Stimulation devices and methods for treating dry eye

ES 2 809 599 T3

DESCRIPTION

Stimulation devices to treat dry eyes

Countryside

Devices and methods of using the same for treating dry eye or eye strain are described herein. The methods generally include the application of stimulation with spatial and / or temporal patterns to one or more anatomical structures located in an ocular or nasal region. Electrical stimulation can elicit a reflex that activates the lacrimal gland, or it can directly activate the lacrimal gland or the nerves that innervate the lacrimal gland to produce tears.

Background

Dry eye syndrome (“OHS”) is a condition that affects millions of people around the world. More than 40 million people in North America have some form of dry eyes, and many millions more suffer from it around the world. OHS results from the disturbance of the natural tear film on the surface of the eye and can result in eye discomfort, visual disturbances, and vision-related reduction in quality of life. Activities of daily living, such as driving, using the computer, doing housework, and reading, have also been shown to be negatively affected by OHS. Patients with severe cases of OHS are at risk for severe ocular health deficiencies, such as corneal ulcers, and may experience a poor quality of life comparable to moderate to severe angina.

OHS is progressive in nature and generally results from insufficient tear coverage on the surface of the eye. This poor tear coverage prevents healthy gas exchange and nutrient transport to the ocular surface, promotes cell desiccation, and creates a poor refractive surface for vision. Poor tear coverage typically results from: 1) insufficient watery tear production from the lacrimal glands (for example, secondary to postmenopausal hormone deficiency, autoimmune disease, LASIK surgery, etc.), and / or 2) excessive tear evaporation watery resulting from meibomian gland dysfunction. In turn, the low tear volume causes a hyperosmolar environment that induces inflammation of the ocular surface. This inflammatory response induces apoptosis of surface cells, which in turn prevents proper distribution of the tear film on the ocular surface, so that any given tear volume becomes less effective. A vicious cycle begins in which more inflammation can occur and further damage to surface cells, etc. Furthermore, the neural control loop, which controls reflex tear activation, is disrupted because sensory neurons on the surface of the eye are damaged. As a result, fewer tears are secreted and a second vicious cycle develops resulting in further disease progression (fewer tears lead to nerve cell loss, resulting in fewer tears, etc.).

There is a wide spectrum of treatments for OHS, however, none provide adequate treatment for the condition. Treatment options include: artificial tear substitutes, ointments, gels, warm compresses, environment modification, topical cyclosporine, omega-3 fatty acid supplements, tear point plugs, and wet-chamber glasses. Patients with severe disease may receive additional treatment with tear point cauterization, systemic cholinergic agonists, systemic anti-inflammatory agents, mucolytic agents, autologous serum tears, PROSE scleral contact lenses, and tarsorrhaphy. Despite these treatment options, OHS continues to be considered one of the worst-treated diseases in ophthalmology. Therefore, it would be desirable to have a more effective treatment for dry eye.

Summary

Described herein are methods for treating one or more conditions (such as dry eye, eye fatigue, reducing discomfort from wearing contact lenses, etc.) by providing electrical stimulation to an anatomical structure located in an eye region or region. nasal. Exemplary anatomical structures include nerves, muscles, mucosal tissues, skin sensory structures such as Pacini corpuscles, Merkel cells, etc., within these regions. Electrical stimulation, when delivered to certain targets as described herein, is generally capable of initiating a reflex circuit that activates the lacrimal gland to produce tears. The reflex circuit can include stimulation of a nerve directly or a skin sensory cell that in turn activates a nerve that then produces either a sensory input to the brain or a motor input to a nerve that activates a nearby muscle, for example, the eye, which in turn, provides sensory information to the brain and initiates the reflex to activate the lacrimal gland. Electrical stimulation may be capable, additionally or alternatively, when delivered to certain other targets as described herein, of directly exciting efferent fibers innervating the lacrimal gland to produce tears.

More specifically, methods are described for generating lacrimation (tear production) by spatially controlling the delivery of electrical stimuli and / or modifying electrical waveform parameters to generate an afferent or efferent input. These methods generally optimize the flow of direct current through particular paths and / or modify current paths over time. Methods can also optimize

ES 2 809 599 T3 waveforms for a detected paresthesia, for example, a tingling sensation, contraction and / or vibration in the eyelid and / or the proximity of the eyelid, the eyebrow, as well as the temporal and frontal area of ​​the head. Our experimentation has found that these sensations are strongly associated with tearing.

Using the stimuli disclosed herein, sensory nerves are believed to be activated to send input to the brain to produce lacrimation. Additionally or alternatively, the stimuli can activate the motor nerves that cause the muscles in the vicinity of the orbit, the nose, the mouth and / or the frontal or temporal face to vibrate to generate the sensation of tingling or contraction or vibration as an effect, what starts the route reflects and thus leads to lacrimation.

Implantable or handheld devices may be used when electrical stimulation is applied. In some handheld variations, the devices may comprise a stimulator body and a stimulator probe. The stimulator probe can be releasably connected to the stimulator body, and in some cases, the stimulator body is reusable and the stimulator probe is disposable. In some variations, the device further comprises a user interface. The user interface may comprise one or more operating mechanisms to adjust one or more parameters of the stimulus. Additionally or alternatively, the user interface may comprise one or more feedback elements.

In handheld variations that comprise a stimulator probe, the stimulator probe can comprise one or more nasal insertion tips, and the stimulator body can comprise a control subsystem for controlling a stimulus to be delivered to the patient through stimulator probe. In some of these variations, the stimulator probe comprises a single nasal insertion tip, while in other variations the stimulator probe comprises at least two nasal insertion tips. The stimulator probe can comprise at least one electrode, and can comprise a plurality of electrodes. The electrode can comprise a hydrogel, or in other variations, the electrode comprises one or more of platinum, platinum-iridium, gold, or stainless steel. Some variations of the device may comprise return contacts not located on a nasal insertion tip, such as the return contacts on the stimulator body or the stimulator probe.

Electrical stimulation applied to anatomical structures generally includes a plurality of waveform parameters that define a waveform. The delivery of the electrical stimulus can help treat OHS by inducing an increase in lacrimation or modifying the components of the tears produced, and can lead to paresthesia detected by a patient. These waveforms may be able to increase tear production as well as patient comfort during and / or after application of stimulation. In some variations, the stimulus is a biphasic pulse waveform, which can but is required to be symmetric. The frequency of the biphasic pulse waveform can be in some variations between 30 Hz and 80 Hz.

In other variations, the devices can include an implantable microstimulator and an external controller. Exemplary implantable devices that can be used to deliver the electrical stimulation described herein are described in US Patent Application No. 13 / 441,806, filed April 6, 2012, entitled "Stimulation Devices and Methods." (US Patent No. 9,821,159 issued November 21, 2017). Exemplary handheld devices, as well as additional exemplary implantable devices, that can be used to deliver the electrical stimulation described herein are disclosed in U.S. Patent Application No. 14 / 256,915, filed 18 April 2014 and entitled "Nasal Stimulation Devices and Methods" (US Patent 8,996,137, published March 31, 2015) or WO2014172693, entitled "Nasal Stimulation Devices and Methods" or US2012130398, entitled "Systems and methods for treatment of dry eye".

In general, the methods described herein include applying electrical stimulation to an anatomical structure in an ocular region or a nasal region to activate the lacrimal gland, wherein the electrical stimulation is defined by a plurality of waveform parameters, and increasing tear production using electrical stimulation. In some cases, the methods may comprise spatially controlling the delivery of stimulus to target particular anatomical structure (s) and / or modifying current pathways over time. The method may further include confirming the activation of the lacrimal gland by evaluating a detected paresthesia in the ocular region or the nasal region.

The anatomical structure that is stimulated can be a nerve, skin sensory cells (Pacini corpuscles, Merkel cells, etc.), muscles or tissues such as the mucosa or submucosa, in the ocular region or the nasal region. For example, the anatomical structure may be the nasociliary nerve, the anterior or posterior ethmoidal nerve, or the infratrochlear nerve. In some variations, the anatomical structure is a muscle in the eye region or the nasal region. In some variations, the anatomical structure comprises a mucosal or submucosal surface in the ocular region or the nasal region. In some cases, the anatomical structure may be cutaneous sensory cells in the nasal or ocular hairless skin, which naturally detect mechanical input, such as pressure, vibration, tingling, temperature, or pain.

As further described herein, current flow for stimulation can

ES 2 809 599 T3 be spatially controlled. Current can be conducted between particular contacts, and thus through particular routes through tissue, and can be conducted through time through different routes through tissue to spatially model the stimulus. The current directing and / or temporal patterning of the waveform parameters can be optimized for a particular patient to activate the lacrimal gland to produce tear formation and cause paresthesia in that patient. Current steering and / or temporal patterning, in which at least one of the waveform parameters is modulated over time, can also be determined based on other factors, such as clinical markers, including but not limited to be limited to, levels of growth factor and / or osmolarity.

The plurality of waveform parameters defining the stimulation waveforms can be selected from the group consisting of on / off duration, frequency, width, amplitude, and pulse shape. Other suitable waveform parameters can also be used. For example, charge injection, which can be calculated by multiplying the pulse width and amplitude, can be used as a waveform parameter. In some variations, the plurality of waveform parameters are selected from the group consisting of on / off duration, frequency, width, amplitude, and pulse shape. In some of these variations, the on / off duration ranges from about 0.1 to 5.0 seconds on, and from about 0.1 to 5.0 seconds off. In some of these variations, the on / off duration is 1.0 seconds on and 1.0 seconds off. In some of these variations, the on / off duration is 5.0 seconds on and 5.0 seconds off. In some of these variations, the frequency ranges from about 10 to 200 Hz. In some of these variations, the frequency ranges from about 30 to 150 Hz. In some of these variations, the frequency ranges from about 50 to 80 Hz. In some In variations, the frequency is 30 Hz. In some variations, the frequency is 70 Hz. In some variations, the amplitude ranges from about 0.1 to 10 mA. In some of these variations, the maximum amplitude ranges from about 1 to 3 mA. In some variations, the width and pulse width generate a waveform that has a triangular, rectangular, or square shape. In some variations, electrical stimulation is applied continuously. In other variations, electrical stimulation has on and off periods.

A particular combination of current directing and / or spatial or temporal patterning can be applied using a stimulator comprising a plurality of combinations stored in memory. The selection of stored combinations can be random, predetermined, or controlled by a user. In some cases, the stored combinations may be patient-optimized waveforms.

Methods for treating dry eye in a patient in need are described herein. In a variation, the method may comprise contacting the patient's nasal mucosa with an electrode and supplying current from the electrode through the patient's tissue to a return contact, where the electrode is located in a nasal insertion tip. of a stimulator probe of a stimulator, and the return contact is located in a stimulator body of the stimulator, and the stimulator probe can be reversibly attached to the stimulator body. The method may further comprise supplying current from the electrode through the patient's tissue to a second electrode. The second electrode can be located on the nasal insertion tip. In some cases, current is supplied simultaneously from the electrode to the return contact and to the second electrode; in others, current is supplied sequentially from the electrode to the return contact and to the second electrode. The electrode may contact the nasal mucosa in the anterior part of the nasal cavity and, in some cases, may contact the nasal mucosa in a location anterior to a middle or lower turbinate of the nasal cavity.

Also described herein are methods of treating a patient with dry eye using a stimulator comprising a stimulator body and a stimulator probe, wherein the stimulator probe comprises a nasal insertion tip comprising a first electrode and a second electrode. The method may comprise inserting the nasal insertion tip into a nostril of the patient, placing the first electrode and the second electrode in contact with the nasal mucosa on a first side of a patient's septum, placing a return contact in contact with the patient tissue, and supplying an electrical stimulation waveform from the first electrode to the second electrode, and from the first electrode to the return contact. The first and second electrodes can be spaced longitudinally along the length of the nasal insertion tip, or they can be radially spaced around a circumference of the nasal insertion tip. In some variations of the method, no electrodes are placed in contact with the nasal mucosa on a second side of the patient's septum, and delivery of the electrical stimulation waveform results in bilateral lacrimation.

Methods for increasing tear production in a patient are also described herein. The methods may comprise delivering an electrical stimulus to a patient's tissue using a device comprising at least three electrical contacts, wherein the electrical stimulus takes one or more routes between the at least three electrical contacts during delivery, and wherein the one or more electrical stimulus pathways change over time during delivery. The electrical stimulus can take two routes between the at least three electrical contacts, such that a first amount of current takes the first route and a second amount of current takes the second route. In some cases, the ratio of the first quantity to the second quantity changes over time during the supply. The patient can change the reason in some cases using an interface

ES 2 809 599 T3 user of the device. The device can be implantable or it can be handheld. Some variations of the device have a single nasal insertion tip, which may comprise one electrode, two electrodes, or more. Some variations of the device comprise a stimulator body comprising an electrical contact configured to supply current or act as a return contact.

In some variations, the methods described herein comprise applying patterned electrical stimulation to an anatomical structure in an ocular region or nasal region to activate the lacrimal gland, and increase tear production using patterned electrical stimulation, in the that patterned electrical stimulation comprises a biphasic waveform having cathode and anode pulse pairs. In some variations, a subset of the pulse pairs have an initial cathode pulse and a subset of pulses have an initial anode pulse. In some variations, each pulse has a duration and amplitude, where the ratio of duration to amplitude for each pulse is variable over time. In some variations, the biphasic waveform is load balanced. In some of these variations, the duration-to-amplitude ratio for the cathode pulse varies over time according to a function that has an exponentially increasing phase and an exponentially decreasing phase. In some of these variations, the ratio of duration to amplitude for the cathode pulse varies over time according to a sawtooth function. In some of these variations, the ratio of duration to amplitude for the cathode pulse varies over time according to a sinusoidal function.

In some variations, the methods described herein comprise implanting a stimulation device in an ocular region or a nasal region of a subject to activate the lacrimal gland, apply patterned electrical stimulation from the stimulation device, and increase tear production. using patterned electrical stimulation, in which tear production is bilateral. In some variations, tear production is approximately the same in both eyes of the subject. Some variations of the methods described herein comprise delivering a stimulus to an ocular region or a nasal region of a subject to activate the lacrimal gland, where the stimulus is an electrical waveform, and increasing tear production using patterned electrical stimulation, in which tear production is bilateral. In some variations, the stimulus is delivered unilaterally.

The frequency, peak-to-peak amplitude, and pulse width of the waveforms can be constant, but in some variations the stimulator may be configured to vary the frequency, amplitude, and / or pulse width of the waveform. This variation can occur according to a predetermined plan, or it can be configured to occur randomly within given parameters. For example, in some variations, the waveform may be configured so that the peak-to-peak amplitude of the waveform varies over time (for example, based on a sinusoidal function that has a beat frequency, a function sawtooth or an exponential function); In some variations, the waveform can be configured such that the frequency of the waveform varies over time (for example, according to a sinusoidal function, a sawtooth function, or an exponential function). In some variations, rectangular stimulation pulses of varying fundamental frequency are used. In other variations, triangular stimulation pulses can be used and modulated as described for rectangular stimulation pulses.

In some variations, the methods described herein comprise a method of inducing lacrimation. In some variations, the method comprises delivering an electrical stimulus to a patient who has dry eyes, wherein the electrical stimulus is delivered from a handheld stimulator, and wherein the electrical stimulus comprises a waveform having a width of pulse that varies during delivery. In some variations, the method comprises delivering an electrical stimulus to a patient who has dry eyes using a handheld stimulator, wherein the electrical stimulus can be one of a plurality of preset waveforms comprising at least a first waveform. preset and a second preset waveform, and changing the electrical stimulus from the first preset waveform to the second preset waveform while delivering the electrical stimulus. The patient can change the electrical stimulus from the first preset waveform to the second preset waveform.

In some variations, the methods described herein comprise providing a device to a patient having dry eyes, wherein the device is configured to deliver a plurality of electrical waveforms to an anatomical target in a patient, and instructing the patient selecting one or more of the plurality of waveforms based on a detected amount of paresthesia felt during delivery of the waveform. In some of these variations, the anatomical target may be the nasal mucosa. In some of these variations, the anatomical target may be the anterior ethmoid nerve. In other of these variations, the anatomical target may be in an ocular region. In some of these variations, at least one of the plurality of waveforms may have a pulse width that varies over time. In some of these variations, the pulse width can vary over time according to an exponential function.

In some variations, the methods described herein comprise methods of reducing the patient's adaptation to electrical stimuli in an ocular, orbital, or nasal region through the use of patterned waveforms.

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In some variations, the methods described herein comprise methods of preferentially activating different anatomical structures, which comprise implanting a stimulation device, delivering a waveform having a biphasic pulse, and activating a different anatomical structure by modifying the waveform. . In some variations, the waveform is modified by adjusting a biphasic pulse width. In some variations, the waveform is modified by adjusting the order of a cathode pulse and an anode pulse from the biphasic pulse.

Also described herein are devices for delivering an electrical stimulus to the nasal mucosa of a patient. A device may comprise a stimulator probe comprising a nasal insertion tip, wherein a distal portion of the nasal insertion tip comprises first and second electrodes. The first electrode may be configured to supply current. The device may also comprise a return contact located on the stimulator probe at the base of the nasal insertion tip, and may also comprise a user interface configured to allow the patient to adjust an amount of current delivered between the electrodes first and foremost. second and between the first electrode and the return contact. The first electrode, the second electrode and / or the return contact can comprise a hydrogel. In some variations, the return contact has an annular shape. The return contact can be configured to contact tissue in or near a nostril.

A device for delivering an electrical stimulus to the nasal mucosa of a patient with dry eyes may also comprise a first nasal insertion tip, a second nasal insertion tip, and a user interface. The first nasal insertion tip may be configured to insert into a first nostril and may comprise a first electrode. The second nasal insertion tip can be configured to insert into a second nostril, and can comprise a second electrode. The device may be configured to deliver a biphasic load balanced pulsed waveform, wherein the user interface is configured to allow the patient to set an amplitude: duration aspect ratio of the waveform.

Systems for generating and applying the electrical stimulation waveforms are further disclosed herein. The systems may generally include one or more electrodes and a controller, wherein the controller comprises programmable memory configured to store a plurality of patterned stimulation waveforms. The stimulation waveforms may or may not be associated with a detected paresthesia. The controller may also be configured to run a program that cycles through a plurality of stimulus options. A user interface can be included and configured to allow the patient to select one or more of the stored plurality of stimuli.

In some variations, the stimulators are configured for implantation in an ocular region or a nasal region. In some of these variations, the stimulators are configured for placement on a mucosal surface or within submucosal tissue. Stimulators, which can comprise, for example, one, two, three or more active electrodes, can also be configured for placement within a nasal cavity or sinus cavity. In other variations, the controller is configured for placement external to the ocular region or the nasal region. In some variations, electrical stimulation is delivered by an electrode disposed within a nasal cavity or sinus cavity. In some variations, patterned electrical stimulation is delivered by an electrode implanted near the lacrimal gland. In some variations, the systems are configured to activate skin sensors or nerve fibers that innervate skin sensors on the mucosal surface or within submucosal tissue. In some variations, the systems are configured to activate skin sensors or nerve fibers that innervate skin sensors in tissues such as the skin and muscles of the eye region, the forehead, or the temporal area of ​​the head.

In some variations, patterned electrical stimulation is delivered by a stimulator comprising a plurality of patterned stimulation waveforms stored in memory. In some of these variations, the applied patterned stimulation is randomly selected from the plurality of stored patterned stimulation waveforms. In some of these variations, the plurality of stored patterned stimulation waveforms are patient-optimized waveforms. In some variations, the applied pattern stimulation is stored in memory as a waveform optimized for the patient.

In some variations, the systems described herein comprise one or more stimulation electrodes and a controller, wherein the controller comprises a programmable memory configured to store a plurality of patterned stimulation waveforms associated with a detected paresthesia. In some variations, the one or more stimulation electrodes are configured to be implanted in an ocular region or a nasal region. In some of these variations, the controller is configured for placement external to the ocular region or the nasal region. In some variations, the one or more stimulation electrodes are configured for placement on a mucosal surface or within submucosal tissue. In some variations, the one or more stimulation electrodes are configured for placement within a nasal cavity or a sinus cavity.

In some variations, the programmable memory is capable of storing up to 10 patterned stimulation waveforms. In some variations, the system further comprises a user interface for selecting one or more of the stored plurality of patterned waveforms. In some variations, the controller is

ES 2 809 599 T3 configured to run a program that cycles through a plurality of waveform parameter options.

In some variations, the devices described herein comprise a handheld stimulator comprising a stimulator body comprising a user interface, and a stimulator probe comprising a nasal insertion tip comprising an electrode. The stimulator may be configured to deliver a plurality of electrical waveforms, and the user interface may be configured to select one of the plurality of electrical waveforms. Each of the waveforms can have at least one pulse shape, peak amplitude, pulse width, or frequency that is modulated over time. In some of these variations, each of the waveforms has at least two of a pulse shape, peak amplitude, pulse width, or frequency that is modulated over time. In some variations, each of the waveforms has a pulse shape that modulates over time. In some variations, the waveform comprises a first period comprising a biphasic current controlled waveform, and a second period comprising a current controlled phase followed by a voltage controlled phase. The invention is set forth in the appended claims.

Brief description of the drawings

Figure 1 illustrates a proposed pathway of processed sensory output in various peripheral nervous system ganglia and central nervous system nuclei.

Figures 2A-2C depict an exemplary implantable microstimulator.

Figure 3 depicts an exemplary external controller for an implantable microstimulator.

Figures 4A-4C depict an exemplary handheld stimulator.

Figures 5A-5C show exemplary waveforms.

Figures 6A-6D illustrate exemplary amplitude variations over time.

Figures 7A-7D illustrate exemplary pulse width variations over time.

Figure 8 shows an exemplary function defining pulse widths that increase and decrease according to an exponential function.

Figure 9 shows a flow chart illustrating a method used to determine an optimized waveform for the patient.

Figure 10 illustrates exemplary shape modulation.

Figure 11 illustrates an exemplary pulse width modulation.

Figures 12A-12E illustrate exemplary modulations of amplitude and frequency waveform parameters.

Figures 13A-13E depict exemplary waveforms showing multiple parameters modulating simultaneously over time.

Figure 14A represents the paresthesia felt with stimulation applied at 30 Hz (no pattern). Figure 14B illustrates exemplary mobile paresthesia obtained with waveform pattern formation. Figure 14C illustrates another exemplary mobile paresthesia obtained with waveform pattern formation. Figure 14D depicts paresthesia felt by waveform pattern formation.

Figure 15 is a bar graph diagram comparing tear formation results from baseline tear formation (left, no stimulation) to 30 Hz non-patterned waveform stimulation (center) with waveforms of patterned stimulation optimized for the patient (right).

Figure 16A shows bilateral Schirmer scores with no stimulation, 30 Hz no-pattern stimulation, and patient-specific patterned waveforms. Figure 16B shows contralateral Schirmer scores with no stimulation, 30 Hz no-pattern stimulation, and patient-specific patterned waveforms.

Figures 17A-17B show bilateral responses to 30 Hz patternless stimulation (17A) and patient-specific patterned waveforms (17B).

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Figure 18 shows the Schirmer scores for the stimulation of the left frontal nerve areas in rabbits.

Figures 19A-19B illustrate exemplary nasal insertion tip distal portions.

Figure 20 shows a distal portion of an exemplary handheld nasal stimulator having two nasal insertion tips.

Figures 21A-21B depict perspective views of an exemplary handheld nasal stimulator having a single nasal insertion tip.

Figure 22A shows a distal portion of an exemplary nasal insertion tip. Figure 22B shows a cross-sectional view of the nasal insertion tip of Figure 22A.

Figure 23A shows a distal portion of an exemplary handheld nasal stimulator having two nasal insertion tips. Figure 23b shows a cross-sectional view showing the interior of the hand-held nasal stimulator of Figure 23A.

Figure 24 depicts a perspective view of an exemplary handheld nasal stimulator having a single nasal insertion tip.

Figure 25 illustrates a distal portion of an exemplary nasal insertion tip.

Figure 26 shows a perspective view of an exemplary handheld nasal stimulator having a single nasal insertion tip.

Figures 27A-27C, 28A-28B, and 29A-29B are perspective views of exemplary handheld nasal stimulators having return contacts.

Figures 29C-29E show schematic illustrations of handheld nasal stimulator configurations of Figures 29A-29B.

Figure 30A depicts an exemplary handheld stimulator comprising two nasal insertion tips. Figures 30B-30E depict variations of how current can be conducted between the stimulator electrodes of Figure 30A.

Figure 31 depicts how current can be conducted between electrodes and a return contact of an exemplary handheld stimulator having a single nasal insertion tip.

Figures 32A-32B illustrate how current can be conducted between electrodes of an exemplary handheld stimulator having two nasal insertion tips. Figure 32C shows a schematic illustration of a portion of the stimulator circuitry of Figures 32A-32B. Figure 32D shows a schematic illustration of a portion of an alternative circuitry configuration for the stimulator of Figures 32A-32B.

Figure 33 shows a cross-sectional view showing the interior of the stimulator of Figures 23A-23B with representations of how current can be directed between the electrodes.

Detailed description

Described herein are devices, systems, and methods for treating one or more conditions (such as dry eye, eye strain, eye discomfort from contact lens wear, etc.) by providing electrical stimulation to an anatomical structure located in a region. eye or nasal region. Specifically, the methods described herein generally include applying electrical stimulation to an anatomical structure in an ocular region or a nasal region to activate the lacrimal gland, wherein the electrical stimulation is defined by a plurality of waveform parameters. Electrical stimulation can result in effects such as increased tear production during or after delivery of the stimulus.

In general, the methods described herein include electrically stimulating nerves, muscles (thus indirectly nerves through muscle spindles and Golgi tendon receptors that provide sensory information back to the central nervous system) and / or glands in the eye orbit or nasal mucosa and submucosa. With that approach, neural tissue can be activated in some way. For example, referring to Figure 1, the inventors hypothesize that activation at an intranasal location 102 or at an ocular location 104 causes antidromic and orthodromic action potentials to be executed from the trigger point if the electrode You are activating nerves directly, and orthodromically in afferent nerves if glands and muscles are activated to cause sensory input into the brain. Sensory input to the brain reaches the lacrimal nucleus in the pons, after passing through several ganglia along the way, as shown by

ES 2 809 599 T3 arrows 106, 108, 110 and 112. In this case, neural computation and data reduction is likely to occur in each of the ganglia, as well as in the nuclei in the pons before the information it is relayed further to the sensory cortex areas in the brain. Consequently, activation of neural tissue, directly or indirectly, can make circuitry in the central nervous system (e.g. brain, spinal cord, potentially ganglia in the peripheral nervous system (PNS)) to respond to input. . The outlet of the brainstem 118 can then send feedback, as shown by arrow 114, to the lacrimal gland.

Example stimulators

The stimulation waveforms described herein can be delivered through implanted or non-implanted stimulators (eg, handheld).

Implantable microstimulators as an example

When the stimulation waveforms described herein are applied using an implantable stimulator, the stimulator may comprise a microstimulator comprising a housing and a corresponding complementary flexible extension connected to the housing, forming a unitary microstimulator. An example is shown in Figures 2A-2C. As shown therein, the microstimulator 200 may comprise a housing 202 and a flexible extension 204 connected to the housing 202. The housing 202 may be hermetically sealed and may contain some or all of the stimulation circuitry therein. Microstimulator 200 may comprise any suitable stimulation circuitry, such as those described in US Patent Application No. 13 / 441,806. Housing 202 can be formed of one or more metals (eg, titanium) or other biocompatible materials.

Extension 204 may be formed of a flexible material such as silicone, and may comprise a first electrode 206, a second electrode 208, and a coil 210. Although shown to have two electrodes, implantable stimulators may have fewer (eg, one ) or more (for example, three, four, five, six or more) electrodes. When the implantable stimulator comprises a plurality of electrodes, the current paths through the tissue can be controlled by supplying the current to / from various electrodes, which can be varied over time. In some variations, extension 204 can be a molded component, such as molded silicone. The extension may have a shape corresponding to and complementary to the housing, so that the extension and the housing together have a unitary shape, as shown in Figures 2A-2B. Flexible extension 204 can conform to one or more parts of the anatomy (eg, the orbit or lacrimal gland) when implanted in tissue. Figure 2B shows a side view of the microstimulator 200. As shown therein, the thickness of the extension 204 may be less than that of the housing 202, and may increase to the thickness of the housing 202. In addition, the width of the extension 204 is shown in FIG. 2A as greater. than the width of the housing 202, and may decrease to the thickness of the housing 202.

Electrodes 206 and 208 and coil 210 can be connected to microstimulator circuitry through one or more pathways. For example, Figure 2C shows a perspective view of housing 202 with extension 204 removed. As shown therein, housing 202 may comprise a plurality of passageways 212 extending through housing 202. One or more elements (eg, one of electrodes 206 or 208 or coil 210) can be electrically connected to hermetically sealed stimulation circuitry by connection to pathways 212. Additionally, some of the passageways 212 may comprise an insulating element 214 that can electrically isolate the passageway 212 from the housing 202. This and other implantable stimulators that can deliver the electrical stimuli described herein are described in US Patent Application No. 13 / 441,806; and in US Patent Application No. 14 / 256,915.

When the stimulator is an implantable microstimulator, the system may further comprise a controller, which can communicate with the microstimulator to transmit and / or receive energy, information, or the like. For example, in variations in which a stimulation system comprises a microstimulator that has a passive stimulation circuit (or a stimulation circuit that does not otherwise include a battery or internal power supply), the signal from the controller can power the stimulator via the controller output signal. The controller can communicate with the microstimulator wirelessly and / or via a wired connection. The controller may be configured for implantation within the body, or it may be configured to remain external to the body. The controller can be disposable, it can be reusable, or it can be partially reusable. In some cases, the controller can be rechargeable.

Figure 3 represents an external controller by way of example. As shown therein, a stimulation system 300 includes a controller 302 comprising a handheld device. Controller 302 can approximate an implanted microstimulator 306, and can produce an output signal 308 received by implanted microstimulator 306. The implanted microstimulator may in turn generate a stimulation signal 310 used to stimulate an anatomical target, as described in more detail herein. This and other controllers that can be used to deliver electrical stimuli are described.

ES 2 809 599 T3 described herein in US Patent Application No. 13 / 441,806.

The length and width of the microstimulator can be selected to allow the placement of a part of the microstimulator, partially within or around the lacrimal gland, or adjacent to a desired tissue, such as the lacrimal gland or a nerve that wishes to be stimulated, such as but not limited to the nasociliary nerve or the anterior ethmoidal nerve. Some of these implantation locations are described in more detail in US Patent Application No. 13 / 441,806; in US Patent Application No. 14 / 256,915; and in US Patent Application No. 14 / 207,072, filed March 12, 2014 and entitled "Implant Delivery Devices, Systems, and Methods" (US Patent 9,717,627 published September 18, 2017).

The microstimulator can be injected into a patient using a delivery system. The delivery system may comprise an insertion device (such as a conduit, a shaft to which the microstimulator can be removably attached, or the like) and / or a dissection tool. In some variations, the insertion device is a 12-gauge or larger needle. In other variations, the insertion device comprises a cannula. In some variations, the inserter may comprise a piston assembly, which in some variations may be spring loaded. The microstimulator can be loaded into the insertion device, and the insertion device can be inserted into an insertion route. In some variations where the microstimulator is implanted in an ocular region, using an anatomical landmark at the corner of the eye, a delivery device (eg, a needle) can be placed in the vicinity of the lacrimal gland, and can deploy the microstimulator using the delivery device. Anatomical landmarks include, but are not limited to, the lateral canthus, an eyelid margin, an eyelid lobe of the lacrimal gland, the orbital rim, a bony protrusion on the superior-lateral aspect of the orbit, the vascular bed, or similar. In some variations, a microstimulator can be implanted by lifting the eyelid, forming an insertion route through the conjunctiva under the eyelid, and advancing the microstimulator into the insertion route. The insertion route can be formed using a dissection tool. In some variations, the insertion path can be formed using a dissecting element of an insertion tool. In some variations, the route of insertion can be formed between the periosteum and the orbital bone. In other variations, the route of insertion can form between the periosteum and the lacrimal gland. The microstimulator may have one or more features to facilitate minimally invasive recovery. US Patent Application No. 14 / 207,072 describes other variations of insertion devices that can be used to implant microstimulators described herein.

Hand-held stimulators as an example

The stimulator described herein can also be hand-held. Handheld stimulators may comprise a stimulator body and a stimulator probe. The stimulator probe may comprise at least one nasal insertion tip configured to be inserted into a nostril of a subject. The stimulator body can be configured to generate a stimulus, which can be delivered to the subject through the nasal insertion tip. The stimulator body may comprise a control subsystem and a power supply, which together can generate and control the stimulus.

In Figures 4A-4C, a variation of a handheld stimulator is shown. These figures show perspective views, rear in cross-section showing the interior and side in cross-section showing the interior, respectively, of a handheld stimulator 400, respectively. Stimulator 400 comprises a stimulator body 402 and a stimulator probe 404. Stimulator body 402 may comprise a front housing 438, a rear housing 440, and a proximal housing 442, which can be fitted together to define a body cavity 454. The body cavity 454 may contain a control subsystem and a power source 452.

The stimulator body may comprise a user interface comprising one or more operating mechanisms to adjust one or more parameters of the stimulus, as described in more detail below. The operating mechanisms may provide information to the control subsystem, which may comprise a processor, memory, and / or stimulation subsystem. In some variations, the operating mechanisms may comprise first and second buttons, as illustrated, for example, in Figures 4A and 4C as 414 and 416. In some variations, pressing the first button can turn on the stimulator and / or change the stimulator. stimulus waveform, while pressing the second button can turn off the stimulator and / or change the stimulus waveform. Additionally or alternatively, the user interface may comprise one or more feedback elements (eg based on light, sound, vibration, or the like). As shown in FIG. 4A, the user feedback elements may comprise light-based indicators, shown therein as indicators 418, that can provide information to the user. It should be appreciated that these features may be present in each of the handheld stimulator devices encompassed herein.

For each handheld stimulator described herein, in some variations, the stimulator body and the stimulator probe can be reversibly joined. Part or all of the stimulator can be disposable, and part or all of the stimulator can be reusable. For example, in variations where the stimulator probe is releasably connected to the stimulator body, the stimulator body can be reusable, and the stimulator probe can be disposable and periodically replaced. In some of these variations, the device comprises a deactivation mechanism that prevents the delivery of stimulus to the subject.

ES 2 809 599 T3 when the stimulator probe is reconnected to the stimulator body after being disconnected from the stimulator body. Additionally or alternatively, the device may comprise a locking mechanism that prevents the stimulator probe from being reconnected to the stimulator body after being disconnected from the stimulator body. In some variations, the device further comprises a removable protective cap. The stimulators described herein may have additional features as described in more detail in US Patent Application No. 14 / 256,915.

For each handheld stimulator described herein, the stimulator probe may comprise at least one nasal insertion tip. In the handheld stimulator variation shown in Figures 4A-4C, for example, the stimulator probe 404 may comprise two nasal insertion tips 406 and 408. Nasal insertion tips can self-align when inserted into the patient's nostrils. Stimulator probe 404 may further comprise projections 420, which may allow the patient to more easily grasp probe 404. The nasal insertion tip may be configured to be at least partially inserted into the nasal cavity of a patient. A nasal insertion tip may extend from a base member of the stimulator probe and may comprise an elongated portion having a distal portion at its distal end. The length of the nasal insertion tips is desirably long enough such that the tips can reach the desired stimulation location (eg, the nasal mucosa superior to the columella, such as near the contact surface between the nasal bone and the superior lateral cartilage) in a range of patients. A nasal insertion tip may comprise a flexible material (eg, a flexible polymer, such as a thermoplastic elastomer (eg, a thermoplastic elastomer alloy (eg, Versaflex ™), thermoplastic polyurethane, or the like), silicone, or similar) to allow the nasal insertion tip to self-align with respect to the desired stimulation location when inserted into the nasal cavities of a user and / or be atraumatic to nasal tissue during regular use and insertion, and / or during a sudden movement (for example, a sneeze). This can also improve user comfort. In some variations, the desired hardness of the material can be between about 40D and about 90D, between about 50D and about 80D, between about 60D and about 70D, or about 65D. In addition to having material properties that can be atraumatic to nasal tissue, it may be desirable for the distal end of the nasal insertion tip to have rounded edges to help minimize the risk of tissue damage during advancement of the tip into the nose.

In some variations, the distal portion may have a diameter (or largest cross-sectional dimension) that is greater than the diameter (or largest cross-sectional dimension) of the elongated portion of the tip proximal to the distal portion. This can allow a portion of the distal portion (eg, one or more electrodes, described below) to come into contact with tissue of a subject, while the elongated portion is not in contact with tissue of the subject. For example, the diameter of the nasal insertion tip at the distal portion can in some cases be between about 3mm and about 7mm, while the diameter of the elongated portion can be between about 1mm and about 6mm in diameter. proximal to the distal part. More specifically, in some variations, the diameter of the nasal insertion tip can be about 5mm, and the diameter of the elongated portion can be about 3mm. The proximal portion of the elongated portion may flare outward (i.e., have a diameter or greater dimension in increasing cross-section) toward a base member of the stimulator probe, which in some variations may act as a stop to limit the distance that nasal insertion the tip can be advanced into the nose of a user.

Each nasal insertion tip can comprise at least one electrode. Each electrode can be connected to a cable, which can be connected directly or indirectly to a control subsystem and a power supply, so that an electrical stimulus can travel from the control subsystem, through the cables and through the electrodes, as described in more detail in US Patent Application No. 14 / 256,915.

An electrode can be of any suitable design. For example, an electrode can comprise an arc of a cylindrical surface, it can be ellipsoid, spherical, ovoid, or the like. An electrode can be any suitable length, such as between about 1mm and about 10mm, between about 3mm and about 7mm, about 5mm, or more than about 10mm. An electrode can be located at any suitable longitudinal portion of a nasal insertion tip, and for nasal insertion tips comprising a plurality of electrodes, it can be spaced along the nasal insertion tip. The position of the electrode along the tip can at least partially determine the placement of the electrode in relation to the tissue when the stimulator probe is advanced into the nose. In some variations, an electrode can be located in an intermediate position along a tip. The electrode can be located at any suitable distance from the distal tip of the tip, such as between about 0.1 mm and about 4 mm, between about 4 mm and about 8 mm, or more than 8 mm from the distal tip of the tip. (for example, 1 cm from the distal limb). In some variations, an electrode can be located about 2.5 mm from the distal end of the tip. In some variations where an electrode is configured to supply current, the electrode can be located such that when inserted into the nasal cavity, the electrode is able to reach the nasal mucosa or other area to be stimulated. In some variations, the distance from the base member of the stimulator probe to the longitudinal center of an electrode configured to supply current (i.e., the part furthest from the center of the electrode could be inserted into the nasal cavity) can be between about 25mm and about 45mm. In other variations, the distance from the base element of the

ES 2 809 599 T3 stimulator probe to the longitudinal center of at least one electrode can be between about 30mm and about 40mm. For example, in some variations, the distance from the base member of the stimulator probe to the longitudinal center of at least one electrode can be approximately 32.5mm. However, it should be appreciated that an electrode can be located in other positions, especially when the electrode is configured to be a return electrode. An electrode can also be connected to a distal end of a nasal insertion tip. Generally, when an electrode is positioned at the distal end of a tip, it may be desirable for the electrode to have no edges or have rounded edges, to help minimize the risk of tissue damage during advancement of the electrode in the nose.

In some variations, the electrode comprises a hydrogel, which is described in more detail in US Patent Application No. 14 / 630,471, filed February 24, 2015 and entitled "Polymer Formulations for Nasolacrimal Stimulation" (US Patent 9,770 .583, published September 26, 2017). However, it should be appreciated that the electrodes described herein may comprise other conductive materials, such as metals (eg, stainless steel, titanium, tantalum, platinum or platinum-iridium, other alloys thereof, or the like), ceramics. conductive (eg, titanium nitride), liquids, gels, or the like. In some variations, the electrode may comprise one or more materials configured to promote electrical contact between the electrodes of the stimulator probe and tissue (ie, the entirety of an electrode or a portion of the electrode, such as a cover). In some cases, the impedance provided by the tissue may depend at least partially on the presence or absence of fluid-like materials (eg, mucosa) in the nasal cavity. The material (s) can help minimize the impact of the impedance of the target tissue by providing a wet contact surface between the electrode and the tissue, which can act to normalize the impedance experienced by the electrode. This can in turn normalize the output and feel experienced by the user.

The stimulators described herein may comprise at least one cable configured to electrically connect the electrode (s) to the circuitry of the stimulator body. A wire may extend at least partially through a nasal insertion tip and may be formed of one or more conductive materials (eg, stainless steel, titanium, platinum or platinum-iridium, other alloys thereof, or the like), conductive ceramics (eg, titanium nitride), and may be positioned such that at least a portion of the wire contacts the electrode to provide a conduction path between the wire and the electrode. In some variations, a cable can comprise a spring, but it should be appreciated that a cable can also comprise a conductive loop, pole, or the like.

In the exemplary handheld stimulator 400 of Figures 4A-4C, the probe 404 comprises a first electrode 410 at the nasal insertion tip 406 and a second electrode 412 at the nasal insertion tip 408. As shown in the cross-sectional view showing the interior of stimulator 400 in Figure 4B, electrodes 410 and 412 are connected to leads 430 and 432 located within tips 406 and 408, respectively. Cables 430 and 432 are in turn connected to connectors 422 and 424, respectively. Connectors 422 and 424 extend through lumens 408 and 410 in proximal housing 442, and can be connected directly or indirectly to control subsystem and power source 452. As such, the electrical stimulus can travel from the control subsystem through connectors 422 and 424, through leads 430 and 432, and through electrodes 410 and 412.

Although stimulator 400 is shown to have two nasal insertion tips, each of which comprises a single electrode, in other variations the stimulators may comprise a single nasal insertion tip, and / or may comprise a plurality of electrodes on one tip. nasal insertion. In some variations comprising a plurality of electrodes on a nasal insertion tip, the electrodes may be longitudinally spaced along the length of the nasal insertion tip, such that they are configured to contact nasal tissue at different rates. depths within the anterior part of the nasal cavity when inserted into a nostril. Figure 19A shows an example of the distal end of such a nasal insertion tip 1900, comprising a distal electrode 1902 and a proximal electrode 1904. As shown therein, each electrode comprises a hydrogel contacted by a wire comprising a spring, but it should be appreciated that the electrodes and wires may have other configurations, as described herein. Figure 20 shows a part of an exemplary handheld stimulator 2000 comprising two nasal insertion tips 2006 and 2008, each comprising two of these electrodes: the first electrodes 2010 and 2014 located more proximally at the tip. , and the second electrodes 2012 and 2016 located more distally at the tip.

Although Figures 19A and 20 show the distal and proximal electrodes separated by a distance shorter than the length of each electrode, it should be appreciated that the electrodes may be longitudinally separated by any suitable distance. For example, Figure 19B shows an example of a distal end of a nasal insertion tip 1950, comprising a distal electrode 1952 and a proximal electrode 1954 separated by a distance greater than the length of each electrode. Figures 21A-21B show another exemplary stimulator 2100 comprising a stimulator body 2102 and a stimulator probe 2104 comprising a single nasal insertion tip 2106, wherein the nasal insertion tip comprises two longitudinally spaced electrodes. along the tip. As shown in Figure 21A, the nasal insertion tip 2106 may comprise a first electrode 2110 and a second electrode 2112, spaced longitudinally along the length of the nasal insertion tip a distance greater than the length of the electrodes. . As shown, each electrode

ES 2 809 599 T3 comprises a hydrogel contacted by a wire comprising a spring, but it should be appreciated that the electrodes and wires may have other configurations, as described herein.

In other variations, more than one electrode can be located at the same longitudinal location along the length of the nasal insertion tip. In these variations, the electrodes may be at different locations around the circumference of a nasal insertion tip, that is, spaced radially around the nasal insertion tip, such that they are configured to contact nasal tissue at different locations at the same depth within the anterior part of the nasal cavity when the nasal insertion tip is inserted into a nostril. For example, when placed in a nostril, one electrode may face the front of the nose and another electrode may face the septum. In some cases, each electrode may comprise a partial cylinder (eg, an arc of between about 10 degrees and 180 degrees). Figure 22A shows an example of a distal end of such a nasal insertion tip 2200, comprising a first electrode 2202 and a second electrode 2204 separated by a vertical rib 2206. Figure 22B shows a cross-sectional view of the nasal insertion tip 2200. Figures 23A and 23B show perspective and cross-sectional views showing the interior, respectively, of a handheld stimulator 2300 comprising two nasal insertion tips 2306 and 2308, each having first and second electrodes separated by a vertical rib. More specifically, each nasal insertion tip comprises a pair of electrodes, 2310, 2312 and 2314, 2316, respectively. Electrode pairs 2310, 2312 and 2314, 2316 are located in the same longitudinal location along the length of the nasal insertion tips, spaced around the circumference. As another example, FIG. 24 shows an exemplary stimulator 2400 comprising a stimulator body 2402 and a stimulator probe 2404 comprising a single nasal insertion tip 2406, wherein the nasal insertion tip comprises electrodes 2410 and 2412 first and second radially spaced around the circumference of the nasal insertion tip. Although each electrode in Figures 22-24 is shown as comprising a hydrogel contacted by a wire comprising a spring, it should be appreciated that the electrodes and wires may have other configurations, as described herein. .

In still other variations, the electrodes can be spaced longitudinally along the length of the nasal insertion tip and radially around the circumference of the nasal insertion tip. Figure 25 shows an example of the distal end of such a nasal insertion tip 2500, comprising three electrodes: a distal electrode 2502 and first and second proximal electrodes 2504 and 2506 separated by a vertical rib 2508. As shown therein, electrodes 2504 and 2506 have a common longitudinal location (that is, they are located horizontally adjacent to each other) and are located proximally relative to electrode 2502. FIG. 26 shows an exemplary handheld stimulator 2600 comprising a stimulator body 2602 and a stimulator probe 2604 comprising a single nasal insertion tip 2606, wherein the nasal insertion tip comprises electrodes spaced both longitudinally apart. along the length of the tip as well as radially around the circumference of the tip. Electrode 2610 is located distal to electrodes 2612 and 2614, which are radially spaced around nasal insertion tip 2606 and are separated by a vertical rib 2616. Although each electrode in Figures 25-26 is shown as comprising a hydrogel with which a wire comprising a spring contacts, it should be appreciated that the electrodes and wires may have other configurations, as described herein. .

It should be appreciated that although the examples described above comprise one, two, or three electrodes on the nasal insertion tips, the nasal insertion tips may have more electrodes (eg, four, five, six, or more), which can be longitudinally spaced as long as possible. long and / or radially around a nasal insertion tip in any suitable arrangement. In some cases, each electrode may have a separate lead, while in others, one or more electrodes may have electrically connected leads (that is, they may have the same potential).

Additionally or alternatively, some variations of handheld stimulators may comprise a return contact not located in a nasal insertion tip, which may provide an alternative or additional current path. For example, a handheld stimulator may comprise a return contact located on the base member of a stimulator probe or on a stimulator body. The return contact can be configured to be in contact with various anatomical locations, such as, but not limited to, a hand or an area of ​​tissue near the opening of the nostril, columella, nasolabial fold, or upper lip. Furthermore, it should be appreciated that in the configurations described herein, the return contacts may be configured in place to supply current.

For example, Figures 27A-27B show examples of handheld nasal stimulators each comprising a single tip and a return contact not located on the nasal insertion tip. Handheld nasal stimulators 2700 and 2740 are shown each having return contacts 2702 and 2742 located on stimulator bodies 2704 and 2744, respectively. As such, the return contacts can be configured to be in contact with a user's hand, while the active electrodes 2706 and 2746, 2748 are configured to be in contact with the nasal mucosa. Figure 27C shows a nasal stimulator 2720 comprising two nasal insertion tips each having an electrode, and comprising a return contact 2722 located in a stimulator body 2724. As shown in Figures 27A-27C, handheld stimulators comprising return contacts located on a stimulator body can have any suitable number of electrodes.

ES 2 809 599 T3 located on a nasal insertion tip, such as one per tip (Figures 27A and 27C), two (Figure 27B), three, four, five, six or more active electrodes.

The return contacts in Figures 27A-27C are shown as each comprising a band around the stimulator bodies, but the return contacts configured to contact a user's hand can be of any suitable shape. For example, a return contact may comprise a plurality of bands that are cut to accommodate various ways a user might hold the stimulator, or a plurality of bands or surfaces at the same potential spaced around the stimulator body. It may be desirable for the total surface area of ​​the return contact to be large enough to reduce the impedance to a point where current can be conducted through the return contact without exceeding a maximum voltage. A return contact may comprise any suitable material, such as, but not limited to, one or more conductive materials, such as metals (e.g., stainless steel, titanium, tantalum, platinum or platinum-iridium, other alloys thereof, or similar), conductive ceramics (eg, titanium nitride), or hydrogels.

In other variations, a return contact can be located on the base member of a stimulator probe, near the base of a nasal insertion tip. For example, Figures 28A and 28B show nasal stimulators 2800 and 2820 each having return contacts 2802 and 2822 located on stimulator probes 2806 and 2826, respectively, near the proximal end of insertion tips 2804 and 2824. nasal. Return contacts 2802 and 2822 are shown as having an annular shape near the proximal end of the nasal insertion tips, such that the return contacts are configured to contact an area of ​​tissue near the opening of the nose. the nostril when the nasal insertion tip is inserted into a nasal cavity. By having a return contact located near the nostril opening, it may be possible to have current flow through a desired part of the septum while having a single nasal insertion tip (i.e., one or more electrodes in a single side of the septum), as opposed to at least one electrode on each side of the septum). It should be appreciated that in other variations, the return contacts may have other suitable shapes, such as a plurality of bands or points of contact. As shown in Figures 28A-28B, handheld stimulators comprising return contacts located near a base of a nasal insertion tip may have any suitable number of electrodes located on the nasal insertion tip, such as one per tip (figure 28A), two (figure 28B), three, four, five, six or more electrodes. It should be appreciated that while Figures 28A-28B show a return contact located near the proximal end of a nasal insertion tip of a stimulator comprising a single nasal insertion tip, the return contacts can also be located near the proximal end of a or both nasal insertion tips of a stimulator comprising two nasal insertion tips.

In still other variations, a return contact can be located on the base member of a stimulator probe, away from the proximal end of a nasal insertion tip. For example, Figures 29A-29B show handheld stimulators comprising a single nasal insertion tip configured to insert into a first nostril, and a return contact configured to contact an area of ​​tissue near the opening of a second nostril, against the skin and / or the nasal mucosa. Figure 29A depicts a handheld stimulator 2900 comprising a single stimulator probe 2908. Stimulator probe 2908 comprises a single nasal insert tip 2904 having a single electrode 2906. Base element 2912 of stimulator probe 2908 comprises a return contact 2910. Stimulator 2900 may be configured such that when nasal insertion tip 2904 is inserted into a first nostril, return contact 2910 is in contact with an area of ​​tissue near the opening of a second nostril. Figure 29B shows a similar handheld stimulator 2950 comprising a stimulator probe 2958 comprising a single nasal insertion tip 2954 comprising two electrodes 2956 and 2962, and a base element 2952 comprising a return contact 2960 configured to enter. in contact with an area of ​​tissue near the opening of a second nostril.

In the variation shown in Figure 29B, the leads can have various arrangements, such that each electrode or return contact can be at a different potential, or two can be at the same potential. For example, the wires connected to each of the electrodes 2956, 2962, and the return contact 2960 may be independent in some variations, as schematically illustrated in FIG. 29C. In other variations, one of the two electrodes 2956, 2962 may have a common wire with the return contact 2960, as schematically illustrated in Figure 29D, such that the electrode and the return contact are at the same potential. In still other variations, the two electrodes 2956, 2962 may have a common wire, as shown in FIG. 29E. Optionally, a resistor can be located between one electrode and the return contact, or between the two electrodes, which can affect the distribution of the current supply. For example, Figure 29C shows a resistor 2964 located between electrode 2962 and return contact 2960. These various arrangements can affect spatial current supply, as described in more detail herein.

Spatial control

The electrodes and return contacts described herein can allow stimulus delivery by stimulators to be spatially controlled. That is, current directing can be achieved by conducting particular current paths between the electrodes or the return contacts, and in some

In cases, the current flow path (s) through the tissue may change over time to achieve spatial patterning. The current supplied by or to each electrode can, in some cases, be controlled individually to achieve these effects. For example, each of the electrodes can deliver the same or different waveforms, or none at all, and the stimulus delivery by each of the electrodes can vary over time. Current routing can allow both the current paths and the amount of current along each path to be controlled. Current steering can allow particular tissue areas to be targeted by stimuli, and the formation of spatial patterns can affect a subject's perception of the stimulus and can reduce adaptation. The formation of spatial patterns can provide neural activation to diverse tissues over time (eg, to different sets of nerve branches, such as those of the anterior ethmoid nerve within the nasal mucosa). In some cases, for example, this could be interpreted as something similar to a physical movement of a system that has a single fixed current path, thereby reducing the need for a user to move the electrode within the nose to activate diverse assemblages of neural fibers.

In some variations, exemplary anatomical targets may include nerves, muscles, mucosal or submucosal tissues (eg, nasal or sinus mucosa or submucosa), sensory cells in hairy and hairless skin, glands, or other structures of a patient. involved in the process of lacrimation or glandular vasodilation that can be electrically stimulated. For example, anatomical structures may include, but are not limited to, a lacrimal gland, one or more meibomian glands, tear ducts, cutaneous receptors (mechanoreceptors, Meissner's corpuscles, neurotendinous spindles, Golgi tendon organs, Ruffini's corpuscles, stretch receptors, end organs of the corpuscle of Ruffini, end organs of the corpuscle of Pacini, receptors of the hair follicle, free nerve endings, thermoreceptors, bulboid or Krause corpuscles, nociceptors), nerves, parasympathetic fibers and axons, sympathetic nerves, fibers and axons, lacrimal branches, the lacrimal nerve, perivascular nerves of the lacrimal artery and its branches, nerve fibers that innervate the meibomian glands, cells Lacrimal gland myoepithelial cells, lacrimal gland acinar cells, lacrimal gland ductal cells. In yet another variation, the anatomical structure is the infratrochlear nerve. In other variations, the anatomical structure is a cutaneous receptor responsible for detecting changes in force or temperature over time or a set of cutaneous receptors in an area of ​​the skin that reports changes in the force applied to the direct skin. or indirectly by the movement of hair that grows on the skin, or the nerves that innervate skin receptors that report changes in the force applied to the skin or hair on the skin, or temperature changes in the skin, including the mucosa, submucosa in the nose, or the conjunctiva in the eye.

In some cases, it may be desirable to deliver the electrical stimuli described herein to one or more nerves that innervate the lacrimal gland tissue. In others, it may be desirable to deliver the electrical stimuli described herein to the nasal mucosa. This can cause lacrimation by activating the nasolacrimal reflex. In some cases, the targeted area may comprise tissue innervated by the anterior ethmoid branch of the nasociliary nerve. In another variation, the anatomical structure is the posterior ethmoidal nerve. In some cases, the targeted area of ​​the nasal mucosa may be larger than the columella. In some cases, it may be near the lower end of the nasal bone (that is, near the interface between the nasal bone and the upper lateral cartilage). As such, the stimulus can be delivered between about 20mm and about 35mm into the nasal cavity of the patient, in some cases through an electrode between about 25mm and about 35mm in the patient's nasal cavity. In other cases, the targeted area may be the columella. It may be desirable for the stimulus to be delivered anteriorly of the nasal cavity, within the nostrils and anterior to the turbinates, and in some cases, at a location anterior to the middle turbinate, or at a location anterior to the turbinate lower. The stimulus may be delivered at least partially through or near the septum tissue and, in some cases, it may be desirable to direct the stimulus such that a portion is directed toward the front of the nose. This can allow selective activation of the nerves in the front of the septum (for example, the ophthalmic branch of the trigeminal nerve) while minimizing the activation of the nerves towards the back of the nasal septum, which can reduce negative side effects. that can be produced by the stimulation of nerves that innervate the teeth and that can reduce rhinorrhea. In some cases, it may also be desirable to direct the stimulus to reduce the negative side effects that can result from stimulation of the olfactory area.

One way to achieve stimulation of one or more of these target areas may be current directing. For example, current can be directed to flow in a path such that it is concentrated in areas where a target nerve (for example, the anterior ethmoid nerve) is located (for example, certain parts of the septum) while avoiding areas stimulants that can cause discomfort. or unnecessary unpleasant sensations (for example, parts of the trigeminal nerve that innervate the teeth). By directing current in this manner, preferential activation of particular nerves can be achieved with waveforms that could not otherwise achieve preferential activation.

In handheld stimulation devices comprising one or more nasal insertion tips, for example, current directing can be used to conduct current between electrodes at the same tip and, additionally or alternatively, in devices comprising two nasal insertion tips, between electrodes at different tips. As described herein, handheld stimulation devices may also comprise one or more return contacts to provide additional possible current paths. The control

ES 2 809 599 T3 space can allow both current paths and the amount of current along each path to be controlled, and can allow these to be changed over time. By controlling current pathways, particular tissue areas can be targeted. In some variations, current steering can be used to adjust the location of the stimulus delivery to a desired region of tissue without having to move a temporarily inserted or implanted stimulator.

In some cases, current steering can be achieved by having isolated circuits with independent current sources for each path, each floating without a common ground connection. In other cases, current steering can be achieved using a single current source based on the impedance values ​​of multiple paths. Current routing can also be carried out in some cases using a multiplexer, which can be located within a waveform generator. In other cases, it can be carried out using frequency selectivity, for example by connecting different electrodes to receiving coils that have different resonance frequencies, such that small changes in the frequencies of the controller can allow the selective delivery of stimulus by the drivers. electrodes.

As an example of spatial control, FIG. 30A depicts an illustrative stimulator 3000 comprising two nasal insertion tips 3002 and 3004, each comprising two electrodes 3006, 3008 and 3010, 3012, respectively. Current steering can be used to conduct current through various paths between the four electrodes, including between the two nasal insertion tips, between electrodes on the same nasal insertion tip, or both, which can cause stimulation of different targets. anatomical.

Figures 30B-30E show variations of how current can be directed between the electrodes. In some variations, current can be directed to flow from one or more electrodes at tip 3002 to one or more electrodes at tip 3004. For example, in Figure 30B, current is supplied by electrode 3006, while the electrode 3008 does not supply any current. Current from electrode 3006 is directed to electrodes 3010 and 3012, which function as return electrodes, such that a portion (for example, 50%) of the current flows from electrode 3006 to electrode 3010, and a part (for example, 50%) of the current flows from electrode 3006 to 3012. In Figure 30C, current is also conducted from one nasal insertion tip to the other, but in this configuration, both electrodes 3006 and 3008 supply current, and electrodes 3010 and 3012 act as return electrodes, such that one part (eg 50%) of the total current flows from electrode 3006 to 3010, and a part (eg 50%) of the total current flows from electrode 3008 to electrode 3012. In FIG. 30D, current is conducted from one nasal insertion tip to the other, and both electrodes 3006 and 3008 supply current, and both electrodes 3010 and 3012 act as return electrodes. However, in contrast to the example in Figure 30C, a part (for example, 50%) of the total current flows from electrode 3006 to 3012, and a part (for example, 50%) of the current total flows from electrode 3008 to electrode 3010. It should be appreciated that it is not necessary to divide the current evenly between the routes in these examples, and that more current can be directed through one of the two routes.

While in the examples of Figures 30B-30D current is conducted from an electrode at first tip 3002 to an electrode at second tip 3004, in other variations, current can be directed between electrodes at the same tip. For example, in Figure 30E, current is supplied by electrode 3006, and electrode 3008 at the same tip and electrode 3010 at the other tip act as return electrodes. That is, a part (for example, 80%) of the current can travel from the electrode 3006 at the first tip 3002 to the electrode 3010 at the second tip 3004, while the remaining part (for example, 20%) It can be moved from electrode 3006 to electrode 3008, both located on the first tip 3002. In each arrangement illustrated in Figures 30B-30E, the described current steering can be achieved, for example, by having isolated circuits with independent current sources for each path, each one floating without a common ground connection. Each current directing configuration in Figures 30B-30E can result in different anatomical targets being stimulated near and within the septum.

Current can also be directed between one or more electrodes located on a nasal insertion tip and one or more return contacts. Returning to the handheld nasal stimulator of Figures 29A-29B, each of the electrical configurations of Figures 29C-29E can result in a different spatial current delivery configuration and thus the stimulated anatomical target. For example, Figure 29C shows a resistor 2964 located between electrode 2962 and return contact 2960. In this configuration, if electrode 2956 supplies current, the presence of resistor 2964 results in less current being conducted from electrode 2956 to electrode 2962 and more current being conducted from electrode 2956 to return contact 2960, at compared to a setup without the 2964 resistor. As a result, when the nasal insertion tip 2954 is inserted into a nostril so that the electrodes 2956 and 2962 are in contact with the nasal mucosa, more current can be conducted through the septum, compared to a configuration without the resistor. 2964. In some variations, the resistance can be variable. It can be controllable by one use, so that the user can adjust the stimulation effect.

As another example, Figure 31 illustrates directing current through multiple paths using a handheld stimulator 3150 comprising a nasal insertion tip 3152 comprising first and second electrodes 3154 and 3156, as well as a return contact 3160 configured. to be in contact with the hand of a

ES 2 809 599 T3 user while the first and second electrodes are in contact with the nasal mucosa of a user. As illustrated, the current can be directed such that a portion (e.g., 70%) travels from electrode 3156 to electrode 3154 at the nasal insertion tip 3152, illustrated by arrow 3162, while a some (eg, 30%) travels from electrode 3156 to return contact 3160 on stimulator body 3158, illustrated by arrow 3164. As a result, there may be a higher current density, and thus a higher voltage drop, in the area of ​​one target nerve (for example, the anterior ethmoid nerve), while a lower current density would pass through other areas. It should be appreciated that arrows 3162, 3164 and the other arrows representing current paths herein are not intended to illustrate the exact physical path of current through tissue, but rather the origin and return of the current with respect to to device. The actual path of current through the tissue as it travels from source to return will depend on the shape and properties of the tissue.

The pathways through which the current is directed can be changed over time to form spatial patterns of the stimulus delivery. That is, for example, for a first period of time, the current may be conducted through a first set of path (s), and for a second period of time, the current may be conducted through a second set of path (s). s). This can create the sensation of a moving stimulus, which can reduce the patient's adaptation to the stimulus. For example, the handheld nasal stimulator 3000 may be configured to cycle, either by default, randomly, or under user control, through the current directing patterns shown in Figures 30B-30E.

As another example, Figures 32A-32B show a stimulator 3200 comprising a first nasal insertion tip 3202 and a second nasal insertion tip 3204. The first nasal insertion tip 3202 comprises a first electrode 3206 and a second electrode 3208, while the second nasal insertion tip 3204 comprises a single electrode 3210. Stimulator 3200 may have a first configuration (illustrated in Figure 32A) in which current flows from electrode 3206 at first nasal insertion tip 3202 to electrode 3210 at second nasal insertion tip 3204, and a second configuration ( illustrated in FIG. 32B) in which current flows from electrode 3208 at first nasal insertion tip 3202 to electrode 3210 at second nasal insertion tip 3204. To switch between the first and second configurations, the stimulator 3200 may comprise a switch 3222, schematically illustrated in Figure 32C, which allows selection of the output 3224, resulting in the supply of current from the electrode 3206, or the selection of output 3226, which results in the supply of current from electrode 3208. The variation shown in Figure 32C also shows two signal generators 3212 and 3214, discussed in more detail below, but it should be appreciated that the stimulator may comprise fewer or more signal generators. For example, Figure 32D shows a schematic illustration of a portion of an alternate configuration of circuitry for the stimulator comprising a single 3252 signal generator, the output of which can be routed through the 3258 and 3250 selector switches of the 3260 multiplexer to the first exit 3254 or the second exit 3256. Output 3254 can go to a first electrode (eg, electrode 3206), and output 3256 can go to a second electrode (eg, electrode 3208).

By switching between supplying current to come from different electrodes, the current path can be changed over time, which can allow stimulation of different areas of tissue over time. This may in turn reduce adaptation and / or may allow particular anatomical areas to be targeted. In some cases, it may be desirable to temporarily target particular areas. For example, periodic partial activation of CN-V2 can reduce the sensation of needing to sneeze that might otherwise be felt during anterior ethmoid nerve stimulation.

Similarly, Figure 33 shows a cross-sectional view showing the interior of the stimulator 2300 of Figures 23A-23B. As shown in FIG. 33, stimulator 2300 can be configured such that current can be directed through various paths. For example, current flowing from electrode 2312 in the first nasal insertion tip can be conducted to electrode 2316 in the second nasal insertion tip through path 3202; to electrode 2314 at the second nasal insertion tip via path 3206; or to electrode 2310 at the first nasal insertion tip via path 3204.

In some variations, the current can be directed sequentially through the various paths. This type of spatial patterning can be accomplished in stimulators that comprise a single current source used to conduct through two or more electrodes compared to a common ground. This can be implemented using, for example, a multiplexer. The current can also be directed simultaneously through the various routes. This type of current directing can be accomplished in stimulators comprising a plurality of independent or electrically floating current sources. In these variations, a multiplexer can also be used to control which electrodes receive current from which source.

Although the figures discussed above show the application of current directing to a handheld nasal stimulator, it should be appreciated that current directing can be applied with the use of other devices, such as implantable stimulators (for example, stimulators implanted in ocular or nasal regions. ) described in this document. The ability to target particular tissue areas without moving the electrode contact points can be particularly useful in the case of implantable stimulators.

ES 2 809 599 T3 which have a fixed position relative to the fabric.

When stimulators are configured for stimulus delivery spatial patterning, the spatial patterning can have any suitable parameter. For example, the power supply can be switched between two or more routes at a predetermined frequency, such as approximately every 0.5 seconds, 1 second, 2 seconds, 5 seconds, 10 seconds, or more. In other variations, a user may be able to switch between two or more routes using a user interface, such as a user interface described herein. In still other variations, the route may be selected by a clinician for an individual patient. For example, when the stimulator is an implantable stimulator, a clinician may be able to select a route after implantation so that the stimulated tissue can be personalized after implantation without having to adjust the implantation site.

Waveforms

The waveforms of electrical stimulation delivered by the stimulators described herein can be customized for specific treatment regimens and / or specific patients. In variations of stimulators configured to supply current through two or more paths, different waveforms can be delivered through each path, and the waveform delivered through each path can be changed over time. Returning to FIG. 32C, a stimulator may comprise a first signal generator 3212 configured to generate a first waveform, and a second signal generator 3214 configured to generate a second waveform. A multiplexer 3230 may have corresponding first and second select lines 3218 and 3220. In combination with switch 3222, described above, multiplexer 3230 can allow the waveform from any of the signal generators to be supplied to either electrode on nasal insert tip 3202, or to return 3228. Although FIG. 32C only shows two signal generators and two outputs, it should be appreciated that a similar configuration can be used for any number of signal generators and outputs. The waveform generated by each signal generator can have any suitable parameter, and can be any of the waveforms described in more detail herein.

As described in more detail herein, when temporary patterning of electrical stimulation waveforms is employed, waveform parameters such as pulse shape, frequency, amplitude, and width can be modulated. The frequency, pulse width, and / or amplitude of the waveform can be modulated linearly, exponentially, such as a sawtooth, sinusoidal shape, etc., or they can be randomly modulated. Stimulation can also be interrupted as part of temporary pattern formation. That is, the stimulation can be in an on / off condition, for example, with durations of 1 second on / 1 second off, 5 seconds on / 5 seconds off, etc. Modulation of the shape of the waveform (eg, rectangular vs. triangular vs. exponential) can also be used in a rhythmic or non-deterministic, non-rhythmic mode. Thus, numerous variations in the formation of temporal waveform patterns can be achieved. It should be understood that combinations of these parameter changes over time in a repetitive manner can also be considered time pattern formation. In some cases, random time pattern formation may be employed. Temporary pattern formation can help prevent the patient's habituation to applied stimulation (that is, it can help prevent the patient's response to stimulation from decreasing during stimulation).

In some cases, it may be desirable to configure the stimulation waveform to minimize side effects. In some cases, it may be desirable to promote stimulation of larger diameter nerves (for example, afferent fibers of the trigeminal nerve), which can promote a therapeutic effect, while reducing stimulation of smaller nerves (for example, fibers to -delta, c fibers, sympathetic and parasympathetic fibers), which can result in pain, discomfort, or mucus production. In general, for smaller pulse widths, the activation threshold for larger diameter nerves may be less than the activation threshold for smaller nerve fibers. Conversely, for larger pulse widths, the activation threshold for larger diameter nerves may be greater than the activation threshold for smaller nerve fibers. Accordingly, in some cases, it may be desirable to select a pulse width that preferably acts on the larger diameter ribs. In some variations, the pulse width can be between 50 ps and approximately 1200 ps. As another example, certain waveforms can minimize the activation of trigeminal nerve branches (eg, CN V2) that travel to the teeth. These can include waveforms ranging from 30 ps to 300 ps in pulse width, 10 Hz to 150 Hz in frequency, and 0.1 mA to 5 mA in amplitude.

Stimulation can be given periodically at regular or irregular intervals. Bursts of stimulation can be delivered periodically at regular or irregular intervals. Stimulation amplitude, pulse width, or rate may change during the course of the stimulation. For example, the amplitude of stimulation can ramp up from a low amplitude to a higher amplitude over a period of time. In other variations, the amplitude of stimulation can ramp up from a high amplitude to a lower amplitude over a period of time. The stimulation pulse width can also ramp up from a low pulse width to a greater pulse width over a period of time. The stimulation pulse width can vary in ramp from a high pulse width to a lower pulse width throughout a

ES 2 809 599 T3 period of time. The ramp period can be between 1 second and 15 minutes. Alternatively, the ramp period can be between 5 seconds and 30 seconds.

The patterned stimulation waveforms described herein can be used to increase patient comfort and / or can be used to improve stimulation efficiency, and thus waveform parameters that can be used are described below. alone or in combination to increase comfort and / or effectiveness.

It should be appreciated that the waveforms described herein may be delivered through a multipolar configuration, such as bipolar, tripolar, quadrupole, or higher order polar, or a distal return monopolar configuration. Waveforms can be sinusoidal, quasi-sinusoidal, square wave, sawtooth, ramping, or triangular waveforms, truncated versions of them (for example, where the waveform stabilizes when it reaches a certain amplitude), or the like, as described in more detail herein.

Shape

In some cases, the shape of the waveform or the modulation of the waveform can affect the comfort and / or the effectiveness of the stimulation. When the stimulator (electrode device) is configured to create a pulse-based electrical waveform, the pulses can be any suitable pulse (eg, a square pulse, a semi-universal pulse, or the like). The pulses supplied by these waveforms can be biphasic, alternating monophasic, monophasic, or the like. When a pulse is biphasic, the pulse can include a pair of single phase parts that have opposite polarities (eg, a first phase and a charge balancing phase that has an opposite polarity to the first phase). Each phase of the biphasic pulse can be either voltage controlled or current controlled. In some variations, both the first phase and the charge balancing phase of the biphasic pulse can be current controlled. In other variations, both the first phase and the charge balancing phase of the biphasic pulse can be voltage controlled. In still other variations, the first phase of the biphasic pulse can be current controlled, and the second phase of the biphasic pulse can be voltage controlled, or vice versa. In some cases, a combination of bilateral current-controlled stimulation and voltage-controlled load balancing can allow unilateral stimulation, and modifying the waveform shape can allow switching between areas of stimulation, for example between the nostrils. when the electrodes are located in each nostril, as described herein.

In some variations where the waveform comprises a biphasic pulse, it may be desirable to configure the biphasic pulse to be load balanced so that the net load delivered by the biphasic pulse is approximately zero. In some variations, a biphasic pulse can be symmetrical, such that the first phase and the load balancing phase have the same pulse width and amplitude. Having a symmetrical biphasic pulse can allow the same type of stimulus to be delivered, for example, to each nasal cavity. Pulses from a first phase can stimulate a first side of the nose (while providing a load balancing phase to a second side of the nose), while pulses from the opposite phase can stimulate the second side of the nose ( while providing a load balancing phase to the first side of the nose).

In other variations where the waveform comprises a biphasic pulse, a biphasic pulse may be asymmetric, where the amplitude and / or pulse width of the first pulse may differ from that of the load balancing phase. Even if the biphasic pulse is asymmetric, the biphasic pulse can be load balanced. For example, the cathode pulse may have a lower amplitude but a longer duration than the anode pulse, or the cathode pulse may have a greater amplitude but a shorter duration than the anode pulse. In both cases, the charge injection (amplitude multiplied by duration) can be the same for each pulse, such that the net charge delivered by the biphasic pulse is approximately zero.

The shape of the waveform can be changed to preferentially activate tissue near an electrode. For example, Figures 5A-5C illustrate exemplary waveforms configured to preferentially activate tissue near one of two electrodes, and in which the preferential activation may move closely from one electrode to another over time. In variations where the stimulator is a handheld stimulator configured to have an electrode in each nostril, for example, this preferential activation can allow preferential activation of tissue in one of the two nostrils, which can change along the weather. For example, Figure 5A shows a variation of a biphasic load balanced waveform 518 in which the aspect ratios (amplitude: duration) of the pulses change over time. A waveform is shown that has a first pattern in which an initial cathode pulse has a greater amplitude and a shorter duration compared to the next anode pulse. This pattern is found in the time periods indicated by 510 and 514. The waveform has a second pattern in which the initial cathode pulse has a smaller amplitude and a longer duration compared to the next anode pulse. This pattern is found in the time periods indicated by 512 and 516. It should be appreciated that each time period can have any suitable duration and therefore comprise any suitable number of pulses. As an example, each time period can be approximately 1 second. In other examples, each time period may be less than 1 second, from about 1 to about 5 seconds, from about 5 to about 10 seconds, from about 10 to

ES 2 809 599 T3 about 20 seconds or more.

In some variations, the waveform can transition between two aspect ratios roughly. In other variations, the transition can be gradual, in which the aspect ratio of the cathode pulse can increase over time and then decrease over time, while the aspect ratio of the anode pulse can decrease over time. of time and then increase over time. Figure 5B shows an example of a waveform 520 that gradually transitions between aspect ratios. These increases and decreases can be in any suitable form, such as linear increases and decreases or sinusoidal increases and decreases. In other variations, the transition may be sawtooth shaped, in which the aspect ratio of the cathode pulse increases gradually over time, while the aspect ratio of the anode pulse gradually decreases over time, and then the aspect ratio of the cathode pulse decreases sharply while the aspect ratio of the anode pulse increases sharply.

In some variations, the polarity alternates between a pattern in which the cathode pulse is first and a pattern in which the anode pulse is first. For example, FIG. 5C shows an illustrative version of such a stimulation waveform 522. As shown therein, the time periods indicated by 502 and 506 can have a cathode pulse and then an anode pulse, while the time periods indicated by 504 and 508 can have an anode pulse and then a cathode pulse. It should be appreciated that each time period can be of any suitable duration. As an example, each time period can be approximately 1 second. In other examples, each time period may be less than 1 second, about 1-5 seconds, about 5-10 seconds, about 10-20 seconds, or longer. In some variations, each time period can last for a single pair of pulses, such that the stimulation waveform comprises a repeating pattern of two anode pulses and two cathode pulses.

Although patterns that have varying amplitude: duration aspect ratios, can have a uniform charge injection, they can preferentially activate tissue near one of the two electrodes. That is, when the initial cathode pulse has a greater amplitude and a shorter duration than the anode pulse, the waveform can preferentially activate tissue near a cathode electrode; When the initial cathode pulse has a smaller amplitude and a longer duration than the anode pulse, the waveform can preferentially activate tissue near an anode electrode. Changing the aspect ratios and changing the polarities as described herein can increase the tear response and / or change the composition of the tears that result from stimulation. This may be because polarity switching leads to non-linear addition of stimuli as perceived by the central nervous system, as well as polarity switching reduces the patient's adaptation to stimuli. In addition, some stimulators described herein may be configured so that a user can change the aspect ratios of a biphasic waveform to change the location or scope of the preferred activation, such as by using an interface of Username. For some patients, adjusting the aspect ratio can result in a perception of a more symmetrical waveform and / or a more symmetrically bilateral treatment effect. In some cases, it may be desirable to have an asymmetric bilateral treatment effect or a unilateral treatment effect, for example, in a patient who has more severe dry eyes in one eye than the other. In these cases, a patient can use a user interface to adjust the aspect ratio to achieve the desired asymmetric effect.

Frequency

To treat dry eyes or produce a tearing response by stimulating tissue, the stimulators described herein may be configured to generate one or more waveforms at appropriate frequencies to stimulate the targeted tissue (eg, a nerve). . Rate can affect comfort and / or effectiveness of stimulation. Generally, the frequency is preferably between about 0.1Hz and about 200Hz. In some of these variations, the frequency is preferably between about 10 Hz and about 200 Hz. In some of these variations, the frequency is preferably between about 30 Hz and about 150 Hz. In other of these variations, the frequency is preferably between about 50 Hz and about 80 Hz. In other of these variations, the frequency is preferably between about 30 Hz and about 60 Hz.

In some variations, about 70 Hz, about 30 Hz, about 40 Hz, about 50 Hz, the frequency can be about 150 Hz, about 32.5 Hz, about 42.5 Hz, about 52.5 Hz, about 1, 5 Hz, approximately 25 Hz, approximately 35 Hz, approximately 45 Hz, approximately 55 Hz, about 10.25 Hz, about 27.5 Hz, about 37.5 Hz, about 47.5 Hz, about 57.5 Hz, about 60 Hz, about 62.5 Hz, or about 65 Hz. In some variations, high frequencies, such as those between about 145 Hz and about 155 Hz, they may be too high for each pulse to stimulate / activate the target tissues. As a result, the patient may interpret the stimulation to have an element of randomness, which in turn can help reduce the patient's habituation. The frequencies described herein may be suitable for stimulating the targeted tissue to initiate a reflex circuit that activates the lacrimal gland to produce tears, and / or suitable for directly exciting efferent fibers innervating the lacrimal gland. In some cases, the frequency can be chosen for preferential activation of certain anatomical targets, as described herein.

ES 2 809 599 T3

Amplitude

To treat dry eye or otherwise produce a tearing response by stimulating tissue, the stimulators described herein may be configured to deliver a suitable current to stimulate the targeted tissue (eg, a nerve). The maximum amplitude or modulation of the same can affect the comfort and / or effectiveness of the stimulation. When the stimulus comprises a biphasic pulse and the first phase of the biphasic pulse is current controlled, the first phase may preferably have an amplitude of between about 1.0 mA and about 10 mA. The amplitudes within these ranges can be high enough to stimulate the targeted tissue, but low enough to avoid any significant heating of the tissue, ablation of tissue, or the like. In some variations, the amplitude can be between about 1.0 mA and about 5.0 mA. In other variations, the first phase may have an amplitude of about 0.1 mA, about 0.2 mA, about 0.3 mA, about 0.4 mA, about 0.5 mA, about 0.6 mA, about 0 .7 mA, about 0.8 mA, about 0.9 mA, or about 1.0 mA. In some variations, the amplitude can be variable. For example, the amplitude can vary between about 1.3 mA and about 1.5 mA, between about 2.2 mA and about 2.5 mA, between about 3.2 mA and about 3.7 mA, between about 4, 3 mA and approximately 5.0 mA. When the first phase of a biphasic pulse is voltage controlled, the first phase may preferably have an amplitude between about 10 mV and about 100 V.

When a stimulator is configured to deliver a pulse-based waveform, in some variations, the amplitude of the pulses can be constant over time. In other variations, the amplitude of the pulses can vary over time. This can reduce the adaptation of the patient. In some variations, the amplitude of the pulses can increase (linearly, exponentially, etc.) from a minimum value to a maximum value, decrease to the minimum value, and repeat as necessary. In some variations, the amplitude of the pulses can vary according to a sinusoidal profile. In another variation, as illustrated in Figure 6A, the amplitude may periodically increase from a basal amplitude (A) to a higher amplitude (B) for a single pulse. In yet another variation, as illustrated in Figures 6B-6C, the amplitude of the pulses can follow a pattern that increases and decreases periodically between two smaller amplitudes (A, B), and periodically increases to a greater amplitude (C). for a single pulse (Figure 6B) or for a plurality of pulses (for example, two pulses) (Figure 6C). In yet another variation, as illustrated in Figure 6D, a pulse (or pulses) of greater amplitude may be preceded by a brief pause (ie, no current supply). Each of these types of amplitude modulation can be implemented alone or in combination with any other type of amplitude modulation, and can reduce patient adaptation.

In some variations where the amplitude varies over time, the amplitude may vary at a suitable frequency to reduce patient adaptation or increase patient comfort, such as between about 0.1 Hz and about 5 Hz, between about 1 Hz and about 5 Hz, between about 1 Hz and 2 Hz, between about 2 Hz and 3 Hz, between about 3 Hz and 4 Hz, or about 4 Hz and about 5 Hz. In some variation, the amplitude can vary at a frequency of about 1.0 Hz, about 1.4 Hz, about 1.8 Hz, about 2.2 Hz, about 2.6 Hz, about 3.0 Hz, about 3 , 4 Hz, approximately 1.1 Hz, approximately 1.5 Hz, approximately 1.9 Hz, approximately 2.3 Hz, approximately 2.7 Hz, approximately 3.1 Hz, approximately 3.5 Hz, approximately 1.2 Hz, approximately 1.6 Hz, approximately 2.0 Hz, approximately 2.4 Hz, approximately 2.8 Hz, approximately 3.2 Hz, approximately 3.6 Hz, approximately 1.3 Hz, approximately 1.7 Hz, approximately 2.1 Hz, approximately 2.5 Hz, approximately 2.9 Hz, approximately 3 , 3 Hz about 3.7 Hz, about 3.8 Hz, about 3.9 Hz, or about 4.0 Hz. In other variations, the stimulation waveform can be a modulated high frequency signal (eg, sinusoidal), which can be modulated at a beat frequency in the ranges described above. In such variations, the carrier frequency can be between about 100 Hz and about 100 kHz.

Pulse width

To treat dry eye or produce a tearing response by stimulating tissue, the stimulators described herein may be configured to deliver a waveform in which the first phase may preferably have a pulse width of between about 1 ps and approximately 10 ms. In some of these variations, the pulse width can be between about 10 ps and about 100 ps. In other variations, the pulse width can be between about 100 ps and about 1 ms. In still other variations, the pulse width can be between about 0 ps and about 300 ps. In still other variations, the pulse width can be between about 0 ps and 500 ps. As described above, it may be desirable to select a pulse width that preferably acts on larger diameter ribs. In some variations, the pulse width can be between 50 ps and approximately 1200 ps. As another example, pulse widths of 30 ps to 300 ps can minimize activation of the trigeminal nerve branches.

ES 2 809 599 T3 (eg CN V2) that travel to the teeth.

In some variations, the amplitude of the pulses can be constant over time. In other variations, the pulse width can vary over time. Pulse width modulation over time can increase the effectiveness and / or comfort of stimulation. In some variations, the pulse width can increase (linearly, exponentially, etc.) from a minimum value to a maximum value, decrease to the minimum value, and repeat as necessary. In some variations, the pulse width can vary based on a sinusoidal profile. In another variation, as illustrated in Figure 7A, the pulse width may periodically increase from a basal pulse width (A) to a longer pulse width (B) for a single pulse. In yet another variation, as illustrated in Figures 7B-7C, the pulse width can follow a pattern that increases and decreases periodically between two shorter pulse widths (A, B), and periodically lengthens to one pulse width. longest (C) for a single pulse (Figure 7B) or for a plurality of pulses (eg two pulses) (Figure 7C). In yet another variation, as illustrated in Figure 7D, a longer pulse width pulse (or pulses) may be preceded by a brief pause (ie no current supply). Each of these types of pulse width modulation can be implemented alone or in combination with any other type of pulse width modulation. In any form of pulse width modulation, the pulse width can vary at any suitable frequency. In some variations, the pulse width can vary to about 0.1 Hz, about 0.2 Hz, about 0.3 Hz, about 0.4 Hz, about 0.5 Hz, about 0.6 Hz, about 0, 7Hz, about 0.8Hz, about 0.9Hz, about 1Hz, about 1.1Hz, about 1.2Hz, about 1.3Hz, about 1.4Hz, or about 1.5Hz. In some variations, pulse width modulation at a frequency between about 0.5 Hz and 1 Hz may be desirable to increase patient comfort during stimulation.

In some variations, the increase and decrease in pulse width can be defined by a function implemented by the stimulator. For example, the pulse width can be defined by a function such that the pulse width varies exponentially. In a variation, the pulse width defining function may comprise two phases: a first phase during which the pulse width of the initial pulse increases over time, and a second phase during which the pulse width of the pulse initial decreases over time. During the first phase, the pulse width of the initial pulse approaches the maximum pulse width according to an exponential function, where at time t, PW {t} is defined by the equation

PW {t} = (PWmax - PWmin) (1 - e ^)) where PWmax is the maximum allowed pulse width, PWmin is the minimum allowed pulse width, and τ is a time constant.

After a predetermined amount of time has elapsed (a multiple of the time constant τ), pulse width modulation can enter the second phase. During the second phase, the pulse width of the initial pulse decreases exponentially from its maximum value to a minimum value following the exponential equation

PW {t} = (PWmax - PWmin) (e ^))

After a predetermined amount of time has elapsed (a multiple of the time constant τ), the pulse width modulation can re-enter the first phase and the cycle can be repeated. The pulse width of the secondary pulse (load balancing) increases and decreases accordingly to retain full load balance. PWmax, PWmin, and τ can have any suitable value to achieve the pulse widths described herein, but in one example the waveform can have PWmax of 300 ps, ​​PWmin of 0 ps, ​​and τ of 1/5 ps. In other variations, for example, PWmax, can be about 100 ps, ​​about 200 ps, ​​about 300 ps, ​​about 400 ps, ​​or about 500 ps; PWmin can be about 0 ps, ​​about 10 ps, ​​about 50 ps, ​​or about 100 ps; and τ can be about 1/3 ps, about 1/4 ps, about 1/5 ps, or about 1/6 ps. An example function that defines exponentially increasing and decreasing pulse widths is shown in Figure 8.

On / off periods

In some cases, the waveforms described herein may be supplied continuously, while in other cases, the waveforms may be supplied non-continuously having on and off periods, which can reduce tailoring. of the patient. Example on / off durations include, but are not limited to, 1 second on / 1 second off, 1 second on / 2 seconds off, 2 seconds on / 1 second off, 5 seconds on / 5 seconds off, 0.2 seconds on / 0.8 seconds off, less than 1 second on / less than 10 seconds off.

ES 2 809 599 T3

Waveforms as an example

It should be appreciated that any of the waveform parameters and variations in the above parameters can be combined to generate a patterned waveform as described herein, and these waveforms can be delivered by any of the stimulators. described in this document.

For example, in variations where the waveform comprises a biphasic pulse, the biphasic pulse can have any suitable frequency, pulse width, and amplitude. Stimulation amplitude, pulse width, and rate may be the same from pulse to pulse, or may vary over time, as described in more detail herein. Combinations of these parameters can increase the efficacy and / or comfort of stimulation, and in some cases, the efficacy and / or comfort may differ depending on the individual patient, as described in more detail herein. Example waveform parameters classified by device type are listed below in Table 1.

Table 1. Example waveform parameters

<td rowspan="2">Type of device</td><td colspan="5">Waveform parameters</td>

<td>Stimulation target</td><td>On off</td><td>Frequency (Hz)</td><td>Pulse width (PW, pulse width)</td><td>Amplitude (mA)</td>

<td rowspan="9">Eye stimulator (implantable)</td><td rowspan="9">Orbital nerves (afferent and efferent)</td><td>Constant on</td><td> 30</td><td rowspan="6">Fixed from 50 ps to 1200 ps</td><td rowspan="9">0.1 to 10</td>

<td>1 s on / 1s off</td><td> 30</td>

<td>5 s on / 5 s off</td><td> 30</td>

<td>1 s on / 1s off</td><td> 70</td>

<td>1 s on / 1s off</td><td> 155</td>

<td>Constant on</td><td>Modulated from 30 to 70 in triangular mode</td>

<td>Constant on</td><td> 30</td><td>Triangular modulated from 50 ps to PW max. at 0.5 Hz</td>

<td>Constant on</td><td> 30</td><td>Triangular modulated from 50 ps to PW max. at 1 Hz</td>

<td>Constant on</td><td> 70</td><td>Triangular modulated from 50 ps to PW max. at 0.5 Hz</td>

<td rowspan="6">Nasal stimulator (handheld or implantable)</td><td rowspan="6">Internal and external nasal nerves. (for example, anterior ethmoid nerve)</td><td>Constant on</td><td> 30</td><td rowspan="6">0 ps to 300 ps</td><td rowspan="6">0.1 to 10</td>

<td>Constant on</td><td> 50</td>

<td>Constant on</td><td> 80</td>

<td>Constant on</td><td> 150</td>

<td>1 s on / 1s off</td><td> 30</td>

<td>1 s on / 1s off</td><td> 50</td>

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<td rowspan="3"></td><td rowspan="3"></td><td>1 s on / 1s off</td><td> 80</td><td rowspan="3"></td><td rowspan="3"></td>

<td>Constant on</td><td> 30</td>

<td>1 s on / 1 s off</td><td> 70</td>

In variations where a waveform is an alternating monophasic pulsed waveform, each pulse delivered by the stimulator can have a single phase, and successive pulses can have alternating polarities. In general, alternating single-phase pulses are supplied in pairs at a given frequency (such as one or more of the frequencies mentioned above, such as between 30 Hz and 80 Hz), and may have a pulse-to-pulse interval between the first and second pulses. torque (for example, approximately 100 ps, ​​between 50 ps and 150 ps or similar). Each pulse can be current or voltage controlled, and consecutive pulses need not be both current or both voltage controlled. In some variations where the pulse waveform is load balanced, the waveform may comprise a passive load balancing phase after the supply of a single-phase pair of pulses, which can allow the waveform to wave compensate for differences in charge between pulses.

When a stimulator configured to deliver an electrical stimulation waveform is positioned to place an electrode on either side of the nasal septum, alternating monophasic pulses can promote bilateral stimulation of nasal tissue. Pulses from a first phase can stimulate a first side of the nose (while providing a charge balancing phase to a second side of the nose), while pulses from the opposite phase can stimulate the second side of the nose (while provides a charge balancing phase to the first side of the nose), as the nerves may respond differently to anodic and cathodic pulses. The interval between pulses can allow time for the stimulation provided by a first phase pulse to activate / polarize the target nerves before being reversed by an opposite phase pulse.

Stimuli comprising the waveforms described herein can be delivered to these anatomical targets using stimulators such as those described herein according to the treatment regimens described in US Patent Application No. 13 / 441,806, incorporated herein. previously by reference in its entirety, and in US Patent Application No. 14 / 256,915, which was previously incorporated by reference in its entirety.

Waveforms optimized for the patient

Our experimentation has found that, in some cases, stimulation-induced lacrimation can be increased by identifying one or more patient-optimized waveforms for a particular patient, wherein the waveforms optimized for the patient may comprise combinations of the waveform parameters described herein. As such, a method for the identification of waveforms optimized for the patient is desirable. Our experimentation has also found that detected paresthesia is strongly associated with lacrimation and thus patient perceptions of paresthesia can be used in identifying waveforms optimized for the patient. An exemplary method of obtaining patient-optimized waveforms in a patient having a microstimulator implanted in an ocular region is illustrated in Figure 9. It may be desirable to perform this method for each individual to increase the effectiveness of stimulation (eg, to increase lacrimation). The stimulation waveform (s) and / or current steering may also be configured to optimize certain clinical indicators of efficacy, including but not limited to levels of growth factors and / or osmolarity.

As shown therein, a waveform can be evaluated to determine whether it is a waveform optimized for the patient by delivering an electrical stimulus comprising the waveform to the patient using a stimulator described herein. The method may comprise first supplying a waveform at the lower pulse width and / or amplitude and asking the patient for feedback on sensation as the pulse width and / or amplitude increases. The method may then comprise evaluating whether the patient feels any sensation during the delivery of the electrical stimulus. If not, a different waveform can be selected (eg, having a different combination of parameters, such as frequency, amplitude, pulse width, on / off period, or the temporal modulation of these parameters). The method may further comprise ensuring that the patient does not experience discomfort. If the patient experiences discomfort, the method can be restarted with a new waveform, or the amplitude and / or pulse width can be reduced to alleviate discomfort. Similarly, the method may comprise ensuring that the feeling during the application of the waveform is comfortable for the patient. Pulse width and / or amplitude can be adjusted for patient comfort. Comfort can be assessed with both the patient's eyes open and closed.

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A waveform can be designated as a patient-optimized waveform if the patient perceives the waveform as the most comfortable and / or effective waveform felt that day; and / or if the patient feels that his eyes are wet; and / or if the patient perceives paresthesia, more particularly, if both tickling and vibration are perceived as motives in the eyelid. If the patient senses a tickling in the eyelid but no vibration, the amplitude and / or pulse width can be adjusted to achieve a greater perception of tingling and / or vibration. If the patient senses a vibration but not tickling, the amplitude and / or pulse width can be adjusted to achieve a greater sense of movement from the vibration (for example, between the eyelid and the eyebrow). It may also be desirable for a patient to feel a sensation (eg, tingling or vibration) after the stimulus delivery ends. In each case of an identified patient optimized waveform, a lower pulse width and / or amplitude may be tested to determine if the same sensation can be achieved using a lower pulse width and / or amplitude. In variations of stimulators configured to allow spatial control of current paths, optimization for the patient may also comprise testing different current paths or combinations of current pathways.

While the method in Figure 9 is described with respect to a patient having an implantable stimulator located in an ocular region, it should be appreciated that a similar method can be used to identify one or more patient-optimized waveforms for an implantable stimulator. in another region (for example, a nasal region) or for a handheld stimulator. Once a patient-optimized waveform or waveforms are identified, a stimulator may be configured to deliver the waveform (s). In some variations, an external device can be used to configure the stimulator to deliver the identified waveform (s). In variations where the system comprises a controller for use with an implantable stimulator having a passive stimulation circuit, a controller configured to generate an output signal that results in the shape (s) of identified stimulation wave (s).

Devices that have a plurality of waveforms

Some variations of the stimulators described herein may be configured with a plurality of waveforms, such that a clinician and / or patient can select a desired waveform from the plurality of available waveforms. For example, the stimulator can include a plurality of stimulation waveforms stored on a chip. For example, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 stimulation waveforms can be saved on a chip. In one variation, two to ten stimulation waveforms are stored on a chip. In other variations, two to eight stimulation waveforms, or three to five stimulation waveforms, can be stored on the device chip. In some variations, a clinician can pre-select a preferred set of waveforms to be saved in a stimulator based on initial testing of a variety of stimulation waveforms for a particular patient, such as through the method described above. . It may be useful if the saved stimulation waveforms are those that cause strong paresthesia in the patient, because our experimentation has found that the detected paresthesia is most strongly associated with lacrimation, as described herein. . In other variations, a stimulator may be preconfigured with a plurality of stimulation waveforms that are not unique to an individual patient.

In some variations, for each stimulation delivered during the day, a different waveform may be randomly selected from the stored plurality of waveforms. By randomly selecting a different waveform each time, the risk of the patient developing tolerance to any particular stimulation pattern can be reduced. In another implementation, a multiplexer can be used to provide different combinations of internally stored waveforms to form a "nearly non-repeating" waveform when fragments of different repeating waveforms are combined. By multiplexing different waveforms into a combined waveform, habituation to the waveform can potentially be further limited. For stimulators that have a plurality of possible current paths, the same or different waveforms can be delivered through each path.

In some variations, a patient can selectively choose from the plurality of stimulation waveforms stored in the stimulator, for example, using a user interface such as a user interface as described herein. In variations having such a user interface, the user interface may comprise one or more operating mechanisms, which may allow the user (ie, the patient) to control the stimulation waveform. For example, the user interface may comprise one or more structures, such as but not limited to, a button, slider, lever, touch panel, knob, or deformable / squeezable part of the case, which can allow the user to change the stimulation waveform.

The different waveforms can be configured in such a way that a patient can perceive them as spanning a range of intensities. In variations in which the stimulator is configured to deliver waveforms with different shapes, a patient can change the tissue that is preferentially stimulated by the waveform as described herein by selecting a waveform that has a different shape (for example, switching from a waveform that has a cathode pulse first to a waveform that has an anode pulse first). In some variations, when a patient turns on the stimulator during a second or subsequent treatment period, the stimulator may initially turn on with a waveform

ES 2 809 599 T3 previously selected by the patient (eg, the waveform used during the previous treatment session, the waveform most commonly used during a plurality of treatment sessions, etc.).

For example, in the case where a handheld nasal stimulator is used, after the user has placed a part of the stimulator in contact with the nasal tissue, the user can increase the perceived intensity of the stimulus by switching between the plurality of forms of stimulation wave. It may be desirable for the patient to increase the intensity of the stimulus until the stimulus causes the preferred paresthesia (eg, tingling, tingling, pricking) without causing discomfort. As such, the patient can self-determine the appropriate stimulation intensity and self-adjust the stimulus to an effective waveform to achieve the desired result (eg, tear production). It may be desirable for the user to slowly increase the intensity of the stimulus to minimize discomfort. Some patients may prefer that their level of sensation changes over time. They may want to start with a strong sensation, followed by a weak sensation. They may prefer to start with a weak sensation (eg mild tingling) followed by a stronger temporary sensation (eg mild discomfort for a very short time). Some patients can reduce the feeling of needing to sneeze during stimulation by varying the strong and weak sensations.

In a particular example, a stimulator may be configured to deliver a plurality of different waveforms, each of which has a combination of one or more of shape modulation, maximum amplitude modulation, pulse width modulation, and pulse width modulation. frequency, as described herein.

One or more of the waveforms can have a pulse shape that modulates over time. In a variation illustrated in Figure 10, the pulse shape can alternate between four periods. The first period may comprise a biphasic current controlled waveform with symmetrical phases. The second period may comprise a current controlled first phase, followed by a voltage controlled second phase. This can help to preferably stimulate a location closer to an electrode. The first phase can have a current originating from a first electrode and having a second electrode as a sink, while the second phase can have a current originating from the second electrode and having the first electrode as a sink. The third period may comprise a biphasic current controlled waveform with symmetrical phases (ie the third period may be equal to the first period). The fourth period may comprise a current controlled first phase, followed by a voltage controlled second phase. The first phase can have a current originating from the second electrode and having the first electrode as its sink, while the second phase can have a current originating from the first electrode and having the second electrode as its sink. In each period, the pulses can be balanced in terms of load. The shape of the pulse can be modulated to any suitable frequency, such as about 0.1 Hz.

One or more of the waveforms can have a pulse width that is modulated over time. In a variation, the pulse width of the current controlled phases can be modulated from 0 ps to 300 ps. Modulation can follow an exponential function that describes the increase and decrease in pulse width over time, as illustrated in Figure 11 and as described in more detail with respect to Figure 8.

One or more of the waveforms may have a maximum amplitude that is modulated over time. The amplitude modulation of the current-controlled phases can approximate a triangular shape, a rectangular shape, or any other suitable shape. Exemplary amplitude modulations at various frequencies are illustrated in Figures 12A-12E, showing amplitude modulations having a rectangular shape (Figure 12B) and amplitude modulations that approximate triangular shapes (12C-12E). The maximum amplitude can be modulated to any suitable frequency, such as between about 0.5 Hz and about 3 Hz. It should be appreciated that in some other variations, the maximum amplitude can be constant, as shown in Figure 12A.

Figures 13A-13E depict exemplary waveforms 1310, 1320, 1330, 1340, and 1350, respectively, in which one or more of these parameters are modulated over time, where each type of modulation is independent and simultaneous to the other types of modulation. Boxes 1302, 1304, and 1306 in Figure 13E highlight modulation of shape, pulse width, and maximum amplitude, respectively. In some variations (for example, those of Figures 13B-13E), the three of shape, pulse width and maximum amplitude are modulated over time, but it should be appreciated that in other variations of the waveform (for example , that of Figure 13A), only one or two of these parameters can be modulated over time.

All five waveforms of Figures 13A-13E may be available in the stimulator (eg, stimulator 400 described above with respect to Figures 4A-4C, or microstimulator 200 described above with respect to Figures 2A-2C). , and the stimulator may be configured such that the patient can use a user interface (eg, an interface comprising two buttons) to select between the five different waveforms. In some variations of the device, when the device is used for a treatment period, turned off and back on for an additional treatment period, the device may automatically turn on in the last stimulation setting used.

ES 2 809 599 T3

Configuration 1, illustrated in Figure 13A, may have a stimulation frequency of 30 Hz; a minimum stimulation current amplitude of 0.7 mA, a maximum stimulation current amplitude of 0.7 mA and therefore no variation in the maximum stimulation current amplitude (as shown in Figure 12A) ; a minimum pulse width of 0 ps; a maximum pulse width of 300 ps; a 1 Hz pulse width modulation frequency (rising and falling according to an exponential function, as shown in Figure 11); a minimum charge injection per phase (with a pulse width of 0 ps) of 0 pC; a maximum charge injection per phase (at 0.7 mA and 300 ps) of 0.21 pC; and a pulse shape that is modulated as described above with respect to Figure 10.

Configuration 2, illustrated in Figure 13B, can have a stimulation frequency of 37.5 Hz; a minimum stimulation current amplitude of 1.33 mA, a maximum stimulation current amplitude of 1.5 mA, a variation in the maximum stimulation current amplitude of 0.17 mA, and an amplitude modulation frequency of 2 , 1 Hz (as shown in Figure 12B); a minimum pulse width of 0 ps; a maximum pulse width of 300 ps; a 1 Hz pulse width modulation frequency (rising and falling according to an exponential function, as shown in Figure 11); a minimum charge injection per phase (with a pulse width of 0 ps) of 0 pC; a maximum charge injection per phase (at 1.5 mA and 300 ps) of 0.45 pC; and a pulse shape that is modulated as described above with respect to Figure 10.

Configuration 3, illustrated in Figure 13C, can have a stimulation frequency of 45 Hz; a minimum stimulation current amplitude of 2.17 mA, a maximum stimulation current amplitude of 2.5 mA, a variation in the maximum stimulation current amplitude of 0.33 mA, and an amplitude modulation frequency of 2 , 6 Hz (as shown in Figure 12C); a minimum pulse width of 0 ps; a maximum pulse width of 300 ps; a 1 Hz pulse width modulation frequency (rising and falling according to an exponential function, as shown in Figure 11); a minimum charge injection per phase (with a pulse width of 0 ps) of 0 pC; a maximum charge injection per phase (at 2.5 mA and 300 ps) of 0.75 pC; and a pulse shape that is modulated as described above with respect to Figure 10.

Configuration 4, illustrated in Figure 13D, can have a stimulation frequency of 52.5 Hz; a minimum stimulation current amplitude of 3.2 mA, a maximum stimulation current amplitude of 3.7 mA, a variation in the maximum stimulation current amplitude of 0.5 mA, and an amplitude modulation frequency of 2 , 8 Hz (as shown in Figure 12D); a minimum pulse width of 0 ps; a maximum pulse width of 300 ps; a 1 Hz pulse width modulation frequency (rising and falling according to an exponential function, as shown in Figure 11); a minimum charge injection per phase (with a pulse width of 0 ps) of 0 pC; a maximum charge injection per phase (at 3.7 mA and 300 ps) of 1.11 pC; and a pulse shape that is modulated as described above with respect to Figure 10.

Configuration 5, illustrated in Figure 13E, can have a stimulation frequency of 60 Hz; a minimum stimulation current amplitude of 4.3 mA, a maximum stimulation current amplitude of 5.0 mA, a variation in the maximum stimulation current amplitude of 0.67 mA, and an amplitude modulation frequency of 2 , 5 Hz (as shown in Figure 12E); a minimum pulse width of 0 ps; a maximum pulse width of 300 ps; a 1 Hz pulse width modulation frequency (rising and falling according to an exponential function, as shown in Figure 11); a minimum charge injection per phase (with a pulse width of 0 ps) of 0 pC; a maximum charge injection per phase (at 5.0 mA and 300 ps) of 1.5 pC; and a pulse shape that is modulated as described above with respect to Figure 10.

Through patterned waveforms having these parameter combinations, a large parameter space can be provided in a single device with a simple user interface and a limited number of settings. This can increase the ability of a single device that has a limited number of preset waveforms to deliver a waveform that is as effective or nearly as effective for an individual patient as a waveform in which the parameters are individually adjusted. for each patient. The invention is defined by claim 1. Preferred embodiments are defined by the dependent claims.

Examples

The following examples further illustrate electrical stimulation patterns and their effects as disclosed herein, and should not be construed as limiting their scope in any way.

Example 1: Stimulation using a tear implant

Patients who had micro-stimulators implanted in an ocular region were tested, with stimulation without a 30 Hz pattern (control) and with on / off patterns (1 second on / 1 second off, 2 seconds on / 2 seconds off, and 5 seconds on / 5 seconds off) at different frequencies (30 Hz, 70 Hz and 155 Hz). The implanted microstimulators had the characteristics shown in Figures 2A2C and described herein.

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Patient perception of the stimulus differed between the 30 Hz non-patterned waveform control and the time-patterned waveforms. Specifically, while 3 patients who received the 30 Hz non-patterned waveform felt their perception of the waveform fade during the stimulation period, when they received time-patterned waveforms, no patient reported that their perception of the waveform faded. perception of the waveform throughout the stimulation period. When the stimulus was a 30 Hz on / off waveform for 1 second ("pattern 1"), 3 patients perceived the waveform as continuous, while 15 perceived the waveform as intermittent. When the stimulus was a 30 Hz on / off waveform for 5 seconds ("pattern 2"), all patients perceived the waveform as intermittent. When the stimulus was a 70 Hz on / off waveform for 1 second ("pattern 3"), 2 patients perceived the waveform as continuous and 10 perceived the waveform as intermittent. Patients reported that they perceived pattern 3 as "stronger," "faster," and "more intense" than the other waveforms. When the stimulus was a 155 Hz on / off waveform for 1 second (“pattern 4”), whether patients perceived the waveform as continuous or intermittent depended on amplitude, and qualitative perceptions varied, including the waveform reports as "weaker", "stronger" or a "pinch".

In addition, patients reported a change in the quality and / or location of paresthesia. Figure 14A depicts area 1402 of paresthesia felt with stimulation using the 30 Hz unpatterned waveform. With the time-patterned waveforms, patients felt the movement of paresthesia (in the form of vibration and / or tingling), as shown in Figure 14B (vibration and / or tingling moved along your eyelid in the directions of the arrows 1404). Some patients felt vibration present continuously in one area 1408 and continuously present or sensation or tingling that appears and partially reappears in other areas 1406, as shown in FIG. 14C. Other patients experienced an increase in the area affected with paresthesia with temporal patterned waveforms, as shown in Figure 14D as area 1410 running along one or both eyebrows and / or along or into the nose. .

Patient perceptions after cessation of stimulation also differed between the 30 Hz non-patterned waveform and the time-patterned waveforms. While patients did not perceive paresthesia after cessation of control, patients reported that they perceived paresthesia in the form of a tingling sensation after cessation of patterns 1, 3 and 4.

Schirmer scores increased with time-patterned waveforms compared to the 30 Hz non-patterned waveform control. With pattern 1, one-third of patients had Schirmer scores that increased by 50%. With pattern 3, three-quarters of the patients had Schirmer scores that increased by 50-100%. With pattern 4, three-eighths of the patients had Schirmer scores that increased by 100% or more.

Some of the patterned waveforms also provided additional benefits. For example, pattern 1 used less energy than control while patient adaptation was reduced; and pattern 4 allowed for both nerve stimulation and block.

Example 2: Stimulation using a tear implant (2)

In patients who had a microstimulator implanted in an ocular region, the use of patterned waveforms resulted in an increase in lacrimation measured by the Schirmer test compared to baseline lacrimation (control 1 = no electrical stimulation) and compared to 30 Hz stimulation (no pattern) (control 2). The implanted microstimulators had the characteristics shown in Figures 2A-2C and described herein. Data is provided in Table 2 below, and a bar graph diagram comparing tearing results averaged from baseline tearing (left, no stimulation) to 30 Hz unpatterned waveform stimulation (center). with stimulation waveforms optimized for the patient, with temporal pattern (right) are shown in figure 15. According to the data in Table 2, the average value for baseline lacrimation was 4.71 mm, the average value was 4.96 mm for stimulation without a 30 Hz pattern, and the average value was 8.29 mm. when temporal pattern stimulation was used. Overall, the mean Schirmer score increase using 30 Hz no pattern stimulation was approximately 5% compared to baseline lacrimation, and the mean Schirmer score increase using time patterned waveforms was approximately 5%. approximately 76% compared to basal lacrimation. Thus, patient-optimized patterned waveforms were able to increase lacrimation by a much greater amount (in this case, more than 70 percentage points) than a 30 Hz non-patterned waveform.

Table 2. Schirmer scores of 12 patients.

<td>Implanted side</td><td>Baseline Schirmer score (mm)</td><td>Schirmer score without 30 Hz pattern (mm)</td><td>Schirmer score with pattern (mm)</td><td>Waveform with pattern</td>

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<td></td><td>I</td><td>D</td><td>Prom.</td><td>I</td><td>D</td><td>Prom.</td><td>I</td><td>D</td><td>Prom.</td><td></td>

<td>D</td><td> 8</td><td> 5</td><td> 6,5</td><td> 3</td><td> 4</td><td> 3,5</td><td> 8</td><td> 5</td><td> 6,5</td><td>30 Hz amplitude modulated by approximately 30%</td>

<td>I</td><td> 3</td><td> 8</td><td> 5,5</td><td> 3</td><td> 5</td><td> 4</td><td> 5</td><td> 8</td><td> 6,5</td><td>70 Hz amplitude modulated by approximately 30%</td>

<td>I</td><td> 3</td><td> 2</td><td> 2,5</td><td> 3</td><td> 5</td><td> 4</td><td> 3</td><td> 8</td><td> 5,5</td><td>70 Hz, 1 s on, 1 s off</td>

<td>I</td><td> 2</td><td> 3</td><td> 2,5</td><td> 5</td><td> 5</td><td> 5</td><td> 5</td><td> 3</td><td> 4</td><td>70 Hz amplitude modulated by approximately 30%</td>

<td>I</td><td> 12</td><td> 18</td><td> 15</td><td> 10</td><td> 9</td><td> 9,5</td><td> 13</td><td> 19</td><td> 16</td><td>30 Hz amplitude modulated at 100%</td>

<td>I</td><td> 4</td><td> 3</td><td> 3,5</td><td> 6</td><td> 6</td><td> 6</td><td> 7</td><td> 7</td><td> 7</td><td>70 Hz amplitude modulated by approximately 30%</td>

<td>D</td><td> 2</td><td> 3</td><td> 2,5</td><td> 3</td><td> 3</td><td> 3</td><td> 8</td><td> 7</td><td> 7,5</td><td>30 Hz, 1 s on, 1 s off</td>

<td>I</td><td> 5</td><td> 7</td><td> 6</td><td> 5</td><td> 5</td><td> 5</td><td> 8</td><td> 8</td><td> 8</td><td>70 Hz, 1 s on, 1 s off</td>

<td>I</td><td> 2</td><td> 2</td><td> 2</td><td> 2</td><td> 1</td><td> 1,5</td><td> 5</td><td> 5</td><td> 5</td><td>70 Hz amplitude modulated by approximately 30%</td>

<td>D</td><td> 4</td><td> 2</td><td> 3</td><td> 12</td><td> 6</td><td> 9</td><td> 18</td><td> 12</td><td> 15</td><td>30 Hz, 5 s on, 5 s off</td>

<td>I</td><td> 4</td><td> 2</td><td> 3</td><td> 7</td><td> 2</td><td> 4,5</td><td> 7</td><td> 7</td><td> 7</td><td>30 Hz, 1 s on, 1 s off</td>

<td>I</td><td> 4</td><td> 5</td><td> 4,5</td><td> 5</td><td> 4</td><td> 4,5</td><td> 7</td><td> 16</td><td> 11,5</td><td>30 Hz to 70 Hz with randomized modulated frequency</td>

Temporal patterned waveforms were also able to generate paresthesia in patients in whom no paresthesia was felt during stimulation or who only experienced paresthesia of short duration (for example, less than 30 seconds, often only less than 10 seconds, of felt paresthesia even if stimulation was delivered continuously). The newly acquired or reacquired paresthesia was also accompanied by increased lacrimation and better patient satisfaction.

Patients often reported feeling vibrating during stimulation and tingling during pauses in stimulation (for example, during off portions of waveforms that have a 1 second on / 1 second off pattern), and in certain cases for seconds or minutes after stimulation stopped after application. There were several reports of patients who felt the vibration or tingling physically move along their eyelids and eyebrows, in two cases even in their nasal area (outside and / or inside the nose). The reception of the patient was generally very positive.

Example 3: Stimulation using a tear implant (3)

Nineteen patients had microstimulators implanted in one ocular region. (Twelve of these patients are the same patients as in example 2). For each patient, a patient-optimized time-patterned waveform was determined by modulating the waveform frequency, pulse width, and on / off periods while collecting patient feedback to maximize performance. Reported paresthesia in the orbit area, as previously described.

Each waveform was provided using the same driver / driver for each patient. Waveforms tested for each patient included:

• 30 Hz • 30 Hz, 1 second on, 1 second off • 30 Hz, 5 seconds on, 5 seconds off • 70 Hz, 1 second on, 1 second off • 30 Hz, pulse width modulated from 100% to 0% and back to 100% in 1 second

ES 2 809 599 T3 • 30 Hz, pulse width modulated from 100% to 70% and back to 100% in 1 second • 70 Hz, pulse width modulated from 100% to 70% and back up to 100% in 1 second • frequency modulated from 30 Hz to 70 Hz approximately linearly in steps of 5 Hz (ie for the increasing part of the frequency modulation, 30 Hz, 35 Hz, 40 Hz, 50 Hz , 55 Hz, 60 Hz, 65 Hz, 70 Hz), modulated up and down in 1 second (from 70 to 30 and back to 70 in one second) • frequency modulated from 30 Hz to 70 Hz randomly, with frequencies 5 Hz apart (30 Hz, 35 Hz, 40 Hz , 45 Hz, 55 Hz, 60 Hz, 65 Hz, 70 Hz)

The patients were asked a series of questions for each waveform, including:

• if the waveform was causing annoyance;

• how they would compare the feel of the waveform to other waveforms, including the 30 Hz non-patterned waveform, and any other waveforms previously tested on the same day;

• if they had the sensation that their eyes were getting wet;

• if you felt a combination of tingling and vibration;

• if the sensation (tingling and / or vibration) felt like it was moving (this suggests a lower likelihood of adaptation); and • the location of the sensation.

It was desirable for the patient to feel sensation in the upper eyelid, as this was considered likely to correspond to activation of the lacrimal and frontal nerves in the orbit. The closer the sensation was to the eye itself and the larger the area of ​​paresthesia, the more optimal the waveform was ranked. Additionally, waveforms that were perceived as a mixture of tingling and vibrating sensations at locations corresponding to the sensory pathways of the ophthalmic branch of the trigeminal nerve (CN V1) were desirable. These locations included not only the eyelid, but also the eyebrow, the temporal area of ​​the forehead, the nose (especially the inside of the nose), and certain areas of the forehead.

For each patient, three Schirmer scores were recorded: a baseline Schirmer score without any stimulation ("Baseline Schirmer"), an acute Schirmer score during application of a 30 Hz unpatterned waveform ("30 Hz Schirmer ”) And an acute Schirmer score during application of the patient-optimized patterned waveform for each patient (“ Patterned Schirmer ”).

The mean bilateral 30 Hz Schirmer scores and the mean bilateral patterned Schirmer scores were both higher than the mean baseline bilateral Schirmer scores. The mean bilateral patterned Schirmer scores were greater than the 30 Hz mean bilateral Schirmer scores. Specific data for mean bilateral Schirmer scores are shown in Figure 16A. As shown therein, the 15 patients with severe OHS (defined as having baseline Schirmer scores &lt;10 mm) averaged a 22% increase over baseline Schirmer scores for 30 Hz Schirmer scores and an increase 78% of baseline Schirmer scores for patterned Schirmer scores.

More patients showed an increase in bilateral Schirmer scores when stimulated using the patient-optimized temporal patterned waveform than the 30 Hz non-patterned waveform. As shown in Figures 17A-17B, among the 15 patients with severe OHS, the number of non-responders decreased from 47% (as shown in Figure 17A) using the 30 Hz waveform at 20% (as shown in Figure 17B) using patient optimized time patterned waveform.

Comparison of ipsilateral (that is, the eye on the same side as the ocular implant), contralateral (that is, the opposite eye to the ocular implant), and bilateral Schirmer scores (that is, the average of both eyes) indicated that the Single ocular implant stimulation resulted in bilateral tear production, but the effect was more pronounced for patient-optimized time-patterned waveform stimulation. The ipsilateral 30 Hz Schirmer scores were found to be higher than the bilateral 30 Hz Schirmer scores, indicating that the 30 Hz stimulation resulted in greater tear production in the ipsilateral eye than in the contralateral eye; and conversely, it was found that the Schirmer scores

The contralateral 30 Hz ES 2 809 599 T3 were lower than the bilateral 30 Hz Schirmer scores, indicating that the 30 Hz stimulation resulted in less tear production in the contralateral eye than in the ipsilateral eye.

In contrast, the ipsilateral and contralateral patterned Schirmer scores were found to be similar to the bilateral patterned Schirmer scores. This suggested that time pattern stimulation stimulated tear production in the contralateral eye better than 30 Hz stimulation, so that the patient-optimized time pattern waveform was equally effective in stimulating tear production in both the eyes ipsilateral as contralateral. It was hypothesized that this was the result of reflexive arousal (activated by stimulation of the lacrimal and frontal nerves) in addition to direct arousal (the lacrimal nerve only). Figure 16B shows contralateral Schirmer scores for the 15 patients with severe OHS. As shown therein, patients averaged a 9% increase over baseline Schirmer scores for 30 Hz Schirmer scores and an 82% increase over baseline Schirmer scores for patterned Schirmer scores.

When switching frequencies, either linearly or randomly, the patients experienced a mixture of vibration and tingling. By switching to the frequency greater than 70 Hz with 1 second on / 1 second off, modulating the frequency (from 30 to 70 Hz in 5 Hz increments) and / or changing the pulse width, specific patients reported a tingling sensation in addition to vibration, tickling alone or the impression of a moving vibration, often in combination with a moving tickling sensation. It was also found that stimulation with a patient-optimized time-patterned waveform allowed patients to find the location to hold the drivers / drivers to engage the implant more quickly and repeatedly.

Example 4: Electrical stimulation of the nasal mucosa

A patterned waveform was delivered to the nasal mucosa of the subjects using a device as described with respect to Figures 4A-4C. The time patterned waveforms provided included the waveforms shown in Figures 13A-13E and described herein, as well as 30 Hz, 70 Hz, and 155 Hz waveforms with 1 second on / off periods. on / off and 5 seconds on / off. Tear production at the same level as no-pattern stimulation could be achieved while reducing the subject's tendency to sneeze. Subjects also reported the sensation of a nasal massage which in most cases was considered a better sensory impression. Furthermore, subjects were able to use increased stimulation amplitudes during nasal stimulation, which led to increased lacrimation without discomfort, since the maximum load amplitude used for stimulation was only applied for a short time. The reception of the subjects was generally very positive.

Example 5: Frontal nerve stimulation (rabbit)

Fine wire electrodes were implanted in a rabbit in the area of ​​the left frontal nerve, and stimulation was applied at 30 Hz with amplitudes between 0.1 mA and 5.0 mA. Stimulation and baseline measurements were repeated 3 times each. As shown in Table 3 below and Figure 18, although an increase in lacrimation was observed with the 30 Hz waveform (no pattern), the increase in lacrimation was more pronounced using time-patterned stimulation. with on and off periods of 10 seconds each, measured by Schirmer scores taken during the delivery of the stimulus.

Table 3.

Basal Waveform with pattern 30 Hz PROM. DEV. ITS T. PROM. DEV. ITS T. PROM. DEV. ITS T. No stimulation Right eye 5.5 0.7 7.8 0.4 5.3 3.2 Eye estim. Left eye 5.0 1.4 16.5 2.8 9.0 2.8