irritations resulting from electrochemical reactions at the skin-electrode interface.
  • the stimulation pulse starts at t 1 and ends at t 2 .
  • zero-baseline monophasic pulse form of opposite polarity (with net dc current) are not used by preferred embodiments either.
  • Meissner corpuscles (belonging to FA I mechanoreceptors) are located in superficial parts of the skin, i.e., in less than 1 mm depth. They react most strongly to low frequency vibration (20-70 Hz), with a resonant frequency at around 30 Hz.
  • Pacinian corpuscles (belonging to FA II mechanoreceptors) are located in the deeper parts of the skin, in about 2 mm depth, and react to high frequency vibrations 100-400 Hz, with a resonant frequency around 250 Hz.
  • Merkel cells MCs are found in the stratum basale, in the bottom part of the epidermis (i.e., the superficial layer of the skin). They are associated with slowly adapting (SA1) somatosensory nerve fibers and respond to low vibrations (5–15 Hz) as well as deep static touch corresponding to shapes and edges.
  • FIG.28 is a schematic illustrating a monophasic pulse form with non-vanishing baseline and zero average current as used in another embodiment.
  • the long negative phases (with amplitude I C ) counterbalances the main (positive) stimulation phase with amplitude I E and duration TE.
  • the main (positive) stimulation phase starts at t1 and ends at t2.
  • Meissner (FA I) mode One embodiment uses anodic (+) pulses at frequencies ranging from 1 Hz up to 120 Hz and more, e.g., 250 Hz and even more, e.g., 400 Hz or 500 Hz with pulse amplitudes around 2.4 mA, e.g., in a range from 0.5 mA – 10 mA, and pulse width around 0.1 ms, e.g., in a range from 0.005 ms – 1 ms and more, e.g., 2 ms or even up to 5 ms.
  • Pacinian mode (FA II) Yet another embodiment uses cathodic (-) pulses with the same pulse width and ranges as for the Meissner mode (but larger electrode dimensions).
  • Calibration of electrotactile stimuli comprises different methods, used by different embodiments: [00264] Constant current stimulation: To cope with physiological impedance changes, standard techniques for constant current stimulation are used. Some embodiments additionally use standard model-based methods to enable sufficiently constant perception of electrotactile stimuli.
  • Electrotactile threshold For each single modality, i.e., for the Meissner, Merkel as well as the Pacinian mode, threshold tests can be used to calibrate the therapeutic amplitudes I E and durations T E or determine effective ranges of I E and T E as well as the pause P E ( Figure 8). In addition, the electrotactile threshold can be used to monitor treatment effects. [00266] Cross-modal comparison: In one embodiment, the electrotactile stimuli of the different modes, i.e., Meissner, Merkel and Pacinian mode, are calibrated to be perceived equally equal “loud”, i.e., equally strong.
  • This comparison can be done subjectively by means of an “equal loudness” comparison and/or by comparing the amplitudes of relevant peaks of evoked vibrotactile and evoked eletrotactile EEG responses. 35 S23-357-PCT P. Tass et al. Atty. Dkt.102354-0785 [00267]
  • the strength of electrotactile stimuli of the three different modes can each be calibrated by comparing with a reference vibratory stimulus. This comparison can be done subjectively by means of an “equal loudness” comparison and/or be comparing the amplitudes of relevant peaks of evoked vibrotactile and evoked eletrotactile EEG responses.
  • FIG.29 is a waveform diagram illustrating a monophasic pulse form with non- vanishing baseline and zero average current as used in another embodiment.
  • the long positive phases (with amplitude IC) counterbalances the main (negative) stimulation phase with amplitude I E and duration T E .
  • the main (negative) stimulation phase starts at t 1 and ends at t 2 .
  • FIG.30 is a waveform diagram illustrating a balanced biphasic pulse form with vanishing baseline and zero average current as used in another embodiment.
  • the second, negative phase (with amplitude -I E and duration T E ) counterbalances the first, positive stimulation phase with amplitude IE and duration TE.
  • PE denotes the inter-pulse-pause.
  • the main (positive) stimulation phase starts at t1 and ends at t2.
  • FIG.31 is a waveform diagram illustrating a balanced biphasic pulse form with vanishing baseline and zero average current as used in another embodiment.
  • the second, positive phase (with amplitude IE and duration TE) counterbalances the first, negative stimulation phase with amplitude I E and duration T E .
  • P E denotes the inter-pulse-pause.
  • the main 36 S23-357-PCT P. Tass et al. Atty. Dkt.102354-0785 (negative) stimulation phase starts at t 1 and ends at t 2 .
  • FIG.32 is a waveform diagram illustrating an asymmetric balanced biphasic waveform with vanishing baseline and zero average current as used in another embodiment.
  • the second, negative phase (with amplitude -I E /2 and duration 2T E ) counterbalances the first, positive stimulation phase with amplitude IE and duration TE.
  • PE denotes the inter-pulse-pause.
  • Other embodiments may use pulse forms with opposite polarity, i.e., first negative phase, followed by a positive phase.
  • the main (positive) stimulation phase starts at t 1 and ends at t 2 .
  • Coordinated Reset (CR) stimulation means to stimulate different subpopulations at different times by delivering sequences of stimuli at different stimulation sites at different times.
  • the present embodiments use a radically different approach: By using 3 different physiological channels, FA I, FA II, SA I fibers, one embodiment periodically delivers stimuli of varying mode to the same stimulation site, e.g., to the identical fingertip.
  • One embodiment uses 3-channel electrotactile CR stimulation (FIG.33) with period which defines the CR frequency at which the same stimulation site, e.g., same fingertip receives the stimuli of Channel 1, channel 2, channel 3 denote Meissner mode, Merkel mode and Pacinian mode stimuli, delivered to the same fingertip through the corresponding electrodes (as illustrated in FIGs.23 and 24) and with parameters and polarity as explained above.
  • the same fingertip receives stimuli periodically, at multiples of During one CR period one fingertip receives exactly one channel 1 (Meissner mode) one channel 2 (Merkel mode) stimulus and one channel 3 (Pacinian mode) stimulus, where the sequence of channels may vary from one CR period to another.
  • FIG.33 is a waveform diagram of 3:2 ON-OFF CR RVS (rapidly varying sequences) stimulation with electrotactile stimulation. Timing parameters described in more 37 S23-357-PCT P. Tass et al. Atty. Dkt.102354-0785 detail below can be used, except as follows here.
  • Each vertical bar represents either a single electrotactile stimulus as in Figures 6-10 or a burst (group) of these stimuli delivered to the same stimulation site.
  • the different channels denote stimuli of different modes, e.g., Meissner mode (channel 1), Merkel mode (channel 2) and Pacinian mode (channel 3).
  • the CR frequency is typically selected around 1.5 Hz or 2 Hz or, in general, in a range from 0.5 Hz – 5 Hz. Other embodiments use values of outside this range, e.g., between 0.1 Hz-0.5Hz or between 5 Hz – 20 Hz.
  • some embodiments use temporal jitters as well as (e.g., randomly) varying amplitudes TE (as explained in more detail below) to further improve the stimulation effect.
  • Electrotactile 3-channel stimulation can be delivered through one fingertip.
  • Other embodiments may use more than one fingertip, where stimulus sequences are delivered in a synchronized manner to different fingertips.
  • all fingertips receive channel 1 (Meissner) stimuli at the same time.
  • channel 2 Mekel
  • channel 3 Pacinian
  • Another embodiment varies the assignment between fingertip number and channels, e.g., in a random, deterministic, stochastic and/or combined deterministic-stochastic manner.
  • R1 and R2 Assign channels 1,2,3 of finger R1 to channels j,k,l of finger R2 during a certain period of time, e.g., a group of 3 ON cycles (3301, 3302 in FIG.33) or during a period of time ranging from 1-10 min or more.
  • the controller is done with a simple watch-like band over the palm area and does not translate or vibrate in any significant way during therapy. It mounts softly on the outside of the hand where external effects are naturally at a minimum. This enables to reduce moisture buildup, friction as well as unwanted mechanical and proprioceptive stimulation.
  • Strongly reduced contact pressure To reduce unwanted stimulation by the controller and fixation band, both are low weight, especially controller and battery.
  • the band is adjustable to accommodate all hand sizes with the perfect fit and has a soft and porous fabric for 39 S23-357-PCT P. Tass et al. Atty. Dkt.102354-0785 skin ventilation and comfort. This design provides a convenient fit for a large range of hand sizes.
  • Adaptive break away design of single digit cables For safety reasons each fingertip stimulator is connected through one cable by means of a standard headphone type jack connector where the female side of each connection resides in the controller and the male side of each connection is securely integrated with designated tapper cable.
  • the cables can easily be unplugged in the case that the wires get snagged. This is mandatory for patient safety and it allows rapid replacement to various cable lengths to the optimal cable routing arrangement. Cables are specifically designed to be highly flexible while being provided with various length options to insure minimal finger contact or flexure resistance.
  • the controller can also be placed on the reverse side, in the palm. However, for safety and ergonomic reasons the placement on the back of the hand is superior.
  • FIG.34 is a top view of an example controller (3402-L, 3402-R) with fixation band, the high flexure cables and (in this embodiment, vibrotactile) fingertips stimulators (in the case of large hands).
  • FIG.35 is a top view of a controller (3402-L, 3402-R) with fixation band, the high flexure cables and (in this embodiment vibrotactile) fingertips stimulators (in the case of small hands).
  • FIG.38 is a bottom view of example fixation band 3702, the high flexure cables 3704 and (in this embodiment vibrotactile) fingertips stimulators 3706 in case of a small hand.
  • FIG.39 is a side view of example fixation band 3702, the high flexure cables 3704 and (in this embodiment vibrotactile) fingertips stimulators 3706 in case of a large hand.
  • FIG.41 is a side view of example fixation band 3702, the high flexure cables 3704 and (in this embodiment vibrotactile) fingertips stimulators 3706 in case of a small hand.
  • FIG.41 illustrates another possible embodiment. This example illustrates a placement 4102 of the controller that is particularly comfortable based on patient testing.
  • Glove and/or fingertip stimulation
  • Glove can be useful for the therapy of Parkinson’s and other applications.
  • the embodiments can potentially be applied to a wide range of disorders.
  • Abnormal neuronal synchronization and abnormal synaptic connectivity patterns are not only found in Parkinsons disease, but are also characteristic of a larger number of disorders of the central and peripheral nervous system, for instance, movement disorders, essential tremor, tic disorders, Tourette’s syndrome, tremor in multiple sclerosis, dystonia, chronic stroke, epilepsy, depression, migraine, tension headache, incomplete spinal cord injury, obsessive-compulsive disorder, attention deficit hyperactivity disorder (ADHD), irritable bowel syndrome, chronic pain syndromes, e.g., complex regional pain syndrome, neuropathic pain and trigeminal neuralgia, pelvic health disorders, e.g., pelvic pain or overactive bladder, tinnitus, dissociation in borderline personality disorder and posttraumatic stress disorder.
  • ADHD attention deficit hyperactivity disorder
  • the main difference between the apparatus for the solely vibrotactile and the apparatus for the hybrid (vibrotactile and electrotactile) stimulation according to some embodiments is the contactor.
  • the contactor For illustration, reference is made to the example contactors for solely vibrotactile stimulation as shown in FIG.12. 41 S23-357-PCT P. Tass et al. Atty. Dkt.102354-0785
  • a contactor i.e., the part of the mechanical stimulator that interacts with the patient’s skin and deeper layers
  • the contactor and corresponding mechanical stimulator can be mounted on a patient’s fingertips or, in other embodiments, on any part of the skin.
  • the outer perimeter of the hybrid contactor is chosen to be an Octaberry – or any object that has a circumference that is greater than that of a circle.
  • the contactor surface of the hybrid contactor is not planar, but, e.g., concave or (preferred) convex, with the inner part being closest to the skin. Instead of a hole, added are one or more “annular holes” located between inner and outer electrode.
  • FIG.42 is a schematic showing a base of one example embodiment of a circular hybrid contactor 4200 (with diameter d) with an inner, disk-like active inner electrode 4201 with diameter a, and an outer/surrounding, annular dispersive return electrode 4202 with outer diameter c and inner diameter b.
  • the contactor surface is not planar, but, e.g., convex (with the inner electrode being closest to the skin) - to strengthen vibrotactile stimulation effects.
  • the insulating surface 4203 between inner and outer 42 S23-357-PCT P. Tass et al. Atty. Dkt.102354-0785 electrode can be deepened (and, hence, in greater distance to the skin compared to the rest of the contactor surface) to further strengthen vibrotactile stimulation effects.
  • Some design principles of hybrid stimulation with a contactor containing at least two electrodes according to some embodiments will now be described.
  • Smaller inner electrode and smaller surrounding electrode In one embodiment, the contactor contains an inner 4201 and an outer electrode 4202, with inner electrode diameter around 1 mm and inner diameter of the outer, surrounding (reference) electrode around 6 mm.
  • Another embodiment contains an inner electrode with 3 mm diameter and an outer electrode with 10 mm inner diameter. The latter values can vary from 2.5-3.5 mm or 1.5-4.5 mm (inner electrode diameter) and from 9 mm-11 mm or 7.5-12 mm (inner diameter of the outer electrode).
  • Another embodiment has one or more inner electrodes with other (non-disk) shapes, e.g., oval shapes, elliptic shapes or other shapes with increased circumference.
  • FIG.43 is a schematic showing a base of one embodiment of a stretched octaberry 4300 (with outer circumference formed by a stretched octagon and added semi- circles) hybrid contactor (with diameter d) with a pair of identical inner (active) electrodes (4302-1, 4302-2) with diameter , and outer (dispersive return) electrodes (4304-1 and 4304-2) with inner diameter .
  • the contactor surface is not planar, but, e.g., convex (with the inner electrodes being closest to the skin) - to strengthen vibrotactile stimulation effects.
  • the insulating surfaces between inner and outer electrodes can be deepened (and, 43 S23-357-PCT P. Tass et al. Atty.
  • Dkt.102354-0785 hence, in greater distance to the skin compared to the rest of the contactor surface) to further strengthen vibrotactile stimulation effects.
  • FIG.42 illustrates the how the pair of electrodes is contained in the contactor, stronger vibrotactile stimulation effects can be elicited with a non-circular, e.g., octaberry perimeter (FIG.43).
  • Other embodiments can be applied to other parts of the body, not only the fingertips, e.g., to other parts of the hand or to the forearm, feet, leg and/or trunk.
  • the inner diameter a (FIG.42) of the inner, active electrode typically amounts to 1-10 mm
  • b is the inner diameter (FIG.42) of the outer, dispersive return electrode, but may also attain values outside these ranges.
  • Different embodiments use different combinations of vibrotactile and electrotactile stimulation, as will now be described.
  • One embodiment uses vibratory stimuli with constant indentation of, e.g., 0.5 mm-1.00 mm without and/or with pedestals as explained in more detail below.
  • FIG.44 is a schematic illustrating an example 100 ms vibratory pulse 4402 starting at 0.1 s, around a constant indentation 0.5 mm.
  • Steplike indentation stimuli Another embodiment uses steplike mechanical stimuli. Different embodiments may use steplike stimuli starting with vanishing (FIGs.45 and 46) or non-vanishing indentation (FIG.47). Other embodiments use other pulse shapes, e.g., with different rise and fall shapes, typically containing a plateauing shape in between.
  • Rise and fall times may be short (FIG.45) or long (FIG.46), e.g., in the order of, e.g., 1-10 ms or more, e.g., 100 ms or more.
  • rise and fall time may differ from each other.
  • Some embodiments use long rise and fall times when the vibrotactile stimulus mainly serves to ensure sufficient indentation and, hence, electrode-skin contact for electrotactile stimulation.
  • Mechanical stimuli of this kind especially those with short rise and fall time, stimulate all four types of mechanoreceptors (FA I, FA II, SA I, SA II) of the glabrous skin of the hand.
  • Stimulation duration may range from 1 ms – 100 ms and more, e.g., 200 ms or up to 1 s and more.
  • Yet another embodiment may use a series of steplike indentation stimuli. 44 S23-357-PCT P. Tass et al. Atty. Dkt.102354-0785
  • FIG.45 is a waveform diagram of an example steplike stimulus starting at t 1 and ending at t2, with vanishing indentation baseline according to embodiments.
  • FIG.46 is a waveform diagram of an example smooth steplike stimulus starting at t 1 and ending at t 2 , with vanishing indentation baseline according to embodiments.
  • FIG.47 is a waveform diagram of an example steplike stimulus starting at t 1 and ending at t2, with non-vanishing indentation baseline according to embodiments. Dashed line for comparison to FIG.45.
  • electrotactile stimulation i.e., stimulation of sensory nerves by administration of electrical current over the skin, has several advantages including low latency and energy efficiency.
  • Changes of the impedance of the electrode-skin interface change the perceived sensation intensity. This constitutes a relevant limitation of electrotactile stimulation. Impedance changes are caused by mechanical as well as physiological changes.
  • Different types of current-balanced pulse forms can be used by different embodiments, for instance: monophasic pulse forms with non-vanishing baseline and zero average current of positive (e.g. FIG.49) or negative polarity (e.g. FIG.50), balanced biphasic pulse forms with vanishing baseline and zero average current (e.g. FIGs.51 and 52) or asymmetric balanced biphasic waveforms with vanishing baseline and zero average current (e.g. FIG.53).
  • Other embodiments may use other current-balanced pulse forms.
  • example parameter ranges are: 45 S23-357-PCT P. Tass et al. Atty.
  • Dkt.102354-0785 pulse amplitude I E up to 50 mA pulse width TE : 2-1000 s inter-pulse-pause P E : 0-1000 s, typical values are around 40-50 s Pulse rates, i.e., the rate at which the pulse forms mentioned above are delivered: 1 Hz-25 kHz Pulses can be delivered as bursts, i.e., groups of sequentially delivered pulses. Burst rate: 1 – 1000 Hz Time between bursts: 1-1000 ms [00318] Some embodiments may use values outside the parameter ranges above.
  • FIG.48 is a waveform diagram illustrating a zero-baseline monophasic pulse form with non-vanishing net dc current with amplitude IE and duration TE. Some embodiments do not use such pulse forms for electrotactile stimulation since they can cause rapid skin irritations resulting from electrochemical reactions at the skin-electrode interface. The stimulation pulse starts at t1 and ends at t2. Analogously, zero-baseline monophasic pulse form of opposite polarity (with net dc current) are not used by preferred embodiments either. [00320] Different embodiments use different electrode designs to stimulate different mechanoreceptors, located in different skin depth and having different preferential nerve fiber directions (relative to the skin surface).
  • Meissner corpuscles (belonging to FA I mechanoreceptors) are located in superficial parts of the skin, i.e., in less than 1 mm depth. They react most strongly to low frequency vibration (20-70 Hz), with a resonant frequency at around 30 Hz.
  • Pacinian corpuscles (belonging to FA II mechanoreceptors) are located in the deeper parts of the skin, in about 2 mm depth, and react to high frequency vibrations 100-400 Hz, with a resonant frequency around 250 Hz.
  • Merkel cells are found in the stratum basale, in the bottom part of the epidermis (i.e., the superficial layer of the skin). They are associated with slowly adapting (SA1) somatosensory nerve fibers and respond to low vibrations (5–15 Hz) as well as deep static touch corresponding to shapes and edges. 46 S23-357-PCT P. Tass et al. Atty. Dkt.102354-0785 [00324] Different embodiments use different electrode configurations and dimensions (introduced above) together with different stimulation parameters to induce specific effects, as will be described below.
  • FIG.49 is a schematic illustrating an example monophasic pulse form with non- vanishing baseline and zero average current as used in another embodiment.
  • the long negative phases (with amplitude IC) counterbalances the main (positive) stimulation phase with amplitude I E and duration T E .
  • the main (positive) stimulation phase starts at t 1 and ends at t 2 .
  • the following aspects are considered.
  • Pacinian mode (FA II) Yet another embodiment uses cathodic (-) pulses with the same pulse width and ranges as for the Meissner mode (but larger electrode dimensions).
  • Calibration of vibrotactile stimuli with or without pedestals is described in more detail below. Calibration of electrotactile stimuli comprises different methods, used by different embodiments, as described as follows: [00332] Constant current stimulation: To cope with physiological impedance changes, standard techniques for constant current stimulation are used. Some embodiments additionally 47 S23-357-PCT P. Tass et al. Atty. Dkt.102354-0785 use standard model-based methods to enable sufficiently constant perception of electrotactile stimuli.
  • Electrotactile threshold Threshold tests can be used to calibrate the therapeutic amplitudes I E and durations T E or determine effective ranges of I E and T E as well as the pause P E (e.g. FIG.51). In addition, the electrotactile threshold can be used to monitor treatment effects.
  • Cross-modal comparison The strength of electrotactile stimuli can be calibrated in comparison with a reference vibratory stimulus. This comparison can be done subjectively by means of an “equal loudness” comparison and/or be comparing the amplitudes of relevant peaks of evoked vibrotactile and evoked eletrotactile EEG responses.
  • FIG.50 is a waveform diagram illustrating an example monophasic pulse form with non-vanishing baseline and zero average current as used in another embodiment.
  • the long positive phases (with amplitude I C ) counterbalances the main (negative) stimulation phase with amplitude I E and duration T E .
  • the main (negative) stimulation phase starts at t 1 and ends at t 2 .
  • FIG.51 is a waveform diagram illustrating an example balanced biphasic pulse form with vanishing baseline and zero average current as used in another embodiment.
  • FIG.52 is a waveform diagram illustrating an example balanced biphasic pulse form with vanishing baseline and zero average current as used in another embodiment.
  • FIG.53 is a schematic illustrating an example asymmetric balanced biphasic waveform with vanishing baseline and zero average current as used in another embodiment.
  • the second, negative phase (with amplitude -I E /2 and duration 2T E ) counterbalances the first, 48 S23-357-PCT P.
  • P E denotes the inter-pulse-pause.
  • Other embodiments may use pulse forms with opposite polarity, i.e., first negative phase, followed by a positive phase.
  • the main (positive) stimulation phase starts at t1 and ends at t2.
  • Steplike mechanical stimuli serve two example purposes: [00341] 1. They stimulate all four types of mechanoreceptors (FA I, FA II, SA I, SA II) of the glabrous skin of the hand, with FA I and FA II typically showing strongest responses when indentation starts and/or stops, while SA I and SA II typically also respond while the indentation plateaus. [00342] 2. They enable a sufficiently strong and reliable contact pressure for the electrotactile stimulation.
  • FIG.54 is a waveform diagram illustrating an example steplike mechanical stimulus 5402 and the corresponding electrotactile stimulus train 5404.
  • Each vertical bar represents either a single electrotactile stimulus as in FIGs.49-53 or a burst (group) of these stimuli.
  • Other embodiments can use trains with non-constant rate of stimulus delivery or any other sequence of stimuli or bursts of stimuli from FIGs.49-53.
  • Electrotactile stimuli are typically delivered when the mechanical stimulus enables sufficient indentation and, hence, electrode-skin contact.
  • Embodiments described herein favorably administer electrotactile stimuli during phases of the vibratory stimuli with sufficiently strong indentation, in this way enabling reliable contact pressure for the electrotactile stimulation. Consequently, the quality of the electrotactile stimulation increases, especially for dry skin.
  • Different embodiments use different combinations of vibratory stimuli and electrotactile stimuli for different purposes, as follows. 49 S23-357-PCT P. Tass et al. Atty. Dkt.102354-0785 [00345] 1.
  • Low-frequency ( ⁇ 100 Hz, e.g., around 30-60 Hz) vibratory stimulus mainly stimulating FA I mechanoreceptors
  • phase-locked electrotactile stimuli in Meissner (FA I) mode see above:
  • the bimodal, i.e., combined vibratory and electrotactile, FA I stimulation provides strong stimulation, in this way enabling short stimuli.
  • a larger number of, for example, more than 20 vibration periods only a few ( ⁇ 10) vibration periods provide strong stimulation. This is a major advantage since it significantly reduces in-channel masking and enables temporal jitter of stimulus delivery (described in more detail below).
  • Meissner corpuscles can be strongly stimulated by means of electrotactile stimuli (in Meissner mode, see above) not only at frequencies smaller, but also greater than 100 Hz.
  • electrotactile stimuli in Meissner mode, see above
  • a bimodal, i.e., combined vibratory (FA II) and electrotactile (FA I), phase-locked stimulation e.g. FIG.54
  • FA II and FA II electrotactile
  • FIG.54 Phase-locked stimulation
  • Propagation delays of vibratory stimuli and electrotactile stimuli can be detected with evoked responses, i.e., by delivering an ensemble of (identical) vibratory stimuli as well as an ensemble of (identical) eletrotactile stimuli.
  • varying cycle ratio patterns can be used to induce specific evoked responses, e.g., to strengthen late responses of brain areas other than primary sensory cortex, in this way increasing the propagation of stimulus effects in brain circuits.
  • vibratory and electrotactile stimulus can be of different duration (e.g. FIG.62).
  • Yet another embodiment uses a phase shift between vibratory and electrotactile stimuli to compensate for propagation delay differences. [00349] 3.
  • Vibratory stimuli and electrotactile stimuli can have different frequencies, e.g., to induce different perceptions.
  • different m:n cycle ratios between vibratory and electrotactile stimulation can be used, e.g., electrotactile stimulation at half the vibratory frequency (e.g. FIGs.58, FIG. 66), bursts of 2 (e.g. FIG.59) or 3 (e.g.
  • FIG.60 per vibration cycle (close to maximum indentation).
  • Other embodiments use phase shifts between vibratory and electrotactile stimuli to compensate for propagation delay differences.
  • FIG.43 For contactors housing more than one electrode pair for electrotactile stimulation, identical and/or different electrotactile stimnuli can be delivered through the different electrode pairs at the same 51 S23-357-PCT P. Tass et al. Atty. Dkt.102354-0785 time. Other embodiments may use more than one electrode pair to enable skin to recover from potential stimulation side effects such as skin irritation and/or prevent from long term side effects and skin irritation.
  • delivery of electrotactile stimuli can be switched from one electrode pair to another, e.g., after every vibratory sequence or after gourps of vibratory sequences, e.g., ON groups when applying n cycles ON, m cycles OFF vibrotactile coordinated reset stimulation.
  • Sub-threshold vibratory (pedestal, as described below) combined with phase- locked suprathreshold electrotactile stimulation Some embodiments use this type of hybrid stimulation, e.g., to provide sufficient electrode-skin contact for the electrotactile stimulation.
  • FIG.55 is a waveform diagram illustrating an example 1:1 phase locked hybrid (i.e., combined vibratory and electrotactile) stimulation with zero phase shift.
  • FIG.56 is a waveform diagram illustrating an example 1:1 phase locked hybrid (i.e., combined vibratory and electrotactile) stimulation with non-zero phase shift. The non-zero phase shift may compensate for different propagation delays of FA I and FA II mechanoreceptors.
  • Each vertical bar superimposed on the vibrotactile waveform represents either a single electrotactile stimulus as in FIGs.49-53 or a burst (group) of these stimuli.
  • FIG.57 is a waveform diagram illustrating an example hybrid (i.e., combined vibratory and electrotactile) stimulation with increasing 1:n cycle ratio between vibratory and electrotactile (e.g., with n increasing from 1 to 3 in the course of the vibratory burst.
  • Each vertical bar superimposed on the vibrotactile waveform represents either a single electrotactile stimulus as in FIGs.49-53 or a burst (group) of these stimuli. 52 S23-357-PCT P. Tass et al. Atty.
  • FIG.58 is a waveform diagram illustrating an example 2:1 phase locked bimodal (i.e., combined vibratory and electrotactile) stimulation with zero phase shift, where one electrotactile stimulus is delivered per 2 vibratory cycles. Each vertical bar superimposed on the vibrotactile waveform represents either a single electrotactile stimulus as in FIGs.49-53 or a burst (group) of these stimuli.
  • FIG.59 is a waveform diagram illustrating an example 1:2 phase locked bimodal (i.e., combined vibratory and electrotactile) stimulation with zero phase shift, where two electrotactile stimuli are delivered per vibratory cycle.
  • FIG.60 is a waveform diagram illustrating an example 1:3 phase locked bimodal (i.e., combined vibratory and electrotactile) stimulation with zero phase shift, where three electrotactile stimuli are delivered per vibratory cycle.
  • Each vertical bar superimposed on the vibrotactile waveform represents either a single electrotactile stimulus as in FIGs.49-53 or a burst (group) of these stimuli.
  • FIG.61 is a waveform diagram illustrating an example 1:1 phase locked hybrid (i.e., combined vibratory and electrotactile) stimulation with zero phase shift.
  • a subthreshold pedestal with a 100 ms suprathreshold vibratory burst (described in more detail below) is delivered together with electrotactile stimuli phase locked to maxima of the suprathreshold burst.
  • Each vertical bar superimposed on the vibrotactile waveform represents either a single electrotactile stimulus as in FIGs.49-53 or a burst (group) of these stimuli.
  • FIG.62 is a waveform diagram illustrating an example 1:1 phase locked hybrid (i.e., combined vibratory and electrotactile) stimulation with zero phase shift, with different vibratory and electrotactile stimulus duration.
  • a subthreshold pedestal with a 100 ms suprathreshold vibratory burst (described in more detail below) is delivered together with 10 electrotactile stimuli phase locked to maxima of the suprathreshold burst.
  • Each vertical bar superimposed on the vibrotactile waveform represents either a single electrotactile stimulus as in FIGs.49-53 or a burst (group) of these stimuli.
  • FIG.63 is a waveform diagram illustrating an example phase locked hybrid (i.e., combined vibratory and electrotactile) stimulation with zero phase shift, with temporally 53 S23-357-PCT P. Tass et al. Atty. Dkt.102354-0785 patterned electrotactile stimulus and more complex cycle ratio between vibratory and electrotactile stimulation.
  • a subthreshold pedestal with a 100 ms suprathreshold vibratory burst (described in more detail below) is delivered together with 3 electrotactile stimuli at vibratory onset and 8 electrotactile stimuli at the end of the vibratory burst, all phase locked to maxima of the suprathreshold burst.
  • FIG.64 is a waveform diagram illustrating an example phase locked hybrid (i.e., combined vibratory and electrotactile) stimulation with zero phase shift, with temporally patterned electrotactile stimulus and more complex cycle ratio between vibratory and electrotactile stimulation, where the m:1 cycle ratio changes during a vibratory burst, with m decreasing from 3 to 1.
  • a subthreshold pedestal with a 100 ms suprathreshold vibratory burst (described in more detail below) is delivered together with electrotactile stimuli.
  • FIG.65 is a waveform diagram illustrating an example phase locked hybrid (i.e., combined vibratory and electrotactile) stimulation with zero phase shift, with temporally patterned electrotactile stimulus and more complex cycle ratio between vibratory and electrotactile stimulation, where the final 4 electrotactile stimuli are delivered phase locked to the pedestal.
  • a subthreshold pedestal with a 100 ms suprathreshold vibratory burst (described in more detail below) is delivered together with electrotactile stimuli.
  • FIG.66 is a waveform diagram illustrating an example 2:1 phase locked hybrid (i.e., combined vibratory and electrotactile) stimulation with zero phase shift, with phase locked electrotactile stimuli coinciding with half of the maxima of the vibratory burst.
  • a subthreshold pedestal with a 100 ms suprathreshold vibratory burst (described in more detail below) is delivered.
  • FIG.67 is a waveform diagram illustrating an example 4:1 phase locked hybrid (i.e., combined vibratory and electrotactile) stimulation with zero phase shift, with phase locked electrotactile stimuli coinciding with a fourth of the maxima of the vibratory burst.
  • a subthreshold pedestal with a 100 ms suprathreshold vibratory burst (described in more detail below) is delivered.
  • Each vertical bar superimposed on the vibrotactile waveform represents either a single electrotactile stimulus as in FIGs.49-53 or a burst (group) of these stimuli.
  • embodiments may use the same or similar stimulation patterns as described in more detail below, with vibratory stimuli using pedestals and/or only suprathreshold stimuli (i.e., no pedestals).
  • An additional advantage of hybird stimulation is a consequence of the short duration of effective electrotactile stimuli. Accordingly, some embodiments use temporal jitter between the onset times of the vibrotactile and the electrotactile stimuli, as illustrated in FIG. 68.
  • FIG.68 is a waveform diagram illustrating an example hybrid stimulation with temporal jitter between vibrotactile and electrotactile stimuli.
  • FIG.49-53 Schematic shows two channels of hybrid stimuli with different onsets of vibratory stimuli, here suprathreshold vibratory stimuli, standing out from ongoing vibratory pedestals (described in more detail below), and onsets of electrotactile stimuli, here groups of three vertical bars. Each vertical bar superimposed on the vibrotactile waveform represents either a single electrotactile stimulus as in FIGs.49-53 or a burst (group) of these stimuli.
  • the present embodiments relate to methods and apparatuses that enable more effective vibrotactile stimulation, i.e., stronger physiological effects with less vibration power/amplitude.
  • one or more embodiments enable spatially more focal 55 S23-357-PCT P. Tass et al.
  • Compound stimuli are one important aspect of some embodiments.
  • the vibrotactile stimuli used for vCR are circumscribed in time, i.e., their amplitude is non-zero only during stimulus delivery [P.A. Tass: Vibrotactile Coordinated Reset Stimulation for the Treatment of Neurological Diseases – Concepts and Device Specifications. Cureus 9(8) (2017) e1535] (Firgue 1). Apart from sine signals, one can use narrow-band, triangular, sawtooth and other signals.
  • the vibrotactile (mechanical) stimulation signal reads [00372] amplitude of the mechanical stimulation signal, and represents part of . can be a sine such as: [00373] where, e.g., in case of a high-frequency burst (see above), 250 Hz.
  • a mechanical (vibrotactile) stimulator does not deliver any stimulation, , and stimuli (with ) are circumscribed in time ( Figure 1). The goal of these circumscribed stimuli is to cause a phase reset of abnormal, disease-related synchronized oscillatory neuronal activity.
  • FIG.69 illustrates an example of a standard vibration signal with high (250 Hz) intra-burst frequency with constant 0.5 mm indentation.
  • a vibration signal typically oscillates around a constant indentation of, e.g., 0.5 mm (FIG.69), see US Patent Publ. No.20210401664, the contents of which are incorporated herein by reference.
  • a type of vibrotactile stimulus uses a pedestal (i.e., sub-perception stimulus) to render the nervous system more susceptible.
  • the pedestal can be circumscribed in time (e.g. FIG.70) or – more preferred, since even more effective – sufficiently long (compared to eth suprathreshold part) or even continuous (e.g. FIG. 71).
  • FIG.70 illustrates an example of a vCR vibration signal 7002 according to embodiments with high (250 Hz) intra-burst frequency with constant 0.5 mm indentation and sub-threshold pedestal, circumscribed in time.
  • the vibratory perception threshold is indicated by the dashed line.
  • a pedestal of sufficient length e.g., a pedestal duration exceeding the duration of the suprathreshold burst several, e.g., 2-3 (or more) times is typically more effective, so that a shorter suprathreshold stimulus part is sufficient to induce the same stimulus effect, i.e., the same perceptual strength or the same amount of phase reset of the abnormal neuronal brain rhythm and/or the same peak amplitude of the evoked brain response.
  • Pedestal-boosted vibratory bursts enable similar/same stimulus effects at smaller amplitudes, where longer and/or continuous pedestals are typically superior to pedestals of limited duration (compared to the duration of the suprathreshold part of the compound stimulus).
  • Vibratory perpendicular sinusoidal skin displacements in the 5-60 Hz, especially 30 to 60 Hz range are optimal stimuli for fast-adapting type I (FA I) mechanoreceptors, whereas vibratory stimuli in the approx.40-400 Hz, especially 100-300 Hz range are optimal stimuli for fast-adapting type II (FA II) mechanoreceptors.
  • the FA I-related frequency range will be denoted low-frequency range (e.g., 30-60 Hz), and FA II-related frequency range will be denoted as high-frequency range (e.g., 100-300 Hz).
  • Pedestals and suprathreshold stimulus parts with same frequency The pedestal-mediated boost can be applied to high- and low-frequency bursts alike. However, to this end, pedestal and suprathreshold stimulus parts should either be of the same frequency (or - less preferred - of similar frequency within either the high- or the low-frequency band). A preferred version is to have the same frequency for both pedestals and suprathreshold stimulus parts.
  • pedestal and suprathreshold stimulus parts should never be of different frequency ranges, e.g., high-frequency pedestal combined with low-frequency suprathreshold stimulus part or vice versa, since this typically impairs the effect of the suprathreshold stimulus part.
  • Pedestals and suprathreshold stimulus parts with narrow-band noise As an alternative to a sine signal with single frequency and time-varying amplitude as illustrated in FIGs.73 and 74, one can also use a narrow-band signal with amplitude . Of note, the narrow-band signal should be either in high-frequency or in the 58 S23-357-PCT P. Tass et al. Atty.
  • the frequency range of the narrow band signals should be adapted to the high-frequency or low-frequency ranges provided above, respectively.
  • low-frequency narrow-band noise could be centered around 20 Hz (0 dB), with spectral values of, e.g., -25 dB at 10 Hz and -57 dB at 60 Hz.
  • a high-frequency narrow-band noise could, e.g., be centered around 200 Hz (0 dB), with spectral values of -40 Hz at 100 Hz and -35 dB at 400 Hz.
  • both pedestal and suprathreshold stimulus parts should be in the same frequency range, either low- or high- frequency.
  • Continuous stimulation with amplitude modulation Importantly, pure sine pedestals and suprathreshold stimulus parts (both with the same single frequency ) are typically more effective than pedestals and suprathreshold parts using narrow-band noise. Accordingly, one embodiment uses continuous stimulation with one frequency , while varying the amplitude .
  • pauses of a few seconds or minutes may be used to intersect the stimulation occasionally or regularly. During these pauses, the pedestals may vanish and upon restart of the pedestals a different frequency (for both pedestals and suprathreshold stimulus parts) may be chosen. Pedestal-free pauses may occur during OFF periods (e.g. FIG.73) or during pauses occurring on a longer time scale.
  • the circumscribed pedestals may have considerably longer rise times and fall times, e.g., 25 ms.
  • the shape of the amplitude should favorably be more complex, including asymmetric 59 S23-357-PCT P. Tass et al. Atty. Dkt.102354-0785 shapes for rise and fall as well as slowly oscillating wave forms as opposed to plateauing amplitudes.
  • Circumscribed pedestals can be terminated quickly, even immediately after a suprathreshold vibratory burst, e.g., with fall times of 25 ms.
  • the part of the pedestal preceding the suprathreshold vibratory burst should be of sufficient length, typically in the range of 3-7 times the (average) duration of the (suprathreshold) vibratory bursts (or longer).
  • the differences in rise times and fall times of pedestals vs. suprathreshold stimulus parts were not taken into account in the figures.
  • the parts of the pedestal preceding and following the suprathreshold stimulus part do not need to be symmetric, in particular, they do not need to be of the same length. Typically, they are not symmetric (see above).
  • Using a pedestal means to deliver a long vibratory stimulus with time-varying amplitude. Contrary to previous patents and applications (e.g., US 2013/0041296 A1), the compound stimuli are smeared out in time. The onset timing relationships of subthreshold and suprathreshold parts of the compound stimuli delivered through different channels can differ.
  • the onsets of the subthreshold parts of compound stimuli delivered through two or more channels can coincide, while their supra-threshold parts can be delivered at different times (e.g. FIG.73).
  • the time-course of the subthreshold and the supra- threshold parts of the compound stimuli can attain different shapes.
  • “pedestal” is a term used in proprioceptive physiology in the context of negative masking: A pedestal with a strength close to threshold reduces the actual perception threshold. This example definition is provided for context only and is not intended to limit the present embodiments.
  • onset and offset of suprathreshold vibratory burst preferably should be in phase with pedestal (e.g. FIG.70). This causes a quantization of stimulus onset and offset times. 60 S23-357-PCT P. Tass et al. Atty. Dkt.102354-0785 [00406]
  • the compound stimuli are applied to CR stimulation.
  • the compound stimuli can be used for various single- and multichannel stimulation patterns aiming at inducing long-lasting neuronal desynchronization.
  • vCR stimulation without pedestal is characterized by the vCR period , which sets the CR frequency at which individual fingertips received burst stimuli. Individual fingertips receive stimuli at multiples of such that each fingertip exactly one stimulus per Beside this stimuli are delivered to randomly selected fingertips.
  • This type of CR stimulation is to as CR with rapidly varying sequences (CR RVS).
  • the method uses an m:n ON-OFF pattern by delivering stimuli for an ON-period of, e.g., three CR periods, , and paused the stimulation for an OFF period of, e.g., two CR periods afterwards.
  • FIG.72 is a waveform illustration of 3:2 ON-OFF CR RVS (rapidly varying stimulation without pedestals.
  • Channels 1-4 denote, e.g., fingertips of index finger, middle finger, ring finger, and pinky of one hand, respectively.
  • Dashed lines 7202 indicate multiples of the vCR period and dotted lines 7206 multiples of during individual CR periods.
  • Stimulation bursts marked by gray rectangles 7204.
  • Hz ( ms) burst duration ms, and Hz.
  • the OFF period by three ON followed by two OFF periods.
  • FIG.73 illustrates the corresponding vCR stimulation pattern with pedestals.
  • FIG.73 is a waveform illustration of 3:2 ON-OFF CR RVS (rapidly varying sequences) stimulation with pedestals, optimally calibrated for each channel (e.g., finger) separately, with the same format as in FIG.72.
  • the figure shows an OFF period followed by three ON periods which in turn are followed by two OFF periods.
  • the novel compound pulses enable to personalize stimuli to the individual finger of every individual patient.
  • the device automatically determines the threshold amplitude.
  • test stimuli are delivered to the subject, optimally for each stimulus site, 61 S23-357-PCT P. Tass et al. Atty. Dkt.102354-0785 e.g., each fingertip, - less optimally at one or a few (but not all) stimulation sites. In the latter case, the minimum of the measured thresholds is used as threshold for all other stimulation sites.
  • the duration and all other parameters of the test stimuli are identical to those of the pedestals.
  • the duration of the test stimuli will be selected as, e.g., 3-10 s.
  • Threshold detection For a single stimulation site, the amplitude of the test stimuli is varied in ascending and/or descending and/or randomized order. Subjects are, e.g., asked whether they perceive a test stimulus within a certain time window. The minimum vibration amplitude of perceived stimuli is considered as threshold. The maximum vibration amplitude belonging to non-perceived stimuli is selected as pedestal amplitude.
  • Another option for robust threshold calibration is the two-interval forced choice (2IFC) method, where a subject would be presented with a series of two-interval trials where a stimulus is presented in either the first or second interval (J. Zwislocki, F. Maire, A. S. Feldman, H. Rubin: On the Effect of Practice and Motivation on the Threshold of Audibility. The Journal of the Acoustical Society of America 30, 254 (1958)).
  • Pedestal amplitude is chosen in the range 60%-95% of the (pedestal-free) threshold, preferably in the range 70%-95%.
  • Post-calibration test To make sure the pedestals are subthreshold, test stimuli with the selected pedestal amplitude are administered a few more times and the subject is instructed by embodiments of the device to report (i.e., press a button or give a verbal feedback) whether the subject perceives a stimulus in the corresponding time windows. In case one or more of the test stimuli are suprathreshold (i.e., perceived by the subject), the vibration amplitude is further reduced by the device and a series of test stimuli and/or a 2IFC series is re- administered.
  • This post-calibration test can also be performed with a mixture of subthreshold and suprathreshold stimuli, e.g., with a 2IFC series design. The goal here is whether the subthreshold stimuli are detected by the subject.
  • vibratory thresholds can vary with temperature, measuring thresholds and, in general, threshold-based calibration should be performed at representative temperatures at which subjects use the device, e.g., at room temperature.
  • vibration amplitudes of all other stimulation sites e.g., fingers of both hands are calibrated by means of an equal loudness match, i.e., the vibration 62 S23-357-PCT P. Tass et al. Atty.
  • the device uses a temporal jitter of the stimulus onsets.
  • the onset of the jth vibratory burst of the kth channel is calculated by , [00417] temporal jitter of the temporal onset of the vibratory stimulus in the k-th channel of the j-th period, where (e.g. FIG.74). can be uniformly distributed. In another can distribution, e.g., a Gaussian distribution.
  • the width of the jitter window is constant for all stimuli applied in a particular channel.
  • the width of the jitter window may vary in time.
  • the width of the jitter window may be identical in all channels, see, e.g., FIG.74, where is constant and identical for all channels.
  • the width of the jitter window as well as its possible time course may differ between different channels.
  • FIG.74 provides an illustration of the first period of a jitter-free CR sequence (blue hatched stimuli 7402) with jitter intervals (blue rectangles) and final stimuli (solid blue stimuli 7404) (following an OFF period).
  • the vibration amplitudes are randomized. Amplitude randomization means that for each single vibratory burst the vibration amplitude is randomly drawn from a uniform distribution . Another uses other distributions, e.g., a Gaussian distribution. 63 S23-357-PCT P. Tass et al. Atty. Dkt.102354-0785 [00420] denotes the maximal vibration amplitude, i.e., the vibration amplitude as determined by means of the calibration procedure.
  • FIG.75 is a a vibrotactile 3:2 ON-OFF CR RVS pattern with pedestals and uniform randomization of the vibration amplitude.
  • the figure shows an OFF period followed by three ON periods which in turn are followed by two OFF periods.
  • there is a temporal jitter of the durations of the vibratory bursts as illustrated in FIG.76 for the vibrotactile 3:2 ON-OFF CR RVS pattern with pedestal.
  • the vibratory burst durations are randomized. Burst duration randomization means that for each single vibratory burst the duration is randomly drawn from a uniform distribution . Another other distributions, e.g., a Gaussian [00424] denotes the maximal burst duration. Different embodiments use different types of minimal vibration amplitudes . In one embodiment, .
  • the burst duration range is constant for all stimuli applied in a particular channel.
  • as well as its possible time course may differ between different channels.
  • FIG.76 is a a vibrotactile 3:2 ON-OFF CR RVS pattern with pedestals and uniform randomization of the vibratory burst durations.
  • the amplitude of the pedestals can be varied in a deterministic, random (stochastic) or combined deterministic-stochastic manner, as schematically illustrated in FIG.77.
  • pedestal variation algorithms are used which make sure the amplitude of a pedestal does only change a little or moderately (e.g., not more than 10% or 25%) within a time window amounting to 3-5 times the burst duration of the subsequent stimulus part.
  • pedestals change slowly, and variations of the pedestals should not come with rise times and fall times of the pedestals exceeding 25 ms.
  • FIG.77 is a waveform diagram illustrating slow random variation of the pedestal 7702 in channel 1. Perception threshold is highlighted by dashed horizontal line. Both channels use different frequencies: 250 Hz in channel 1 and 200 Hz in channel 2. While the amplitude of the pedestal in channel 1 varies in time, the burst amplitudes and are identical. [00429] In one embodiment the vibration frequency is varied in time. Note, the vibration frequency belongs to both subthreshold and suprathreshold parts of the compound stimulus (e.g. FIG.78). In contrast, in other embodiments described above, the frequency is used like a constant carrier. Stimulation effects are induced by modulating its amplitude. To avoid habituation effects, the carrier frequency can be varied in time.
  • the vibration frequency can vary slowly, as schematically illustrated in FIG.78.
  • the variation of the frequency can be governed by a deterministic, random (stochastic) or combined random and deterministic process.
  • the variation of is a slow process compared to the duration of 3-5 times the duration for the vibratory bursts to ensure an effective phase entrainment of the neuronal discharges of the activated mechanoreceptors as well as the corresponding thalamic sensory neurons and associated cortical neurons.
  • the variation of is a slow process compared to the duration of 3-5 times the duration for the vibratory bursts to ensure an effective phase entrainment of the neuronal discharges of the activated mechanoreceptors as well as the corresponding thalamic sensory neurons and associated cortical neurons.
  • the variation of the frequency is performed in a way that remains within either the high-frequency or the low-frequency band connected with different mechanoreceptors (see above), e.g., slowly varying within an interval , where is a pre-set center value, and amounts to 10%, 20%, 30% or .
  • the vibratory (perception) on the vibration frequency to vary only in a relatively small interval, i.e., by choosing , and using, e.g., the mean or minimum (perception) threshold obtained by the thresholds obtained for , , and .
  • other parameters, in particular the amplitude can be varied too, as explained above and illustrated in Figure 10.
  • FIG.78 is a waveform diagram illustrating a combination of a slow variation of the carrier-type frequency , a slow random variation of the pedestal and a variation of the burst amplitude (7802-1, 7802-2) in channel 1. Perception threshold is highlighted by dashed horizontal line and, for illustration and simplicity, assumed to be independent of .
  • Channel 1 uses a constant 250 Hz.
  • Stepwise variation of the vibration frequency In another embodiment, the vibration frequency is kept constant as long as the pedestal amplitude is greater than zero, e.g., during consecutive ON periods (e.g. FIG.73) and stepwise varied for the subsequent phase with non-vanishing pedestal amplitude, e.g., the subsequent group of ON periods.
  • the center frequency of narrow band signals is varied in time in an analogous way as described here.
  • the center frequency of narrow band signals is varied in time in an analogous way as described here.
  • Pentatonic tones are typically perceived as pleasant and, when delivered sequentially, simultaneously or in an overlapping mode, do not produce dissonances.
  • Headband M mechanical stimulators (i.e., vibratory stimuli) are placed on the forehead, e.g., symmetrically aligned, half of the stimulators on the right and left side, 66 S23-357-PCT P. Tass et al. Atty. Dkt.102354-0785 respectively.
  • Different pentatonic tones are assigned to the different stimulators, e.g. and to the right side and and to the left side. Alternatively, the frequency assignment can also change over time.
  • different stimulators are assigned different pentatonic calculated in the [00438]
  • Pentatonic scale There are different pentatonic scales.
  • Pentatonic tones multiples of fundamental pentatonic tones with octave relationship
  • the IMP can be determined with classical masking experiments known to the expert. In that case, for feasibility reasons, the IMP will be determined for only on burst duration or, if the latter varies, for the maximum or average of the burst durations. In addition, for feasibility reasons, the IMP can be detected experimentally for one finger, e.g., the index finger, and – by way of extrapolation – be used for all other fingers, too.
  • Different embodiments can use different methods to prevent in-channel masking, e.g., the different options: [00456] Option #1: Discard unfavorable sequences and replace by favorable sequences [00457] Option #2: Discard (only) unfavorable stimuli [00458] Option #3: Reduce duration of preceding stimuli to reduce IMP pause [00459] In another embodiment the user, e.g., the clinician and/or clinician assistant, can change options, e.g., depending on the clinical outcome. [00460] These in-channel masking prevention methods presented here work for stimulation patterns with and without pedestals, as illustrated in FIGs.79 and 80 (without pedestals) and FIG.81 (with pedestal), respectively.
  • FIG.79 is a waveform illustration of an in-channel masking prevention (IMP) pause (illustrated by shaded rectangle) of three times the duration of the vibratory burst. The encircled vibratory burst in channel 3 violates the IMP pause.
  • IMP in-channel masking prevention
  • Option #2 Discard unfavorable stimuli: [00479] Discard all stimuli that violate IMP pauses, without replacing them. For instance, in FIG.79 in the third cycle one can discard (only) the first stimulus administered through channel 3. Hence, there will be a missing stimulus.
  • Option #3 Reduce duration of preceding stimuli to reduce IMP pause: [00481] One can reduce the duration of the stimulus causing an IMP pause which leads to a conflict with a subsequent stimulus.
  • FIG.80 is a waveform illustration of an in-channel masking prevention (IMP) pause (illustrated by shaded rectangle) of three times the duration of the vibratory burst.
  • IMP in-channel masking prevention
  • FIG.81 is a waveform illustration of jitter-free CR sequence with in-channel masking prevention pauses (red bars 8102). No stimulus violates and IMP.
  • Multi-frequency stimulation here means that the mean rate of vibratory burst delivery in the different channels, e.g., fingers, is different.
  • FIG.82 is a waveform illustration of the period between vibratory bursts and in the j-th channel, here and .
  • pulse train in one or more channels is purely periodic, e.g., for all k.
  • the mean periods in all channels are different for as illustrated in FIG.83.
  • the stimulus trains need not start at the same time difference between the pulse train onsets in channels j and l are denoted by .
  • FIG.83 is a waveform illustration of stimulus trains with different mean period, here and onset time difference .
  • In one favorable long-term are induced by using ratios of the mean period that are close to incommensurate, i.e., with large j and l.
  • variations of the period take into account the IMP, i.e., IMP for all .
  • CR stimulation patterns as defined above, and differences in the mean periods are introduced by skipping a different percentage of vibratory stimuli in the different channels.
  • the percentage of vibratory stimuli omitted in channel j is denoted by .
  • Skipped stimuli can be selected by means of random, stochastic, deterministic, chaotic or combined deterministic-stochastic algorithms.
  • multi-frequency stimulation is applied to stimuli with pedestals. In this case, the suprathreshold parts of the vibratory bursts are selected as explained above.
  • FIG.84 is a waveform illustration of a (jitter-free) CR sequence with different percentage of skipped (i.e., inactivated) stimuli (illustrated by shaded rectangles in channels 1 and 3).
  • the Coordinated Reset technology aims at disrupting abnormally synchronized neuronal activity by delivering phase resetting stimuli to different neuronal subpopulations engaged in the abnormal synchrony. Reducing the amount of abnormal neuronal synchrony over longer periods of time enables to reduce symptoms and to make networks unlearn their abnormal synaptic plasticity.
  • this desynchronization-based approach has limitations since its effects might depend on the amount of synchrony as well as on the specific stimulation parameters compared to the dominant frequency of the abnormal brain rhythm, in particular, when there are more than just one abnormal rhythm (as seen in many brain disorders).
  • the present embodiments do not depend on the indirectly reducing synaptic connectivity through desynchronization. Rather, by enabling more dynamic and random stimulus patterns (with pronounced temporal jitters and/or randomization/variation of burst amplitudes and/or burst durations and/or pedestal amplitudes and/or carrier frequencies) it directly and effectively reduces synaptic weights and is more robust with respect to parameter variations, e.g., compared to the dominant frequencies of abnormal neuronal rhythms.
  • the present embodiments include different mechanisms of action and focuss primarily on a reduction of synaptic weights – irrespective of whether the stimuli induce an acute desynchronization (i.e., desynchronization during stimulus delivery).
  • one or more embodiments employ stimulus-evoked responses and, hence, do not rely on the presence of abnormal neuronal synchrony.
  • the methods preventing in-channel masking work with and without pedestals.
  • Different hardware realizations can include devices such as thoracic breathing sensors + vCR delivered to gastric dermatomes (in particular, TH (5), 6-9, left) for gastric dysfunction (constipation etc.) in PD.
  • vibrotactile stimulators can be mounted to different parts of the hand, e.g., to the fingertips and/or the back of fingers (e.g., the proximal part of the back of fingers).
  • vibrotactile stimulators are mounted to different parts of the forearm, in parallel or vertically 72 S23-357-PCT P. Tass et al. Atty.
  • headbands can comprise different variants/alignments, enabling forehead stimulation (Trigeminal nerve 1) and/or occiput stimulation (cervical segments C2 and C3).
  • forehead stimulation Trigeminal nerve 1
  • occiput stimulation cervical segments C2 and C3
  • Stimulator alignment can be in the form of a linear array (e.g., comprising 4-8 vibrotactile stimulators) or two-dimensional array.
  • embodiments can be used for the treatment of dysphagia (swallowing problems), e.g., due to Parkinson’s disease, and sialorrhea (excessive drooling), e.g., due to Parkinson’s disease.
  • Stimulator alignment can be in the form of a two-dimensional array 2x4 alignment.
  • a high carrier frequency e.g., 250 Hz can be used.
  • 8 tactors placed in different dermatomes e.g., T10-L5.
  • vibrotactile stimulators can be arranged in dermatomes in L1-L4 (front of thigh) and/or S1-S2 (back of thigh).
  • Parkinson’s disease pelvic health disorders, e.g., pelvic pain or overactive bladder.
  • vibrotactile stimulators can be arranged in dermatomes in L2-L5 and/or S1-S2.
  • Applications Parkinson’s disease, pelvic health disorders, e.g., pelvic pain or overactive bladder.
  • Insole applications between 1, 2 or – more preferred at least 3 – up to 20 and more vibrotactile stimulators in the sole.
  • Parkinson’s disease impairment of balance and gait caused by aging and various diseases.
  • a therapy and device can potentially be applied to a wide range of disorders.
  • Dkt.102354-0785 connectivity patterns are not only found in Parkinson’s disease, but are also characteristic of a larger number of disorders of the central and peripheral nervous system, for instance, movement disorders, essential tremor, tic disorders, Tourette's syndrome, tremor in multiple sclerosis, dystonia, chronic stroke, epilepsy, depression, migraine, tension headache, incomplete spinal cord injury, obsessive-compulsive disorder, attention deficit hyperactivity disorder (ADHD), irritable bowel syndrome, chronic pain syndromes, e.g., complex regional pain syndrome, neuropathic pain and trigeminal neuralgia, pelvic health disorders, e.g., pelvic pain or overactive bladder, tinnitus, dissociation in borderline personality disorder and post-traumatic stress disorder.
  • Parkinson Parkinson’s disease
  • tremor in multiple sclerosis dystonia
  • dystonia chronic stroke
  • epilepsy depression
  • migraine tension headache
  • incomplete spinal cord injury obsessive-compulsive disorder
  • ADHD attention deficit hyper
  • Embodiments described as follows can include apparatuses that communicate with each other for a combined therapy.
  • An apparatus is explained for the example of two wirelessly connected vibration gloves. However, the same apparatus can be applied to a number of other applications listed below.
  • the solution involves tight synchronization between each finger stimulated in order to deliver optimum treatment. Synchronizing between fingers on the same hand is usually a more trivial exercise as a single clock source can be used along with precise counters as described in examples above. However, that solution does not scale well across the fingers of separate hands.
  • One possible alternate includes providing a wiring harness between hands to allow for synchronization.
  • WiFi is inherently asynchronous, so it would have to be adapted to create synchronization.
  • Zigbee is a low power wireless technology created for sensors and IoT and could be adapted to provide wireless synchronization.
  • Bluetooth classic is traditionally a wireless technology meant for audio connections. It’s typically higher power and bandwidth, so it is not as effective in low power situations.
  • BLE is a low power wireless technology made for passing low bandwidth data with a focus on quality of service over timeliness.
  • BLE has an advantage that is the technology predominantly used to connect with smart phones.
  • Sub- GHz solutions typically allow for long range in a very favorable band. In this case however, given the fact that the range is within approximately 6 feet, sub-GHz solutions don’t provide any practical benefit.
  • the timeliness of data can be partially addressed by limiting the re-transmissions to a minimal amount. Custom transmissions in BLE can accomplish this or even recently added isochronous transmission can as well.
  • a session timer is used to provide the master timing and sequencing between all of the fingers. It is expected that the session timer can be wirelessly 75 S23-357-PCT P. Tass et al. Atty. Dkt.102354-0785 communicated in a very accurate manner so that all fingers can remain in sync throughout a treatment.
  • the establishment of a session timer is created on one of the devices and then is accurately conveyed to all of the other elements in the system via wireless synchronization (e.g.
  • FIG.85 is a block diagram illustrating the interaction between master session timer 8502 and local session timer 8504.
  • status parameter synchronization is also critical. Items such as battery status, user interface items like a button or LED, faults, etc are all items that would be beneficial for each glove to see it’s link partner’s status.
  • These basic items being exchanged can also be an expanded list and include items such as: Battery status/life, Button inputs, LED status, Other UI elements, Faults, Tapper status, Waveform parameters, especially parameters that need to be common or related between the gloves, Firmware/hardware versions, Session counts, and a random/pseudo-random seed that needs to be common.
  • a separate data channel can be used to exchange data parameters. These data parameters can generally be exchanged in several different manners: on demand (when needed), when changed usually via a notification or indication, or periodically pushed/polled. There are cases where certain methods may be more advantageous given the parameters.
  • the firmware version may only need to be checked at the start of a link as that cannot change during the link.
  • an item such battery status would be better suited as a notification or even periodically pushed or polled.
  • GATT Generic Attribute profile
  • Tass et al. Atty. Dkt.102354-0785 synchronization has a time precision of typically ⁇ 0.5 ms between wirelessly connected devices.
  • Embodiments are explained herein for the case of vibrotactile and/or electrotactile stimulation of four fingers on both hands (see, e.g. US Patent App. Publ. No. 2021/0401664, the contents of which are incorporated herein by reference in their entirety).
  • An important principle of the example stimulation patterns provided herein is to avoid and/or reduce coincident stimulation of anatomically identical or closely related neuronal populations of two different hemispheres by introducing appropriate pairing patterns.
  • Coincidently activating the same fingers of right and left hand may interference with therapeutic stimulus effects due to interhemispheric inhibition.
  • anatomically coinciding pairs i.e., R1 – L1, R2 – L2, R3 – L3, R4 – L4, have to be (i) completely avoided or (ii) used less frequently.
  • the precise wireless pairing should be time-varying.
  • Time-variation can be realized on a (iii) slow time scale or, thanks to the high wireless precision, with (iv) temporal jitter. [00531] All methods, (i)-(iv), increase the therapeutic efficacy. [00532]
  • Pairs2 R1-L3, R2-L4, R3-L1, R4-L2 [00536] Pairs3: R1-L4, R2-L1, R3-L2, R4-L3 [00537] Pairs1: R1-L2, R2-L3, R3-L4, R4-L1 [00538] Pairs2: R1-L3, R2-L4, R3-L1, R4-L2 [00539] Pairs3: R1-L4, R2-L1, R3-L2, R4-L3 [00540] Pairs1: R1-L2, R2-L3, R3-L4, R4-L1 [00541] Pairs2: R1-L3, R2-L4, R3-L1, R4-L2 [00542] Pairs3: R1-L4, R2-L1, R3-L2, R4-L3 etc.
  • the sequence of pairs 1, pairs 2, pairs 3 is repeated periodically. Variation can also be based on deterministic, stochastic, random, chaotic and combined deterministic-stochastic rules.
  • Example (i) - reduce stimulation of anatomically coinciding pairs [00545] Pairs1: R1-L1, R2-L2, R3-L3, R4-L4 (anatomical coinciding) [00546] Pairs2: R1-L2, R2-L3, R3-L4, R4-L1 [00547] Pairs3: R1-L3, R2-L4, R3-L1, R4-L2 [00548] Pairs4: R1-L4, R2-L1, R3-L2, R4-L3 [00549] Pairs1: R1-L1, R2-L2, R3-L3, R4-L4 (anatomical coinciding) [00550] Pairs2: R1-L2, R2-L3, R3-L4, R4
  • One embodiment repeats the sequence of pairs 1, pairs 2, pairs 3, pairs 4 periodically. Other embodiments can select the pairs based on deterministic, stochastic, combined deterministic-stochastic, random, chaotic rules, e.g., to simply further reduce the frequency of occurrence of the anatomical coinciding pairs. 78 S23-357-PCT P. Tass et al. Atty. Dkt.102354-0785 [00559] The embodiments can be applied to a larger variety of different non-invasive devices, embodiments including, but not limited to those described in US Patent Publ. No. 2021/0401664, the contents of which are incorporated herein by reference in their entirety.
  • Thoracic stimulation array vibrotactile and/or electrotactile CR delivered to gastric dermatomes (in particular, TH (5), 6-9, left) for gastric dysfunction (constipation etc.) in Parkinson’s disease.
  • Fingertip stimulation arrays or “gloves” vibrotactile and/or electrotactile stimulators are mounted on different parts of the hand, e.g., the fingertips.
  • Forearm arrays/cuff vibrotactile and/or electrotactile stimulators are mounted to different parts of the forearm, in parallel or vertically oriented to the forearm’s longitudinal direction or in a more complex arrangement.
  • Headband Headbands can comprise different variants/alignments, enabling forehead stimulation (Trigeminal nerve 1) and/or occiput stimulation (cervical segments C2 and C3).
  • Forehead/ophthalmic nerve (trigeminal nerve 1st branch) stimulation For the treatment of migraines, headaches, depression, obsessive-compulsive disorders, borderline personality disorder and other psychiatric disorders.
  • Stimulator alignment Linear array (e.g., comprising 4-8 vibrotactile and/or electrotactile stimulators) or two-dimensional array.
  • Occiput/C2 and C3 dermatomes stimulation For the treatment of dysphagia (swallowing problems), e.g., due to Parkinson’s disease, and sialorrhea (excessive drooling), e.g., due to Parkinson’s disease.
  • Stimulator alignment two-dimensional array 2x4 alignment
  • Torso-band High vibrotactile carrier frequency, e.g., 250 Hz. For instance, 8 tactors placed in different dermatomes, e.g., T10-L5.
  • Thigh band Vibrotactile and/or electrotactile stimulators arranged in dermatomes in L1-L4 (front of thigh) and/or S1-S2 (back of thigh).
  • Parkinson’s disease pelvic health disorders, e.g., pelvic pain or overactive bladder.
  • Shank band Vibrotactile stimulators arranged in dermatomes in L2-L5 and/or S1-S2.
  • Applications Parkinson’s disease, pelvic health disorders, e.g., pelvic pain or overactive bladder.
  • Insole Between 1, 2 or – more preferred at least 3 – up to 20 and more vibrotactile and/or electrotactile stimulators in the sole. For the treatment of Parkinson’s disease, impairment of balance and gait caused by aging and various diseases.
  • Detailed tests of two devices revealed a timing deviation between stimulus delivery of both sides of about +/- 50us.
  • the example embodiments that will now be described relate to a method and device that delivers non-invasive, in particular sensory stimulation treatment in a way that counteracts habituation, e.g., by increasing and rewarding patients’ attention, alertness, curiosity level and activating additional brain areas besides primary sensory brain areas. In this way, these and other embodiments counteract habituation and increases the therapeutic effects, e.g., by boosting the propagation of desynchronizing effects through disease-related brain circuits.
  • the rare mode occurs during smaller integral time portions, with an occurrence probability of less than 0.2 or 0.1 in relation to the entire stimulation duration.
  • the times when the rare mode is activated denoted by t 2 , t 4 , t 6 in FIG.87, can be chosen based on a deterministic, stochastic (i.e., random) or combined deterministic-stochastic or chaotic algorithm.
  • the duration of the rare mode sessions denoted by t3-t2, t5-t4, t7-t6 in FIG.87, can be constant or varying (from one rare mode session to another one).
  • FIG.87 is a waveform illustration of the intermingled administration of main stimulation mode (“main mode”) and rare stimulation mode (“rare mode”).
  • main mode main stimulation mode
  • rare mode rare stimulation mode
  • the durations of the main mode sessions are given by t2-t1, t4-t3, t6-t5, t8-t7.
  • the durations of the rare mode sessions are t 3 -t 2 , t 5 -t 4 , t 7 -t 6 .
  • the same type of stimulation as in the main mode stimulation but with perceptually significantly different parameters, e.g., perceptually different vibration amplitude (e.g., significantly stronger) and/or period TCR (e.g., significantly faster) and/or stimulus duration (e.g., significantly longer vibratory stimuli).
  • FIG.88 illustrates a vCR stimulation pattern without any rare mode stimulation.
  • FIG.89 shows an example with intermingled rare mode stimulation. Perceptually different means that the patient can clearly perceive the difference of the main mode stimuli vs.
  • the rare mode stimuli when compared head to head in a psychophysical comparison task (as known to the expert, e.g., by simple pairwise comparison).
  • qualitatively very different stimuli of the same or different sensory modality For instance, one long stimulus with complex time course of the vibration amplitude.
  • longer sequences (containing more than 4 single stimuli) that are qualitatively different, in particular, more complex with respect to their mutual timing characteristics. These stimulus sequences are called sensory tunes.
  • no stimulus is delivered during the rare mode stimulation. This type of rare mode is simply a pause.
  • the rare mode sessions can be applied symmetrically (i.e., the exact same rare modes are used) and/or coincidentally (at the same onset and offset times).
  • the rare mode sessions can be applied symmetrically (i.e., the exact same rare modes are used) and/or coincidentally (at the same onset and offset times).
  • the rare mode sessions can be applied in an asymmetric manner (e.g., different rare mode sessions are applied to both hands) and/or not coincidentally, e.g., with a constant and/or time-varying time shift.
  • the time-varying time shift can vary based on be calculated by means of a deterministic, chaotic, stochastic, random algorithm or combinations thereof.
  • a pause (as in one previous embodiment described above) is a particularly effective type of rare mode in the case of bilateral stimulation, when the pause is only applied to one of the hands at a time, e.g., in FIG.90, when rare mode 2 is a pause. Applying different types of rare mode stimulation (listed above) to bilateral hand stimulation is illustrated in FIG.90.
  • FIG.88 is a waveform illustration of the intermingled administration of the main stimulation mode (“main mode”) and two rare stimulation modes (“rare mode 1” and “rare mode 2”), where the two different rare modes do not immediately follow each other. There is a main mode in between different rare modes.
  • FIG.89 is a waveform illustration of the intermingled administration of the main stimulation mode (“main mode”) and two rare stimulation modes (“rare mode 1” and “rare mode 2”), where the two different rare modes may immediately follow each other (without main mode in between).
  • FIG.90 is a waveform illustration of the intermingled administration of the main stimulation mode (“main mode”) and three rare stimulation modes (“rare mode 1”, “rare mode 2” and “rare mode 3”) for the case of bilateral stimulation where rare mode sessions are not symmetrically (and coincidentally) applied to both sides, e.g., both hands.
  • FIG.91 is a waveform illustration of regular 3:2 ON-OFF CR RVS (rapidly varying sequences) pattern. Dashed lines indicate multiples of the vCR period TCR and dotted lines multiples of TCR/4 during individual CR periods. A CR period is also called a cycle.
  • FIG.92 is a waveform illustration of an embodiment #1 rare mode cycle C r interspersed in the main mode vCR pattern from FIG.91.
  • the vibration amplitude is the only parameter that differs compared to the main mode cycles Cm.
  • FIG.93 is a waveform illustration of two rare mode cycles C r interspersed in the main mode vCR pattern from FIG.91.
  • the vibration amplitude is the only parameter that differs compared to the main mode cycles Cm.
  • one or more rare mode cycles can be intermingled with the main mode stimulation.
  • the rare mode stimulation need not be confined to administration of complete rare mode cycles.
  • FIG.94 is a waveform illustration of two rare mode cycles C r interspersed in the main mode vCR pattern from FIG.91.
  • the vCR period is the only parameter that differs compared to the main mode cycles Cm:
  • the rare mode vCR period TCR2 is shorter compared to the main mode vCR period T CR1 .
  • FIG.95 is a waveform illustration of an embodiment of rare mode cycle C r interspersed in the main mode vCR pattern from FIG.91.
  • FIG.96 is a waveform illustration of an embodiment of rare mode cycle C r interspersed in the main mode vCR pattern from FIG.91.
  • the sensory (here vibratory) tune can be delivered during the same period of length TCR.
  • FIG.97 is a waveform illustration of an embodiment of rare mode cycle C r interspersed in the main mode vCR pattern from FIG.91.
  • the sensory (here vibratory) tune can also be delivered during more than one cycle, where the cycles length differs from the period length TCR.
  • Stimuli with pedestals Another embodiment uses pulsatile sensory stimuli and/or non-invasive (non-sensory) stimuli with pedestals instead of stand-alone pulsatile stimuli (without pedestals).
  • a variety of stimulus can be used, such as Sensory stimuli (vibrotactile, vibratory, pressure, auditory, visual, thermal (warm and/or cold), olfactory) and Non-invasive, non-sensory stimuli / transcutaneous (electrical, transcutaneous magnetic, transcutaneous ultrasound, transcutaneous laser (e.g., infrared) light).
  • Sensory stimuli vibrotactile, vibratory, pressure, auditory, visual, thermal (warm and/or cold), olfactory
  • Non-invasive, non-sensory stimuli / transcutaneous electrical, transcutaneous magnetic, transcutaneous ultrasound, transcutaneous laser (e.g., infrared) light.
  • Abnormal neuronal synchronization and abnormal synaptic connectivity patterns are not only found in Parkinson’s disease, but are also characteristic of a larger number of disorders of the central and peripheral nervous system, for instance, movement disorders, essential tremor, tic disorders, Tourette's syndrome, tremor in multiple sclerosis, dystonia, chronic stroke, epilepsy, depression, migraine, tension headache, incomplete spinal cord injury, obsessive- compulsive disorder, attention deficit hyperactivity disorder (ADHD), irritable bowel syndrome, chronic pain syndromes, e.g., complex regional pain syndrome, neuropathic pain and trigeminal neuralgia, pelvic health disorders, e.g., pelvic pain or overactive bladder, tinnitus, dissociation in borderline personality disorder and post-traumatic stress disorder.
  • Fingertip stimulators or “gloves” vibrotactile stimulators are mounted to different parts of the hand, e.g., to the fingertips and/or the back of fingers (e.g., the distal and/or proximal parts of the back of fingers).
  • Thoracic vibrotactile stimulation array vCR delivered to gastric dermatomes (in particular, TH (5), 6-9, left) for gastric dysfunction (constipation etc.) in PD.
  • Forearm arrays/cuff vibrotactile stimulators are mounted to different parts of the forearm, in parallel or vertically oriented to the forearm’s longitudinal direction or in a more complex arrangement.
  • Headband Headbands can comprise different variants/alignments, enabling forehead stimulation (Trigeminal nerve 1) and/or occiput stimulation (cervical segments C2 and C3).
  • Forehead/ophthalmic nerve (trigeminal nerve 1st branch) stimulation For the treatment of migraines, headaches, depression, obsessive-compulsive disorders, borderline personality disorder and other psychiatric disorders.
  • Stimulator alignment Linear array (e.g., comprising 4-8 vibrotactile stimulators) or two-dimensional array.
  • Occiput/C2 and C3 dermatomes stimulation For the treatment of dysphagia (swallowing problems), e.g., due to Parkinson’s disease, and sialorrhea (excessive drooling), e.g., due to Parkinson’s disease.
  • Stimulator alignment two-dimensional array 2x4 alignment 84 S23-357-PCT P.
  • Torso-band High carrier frequency, e.g., 250 Hz. For instance, 8 tactors placed in different dermatomes, e.g., T10-L5.
  • Thigh band Vibrotactile stimulators arranged in dermatomes in L1-L4 (front of thigh) and/or S1-S2 (back of thigh).
  • Applications Parkinson’s disease, pelvic health disorders, e.g., pelvic pain or overactive bladder.
  • Shank band Vibrotactile stimulators arranged in dermatomes in L2-L5 and/or S1-S2.
  • Parkinson’s disease pelvic health disorders, e.g., pelvic pain or overactive bladder.
  • Insole Between 1, 2 or – more preferred at least 3 – up to 20 and more vibrotactile stimulators in the sole.
  • Parkinson’s disease impairment of balance and gait caused by aging and various diseases.
  • the embodiments to be described as follows relate to methods and apparatuses that enable more effective vibrotactile stimulation, i.e., stronger physiological effects with less vibration power/amplitude. More particularly, the present embodiments relate to methods and apparatuses for automatically/autonomously calibrating relevant stimulation parameters for non-invasive and invasive multichannel CR stimulation and related stimulation techniques, random reset stimulation as well as combinations thereof.
  • vibrotactile and/or electrotactile stimulation uses vibrotactile and/or electrotactile stimulation as described above.
  • There are several important parameters of vibrotactile and/or electrotactile CR stimulation are, e.g., stimulus intensities, temporal jitter, amplitude, CR sequences. These parameters should ideally be adjusted to every individual patient. However, due to the slow wash-in, i.e., the long time it may take until therapeutic effects build up, it is not feasible to calibrate these parameters by trial and error, performed by test stimulations carried out by trained health care professionals. The below explains how embodiments calibrate optimal CR sequences and stimulus amplitudes. Other embodiments, using the same methods, are used to calibrate and optimize the other stimulation parameters mentioned above.
  • a device of embodiments delivers stimuli according to a stimulation pattern that is characterized by a set of stimulation parameters. Stimuli are delivered in cycles of a cycle period T, which will be referred to as CR cycles in the following. Each target site receives exactly one stimulus per CR cycle. The sequence at which the target sites are activated during a CR cycle is referred to as CR sequence in the following. The CR sequence is shuffled after a shuffle period T_shuffle.
  • a random jitter was added to the stimulus onset times (e.g. FIG.99).
  • Shuffling of CR sequences can be done randomly according to a probability distribution which determines the probability to select one of the possible CR sequences.
  • pseudorandom CR sequence selection can be performed, or sequences can be selected according to a deterministic algorithm, that ensures variability of the CR sequences.
  • the stimulation pattern is characterized by a set of stimulation parameters including the stimulus waveform, the stimulus amplitude, the shuffle period, the cycle period (or equivalently, the stimulation frequency 1/T), the number of stimulation sites, the locations of stimulation sites, the range of the random jitter, and the set of possible CR sequences and the corresponding frequencies of occurrence, e.g., characterized by a probability distribution.
  • the device measures stimulation outcome by means of appropriate feedback signals recorded with one or more sensors and comprises a controller which adapts the stimulation pattern (as specified by the set of stimulation parameters) if necessary to achieve a sustained symptom relief during and after individual stimulation epochs.
  • wearables For non-invasive vibrotactile and/or electrotactile stimulation of movement disorders or epilepsies, wearables (such as iPhone, Apple watch) enable feedback of stimulation outcome in terms of patient questionnaires, step-related data (stride characteristics, step count etc.) as well as tremor probability and dyskinesia probability.
  • the parameter adjustment 10002 can be done using a reinforcement learning algorithm with the goal to learn the best-performing stimulation pattern for each assessment outcome (policy) based on the history of both assessment outcomes and delivered stimulation patterns.
  • Possible learning algorithms include dynamic programming and model-free methods such as temporal difference learning methods, e.g., SARSA and Q-learning, and Monte Carlo control. Examples of parameter adjustment using reinforcement learning algorithms are attached.
  • Example 1 Long-lasting desynchronization after stimulation depends on the selected CR sequence and the shuffle period.
  • DBS Standard deep brain stimulation
  • PD medically refractory Parkinson’s disease
  • DBS delivered to the subthalamic nucleus (STN) or globus pallidus internus is not effective for all PD symptoms and may cause relevant side effects [A.M. Lozano, N. Lipsman, H. Bergman, P. Brown, S. Chabardes, J.W. Chang, K. Matthews, C.C. McIntyre, T.E. Schlaepfer, M. Schulder, Y. Temel, J. Volkmann, J.K. Krauss. Deep brain stimulation: current challenges and future directions. Nature Review Neurology 15, 148 (2019)]. Also, PD symptoms return shortly after cessation of DBS [P. Temperli, J. Ghika, J.-G.
  • a theory-based stimulation technique aims at long-lasting desynchronization that persists after cessation of stimulation [P.A. Tass. A model 87 S23-357-PCT P. Tass et al. Atty. Dkt.102354-0785 of desynchronizing deep brain stimulation with a demand-controlled coordinated reset of neural subpopulations. Biological Cybernetics 89, 81 (2003) ; P.A. Tass, M.
  • CRS moves networks from strongly connected synchronized states (SCSS) to weakly connected desynchronized states (WCDS), ultimately inducing effects outlasting stimulation.
  • SCSS strongly connected synchronized states
  • WCDS weakly connected desynchronized states
  • CRS is a multisite stimulation technique during which phase-shifted stimuli are delivered to separate neuronal subpopulations. CR stimuli are sequentially delivered to the different stimulation sites, forming a CR sequence (e.g. FIGs.101F, 101H, and 101J).
  • CRS is delivered in cycles and each stimulation site is activated exactly once per cycle. For four stimulation sites, there are 4 possible CR sequences during each cycle.
  • the CR sequence is typically shuffled after a shuffle period, ⁇ shuffle, (e.g. 88 S23-357-PCT P. Tass et al. Atty. Dkt.102354-0785 FIG.101J).
  • ⁇ shuffle e.g. 88 S23-357-PCT P. Tass et al. Atty. Dkt.102354-0785 FIG.101J.
  • shuffled CRS outperforms non-shuffled CRS regarding long-lasting therapeutic aftereffects in PD monkeys (Wang et al., 2022).
  • CRS is a multisite stimulation technique during which phase-shifted stimuli are delivered to separate neuronal subpopulations.
  • CR stimuli are sequentially delivered to the different stimulation sites, forming a CR sequence (e.g. FIGs.101F, 101H, and 101J).
  • CRS is delivered in cycles and each stimulation site is activated exactly once per cycle.
  • the CR sequence is typically shuffled after a shuffle period, ⁇ shuffle, (e.g. FIG.101J).
  • ⁇ shuffle e.g. FIG.101J.
  • FIGs.101A to 101K illustrate example aspects of CRS of inhomogeneous and homogeneous networks according to embodiments.
  • FIG.101A illustrates synaptic connectivity of an inhomogeneous network. Black dots mark connections between presynaptic neurons at locations ⁇ pre and postsynaptic neurons at locations ⁇ post, in units of the system’s length scale, ⁇ .
  • FIGs.101B-101E illustrate dynamics of the Kuramoto order parameter measuring the degree of synchrony, ⁇ , mean and the synaptic weight, ⁇ ⁇ , before, during (light rose), and after CRS with non-shuffled sequences (FIG.101B) and shuffled sequences for different shuffle periods, ⁇ shuffle, (FIGs.101C-101E), respectively.
  • Large, ⁇ ⁇ 1 indicates in-phase synchronized spiking activity. Colours correspond to different CR sequences (see labels in FIG.101B’).
  • the network approaches either the stable strongly connected 89 S23-357-PCT P. Tass et al. Atty.
  • FIG. 101A’ and 101B’-101E’ are the same as FIGs.101A and 101B-101E but for a homogeneous network.
  • FIG.101F is a raster plot of neuronal spiking activity (black dots) for neurons at different locations during delivery of non-shuffled CR with CR sequence I-II-III-IV, ⁇ . Red colours show the intensity of the spatial stimulus profile (see also panel FIG.101K).
  • the horizontal black bar marks a 50 ⁇ ⁇ time interval.
  • FIG.101G illustrates corresponding, time lags between stimuli delivered to sites I-IV in units of 1/ ⁇ CR .
  • FIGs.101H and 101I are the same as FIGs.101F and 101G but for the CR sequence I-III-II-IV.
  • FIGs.101B-101E and FIGs.101B’-101E’ shown are computational results for different .
  • the mean synaptic weight slowly the stationary values attained for different CR sequences during non-shuffled CRS (compare and non-shuffled CRS in FIGs 101E, 101B).
  • Example 2 Learning optimal CR sequence: In example 2, it is shown how well- performing stimulation parameters for inducing long-lasting desynchronization can be learned using the method and apparatus described in the present disclosure.
  • Embodiments control the degree of neuronal synchrony (associated with Parkinson’s disease symptoms) in a computational model.
  • the neuronal activity in the target brain area is simulated using a 92 S23-357-PCT P.
  • Parameters are set according to Example 1 for the inhomogeneous network.
  • stimulation epochs of 10 sec were used that were followed by a stimulation-off period of 10 sec during which an assessment of neuronal synchrony was performed. This corresponds to the setup shown in FIG.102.
  • neuronal synchrony is measured and the system is classified into a state according to the degree of neuronal synchrony. Considered are two states: synchronous activity, corresponding to state 1 (the patient is assumed to suffer from symptoms) and desynchronous activity corresponding to state 2 (the patient does not experience symptoms).
  • all stimulation parameters are fixed according to the values in the table below and the ones in Example 1 except for the CR sequence.
  • the controller may choose between any of the following CR sequences: [00628] i) I-II-III-IV, [00629] ii) I-II-IV-III, [00630] iii) I-III-II-IV, [00631] iv) I-III-IV-II, [00632] v) I-IV-II-III, [00633] vi) I-IV-III-II.
  • N(s,a) ⁇ N(s,a)+1 Q(s_(k N + t), a_(k N + t)) ⁇ Q(s_(k N + t), a_(k N + t)) + 1/ N(s_(k N + t), a_(k N + t)) ( G_(k N + t) - Q(s_(k N + t), a_(k N + t)) ) Do k ⁇ k+1 94 S23-357-PCT P.
  • the first quantity is the degree of neuronal synchrony, , as quantified by the Kuramoto order parameter .
  • the second quantity is the mean synaptic weight, , corresponding to the average weight of all synapses.
  • a stable strongly connected synchronized state and a stable weakly connected desynchronized state coexist, such that the desynchronized one remains stable in the absence of stimulation if the mean synaptic weight attains low values.
  • only the synchronized state is stable for high mean synaptic weight.
  • the state-action reward sequence for the trajectory shown in FIG.103 is (1,iii,0,1,v,0,1,i,0,2,ii,1, 2,ii,1,2,ii,1,2,ii,1,2,ii,1,2,ii,1,2,ii,1,2,ii,1,2,ii,1,2)ii,1,.
  • Q(1,a) was maximized for action i (CR sequence I-II-III-IV )
  • Q(2,a) was maximized for action ii (CR sequence I-II-IV-III ).
  • To test the robustness of the learning procedure performed were 2 ⁇ 7 simulations and recorded were the actions that maximized Q(1,a) and Q(2,a). The relative frequency at which corresponding actions were learned is shown in FIG.104.
  • FIG.104 shows the relative frequency at which actions i-vi maximized Q( 1 , a), i.e., the expected total future reward when being in the synchronized state, and Q(2,a), i.e., the future reward when being in the desynchronized state, and performing action across 2 ⁇ 7 95 S23-357-PCT P.
  • Example 3 CR with shuffled sequences and non-uniform sequence selection probability -- Based on the observation that stimulation with certain CR sequences leads to lower mean synaptic weights than stimulation with others, Example 3 tests whether synaptic weight reduction during CR with shuffled sequences could be improved when certain sequences were excluded from the pool of CR sequences from which CR sequences are drawn during shuffling. This corresponds to using a non-uniform probability for CR sequence selection during shuffled CR. [00647] To test this hypothesis, performed were simulations for the LIF model, with similar parameters as in Example 1 for the inhomogeneous network.
  • FIG.105B shows that the CR sequence pools are named as follows:”all” contains all 4 possible CR sequences; “without worst” contains all but the CR sequences I-IV-III-II, II-I-IV-III, III-II-I-IV, and IV-III- 96 S23-357-PCT P.
  • FIGs.106A to 106C illustrate mean synaptic weight after stimulation onset averaged over different network and sequence realizations. Results are shown for “best” (blue), “without worst” (red), “all” (black), and “without best” (green) CR sequence pools (see FIG. 105B). Lines show averages and dashed region shows the range between minimum and maximum values during individual simulations. Panels Figures 106A, 106B, 106C show results for different shuffle periods of 0.1 sec, 10 sec and 1800 sec, respectively. Parameters are set to the values used in Example 2. It is found that only drawing sequences from the “best” CR sequence pool during shuffled CR reduces the mean synaptic weight during stimulation substantially across different shuffle periods.
  • Example 4 Reinforcement learning for autonomous stimulation amplitude adjustment
  • a computational model is used to illustrate how reinforcement learning (RL) can be employed to improve stimulation aftereffects of coordinated reset (CR) stimulation over the course of multiple stimulation sessions.
  • stimulation ON stimulation epochs
  • OFF periods pauses
  • an assessment of the patient’s condition is performed and based on the outcome the RL algorithm assigns either positive rewards or a negative rewards.
  • Different stimulation sessions can model either treatments of different patients or multiple treatments of the same patient, e.g., at different visits. Based on the “experience” on effective stimulation parameters during the past 97 S23-357-PCT P. Tass et al.
  • Atty. Dkt.102354-0785 stimulation ON periods the algorithm selects the stimulation parameters for the next ones with the goal to maximize positive rewards.
  • RL is tested to adjust the stimulation amplitude of CR stimulation.
  • DBS deep brain stimulation
  • RL is tested in a computational model to effectively learn stimulation amplitudes for CR stimulation.
  • Embodiments deliver CR stimulation with amplitude for a stimulation epoch of time . Then, embodiments pause stimulation for and evaluate the patients’ condition a survey or biomarkers such as LFP in brain region).
  • the RL algorithm may adjust the stimulation amplitude and the next stimulation epoch starts, followed by another pause and so on. This is stopped after stimulation epochs and subsequent pauses. Following, we refer to stimulation epochs and subsequent pauses as one session. [00654] To employ RL, represented are the described sequence of stimulation epochs, pauses, and evaluated patients’ condition by a Markov Decision Process (MDP).
  • MDP Markov Decision Process
  • States in the MDP represent the simulated patient’s condition which is evaluated using a Likert scale with possible responses: “very bad”, “bad”, “neutral”, “good”, “very good.”
  • the latter simulates the patient’s answers, e.g., in a survey taken during the pause after each stimulation epoch.
  • the responses are simulated by a Gaussian random variable with a mean value that is correlated to the degree of neuronal synchrony and the mean synaptic weight of intrapopulation synapses of a neuronal subpopulation, and a non-zero standard deviation simulating noise in the 98 S23-357-PCT P. Tass et al. Atty. Dkt.102354-0785 patients’ responses.
  • the latter is motivated by the observation that the mean synaptic weight in the pathological synchronized state is of the order 0.4.
  • the mean of these two integer numbers is than used as the mean for the Gaussian distributed random number simulating the patient’s response. To account for noise, a standard deviation of one is used for this random number.
  • the result is than mapped to an integer number between zero (very good) and four (very bad) using numpy.digitize() with bins [0.5, 1.5, 2.5, 3.5 ] .
  • the patient’s condition represents the state in the MDP, i.e., state 0 corresponds to the patient response that they feel “very good” during assessment, state 1 to “good”, state 2 to “neutral”, state 3 to “bad”, and state 4 to “very bad”.
  • CR stimulation is performed with ms and one of the following nine amplitudes or .
  • state After an amplitude patient condition (state): state 0 reward 3, state 1 reward 1.5, state 2 reward 0, state 3 reward -1, state 4 reward -2.
  • Each stimulation session starts with the LIF network being in the strongly connected synchronized state (see Example 1) and the patient condition “very bad”, then stimulation epochs and subsequent pauses are simulated. During each pause an the patient’s condition is performed. The goal of the RL algorithm is to maximize the obtained total reward.
  • RL is implemented using an online Sarsa( ) algorithm [Sutton and Barto, 2018].
  • An example algorithm operates as follows: ⁇ Initialize the state action function for each state and action and an - greedy policy with respect to ⁇ Loop over sessions: o Initialize eligibility , for each state and action .
  • o Initialize state “very bad” state).
  • o Draw action from policy for state o Get reward for performing action in state o
  • o Loop over stimulation epochs ⁇ Draw action from policy for state ⁇ Do the following updates: ⁇ ⁇ ⁇ with respect to Q ⁇ in state .
  • ⁇ Simulate the next stimulation epoch of CR stimulation with amplitude and the subsequent pause for the network of LIF neurons from Example 1.
  • FIG.107 illustrates trajectories of the Kuramoto order parameter ( ⁇ ) and the mean synaptic weight ( ⁇ w>) during a session with stimulation epochs. Horizontal, black bars mark stimulation epochs and vertical, mark assessment times.
  • the learning algorithm adjusts the stimulation amplitude according to an -greedy policy with respect to the current estimate of the state action function Q(s,a) (see above). Parameters: width of stimulation profile L/16pi and CR frequency 10 Hz.
  • FIG.108 illustrates total reward after each session for subsequent sessions achieved by the RL algorithm presented above.
  • case 1 in which a large range of amplitudes leads to a reduction of the mean synaptic weight (parameters as in FIG.107) and case 2 where only one of the possible amplitudes would lead to a reduction of the mean synaptic weight during a single long ( stimulation epoch (width of stimulation profile was set to 6L/8pi and CR frequency to 21 Hz), representing a more difficult test case.
  • the black curve marks the average over the three trials. Note that a total reward of 5.5 corresponds to a case where each of the five possible patient’s conditions occurs equally often during assessment (horizontal dashed line). Parameters: .
  • FIG.108 illustrates traces of the simulated patient’s condition, the Kuramoto order parameter, , and the mean synaptic weight, , during the indicated sessions for the two cases in FIG.108 for the trials represented by black crosses in FIG.108. Grayscale marks results after corresponding number of sessions. 102 S23-357-PCT P. Tass et al. Atty.
  • Dkt.102354-0785 Tested was the learning of the stimulation amplitude for two cases.
  • case 1 other stimulation parameters were adjusted such that CR stimulation with a wide range of stimulation amplitudes would result in a reduction of the mean synaptic weight during a single long ( stimulation epoch, thereby resulting in sustained desynchronization when stimulation is turned off (see, for instance, [Kromer et al., 2020]).
  • case 2 only one of the possible of stimulation amplitudes would cause a reduction of the mean synaptic weight during a single long stimulation epoch, making it a very challenging test case in which a random selection of the stimulation amplitude after each assessment is unlikely to lead to a positive total reward.
  • a device delivers stimuli which activate neurons.
  • Different embodiments may employ electrical stimuli or optical stimuli directly delivered to the brain or spinal cord through implanted electrodes, epicortical electrodes, subdural electrodes, epidural electrodes, implanted or epicortical or epidural optical fibers.
  • stimulation may be delivered non-invasively, e.g., by means of vibrotactile and/or electrotactile stimuli, infrared neural stimuli, or transcranial stimulation such as transcranial electrical, magnetic, ultrasound, or light stimulation.
  • the device stimulates multiple target sites, i.e., locations in the brain or spinal cord or on the skin. In some embodiments one stimulation site may be sufficient. Accordingly, the device comprises one or more depth electrodes with one or more stimulation contacts each. In a different embodiment the device comprises one or more coils for transcranial magnetic stimulation, two or more electrodes for transcranial electrical stimulation, one or more optical fibers for transcranial light or infrared stimulation, one or more epicortical electrodes, one or 104 S23-357-PCT P. Tass et al. Atty.
  • Dkt.102354-0785 more epidural electrodes, one or more ultrasound sources, one or more vibrotactile stimulators, one or more electrical skin or tongue electrodes, one or more thermal skin stimulators.
  • Embodiments can also be applied to invasive or combined invasive and non-invasive stimulation. Examples of invasive stimulation include, but are not limited to deep brain stimulation, spinal cord stimulation, epicortical/epidural stimulation.
  • Supplementary Material [00679] Neuronal network model - Simulations were performed using the model network of excitatory leaky integrate and-fire (LIF) neurons with STDP from Justus A. Kromer, Ali Khaledi-Nasab, and Peter A. Tass.
  • the dynamics of the ith neuron's subthreshold membrane potential, Vi(t), was given by [00681] the leak current, with leakage conductance gleak and resting potential Vrest; the excitatory synaptic input current, with synaptic conductance g syn,i (t) and reversal potential V syn ; the stimulation current I stim (t); and the noisy input current I noise,i (t), modelling input from other brain regions.
  • Neuron i was defined to fire a spike whenever its membrane potential crossed the dynamic threshold potential Vth,i(t), [00682] a duration of ⁇ spike .
  • j is the index of the presynaptic and i the index of the postsynaptic neuron.
  • Independent Poisson input was delivered to the neurons modelling noisy input from other brain areas. To this end, Poisson spike trains with mean firing rate f noise were fed into the neurons through excitatory synapses. The resulting input currents, I noise,i (t), were given by [00686] [00687] spike in the Poisson spike train fed into neuron i.
  • Tass Dendritic and axonal propagation delays determine emergent structures of neuronal networks with plastic synapses. Sci. Rep., 7:39682, 2017).
  • STDP parameters were chosen according to J.A. Kromer, A. Khaledi-Nasab, P.A. Tass. Impact of number of stimulation sites on long-lasting desynchronization effects of coordinated reset stimulation.
  • SSS strongly connected synchronized state
  • WCDS weakly connected desynchronized state
  • the probability for implementing a synaptic connection between any two neurons was set to 7%.
  • the realization of the resulting synaptic connections that was used in the simulations in the main text is shown in FIG.101A'.
  • the neurons were first sorted according to their center coordinates, X. Then, the neurons were separated into four subpopulations such that the first 250 neurons were part of subpopulation one, the second 250 neurons were part of subpopulation two, and so one.
  • Tshuffle 1/fCR, i.e., shuffling after each CR cycle, is often referred to as CR with rapidly varying sequence (RVS CR) (Peter A Tass and Milan Majtanik. Long-term anti-kindling effects of desynchronizing brain stimulation: a theoretical study. Biol. Cybern., 94:58-66,2006; Ilya Adamchic, Christian Hauptmann, Utako Brigit Barnikol, Norbert fawelczyk, Oleksandr Popovych, Thomas Theo Barnikol, Alexander Silchenko, Jens Volkmann, Gunter Deuschl, Wassilios G Meissner, et al.
  • a neuron with center coordinated Xi was affected by a stimulus delivered to site j at a strength of [00701] ⁇ j
  • Simulations were performed as follows: First, a random network of synaptic connections for the considered network type was generated according to the procedure described above.
  • N is the phase function associated with the inter-spike intervals of neuron k.
  • ⁇ k(t) attains subsequent integer values at the subsequent spike times of neuron k and increases linearly during inter-spike intervals (M. Rosenblum, A. Pikovsky, J. Kurths, C. Schaffer, and P. A. Tass. Phase synchronization: From theory to data analysis. In S. Gielen and F. Moss, editors, Neuro-Informatics and Neural Modelling, Handbook of Biological Physics, volume 4, pages 279 ⁇ 321. Elsevier, Amsterdam, 2001). ⁇ (t) approx.
  • Atty. Dkt.102354-0785 the coexistence of a stable SCSS, modelling pathological neuronal synchrony, e.g., in Parkinson's disease, and a stable WCSS, modelling physiological neuronal activity.
  • a stable SCSS modelling pathological neuronal synchrony, e.g., in Parkinson's disease
  • a stable WCSS modelling physiological neuronal activity.
  • the mean synaptic weight was between 0:3 and 0:4 for the inhomogeneous networks (FIGs.101B-101E in the text above and FIGs.113A and 113B) and approx.0-4 for the homogeneous networks (FIGs.101B'-101E' in the text above and FIGs.113C and 113D.).
  • CRS was delivered for 2 h.
  • simulated was the network until the mean synaptic weight approached a stationary value. Resulting trajectories of the mean synaptic weights for various CR patterns and both network types are shown in FIG.101 in the text above.
  • FIG.113 provides statistical analysis of mean synaptic weight before, during, and after stimulation. Mean synaptic weight shortly before cessation of CRS (acute) and approx 5 hours after cessation of CRS (long-lasting) are compared to its values before stimulation (init.).
  • Results are shown for inhomogeneous networks (FIGs.113A, 113B) and homogeneous networks (FIGs.113C, 113D), and prior to stimulation (init.); at the end of a 2h session of CRS for non-shuffled CR (non-shuffled), and for shuffled CR (shuffled) with shuffle periods 0:1s, 10s, and 1800s (FIGs.113A and 113C), and approx 3 hours after cessation of stimulation for the same setups (FIGs.113B and 113D).
  • Results are shown for five network realization (all) and for the CR sequences I-II-II-IV, I-II-IV-III, I-III-II-IV, I-III-IV-II, I-IV-II-III, I-IV-III-II for non-shuffled CR and for 30 realizations of the CR sequence for each shuffle period and network realization. Horizontal bars mark averages over individual sequence and network realizations. Symbols show results for individual simulations. [00709] A more detailed statistical analysis of the mean synaptic weight before, during, and after stimulation is presented as follows.
  • Mean synaptic weight before, during, and after CRS Analyzed was the mean synaptic weight of inhomogeneous and homogeneous networks before, during, and after CRS (FIG.113). Corresponding exemplary trajectories of the mean synaptic weight are shown in FIG.101 in the text above. Additionally, for both inhomogeneous and homogeneous networks, performed were simulations for ive network realizations and recorded the mean synaptic 111 S23-357-PCT P. Tass et al. Atty. Dkt.102354-0785 weights after 3000s of simulation, when the network approached a stationary state. Results are labeled "init.” in FIG.113.
  • any two components so associated can also be viewed as being “operably connected,” or “operably coupled,” to each other to achieve the desired functionality, and any two components capable of being so associated can also be viewed as being “operably coupleable,” to each other to achieve the desired functionality.
  • operably coupleable include but are not limited to physically mateable and/or physically interacting components and/or wirelessly interactable and/or wirelessly interacting components and/or logically interacting and/or logically interactable components.

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Abstract

Les présents modes de réalisation concernent de manière générale des techniques thérapeutiques et, plus particulièrement, un traitement efficace des troubles neurologiques utilisant des méthodes et des appareils non invasifs. Certains modes de réalisation concernent une stimulation vibrotactile plus efficace, c'est-à-dire présentant des effets physiologiques plus puissants avec moins de puissance/amplitude vibratoire, grâce à un stimulateur mécanique vibrotactile (tactor).
PCT/US2024/054294 2023-11-02 2024-11-01 Méthodes et appareils pour le traitement non invasif de troubles du système nerveux Pending WO2025097075A1 (fr)

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US20060015045A1 (en) * 2002-11-08 2006-01-19 Zets Gary A Method and apparatus for generating a vibrational stimulus
US20130109914A1 (en) * 2011-10-26 2013-05-02 Jimmyjane, Inc. Vibratory assembly for articulating members
US20140107542A1 (en) * 2011-02-23 2014-04-17 Shai Y. Schubert Actuator for delivery of vibratory stimulation to an area of the body and method of application
US20180212137A1 (en) * 2017-01-26 2018-07-26 The Trustees Of Dartmouth College Methods and devices for haptic communication
US20230113744A1 (en) * 2020-10-23 2023-04-13 Neosensory, Inc. Method and system for multimodal stimulation

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060015045A1 (en) * 2002-11-08 2006-01-19 Zets Gary A Method and apparatus for generating a vibrational stimulus
US20140107542A1 (en) * 2011-02-23 2014-04-17 Shai Y. Schubert Actuator for delivery of vibratory stimulation to an area of the body and method of application
US20130109914A1 (en) * 2011-10-26 2013-05-02 Jimmyjane, Inc. Vibratory assembly for articulating members
US20180212137A1 (en) * 2017-01-26 2018-07-26 The Trustees Of Dartmouth College Methods and devices for haptic communication
US20230113744A1 (en) * 2020-10-23 2023-04-13 Neosensory, Inc. Method and system for multimodal stimulation

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