Method for pain mitigation during pulsed transcranial electrical stimulation

Abstract

Disclosed herein is a novel technique for reducing scalp pain during delivery of pulsed transcranial electrical stimulation (pTES) therapy. A small-amplitude, high-frequency current (i.e., a "background hum") is applied before and after each pTES pulse near the electrodes used to deliver the pTES pulses.

Description

Attorney Docket: 8350.2025-059WOMethod for Pain Mitigation During Pulsed Transcranial Electrical StimulationRelated Applications

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 703,600, filed October 4, 2024, the contents of which are incorporated herein in their entirety.Government Interest

[0002] This invention was made with United States Government support under contract N65236-19-C-8017 awarded by the U.S. Navy. The United States Government has certain rights in the invention.Background

[0003] Pain management for chronic pain often includes lifestyle modification, exercise therapy, electrical therapy such as transcutaneous electrical stimulation (TENS), cryotherapy, behavioral therapy, pharmacological therapy, noninvasive brain stimulation (NIBS), minimally-invasive interventions, surgery, and complementary integrative approaches. However, many patients fail to achieve meaningful pain management with some or all of these approaches. Brain stimulation for treatment of pain includes invasive deep brain stimulation (DBS), as well as NIBS approaches, which presently include transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS). DBS is anAttorney Docket: 8350.2025-059WO invasive method that requires surgical procedures to implant electrodes in the brain. Current NIBS methods are limited. tDCS uses low amplitude currents to entrain neural activity but typically does not result in sufficient electric field in the brain to directly activate neurons. While TMS is capable of eliciting direct neural activity through pulses of currents, it has some limitations in the waveforms that can be injected and in spatial resolution.

[0004] Pulsed Transcranial Electrical Stimulation (pTES) is a technique that can precisely target brain regions with millimeter (mm) focality. pTES consists of short (<lms) pulses of high-amplitude (20-200 mA) current injected into the brain through electrodes placed on the scalp. This technique is capable of directly activating cortical neurons and exploits the vast connectivity of the pain processing network to other regions of the brain, such as the periaqueductal gray or ventral posterolateral nuclei. When targeting the motor cortex (Ml), pTES can produce direct "D-waves" in the corticospinal tract, eliciting motor-evoked potentials (MEPs) in muscles that can be used to assess integrity of the corticospinal tract, and enable individual calibration of stimulation site and intensity

[0005] Pulsed TES has the potential to alleviate chronic pain in those with pain that is refractory to current treatments. It is advantageous over many alternative options in that it is non-invasive and capable of directly activating cortical neurons. The focality of stimulation (i.e., spatial resolution) and the depth of modulation can be adjusted using different waveform shapes.Attorney Docket: 8350.2025-059WO

[0006] Pulsed TES at current levels strong enough to evoke muscle activity tend to cause a painful sensation on the scalp of the subject due to activation of superficial nociceptors in the scalp and / or meninges. Therefore, it is not currently feasible to perform pulsed TES on awake (i.e., non-anesthetized) subjects due to the significant scalp pain caused when injecting current strong enough to activate cortical neurons. It would therefore be advantageous to provide a method of reducing, mitigating or eliminating the pain associated with pTES such that awake patients can realize the advantages of treatment with this technique.Summary of the Invention

[0007] Disclosed herein is a novel technique for reducing scalp pain associated with pTES. A low-amplitude, high-frequency current (i.e., a "background hum") is added near the pTES stimulating electrodes. The background hum is applied tens to hundreds of milliseconds before and after each primary stimulation pulse.Brief Description of the Drawings

[0008] FIG. 1 is a schematic showing the configuration of electrodes for one possible embodiment of the technique involving upper limb stimulation.

[0009] FIG. 2 is a graph showing an exemplary background hum pulse train with respect to the timing of the application of a pTES pulse.Attorney Docket: 8350.2025-059WO

[0010] FIG. 3 is a schematic showing placement of the background hum electrodes and the pTES electrodes for another possible embodiment, targeting leg and feet MEP.

[0011] FIGS. 4(a-c) illustrate systematic search for optimal hum parameters.Definitions

[0012] As used herein, the terms "approximately" or "approximate" should be interpreted to mean a value within ±10% of a stated value.Detailed Description

[0013] Disclosed herein are descriptions of several techniques which reduce scalp sensations while eliciting MEPs via pTES. The disclosed invention, in some embodiments, comprises adding a pulse train of low-amplitude current pulses (i.e., "background hum") injected at or around the pTES current-injection electrodes. In various embodiments, the invention includes adjusting the temporal waveform of injected currents. The various embodiments may include adjusting spatial configurations of current-injection electrodes. In some embodiments, the described techniques may be used in isolation. In other embodiments, the described techniques may be used in any combination.

[0014] It was experimentally shown that the described techniques may, by themselves, reduce the scalp pain at motor threshold by 1-2 points on a 10 point scale.Attorney Docket: 8350.2025-059WOHowever, by combining the techniques, scalp pain of less than 3 / 10 is achieved (e.g., in a patient affected by fibromyalgia, a chronic pain condition). The novel techniques described herein demonstrate that, for the first time, stimulation pain associated with pTES can be actively attenuated , opening the way for expanded and widespread clinical applications. Several optimal configurations are disclosed herein that have been experimentally shown to elicit motor threshold activation of upper limbs with minimal pain.

[0015] For delivering pTES currents, in one embodiment, two 10-mm gold cup electrodes (anode and cathode) are filled with conductive EEG gel and placed on the scalp, using 10-20 EEG locations for reference. In alternate embodiments, other types of electrodes (e.g., dry electrodes, hydrogels, spike electrodes, etc.) may be used. In an embodiment for upper limb stimulation, as shown in FIG. 1, the typical electrode montage consists of a single anode placed approximately 2 cm medial (i.e., to the right) from C3, and a single cathode placed approximately 2 cm to the right of Cz for right-handed participants (anode: 2 cm medial of C4, cathode: 2 cm to the left of Cz for left handed participants). This configuration was experimentally determined to elicit motor responses in the upper limbs with the lowest injected current and minimal pain. If MEPs could not be elicited with this electrode configuration before a pain intensity higher than 6 on a scale of 1 to 10 was reported, the anode and cathode were moved (e.g., 2 cm along the anteroposterior or mediolateral axis). This configuration places electrodes close to the Ml motor cortical representation of the dominant upper limb. In otherAttorney Docket: 8350.2025-059WO embodiments, other electrode montages may be used. The electrodes used for delivering the background hum pulse train are placed near the pTES electrodes, as most pain associated with delivery of pTES pulses is localized around the anode electrode.

[0016] As would be realized, the method disclosed herein for mitigating pain during pTES is not dependent on a particular arrangement of electrodes used for delivering the pTES therapy. The arrangement of electrodes for eliciting MEP in the upper limbs is only used herein to demonstrate the innovative method.

[0017] Currents are delivered to the pTES electrodes and the background hum electrodes using a commercial floating, isolated constant-current stimulator connected to a computer-controlled data acquisition hardware using custom software. This setup allows flexible customization of the pulse parameters, including width, amplitude, and timings. The pTES pulses can be either monophasic or biphasic. In monophasic pulses, current enters through the electrode acting as the anode and exits via the cathode. In biphasic pulses, current direction reverses each phase, so the functional roles of anode and cathode electrodes alternate.

[0018] Background Hum

[0019] The disclosed techniques include methods to reduce scalp pain associated with pTES and comprise adding a low-amplitude, high-frequency pulse train injected through scalp electrodes located near the high-current pTES electrodes around the time of the stimulation pulse. This technique reduces painful sensationsAttorney Docket: 8350.2025-059WO associated with the pTES treatment. Various parameters of the background hum that can be varied include: pulse duration, pulse amplitude, frequency, pulse train duration and amplitude modulation.

[0020] In one embodiment, the method comprises includes superimposing a background hum on a motor evoked potential (MEP)-inducing pulse during the application of pTES, to reduce the scalp pain elicited. In some embodiments, the background hum may be characterized as high-frequency, having frequencies in a range including, but not limited to approximately 100 Hz to approximately 10 kHz. The hum is delivered via a pulse train having a low amplitude including, but not limited to, less than approximately 4mA, injected near the site of pTES stimulation for a period of time including, but not limited to approximately 100- 1000 ms before and / or after the time of delivery of the pTES pulses. In some embodiments, the background hum may be applied for several hundreds of ms prior to application of the pTES stimulation. An exemplary application of the background hum with respect to the pTES pulse is shown in FIG. 2.

[0021] The parameters of the background hum may be personalized for each subject to provide the optimal pain reduction. For most subjects, the pain reduction achieved with particular parameters stays consistent for different pTES stimulation pulse widths.

[0022] Spatial Configuration of Pain Mitigation Electrodes

[0023] The invention disclosed herein may include methods for the placement of the pain mitigation electrodes on the scalp, and the adjustment thereof. The painAttorney Docket: 8350.2025-059WO mitigation electrodes may be connected to a stimulator that generates and sends pulses through the electrodes. In some embodiments, pain mitigation electrodes may be placed on the scalp using conductive gel, which may be adhesive and help the electrodes stay in place. In some embodiments, electrodes may include gold in their composition. The methods described herein may include a setup including pTES electrodes and background hum electrodes.

[0024] The configuration of electrodes may be adjusted to target different brain regions. Based on the desired brain region(s) to target, the electrode configuration may change. For example, pTES electrodes may be configured to target areas corresponding to different parts of the body. For illustrative purposes, two nonlimiting embodiments are described below.

[0025] FIG. 1 shows an example embodiment targeting the right arm and hand muscles. In this example configuration, there may be six electrodes: three on one side (in this embodiment, left of center) and three slightly center-right (in this embodiment, within ~4 cm from the center). In this exemplary embodiment, the middle electrodes in each group of three are pTES electrodes delivering high- amplitude (in this embodiment, 20-200 mA) pulses. In this example, the remaining four, one on each side of the two pTES electrodes, are pain mitigation electrodes for delivery of the background hum pulse train comprising a high- frequency, low-amplitude train of pulses.

[0026] The configuration may be changed to target a different body parts or areas. For example, in some embodiments, if one wishes to target the left arm, theAttorney Docket: 8350.2025-059WO locations of the electrodes could be reversed from this example (three on the right side and three in the center-middle).

[0027] FIG. 3 shows an example embodiment targeting the leg and feet muscles. This figure represents a configuration of pTES electrodes before the placement of pain mitigation electrodes. In this example configuration, there may be eleven electrodes (two of which are not shown in the figure). The nine electrodes shown (one at the center and eight radially and equidistantly distributed from the center electrode) may he used for pTES. In this example embodiment, current may enter the skull via the center electrode and may be split almost evenly across the eight outer electrodes, where it leaves the skull. Two pain mitigation electrodes are placed on each side of the center pTES electrode. In this example configuration, only one pTES electrode is flanked by pain mitigation electrodes on each side (compared to the example embodiment in FIG. 1).

[0028] In some embodiments, there may be pain mitigation electrodes placed near at least one pTES electrode. In some embodiments, there may be two or more pairs of pain mitigation electrodes placed proximal to two or more pTES electrodes. It has been experimentally determined that one effective location for the pain mitigation electrodes delivering the background hum pulse train is placement of the pain mitigation anode and cathode 2 cm to the left and right of pTES pulse anode and cathode electrodes (See e.g., FIG. 1), resulting in an interelectrode distance of approximately 4 cm for the pain mitigation electrodes. Preferably, the pain mitigation electrodes are placed substantially diametrically oppositeAttorney Docket: 8350.2025-059WO each other with respect to a pTES electrode. In other embodiments, the pain mitigation electrodes might be placed at other locations on the scalp or face, in particular locations near cranial nerves such as the trigeminal nerve.

[0029] Additional Embodiments

[0030] While the primary embodiment uses separate electrodes to deliver the background hum pulse train, in an alternate embodiment, the background hum pulse train may be delivered using the pTES electrodes by combining the pTES pulse with the background hum waveform.

[0031] In some embodiments, this treatment may be adapted for use as treatment for chronic pain, including, but not limited to, lower back and neuropathic pain. In some embodiments, this treatment may be adapted for use as treatment for stroke (including, but not limited to, motor rehabilitation). In some embodiments, machine learning techniques may be utilized to tailor the applied waveform to individual subjects for improved pain reduction. In some embodiments, background hums may be adapted to reduce pain during noninvasive spinal cord stimulation. In some embodiments, given the large parameter space of potential waveforms, pulsed TES treatment may be flexible and personalized to the individual user.

[0032] Experimental Determination of Hum Parameters

[0033] In proof-of-concept experiments, the stimulation pulses consisted of single monophasic anodic rectangular pulses injected through the scalp electrodes. The pulse duration was varied across experiments, ranging from 50 ps to 1000 ps.Attorney Docket: 8350.2025-059WOFor each pulse width, the amplitude of the pulses was gradually increased over multiple blocks until the motor threshold was reached. Stimulation at motor threshold was repeated in blocks of 20 to 30 trials at a frequency of 1 Hz for averaging. After any block of stimulation trials, the participant was asked to report their level of pain from 0-10 using a numerical rating scale with 0 being "no pain" and 10 being "worst pain imaginable". To reduce the motor threshold, the participants were asked to grip a dynamometer at 20% of maximum voluntary contraction throughout the stimulation period.

[0034] For measuring evoked responses in muscles, electromyography (EMG) signals were recorded at 4 kHz using 64-channel high-density EMG patches and additional bipolar electrodes. For upper-limb responses, the EMG patches were placed on the dominant wrist flexor and extensor muscle groups, as shown in FIG. 1. Additionally, bipolar electrodes were used to record EMG signals on the dominant first dorsal interosseous (FDI), abductor poll icis brevis (APB), biceps brachii, and triceps brachii.

[0035] Experiments were conducted to determine the effect of three hum parameters. A sweep of hum parameters was conducted using a Box-Behnken design to systematically vary hum ON time, frequency, and amplitude in three levels each (see FIGS. 4(b-c)) Pain scores were compared to a no-hum case. The duration of the pulse train was kept fixed at 500 ms, as shown in FIG. 4(a). The stimulation pulse was consistently delivered at the midpoint of the 500 ms hum, and the hum amplitude was kept constant throughout the train. For upper-limbAttorney Docket: 8350.2025-059WO stimulation, two pairs of hum-delivering gold cup electrodes were placed, each 2 cm to the left and right of the stimulating anode and cathode.

[0036] The hum anodes were placed laterally from the stimulation electrodes, and the hum cathodes medially, as shown in FIG. 1. A baseline pain score was determined at motor threshold in the absence of the background hum. Following the baseline assessment, the background hums described in the table in FIG. 4(b) were added to the stimulation pulse in a random order, and the pain score was recorded. After all hum conditions were applied, a final baseline pain score was determined in the absence of hum. To adjust for habituation, a linear fit (across session time) was applied between the pre-hum and post-hum baseline pain measurements. The pain scores for all intermediate measurements were corrected for this linear trend. The effect of the hum is characterized by the difference between the pre-hum baseline pain and the corrected hum pain. The pain reduction for points in the hum parameter space not sampled by the Box- Behnken design were calculated using quadratic regression. The systematic hum parameter assessment was performed at four stimulation pulse widths: 100 ps, 200 ps, 300 ps, and 500 ps.

[0037] In general, it was discovered that hums with low amplitude performed worse on average, which seems to indicate that hums need to be of sufficient amplitude to have a beneficial effect. However, hums with high amplitude performed better, unless the hum ON time was too high. This indicates that at high amplitude and ON time, the charge delivered into the scalp by the hum is sufficient to add toAttorney Docket: 8350.2025-059WO the scalp pain due to the high amplitude stimulation pulse. The hum frequency tends to have a smaller effect than the amplitude or ON time.

[0038] Many possible features of and variations of the method have been disclosed herein. For example, the parameters of the background hum may be varied on a per-individual basis to achieve maximal pain reduction. As would be realized, many of these features or variations may be used in any combination or are described in a generalized manner such as to encompass specific embodiments. All possible combinations of features and / or parameters disclosed herein are contemplated to be within the scope of the invention.

Claims

Attorney Docket: 8350.2025-059WOClaims1. A method for reducing pain associated with delivery of pTES therapy comprising: placing pain mitigation electrodes on the scalp of a subject alongside the pTES electrodes used to deliver pTES pulse therapy; and delivering a waveform via the pain mitigation electrodes prior to or prior to and after a time of delivery of each pTES pulse.2 The method of claim 1 wherein the waveform is a train of short pulses.3 The method of claim 2 wherein the train of short pulses is a background hum. The method of claim 1 wherein the pain mitigation electrodes comprise one or more pairs of pain mitigation electrodes placed near one or more pTES electrodes.5 The method of claim 4 wherein each pain mitigation electrode is placed within approximately 2 cm of a pTES electrode.6 The method of claim 5 wherein electrodes in the pair of pain mitigation electrodes are placed diametrically opposite each other with respect to the proximal pTES electrode.Attorney Docket: 8350.2025-059WO7. The method of claim 3 wherein the background hum pulse train is delivered prior to, during and after the delivery of each pTES pulse.

8. The method of claim 3 wherein the background hum pulse train is delivered approximately 100-1000 ms before and / or approximately 100-1000 ms after the delivery of each pTES pulse.

9. The method of claim 3 wherein the background hum pulse train has a frequency in a range between approximately 100 Hz and approximately 10 kHz.

10. The method of claim 3 wherein the background hum pulse train has an amplitude not exceeding approximately 4 mA.

11. The method of claim 1 wherein the therapy is used to alleviate symptoms of chronic pain conditions.

12. A method for reducing pain associated with delivery of pTES therapy comprising: creating a combined waveform comprising a background hum pulse train and a pTES pulse, the background hum pulse train applied prior to or prior to and after the pTES pulse; andAttorney Docket: 8350.2025-059WO delivering the combined waveform via pTES electrodes placed on the scalp of a subject.

13. The method of claim 12 wherein the background hum pulse train is delivered prior to, during and after the delivery of each pTES pulse.

14. The method of claim 12 wherein the background hum pulse train is delivered approximately 100-1000 ms before and / or approximately 100-1000 ms after the delivery of each pTES pulse.

15. The method of claim 12 wherein the background hum pulse train has a frequency in a range between approximately 100 Hz and approximately 10 kHz.

16. The method of claim 12 wherein the background hum pulse train has an amplitude not exceeding approximately 4 mA.

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