Patent Application
20240024664
The invention is generally directed to methods and devices involving treatments of olfactory loss, chronic rhinosinusitis, skull base, intracranial, and cranial nerve pathology and more specifically treatments of regenerating olfaction, improving cranial neuropathies, and treating skull base intracranial pathology via trans-nasal electrical stimulation.
Olfaction is the sensing of odors. Humans detect odors through the olfactory system within the nose. The human olfactory system can detect thousands, and possibly millions, of odorant molecules, which are perceived to yield a smell. Lining a portion of the nasal cavity is the olfactory epithelium, a thin sheet of mucus-coated sensory tissue that contains the olfactory receptor cells (i.e., olfactory neurons), along with supporting cells and basal (stem) cells. Odorant molecules can reach the olfactory epithelium either via the nose, and/or from the mouth. Odorants dissolve into and pass through a layer of mucous overlying the olfactory epithelium and contact the olfactory receptor cells to induce the electrical signaling back to the olfactory bulb and brain allowing for the sensation of smell.
Olfaction is highly impactful on human wellbeing, social interactions, and quality of life. Loss of smelling function not only affects those important factors, but also can be a sign of dysfunction in higher cognitive ability and processing within the brain. Loss of smell leads to a greater than 3 times odds of mortality compared to normal smelling people, and this demonstrates both the importance of smell to our basic protective mechanisms as well as that smell dysfunction can be a sign of many other metabolic, endocrine, neurodegenerative or other systemic issues.
Chronic rhinosinusitis is a disease state of inflammation or infection involving the paranasal sinuses. The sinuses are lined with a mucosal layer made up of respiratory epithelium. This epithelium contains mucus producing glands as well as cells with tiny cilia (hairs) at their surface, which beat at a particular frequency to keep mucus moving at a normal rate and in the correct direction to clear and filter what is breathed into the nose and produced in the sinuses. Inflammation from multiple causes can lead to swelling of the lining, which in turn can cause mucus blockage which then becomes thickened and stagnant, and when it is not moving correctly, this can become a nidus for bacterial growth and infection.
Chronic rhinosinusitis is also highly impactful to quality of life and overall productivity, with yearly productivity costs greater than in those with chronic migraine, chronic asthma and diabetes, and health utility values similar to patients suffering from AIDS.
Cranial nerves control our sense of smell, our vision and ability to see clearly, the ability to move our eyes around and move them in the same direction at the same time in order to only see one clear image instead of multiple or double images, our ability to tear and cry and protect the cornea, our ability to move our facial muscles and therefore eat, smile, close and open our eyes and express emotion via facial expression, our ability to hear, and our ability to move our tongues and speak and swallow. Damage to or within these nerves can cause obvious deficits based on their functions outlined above.
The other ventral skull base structures of the brainstem, pons, pituitary and hypothalamus control multiple vital functions within the body involved with basic metabolic processes. The frontal and temporal lobes control multiple forms of higher-level functioning, including executive decision-making skills, personality and behavior control, memory, speech and hearing. All of these structures and the neurons within can become damaged and lead to changes in or loss of those functions.
Various embodiments are directed towards devices and methods for electrical stimulation to and/or electrical signal recording from biological activity in various tissues accessible via the nasal cavity and surrounding paranasal sinuses. In several embodiments, a device incorporates one or more electrodes at the distal end. In some embodiments, the one or more electrodes is an array. In many embodiments, the one or more electrodes are connected to an amplifier via an insulated track. In various embodiments, the one or more electrodes are disposed on an inflatable balloon or a flat surfaced tool. In several embodiments, the one or more distal electrodes are utilized in a procedure on a subject in which the one or more electrodes traverses through the nasal cavity to a tissue to be treated via electrical stimulation and/or assessed via electrical signal recording. In various embodiments, a tissue to be treated includes the olfactory epithelium, the respiratory epithelium within a sinus cavity, a cranial nerve, or an area of the brain in proximity to the skull base.
In an embodiment, an endoscopic device provides electrical stimulation or performing electrical recording. The device comprises a distal tool, a handle, and an amplifier system. The distal tool comprises endoscopic device for providing electrical stimulation or performing electrical recording and a connector. A portion of each electrode is exposed from the insulated track at the distal end of the distal tool. The connector of the distal tool connects with the handle such that the one or more electrodes is in conductive connection with the amplifier.
In an embodiment, a tool provides electrical stimulation or electrical signal recording. The tool comprises an inflatable balloon extending from a flexible arm at the distal end, a connector extending from the flexible arm at the proximal end, and one or more electrodes disposed on the inflatable balloon. Each electrode is insulated within a track but has an exposed portion on the inflatable balloon. Each insulated track runs along the flexible arm from the inflatable balloon to the connector. And each electrode is capable of being in conductive connection with an amplifier system via the connector.
In an embodiment, a tool provides electrical stimulation or electrical signal recording. The tool comprises a first flat flexible bayoneted surface extending from a first contoured arm at the distal end, a connector extending from the first contoured arm at the proximal end, one or more electrodes disposed on the flat flexible bayoneted surface. Each electrode is insulated within a track but has an exposed portion on the flat flexible bayoneted surface. Each insulated track runs along the first contoured arm from the first flat flexible bayoneted surface to the connector. And each electrode is capable of being in conductive connection with an amplifier system via the connector.
In a further embodiment, the tool further comprises a second flat flexible bayoneted surface at the distal end extending from a second contoured arm, and the connector extending from proximal end of the second contoured arm, forming a bifurcated tool. The second flat surface also comprises one or more distal electrodes disposed thereon.
In an embodiment, a tool provides electrical stimulation or electrical signal recording. The tool comprises a pinpoint electrode that incorporates the one or more electrodes, extending from the distal end of an insulated arm, and the pinpoint electrode having an exposed pinpoint-style distal tip. The tool further comprises a connector extending from the insulated arm at the proximal end. The pinpoint electrode is capable of being in conductive connection with an amplifier system via the connector.
In an embodiment, a method performs electrical stimulation to or electrical signal recording from tissue accessible via the nasal cavity, utilizing a distal tool with an inflatable balloon. The method comprises providing an endoscopic device. The endoscopic device comprises a distal tool, a handle, and an amplifier system. The distal tool comprises a flexible arm, an inflatable balloon extending from the distal end of the flexible arm, a connector extending from the proximal end of the flexible arm, and one or more electrodes disposed on the inflatable balloon and insulated within one or more tracks. A portion of each electrode is exposed from the insulated track at the inflatable balloon. The connector from the proximal end of the flexible arm connects with the handle such that the one or more electrodes is in conductive connection with the amplifier. The method further comprises advancing the inflatable balloon in a deflated state through the nasal cavity to a target site, inflating the balloon at the target site and positioning the one or more electrodes to be in proximity to tissue of the target site; and performing at least one of the following: recording electrical signal from the tissue of the target site using the one or more electrodes, or administering electrical stimulation to the tissue of the target site using the one or more electrodes.
In an embodiment, a method performs electrical stimulation to or electrical signal recording from tissue accessible via the nasal cavity, utilizing a distal tool with a flat bayoneted surface. The method comprises providing an endoscopic device. The endoscopic device comprises a distal tool, a handle, and an amplifier system. The distal tool comprises a first contoured arm, a first flat surface at the distal end of the first contoured arm, a connector extending from the proximal end of the contoured arm, and one or more electrodes disposed on the first flat surface and insulated within one or more tracks. A portion of each electrode is exposed from the insulated track at the first flat surface. The connector from the proximal end of the contoured arm connects with the handle such that the one or more electrodes is in conductive connection with the amplifier. The method further comprises advancing the first flat surface through the nasal cavity to a target site, positioning the one or more electrodes to be in proximity to tissue of the target site, and performing at least one of the following: recording electrical signal from the tissue of the target site using the one or more electrodes, or administering electrical stimulation to the tissue of the target site using the one or more electrodes.
In an embodiment, a method performs electrical stimulation to or electrical signal recording from tissue accessible via the nasal cavity, utilizing a pinpoint electrode distal tool. The method comprises providing an endoscopic device. The endoscopic device comprises a distal tool, a handle, and an amplifier system. The distal tool comprises a pinpoint electrode that incorporates the one or more electrodes, extending from an insulated arm and having an exposed pinpoint-style distal tip, and a connector extending from the proximal end of the insulated arm. The connector from the proximal end of the insulated arm connects with the handle such that the one or more electrodes is in conductive connection with the amplifier. The method further comprises advancing the pinpoint-style distal tip through the nasal cavity and traversing the skull base to a target site, positioning the one or more electrodes to be in proximity to tissue of the target site, and performing at least one of the following: recording electrical signal from the tissue of the target site using the one or more electrodes, or administering electrical stimulation to the tissue of the target site using the one or more electrodes.
The description and claims will be more fully understood with reference to the following figures and data graphs, which are presented as exemplary embodiments of the disclosure and should not be construed as a complete recitation of the scope of the various embodiments.
Turning now to the drawings and data, methods and devices for electrical stimulation and/or electrical signal recording from the olfactory system, nose and paranasal sinuses, cranial nerves and brain tissue in proximity to the skull base are provided in accordance with the various embodiments of the description. In several embodiments, an endoscopic device delivers electrical stimulation to and/or electrical signal recording from a tissue or an organ accessible via the nasal cavity. In many embodiments, an endoscopic device provides electrical stimulation to or electrical signal recording from an epithelium (e.g., olfactory epithelium), cavity (e.g., sinus cavity), a region within the skull base, a region within the brain, or a cranial nerve.
In several embodiments, an endoscopic electrical stimulation or signal recording device incorporates one or more electrodes for electrical stimulation and/or signal recording at the distal end of the device. In many embodiments, the one or more electrodes are in conductive connection with an amplifier via an insulated track. In various embodiments, the one or more electrodes can be disposed on the surface of a distal tool (e.g., balloon, a flat surfaced tool, a pinpoint electrode tool). In many embodiments, a pinpoint electrode tool incorporates one or more electrodes that extend from an insulated arm having an exposed pinpoint-style distal tip, which may be useful for precise electrical stimulation and/or signal recording. In several embodiments, an endoscopic device utilizes interchangeable distal tools (e.g., balloons with electrodes, flat flexible surface electrodes, and pinpoint tip electrodes) such that same device can be utilized to reach and provide electrical stimulation to and/or signal recording from various tissue architectures. For instance, various sized balloon shapes and sizes can be utilized to provide electrical stimulation to and/or signal recording from the various uniquely shaped sinus cavities, a flat-surfaced spatula can be utilized to provide electrical stimulation to and/or signal recording from relatively flat epithelial surfaces, and a pinpoint-styled electrode can be utilized to provide precise electrical stimulation to and/or signal recording from a cranial nerve or a particular region of the brain in proximity to the skull base.
Many embodiments are directed towards methods of endoscopic electrical stimulation and/or signal recording from via the nasal cavity. Accordingly, in several embodiments, an endoscopic device having one or more electrodes is traversed through the nasal cavity to reach an epithelium, a sinus cavity, or further traverses the skull base to reach an area of the brain in proximity to the skull base. To reach a site for electrical stimulation or signal recording, the distal portion of an endoscopic device can include a flexible and steerable arm attached to the balloon or spatula, such that the distal end can be flexed and steered around the various structures and turns within the nose and the paranasal sinus system.
Over 20 million Americans suffer from some level of olfactory loss. Over 80% of human ability to taste food and drink is dependent on olfaction, thus quality of life and sustained nutrition is greatly affected by loss of smell. Additionally, the olfactory system acts as a harbinger of many neurodegenerative diseases and mental disorders, factors largely in human social interaction and may soon be the basis for drug delivery to the brain to bypass the blood brain barrier. There are over 200 different etiologies for loss of olfaction, including inflammation, infection, trauma or degeneration. Various embodiments are directed towards electrically stimulating the olfactory epithelium and the end receptor neurons (collectively known as the olfactory nerve, or cranial nerve I) to incite or speed regeneration of the olfactory nerve after injury.
As noted above, chronic rhinosinusitis is also highly impactful to quality of life and overall productivity, with yearly productivity costs greater than in those with chronic migraine, chronic asthma and diabetes, and health utility values similar to patients suffering from AIDS. Various embodiments are directed towards trans-nasally electrically stimulating the respiratory epithelium and the cilia which transport mucus and keep the sinus lining healthy and functional to incite or speed regeneration of the cilia and respiratory epithelium after injury or inflammation.
Cranial nerves control our sense of smell, our vision and ability to see clearly, the ability to move our eyes around and move them in the same direction at the same time in order to only see one clear image instead of multiple or double images, our ability to tear and cry and protect the cornea, our ability to move our facial muscles and therefore eat, smile, close and open our eyes and express emotion via facial expression, our ability to hear, and our ability to move our tongues and speak and swallow. Damage to or within these nerves can cause obvious deficits based on their functions outlined above. Various embodiments are directed towards trans-nasally electrically stimulating the cranial nerves and their branches within the sinus and skull base region, to incite or speed regeneration of these nerves if damaged and not functional, or modulate or ablate these nerves if they are overactive or overly sensitized after injury or inflammation.
The other ventral skull base structures of the brainstem, pons, pituitary and hypothalamus control multiple vital functions within the body involved with basic metabolic processes. The frontal and temporal lobes control multiple forms of higher-level functioning, including executive decision-making skills, personality and behavior control, memory, speech and hearing. All of these structures and the neurons within can become damaged and lead to changes in or loss of those functions. Various embodiments are directed towards trans-nasally electrically stimulating these regions of the intracranial cavity and brain that are in proximity to the skull base region, to incite or speed regeneration of this neuronal tissue if damaged and not functional, or modulate or ablate the tissue if these regions are overactive or overly sensitized after injury or inflammation.
Several embodiments of the disclosure are directed to endoscopic devices for electrical stimulation and/or electrical signal recording. In many embodiments, an endoscopic device comprises one or more electrodes connected to an amplifier via an insulated track to provide electrical current or record electrical signals. In various embodiments, the one or more electrodes is disposed upon a surface of an inflatable balloon or of a flat surface tool (e.g., spatula or flat flexible electrode array). In some embodiments, the distal tip of one or more electrodes extends from an insulated arm, forming a pinpoint-style tip. In many embodiments, endoscopic devices comprising one or more electrodes are utilized to provide electrical stimulation to and/or electrical signal recording from various epitheliums, cavities, and tissues accessible via the nasal cavity, including (but not limited to) olfactory epithelium, the sinus cavities, cranial nerves and their associated branches and ganglia, and brain tissue in proximity with the skull base.
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Although electrode 103 is depicted as a single electrode, several embodiments are directed to endoscopic devices having a plurality of electrodes. Each electrode (whether singular or within a plurality) can extend along a track and is in conductive connection with the amplifier system. Further, each can be embedded in a carrier material to insulate the electrode. Further, each electrode has an exposed portion to provide electrical stimulation and/or signal recording and is individually operable via the amplifier system. In many embodiments, an electrode terminal is exposed. As shown in
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A distal tool 114 of device 101 can be detachable. As shown in
A singular electrode 103 or a plurality of electrodes can be disposed on the inflatable balloon 115, as depicted in the examples provided in
Several embodiments are directed to an array of electrodes disposed on the inflatable balloon (
In accordance with many embodiments, devices with one or more electrodes disposed on an inflatable balloon are used for electrical stimulation and/or signal recording within a subject, especially within an area of the subject accessible via the nasal cavity. In various embodiments, devices with one or more electrodes disposed on an inflatable balloon are utilized for electrical stimulation to and/or signal recording from the olfactory epithelium and/or within the maxillary, the ethmoid, the frontal, and/or the sphenoid sinus cavities. In such embodiments, the balloon portion of the device traverses through the nasal cavity in a deflated state. Once the balloon portion reaches the target site for electrical stimulation and/or signal recording, the balloon can be inflated such that one or more electrodes are within proximity of an epithelium or sinus cavity wall and the one or more electrodes can be utilized to perform electrical stimulation and/or signal recording thereupon.
Several embodiments are directed to the use of a flat surface tool with one or more electrodes disposed thereupon. Provided in
Many embodiments are directed to an array of electrodes disposed on the flat tool (
In accordance with several embodiments, devices with one or more electrodes disposed on a flat tool are used for electrical stimulation and/or signal recording within a subject, especially within an area of the subject accessible via the nasal cavity. In many embodiments, devices with one or more electrodes disposed on a flat tool are utilized for electrical stimulation to and/or signal recording from the olfactory epithelium. In such embodiments, the flat bayoneted portion of the device traverses through the nasal cavity to an area adjacent to the epithelium and the one or more electrodes can be utilized to perform electrical stimulation to and/or signal recording from thereupon. Curved portions can help navigate and/or locate the flat surface containing electrodes to reach the epithelium.
Several embodiments are directed to the use of a precision electrode, which is a single electrode (or a few bundled electrodes) that have an exposed distal tip extending from an insulated arm. Provided in
In accordance with several embodiments, devices with a precision electrode are used for electrical stimulation and/or signal recording within a subject, especially within an area of the subject that is accessible via the nasal cavity. In many embodiments, devices with a precision electrode are utilized for electrical stimulation and/or signal recording from an area of the brain by traversing the skull base. In such embodiments, the precision electrode of the device traverses through the nasal cavity and through an incision in the skull base to an area of the brain in proximity to the skull base and the precision electrode can be utilized to perform electrical stimulation and/or signal recording thereupon. Bent, kinked, and/or curved portions can help navigate and/or locate the precision electrode to reach the area of stimulation.
In many embodiments, a distal tool of an endoscopic device is detachable and interchangeable such that various tools can be interchanged. Distal tools include (but are not limited to) balloons of various sizes, flexible flat surfaces (singular or bifurcated), and precision electrodes with various arm configurations. Accordingly, a single handle and amplifier can be utilized to perform various treatments and/or recordings of various tissues that are accessible via the nasal canal. It should be understood, however, that various embodiments are directed towards endoscopic devices with a dedicated (i.e., not interchangeable) distal tool, which may or may not be detachable. Accordingly, in various embodiments, a device can incorporate a dedicated balloon, flexible flat surface, or precision electrode.
In several embodiments, endoscopic devices with an electrode are connected to an amplifier system. In some embodiments, the amplifier system and device are further in connection with a computer, which can assist and/or automate the electrical stimulation or electrical recording to be performed. The amplifier system can provide the electrical conductance to the one or more electrodes to perform electrical stimulation. Likewise, the amplifier system can collect the electrical signals for analysis. A computer can provide further analysis of the electrical stimulation and/or electrical recording data generated.
In some embodiments, endoscopic devices are in connection with a visualization aid to help visualize the guidance of the distal portion of the device through the nasal canal and to the site of electrical stimulation and/or electrical recording. Radiographic imaging of the sinus and skull base region can be used for navigation and targeting within the sinuses, skull base or intracranial cavity, or simple endoscopic visualization can be used if navigation is not needed for more superficial structures within the nasal cavity, such as the olfactory epithelium.
Various embodiments are directed towards several methods for electrical stimulation and/or signal recording of the olfactory system, the cilia and cells within the sinonasal mucosal lining, the cranial nerves, and the brain regions in proximity to the ventral skull base. In some embodiments, electrical stimulation and/or signal recording is done in a procedure setting, where an electrode is introduced trans-nasally to stimulate the olfactory epithelium, the sinonasal lining, a cranial nerve or other structure within the intracranial cavity for a set period of time. In some embodiments, electrical stimulation is utilized to treat an injured or a dysfunctional tissue. In some embodiments, the length and width and material of the electrode is adjustable depending on how large of an electrical field is to be created. In some embodiments, this is done in an implant setting where the implant is placed submucosally (high within a mucosal pocket of the septum or superior turbinate where the olfactory fibers are), or a submucosal implant elsewhere in the sinuses, or an intracranial implant, and an external device could be used to turn it on and off. In various embodiments, if the portion of the olfactory system that is affected is the intracranial portion, or other cranial nerves or other intracranial skull base structures are to be treated, then Deep Brain Stimulation (DBS) could be used to stimulate those regions, accessed trans-nasally.
Many embodiments are directed towards assessing an individual for pathologies related to electrical signaling of the olfactory epithelium, cranial nerves, rhinosinusitis cavities, and/or other intracranial skull base pathology. Accordingly, an individual can be assessed as follows:
Several embodiments are directed towards treating an individual for olfactory loss, cranial nerve loss, chronic rhinosinusitis and other intracranial skull base pathology. Accordingly, an individual can be treated as follows:
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Dosing and therapeutic regimens can be administered appropriate to the injury to be treated. In some embodiments, electrical stimulation is administered in a therapeutically effective amount as part of a course of treatment. As used in this context, to “treat” means to ameliorate at least one symptom of the disorder to be treated or to provide a beneficial physiological effect. For example, one such amelioration of a symptom could be improvement in olfactory sensation (e.g., identification of odorants upon testing).
A therapeutically effective amount can be an amount sufficient to prevent reduce, ameliorate or eliminate the symptoms of olfactory loss, other cranial nerve loss, chronic rhinosinusitis, or other ventral skull base pathology. In some embodiments, a therapeutically effective amount is an amount sufficient to increase olfactory sensation, increase acuity or function of other cranial nerves, or increase acuity or function of other intracranial structures.
Trans-Nasal Electrical Stimulation of Olfactory Neurons May Improve Regeneration after Damage
Background: Olfaction is highly impactful on our wellbeing, social interactions, and quality of life. Loss of function not only affects those important factors, but also can be a window into the higher cognitive ability and processing of the brain. Current therapeutic options fall far short of cure. Electrical stimulation has been utilized for multiple purposes in both the central and peripheral nervous systems to improve neuronal regeneration. The purpose of this study was to examine the effects of electrical stimulation on olfactory nerves after damage to the mammalian olfactory epithelium.
Methods: Sprague-Dawley rats were injected intraperitoneally with methimazole, known to be olfactotoxic in rodents, and randomized to receive or not receive electrical stimulation to the olfactory epithelium (OE). Behavioral olfactory testing via food finding assays were carried out at baseline, one week and one month. Rats in each group were sacrificed during this time period for histologic sectioning and labeled with olfactory marker protein (OMP) antibody for qualitative comparison.
Results: The OE of animals that underwent trans-nasal electrical stimulation had improved quality and density of olfactory receptor cells, compared to those that did not, as indicated by anti-OMP immunofluorescence. Furthermore, on two-way ANOVA, stimulated animals had a significantly decreased latency on food finding assays compared to unstimulated animals (p=0.03).
Conclusions: This data suggests that electrical stimulation of the OE speeds recovery from methimazole induced damage. This modality would help human patients suffering from hyposmia and anosmia by improving neuronal regeneration.
The olfactory nerve is unique among all other cranial nerves in that it has the inherent ability to regenerate, and does so continuously throughout an individual's lifetime. However, damage to the olfactory epithelium or other parts of the olfactory system can halt this regeneration and lead to permanent loss of smell. Unfortunately, in the adult human olfactory system, when this occurs, we have very few treatment options, and all with limited efficacy. Currently, olfactory training along with topical and systemic steroids are the most promising treatment modalities, but even these modalities combined help only approximately half of our patients.
The sense of olfaction is commonly undervalued. Serving as an evolutionary defense mechanism, it allows avoidance smoke or other noxious fumes, as well as avoiding rotten food or drink. Additionally, the sense of smell plays a large role in how humans choose partners and lifelong mates and allows one to pick up on and respond to unspoken social cues. Due to the significant impact olfaction has on our ability to taste the flavor of food, both social interaction that commonly occurs over meals and drinks as well as satiation feedback with eating are negatively impaired by dysfunction, commonly leading to social isolation, depression, and swings to either extreme in body mass index (BMI). These factors, along with the multiple neurodegenerative and transmitter disease states for which olfactory loss is an early harbinger, lead to mortality rates over three times higher than those of normosmic people.
Electrical stimulation has been used in a variety of ways within the nervous system, ranging from deep brain stimulation to control motor function in Parkinson's patients, to decreasing pain via stimulation of peripheral sensory neurons, to direct translation of sight and sound via electrical signals. Specifically, in the context of nerve regeneration, electrical stimulation has been used in traumatic brain injury as well as both motor and sensory peripheral nerve injuries. The aim of the study was to examine if electrical stimulation would have a beneficial effect on olfactory nerve regeneration after injury.
Sprague-Dawley rats were first given a behavioral food finding test as a measure of olfaction, using a common buried food pellet rodent protocol, to establish each animal's own baseline. Pellets were buried in standardized depths and rotating locations within 10 cm of bedding in otherwise clean cages. After a 24-hour period of food restriction, rats underwent three sequential timed food finding tests, with a cut-off time of 15 minutes. All rats then underwent chemical injury to their olfactory system via intraperitoneal administration of methimazole (300 mg/kg), an accepted methodology of rapid isolated disruption of the olfactory epithelium (Day 0). One day after injection, animals were randomized to receive electrical stimulation to the olfactory epithelium or not. This was carried out via placement of a thin platinum wire electrode inserted via the rat nostril into the pre-cribriform space intranasally, where the confluence of fibers from the olfactory epithelium coalesce and join together before passing through to the olfactory bulb within the intracranial cavity. Once positioned, an electrical stimulus was produced using a constant current pulse stimulator. A continuous train of 20 Hz square biphasic pulses of positive and negative 3V, 0.1 ms was delivered over one hour to the olfactory epithelium, a protocol based on prior studies using neurostimulation in sensory nerves.
Rats then again underwent food restriction at 6 days post-injury, and on day 7 were given the behavioral food finding test, again with 3 sequential tests per animal. Half these animals were then sacrificed, perfused, and underwent harvesting of the olfactory epithelium and staining with olfactory marker protein (OMP) to evaluate the neuronal structure and density within the olfactory epithelium (OE). This same protocol was repeated for the remaining animals at 30 days post-injury, with food restriction followed by food finding test, sacrifice, and harvesting of the olfactory epithelium.
Baseline mean average time to food finding was slightly faster in the animal group that did not receive electrical stimulation at 221.67 seconds versus 319.11 seconds in the stimulation group, however while both groups had increased food finding times at one week, the group receiving stimulation had less of a change off their baseline. At one month, the electrical stimulation group had improved to a mean actually better than their baseline at 178.00 seconds, whereas the control group remained far off their baseline at 599.83 seconds. (
On two-way ANOVA analysis, to evaluate the significance of this quantitative measure, stimulated animals had a significantly decreased latency on food finding assays compared to unstimulated animals (p=0.003).
The qualitative measure of morphology and density of olfactory receptor neurons within the OE along the superior turbinates of these animals was observed after OMP staining and evaluation under confocal microscopy. While neither the animals who had received electrical stimulation, nor those that had not been stimulated, fully recovered back to normal within the thirty-day time period, the OE of animals that underwent trans-nasal electrical stimulation had improved quality and density of olfactory receptor cells, compared to those that did not, as indicated by anti-OMP immunofluorescence (
With nearly one in four Americans over the age of 40 suffering from some level of alteration of smell (>20% of the population), and a current paucity of treatment options, any innovation in this field could be transformative in these patients' lives.
When olfactory nerve injury occurs, although regeneration is inherent to the system, as the Schwann-like ensheathing cells age or after a particularly inflammatory or damaging insult to the neurons, the expression of regenerative-associated genes declines over time and regeneration begins to fail. Although in rodents, olfactory ability eventually will progress back to normal, unfortunately in humans this does not always occur. Pioneering work in electrical stimulation has been shown to promote axonal regeneration, based on increased expression of regenerative associated genes such as brain derived neurotropic factor (BDNF), leading to increased intracellular cyclic adenosine monophosphate (cAMP) and thereby a sustained increase in expression of tubulin, actin and growth-associated protein (GAP-43). Although much of that work has been done after complete physical nerve transection, recent literature suggests the benefits of electrical stimulation for non-transection nerve injury as well.
The findings in this study demonstrate that electrical stimulation at this specific frequency allows for promotion of neuronal recovery while remaining low enough to prevent neuronal damage.
This data suggests that electrical stimulation of the OE speeds recovery from methimazole induced damage and would help human patients suffering from hyposmia and anosmia by improving neuronal regeneration.
While the above description contains many specific embodiments of the invention, these should not be construed as limitations on the scope of the invention, but rather as an example of one embodiment thereof. Accordingly, the scope of the invention should be determined not by the embodiments illustrated, but by the appended claims and their equivalents.
This application claims priority to U.S. Provisional Application Ser. No. 63/076,656, entitled “Methods of Treatment and Devices for Repair of Neurotransmitter or Metabolic Issues,” filed Sep. 10, 2020, which is incorporated herein by reference in its entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US21/49945 | 9/10/2021 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63076656 | Sep 2020 | US |
