WO2011109080A2

WO2011109080A2 - A device for intranasal and extranasal neuromodulation

Info

Publication number: WO2011109080A2
Application number: PCT/US2011/000379
Authority: WO
Inventors: Michael J. Partsch
Original assignee: Partsch Michael J
Priority date: 2010-03-01
Filing date: 2011-02-28
Publication date: 2011-09-09
Also published as: WO2011109080A3

Abstract

Systems, devices and methods for treating a subject by neuromodulation of a nerve or nerve cluster accessible from the nasal cavity and/or sinuses. Described herein are systems, devices and methods for treating a patient (or for allowing a patient treat themselves) by stimulation of a nerve, such as the olfactory nerve. In one example, the system, methods and devices are for the treatment of obesity by stimulation of the olfactory nerve to generate a percept such as nausea, satiety, hunger, thirst, pain, discomfort, exhaustion, tiredness, exhilaration, happiness, anxiety, restlessness, calmness, peacefulness, anger, disinterest, satisfaction, aversion, or any combination of the above.

Description

A DEVICE FOR INTRANASAL AND EXTRANASAL NEUROMODULATION

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. provisional patent application serial number 61/309,203, filed on March 1, 2010, and titled "A DEVICE FOR INTRANASAL AND EXTRANASAL NEUROMODULATION."

BACKGROUND OF THE INVENTION

[0002] The present invention is in the technical field of neuromodulation. More particularly, the present invention uses one of various modalities to neuromodulate or perform

neurostimulation to create a desired effect. The desired effect, in some embodiments, could be to treat a medical or clinical condition, including (but not limited to) the treatment of depression, obesity, or the like. In other embodiments, the desired effect might be a non-medical

application.

[0003] By way of background, the mammalian nervous system comprises two general components, the central nervous system, which is composed of the brain and the spinal cord, and the peripheral nervous system, which is composed of ganglia or dorsal root ganglia and the peripheral nerves that lie outside the brain and the spinal cord. One of skill in the art realizes that the nervous system may be linguistically separated and categorized, but functionally these regions are interconnected and interactive.

[0004] As mentioned, the central nervous system comprises the brain and spinal cord, which together function as the principal integrator of sensory input and motor output. In general terms, the brain consists of the cerebrum (cerebral hemispheres and the diencephalons), the brainstem (midbrain, pons, and medulla); and the cerebellum. Typically, the cerebrum is the center for most sensory and motor and emotional and cognitive processing. In general, the frontal lobe processes motor, visual, speech, and personality modalities; the parietal lobe processes sensory

information; the temporal lobe, auditory and memory modalities; and the occipital lobe vision. The cerebellum, in general, coordinates smooth motor activities and processes muscle position,

- l - while the brainstem conveys motor and sensory information and mediates important autonomic functions. These structures are of course integrated with the spinal cord which receives sensory input from the body and conveys somatic and autonomic motor information to peripheral targets. Thus, the central nervous system is capable of evaluating incoming information and formulating response to changes that threaten the homeostasis of the individual.

[0005] The peripheral nervous system is commonly divided into the autonomic system (parasympathetic and sympathetic), the somatic system and the enteric system. The term peripheral nerve is intended to include both motor and sensory neurons and neuronal bundles of the autonomic system, the somatic system, and the enteric system that reside outside of the spinal cord and the brain. Peripheral nerve ganglia and nerves located outside of the brain and spinal cord are also described by the term peripheral nerve.

[0006] Information may be conveyed through the nervous system via neuronal cells along their membranes and across synaptic junctions. Thus, the neuronal cells process information by both passive processes (e.g., electrical properties of the membrane which enable spatial and temporal summation) and active processes (e.g., propagation of the action potential, signal amplification or attenuation, and synaptic transmission). Generation of an action potential at the axon initial segment requires passive summation of multiple inputs, as well as signal

amplification before membrane depolarization reaches threshold, thus the passive and active processes are interdependent.

[0007] The generation of the action potential initially depends upon the electrical properties of the cell. It is known that neuronal cells have an electrical voltage difference across their membranes, the membrane potential. Several types of protein pores or ion channels are responsible for maintaining and altering the membrane potential of the cell. Voltage-gated sodium channels, which have a low threshold, are responsible for the explosive depolarization of the membrane potential that forms the action potential or spike, whereas, the voltage-gated potassium channels are responsible for the repolarization of the membrane potential. For excitation, stimulatory input results in a net increase in the inward flow of sodium ions compared to an outward flow of potassium ions results in a depolarizing cell membrane potential change. For inhibitory inputs, potassium and chloride ion channels are opened which drives the membrane potential away from threshold (hyperpolarization). Neurons receive multiple excitatory and inhibitory inputs, thus summation of these inputs occurs, for example temporal and spatial summation. Temporal summation occurs when a series of subthreshold impulses in one excitatory fiber produces an action potential in postsynaptic cell. Spatial summation occurs when subthreshold impulses from two or more different fibers trigger an action potential.

[0008] Once the initial action potential is generated, the information is conveyed via axonal conduction or synaptic transmission (e.g., chemical or electrical). Electrical synapses are found not only in the brain, but in heart and smooth muscle and epithelial liver cells. However, in the brain, electrical synapses (also known as gap junctions) are less common than chemical synapses, and are characterized by rapid speed of transmission and do not readily allow inhibitory actions or long-lasting changes in effectiveness. Gap junctions allow the passage of not only ions, but other small molecules. In humans, astrocytes contain gap junctions to mediate potassium buffering, and they are also present in the retina, inferior olive, vestibular nuclei, nucleus of the trigeminal nerve, and the reticular nucleus of the thalamus.

[0009] Chemical synapses, on the contrary, mediate either excitatory or inhibitory actions, and are generally considered more flexible. Another difference between chemical and electrical transmission is that electrical can be bidirectional since the ion channels connect the cytoplasm of the pre and postsynaptic cells, whereas chemical transmission is typically unidirectional since there is no continuity between the cells. Chemical synapses comprise a presynaptic element that contain vesicles comprising neurotransmitters and a postsynaptic element which contains receptors for the neurotransmitters. Transmitter release is initiated when the nerve terminal is depolarized by an action potential resulting in a rapid influx of calcium ions into the nerve terminal. This rapid influx of calcium ions cause fusion of the vesicles to the presynaptic membrane and ultimately release of the neurotransmitters which then bind to their receptor located on the postsynaptic membrane.

[0010] The ability of the neuronal cell to fire or produce action potentials may vary depending upon its biophysical properties (e.g., types of ionic channels, etc.) and/or its position in the circuit or nervous system. Thus, cells can respond to an input (stimulatory or inhibitory) with a decelerating train of action potentials, an accelerating train of action potentials or a constant firing frequency. For example, an increase in firing of a neuronal cell may be a result from increased amounts of calcium ions or a function of residual increase in calcium ions left over from the first stimulation (also known as facilitation) in the presynaptic element which results in increase release of neurotransmitter. Thus, a second stimulation can occur within milliseconds of the first. Conversely, a second stimulation may result in inhibition and not facilitation of the response if an inhibitory interneuron is activated which feedback to the first neuronal cell to inhibit firing.

[0011] Neuromodulation or neurostimulation may be performed in a number of ways.

Typically, neuromodulation or neurostimulation is performed by using an energy source to affect a specific neuron or group of neurons. The polarization or depolarization of this neuron or group of neurons can result in an action potential. This action potential can be the direct desired result, for instance if the action potential resulted in the contraction or relaxation of a muscle fiber. Alternatively, this action potential can be propagated on to another nerve either in the peripheral or central nervous system. When transmitted to these other portions of the nervous system the action potential results in the desired neural effect.

[0012] Several examples of neuromodulation or neurostimulation exist, such as: deep brain stimulation, vagus nerve stimulation, spinal cord stimulation, retinal implants, and cochlear implants as well as others.

[0013] Deep brain Stimulation (DBS) is a surgical treatment involving the implantation of a medical device called a brain pacemaker, which sends electrical impulses to specific parts of the brain. The deep brain stimulation system typically consists of three components: an implanted pulse generator (IPG), a lead, and an extension. The IPG is a battery-powered neurostimulator encased in a titanium housing, which sends electrical pulses to the brain to interfere with neural activity at the target site. The lead is a coiled wire insulated in polyurethane with four platinum iridium electrodes and is placed in one of three areas of the brain. The lead is connected to the IPG by the extension, an insulated wire that runs from the head, down the side of the neck, behind the ear to the IPG, which is placed subcutaneously below the clavicle or in some cases, the abdomen. The IPG can be calibrated by a neurologist, nurse or trained technician to optimize symptom suppression and control side effects.

[0014] Vagus nerve stimulation (VNS) is an adjunctive treatment for certain types of intractable epilepsy and major depression. VNS uses an implanted stimulator that sends electric impulses to the left vagus nerve in the neck via a lead wire implanted under the skin. VNS implantation devices typically consist of a titanium-encased generator about the size of a pocket watch with a lithium battery to fuel the generator, a lead wire system with electrodes, and an anchor tether to secure leads to the vagus nerve.

[0015] A Spinal Cord Stimulator may be used to exert pulsed electrical signals to the spinal cord to control chronic pain. Spinal cord stimulation (SCS), in the simplest form, consists of stimulating electrodes, implanted in the epidural space, an electrical pulse generator, implanted in the lower abdominal area or gluteal region, conducting wires connecting the electrodes to the generator, and the generator remote control. SCS has notable analgesic properties and, at the present, is used mostly in the treatment of failed back surgery syndrome, complex regional pain syndrome and refractory pain due to ischemia.

[0016] A retinal implant is a biomedical implant technology currently being developed by a number of private companies and research institutions worldwide. The implant is meant to partially restore useful vision to people who have lost their vision due to degenerative eye conditions such as retinitis pigmentosa or macular degeneration. The technology consists of an array of electrodes implanted on the back of the retina, a digital camera worn on the user's body, and a transmitter/image processor that converts the image to electrical signals and beams them to the electrode array in the eye. The technology, while still rudimentary, would allow the user to see a scoreboard type image made up of bright points of light viewed from about arm's length.

[0017] There are two types of retinal implants currently showing promise in clinical trials: Epiretinal Implants (on the retina) and Subretinal Implants (behind the retina). Epiretinal Implants sit on top of the retina, directly stimulating ganglia using signals sent from the external camera and power sent from an external transmitter, where Subretinal Implants sit under the retina, stimulating bipolar or ganglion cells from underneath. Some subretinal implants use signals and power from external circuitry, while others use only incident light as a power source and effectively replace damaged photoreceptors leaving all other structures within the eye untouched. However, due to a lack of an external power source, the image signal in this second type of subretinal implant may not be as strong as that given by an externally powered epiretinal or subretinal implant.

[0018] A cochlear implant is a small, complex electronic device that can help to provide a sense of sound to a person who is profoundly deaf or severely hard-of-hearing. The implant consists of an external portion that sits behind the ear and a second portion that is surgically placed under the skin (see figure). An implant has the following parts: a microphone, which picks up sound from the environment; a speech processor, which selects and arranges sounds picked up by the microphone; a transmitter and receiver/stimulator, which receive signals from the speech processor and convert them into electric impulses; and an electrode array, which is a group of electrodes that collects the impulses from the stimulator and sends them to different regions of the auditory nerve.

[0019] In general terms, implantable stimulation systems include an implantable pulse generating source or electrical stimulation source and one or more implantable electrodes or electrical stimulation leads for applying electrical stimulation pulses to the a predetermined site. In operation, both of these primary components are implanted in the body.

[0020] A percept is a perceived form of external stimuli or their absence. Vivid dreams could also be considered as a form of perception without a clear source of external stimuli. The term is primarily used as sense-datum to explain perception. It is important to discern percept from stimuli or their absence. Stimuli are not necessarily translated into a percept and rarely does a single stimulus translate into a percept. Also, absence of adequate stimuli may be translated into multiple percepts, experienced randomly, one at a time, as in some sensory illusions. And the same stimuli, or absence of them, may result in different percepts depending on subject's culture and previous experiences.

[0021] The olfactory system is the sensory system used for olfaction, or the sense of smell. In mammals, the main olfactory system detects odorants that are inhaled through the nose, where they contact the main olfactory epithelium, which contains various olfactory receptors. These olfactory receptors are membrane proteins of bipolar olfactory receptor neurons in the olfactory epithelium. Rather than binding specific ligands like most receptors, olfactory receptors display affinity for a range of odor molecules. Olfactory neurons transduce receptor activation into electrical signals in neurons. The signals travel along the olfactory nerve, which belongs to the peripheral nervous system. This nerve terminates in the olfactory bulb, which belongs to the central nervous system. The complex set of olfactory receptors on different olfactory neurons can distinguish a new odor from the background environmental odors and determine the

concentration of the odor. SUMMARY OF THE INVENTION

[0022] Described herein generally, and by specific example, are devices, systems and methods for performing neuromodulation or neurostimulation through a target nerve or nerves. In general, the target nerves may be any nerves accessible through the nasal cavity or sinus cavity, in particular, the target nerve may be the olfactory nerve. Unlike other forms of sensory neuromodulation (e.g., retinal implants or cochlear implants) stimulating or modulating the olfactory nerve may be a more direct and simpler method of directly sending a signal to the central nervous system. This is because the olfactory nerves are the only nerve cells in the body to run directly from the brain to the outside of the body.

[0023] Thus, among the inventions described herein are neuromodulation devices that can modulate the neural activity of any one or more of the branches of the target nerves accessible in the sinus cavity or nasal cavity. By modulating the activity of these nerves, one can elicit a specific and desired response in the central nervous system.

[0024] This device may generally consist of a combination of several components. These components may include: a neuromodulation probe, a power/energy source, an actuator to convey the energy source or the modulation modality to the nerve, a signal generator controller which controls the neuromodulation process, as well as relevant housing and connector pieces in order to make the device compact and functional.

[0025] For example, the neuromodulation probe may include a housing which holds and/or delivers the actuator in the appropriate position in order to modulate the target nerve. The probe can be embodied as a long, slender device which can be place either inside a nostril and up into the nasal cavity or sinus cavity. It could also be designed to be placed external to the nostril and adjacent to the face.

[0026] The power/energy source may be either an on-board battery or an external power supply. The energy is typically used to control the neuromodulation process. This control can be, but is not limited to, pulses of electrical energy in a pulse pattern which results in polarizing or depolarizing the target nerves. In another manner, the energy could be used to control the timing of release of biological, biochemical, chemical, or other materials which result in the depolarization or polarization of the target nerves. In another manner, the energy could be used to control the timing of release of optical energy which result in the depolarization or polarization of the target nerves. In another manner, the energy could be used to control the timing of release of electromagnetic pulses or energy which result in the depolarization or polarization of the target nerves.

[0027] The actuator may be the means of actually causing the neuromodulation. In one embodiment, the actuator can be an electrode, or an array of some plurality of electrodes. The electrode will distribute the pulsed energy to the target nerves. In another embodiment, the actuator could be an ultrasound transducer which would send sonic energy to the target nerve. In another embodiment, the actuator could be the combination of some activating material

(biological, biochemical, chemical, etc) and a reservoir which holds that material

[0028] The signal generator controller may embody the control mechanism; for example, the signal generator control may be embodied as an integrated circuit which controls the action of the actuator. If the embodiment is an integrated circuit, then there would be a software component. The signal generator controller could be entirely self-contained, or, in another embodiment, if the controller is implanted, it could have instructions transmitted wirelessly to it by an external controller or transmitter.

Tarfiet Nerves

[0029] There are a number of nerves that qualify as target nerves for the systems, devices and methods described herein. For example, any nerves, sensory or motor, that are accessible in the nasal cavity and/or sinus cavity are potential target nerves. A list of example target nerves includes, but is not limited to, the olfactory nerve and its branches (including olfactory receptor neurons), the trigeminal nerve and its branches, the naso-ciliary nerve, the naso-palatine nerve, the maxiliary nerve and its branches, the facial nerve and its branches, posterior and anterior ethmoidal nerves, the long ciliary nerves, the infraorbital nerves, the spenopalatine nerve, the sphenopalatine ganglion as well as others.

[0030] There are a number of possible embodiments that this device could take, which are described in greater detail below.

[0031] For example, described herein are methods for suppressing or preventing pain, movement disorders, epilepsy, cerebrovascular diseases, autoimmune diseases, sleep disorders, autonomic disorders, urinary bladder disorders, abnormal metabolic states, disorders of the muscular system, and neuropsychiatric disorders in a patient. These methods may include the steps of: positioning at least one actuator probe of a neuromodulation device adjacent to or around at least one target site (wherein the target site is selected from the group consisting of the patient's: superior sagittal sinus; confluence of sinuses; occipital sinus; sigmoid sinus; transverse sinus; straight sinus; inferior sagittal sinus; the dura adjacent the superior sagittal sinus, confluence of sinuses, occipital sinus, sigmoid sinus, transverse sinus, straight sinus, or inferior sagittal sinus; or falx cerebri; activating the at least one actuator probe to apply a signal to the at least one target site). The actuator probe may then deliver a non-electrical energy to the target site. For example, the non-electrical energy may be magnetic, or magnetic induction, ultrasonic, chemical, biological, or biochemical, optical, low energy laser, or high energy laser, or the like. In some variations, the non-electrical energy can be varied in duration, intensity, and/or frequency.

[0032] In general the actuator probe may be part of a neuromodulation device left resident in the target site. The actuator probe may be used in the target site but removed or disabled when not in use. In some variations, the actuator probe is left resident in the target site with any one or more of the controller, the energy supply or other such components of the neuromodulation device external to the target site.

[0033] Also described herein are methods for suppressing, treating or preventing obesity or other metabolic disorders, and addictive disorders in a patient, the method comprising:

positioning at least one actuator probe of a neuromodulation device adjacent to or around at least one target site (said at least one target site selected from the group consisting of the patient's: superior sagittal sinus; confluence of sinuses; occipital sinus; sigmoid sinus; transverse sinus; straight sinus; inferior sagittal sinus; the dura adjacent the superior sagittal sinus, confluence of sinuses, occipital sinus, sigmoid sinus, transverse sinus, straight sinus, or inferior sagittal sinus; or falx cerebri) and activating the at least one actuator probe to apply a signal to the at least one target site. As mentioned, the actuator probe typically delivers energy to the target site. This energy may be magnetic, or magnetic induction, electrical, ultrasonic, chemical, biological, or biochemical, optical, low energy laser, or high energy laser. The energy can be varied in duration, intensity, and/or frequency.

[0034] The actuator probe may be part of a neuromodulation device left resident in the target site, and/or removed or disabled when not in use. For example, the actuator probe may be left resident in the target site with any one or more of the controller, the energy supply or other such components of the neuromodulation device external to the target site.

[0035] Also described herein are methods for suppressing, treating or preventing obesity or other metabolic disorders, eating disorders and addictive disorders in a patient, the method comprising: positioning at least one actuator probe of a neuromodulation device adjacent to or around at least one target site, said at least one target site selected from the group consisting of the patient's: olfactory nerves, olfactory neuron receptors, olfactory epithelium, nasal cavity. The actuator probe may then deliver energy to the target site. The energy may be magnetic, or magnetic induction, electrical, ultrasonic, chemical, biological, or biochemical, optical, low energy laser, or high energy laser. The energy can be varied in duration, intensity, and/or frequency.

[0036] The actuator probe is part of a neuromodulation device left resident in the target site. The actuator probe may be used in the target site but removed or disabled when not in use. The actuator probe may be left resident in the target site with any one or more of the controller, the energy supply or other such components of the neuromodulation device external to the target site.

[0037] The energy may be delivered to the target site induces the target site to modulate the olfactory neurons the modulation of the olfactory neurons may result in a percept in the patient. For example, a percept may bring about a desired state of mind, such as: nausea, satiety, hunger, thirst, pain, discomfort, exhaustion, tiredness, exhilaration, happiness, anxiety, restlessness, calmness, peacefulness, anger, disinterest, satisfaction, aversion, or any combination of the above.

[0038] In some variations, the delivery of the energy is under active control by the patient. The delivery of the energy may be under active control by a physician or clinician or other person other than the patient. The delivery of the energy may be controlled by a preprogrammed controller.

[0039] Also described herein are methods for suppressing, treating or preventing depression, anxiety or other mood disorders, psychiatric disorders in a patient, the method comprising: positioning at least one actuator probe of a neuromodulation device adjacent to or around at least one target site, said at least one target site selected from the group consisting of the patient's: olfactory nerves, olfactory neuron receptors, olfactory epithelium, nasal cavity.

[0040] The actuator probe may deliver energy to the target site. The energy may be magnetic, or magnetic induction, electrical, ultrasonic, chemical, biological, or biochemical optical, low energy laser, or high energy laser. The energy can be varied in duration, intensity, and/or frequency.

[0041] The actuator probe may be part of a neuromodulation device left resident in the target site. The actuator probe may be used in the target site but removed or disabled when not in use. The actuator probe may be left resident in the target site with any one or more of the controller, the energy supply or other such components of the neuromodulation device external to the target site.

[0042] The energy delivered to the target site may induce the target site to modulate the olfactory neurons. For example, the modulation of the olfactory neurons results in a percept in the patient. Modulation of the olfactory neurons may result in, or brings about a desired state of mind, such as (but not limited to): a lessening, mitigating, reduction of, therapy for, or otherwise considered treatment of depression, anxiety or other mood disorder.

[0043] The delivery of the energy may be under active control by the patient. The delivery of the energy may be under active control by a physician or clinician or other person other than the patient. The delivery of the energy may be under control by a pre-programmed controller.

[0044] Also described herein are methods for suppressing, treating or preventing pain, headache or migraine, or other physical disorders which cause physical discomfort in a patient, the method comprising: positioning at least one actuator probe of a neuromodulation device adjacent to or around at least one target site, said at least one target site selected from the group consisting of the patient's: olfactory nerves, olfactory neuron receptors, olfactory epithelium, nasal cavity. The actuator probe typically delivers energy to the target site. The energy may be magnetic, or magnetic induction, electrical, ultrasonic, chemical, biological, or biochemical, optical, low energy laser, or high energy laser. The energy may be varied in duration, intensity, and/or frequency.

[0045] The actuator probe may be part of a neuromodulation device left resident in the target site. The actuator probe is used in the target site but removed or disabled when not in use. The actuator probe may be left resident in the target site with any one or more of the controller, the energy supply or other such components of the neuromodulation device external to the target site.

[0046] The energy delivered to the target site may induce the target site to modulate the olfactory neurons. This modulation of the olfactory neurons may result in a percept in the patient; the percept may bring about a desired state of mind, such as a lessening, reduction in, therapy of or otherwise considered treatment for pain, migraine, headache or other physical disorder which cause physical discomfort in the patient.

[0047] The delivery of the energy may be under active control by the patient, and/or active control by a physician or clinician or other person other than the patient. In some variations, the delivery of the energy is under control by a pre-programmed controller.

[0048] Also described herein are neuromodulation devices and systems for treating obesity by stimulation of the olfactory nerve. These devices and systems may include a probe (neuromodulation probe) configured to delivery energy (e.g., magnetic energy) to the olfactory nerve, a power source (e.g., a source of magnetic energy), an actuator configured to convey the energy from the power source to the nerve (e.g., the olfactory nerve), and a signal generator configured to modulate the applied signal so to achieved the desired neuromodulatory effect. In some variations the actuator and/or probe are configured to deliver energy specifically to the target nerve without substantial stimulation of adjacent, non-target nerves. The signal generator may be specifically designed to stimulate only the target (e.g., olfactory) nerve to achieve modulation of the olfactory nerve or to evoke a specific percept in the patient, such as nausea, satiety, hunger, thirst, pain, discomfort, exhaustion, tiredness, exhilaration, happiness, anxiety, restlessness, calmness, peacefulness, anger, disinterest, satisfaction, aversion, or any combination of the above.

INCORPORATION BY REFERENCE

[0049] All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] The novel features of the invention are set forth with particularity in the claims that follow. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative

embodiments, in which the principles of the invention are utilized, and the accompanying drawings of FIGS. 1 to 15.

[0051] FIG. 1 is a schematic view of the components of the present invention. The components include a controller, a power source, an actuator and a probe. Any number of these components could be combined in any order. For any of the figures involving an external non- implanted power source, this power could be an onboard battery of other power supply.

[0052] FIG. 2 is a schematic view of the components of the present invention where the components are all combined into a compact form factor. FIG. 2 shows a single housing for power and controller and an actuator probe.

[0053] FIG. 3 is a schematic view of the components of the present invention where some of the components are combined into an implantable portion which would be used in conjunction with an external activator.

[0054] FIG. 4 is a schematic view of an external activator that can be used in conjunction with an implanted portion (see, e.g., FIG. 3).

[0055] FIG. 5 is a depiction of one variation of how the device could be used for an embodiment that has an implanted portion and an external actuator. The external activator could be used to send power to the implanted portion.

[0056] FIG. 5a is depiction of how the implanted portion of the device could be placed within the nasal cavity or sinus cavity. The actuator probe would interact with the adjacent target nerves. Placement of the implanted portion of the device could be in the nasal cavity or in the sinus cavity, or both.

[0057] FIG. 6 is a schematic view of a fully implanted device. This embodiment could have all the components housed in a single implantable unit and one or more actuator probes which would interact with the target nerves.

[0058] FIG. 7 is a depiction of how a fully implanted device could be implanted in a person. [0059] FIG. 7a is a depiction of how the fully implanted device could be placed within the nasal cavity or the sinus cavity. The actuator probe would interact with the adjacent target nerves. Placement of the implanted portion of the device could be in the nasal cavity or in the sinus cavity, or both.

[0060] FIG. 8 is a side view depiction of an embodiment where the device has a single probe for external use alongside the face and nose. The energy signal would be sent through the face to the target nerves.

[0061] FIG. 9 is a front view depiction of an embodiment where the device has a single probe for external use alongside the face and nose. The energy signal would be sent through the face to the target nerves. The components show in FIGS. 8 and 9 could be combined as shown in FIG. 2.

[0062] FIG. 10 is a side view depiction of an embodiment where the device has two probes for external use alongside the face and nose. The energy signal would be sent through the face to the target nerves.

[0063] FIG. 1 1 is a front view depiction of an embodiment where the device has two probes for external use alongside the face and nose. The energy signal would be sent through the face to the target nerves. The components shown in FIGS. 10 and 1 1 could be combined into one housing similar to what is shown in FIG. 2, but with the second probe.

[0064] FIG. 12 is a depiction of how a minimally invasive internal use device could be used. In this depiction, some of the components are separate but connected with a connector which can transmit power, information or both.

[0065] FIG. 13 is a depiction of how a compact form of an internal use device could be used up a nostril.

[0066] FIG. 14 is a schematic of how all the components could be combined into a compact form.

[0067] FIG. 15 is a depiction of how a compact form of an internal use device could be used up a nostril. The embodiment shown could include a two-probe device for use in both nostrils. DETAILED DESCRIPTION OF THE INVENTION

[0068] FIGS. 1 and 2 illustrate embodiments of the devices/systems described. In the variation shown in FIG. 2, for example, a minimally invasive device contains most of the elements in a single probe which could be inserted into the nasal/sinus cavity in order to reach the desired target nerves. In this embodiment, all the components (power source, actuator, controller, etc) would be contained in a device which could be inserted either into the nasal cavity or in front of the nasal cavity. The actuator would then be in a position to send a neuromodulation signal to the respective target nerves in order to cause the desired result.

[0069] A second embodiment of this device could be a non-invasive device which has all components of the neuromodulation device fully housed in a device which is kept outside of the nasal/sinus cavity. This device transmits the energy through the appropriate region of the face in order to affect the target nerves in a desired manner by transmitting the appropriate energy through the tissue and skin of the face.

|0070| Another embodiment would be a device may include an implanted portion of the device and a non-implanted portion of the device, as illustrated in FIG. 3-5a. The implanted portion may be placed within the nasal and/or sinus cavity and could contain any number of the components mentioned above. There would be an external portion of the device that would be used to control the activation and performance of the implanted portion. This external portion could be used either by a clinician, a patient, or another individual, in order to enable the implanted portion to cause the desired neurmodulation.

[0071] Yet another embodiment of the device could be a fully implanted device which has all components of the device implanted within the nasal and/or sinus cavity, as shown in FIGS. 6- 7a. The device could be programmed either by some method of onboard controller (an internal application specific integrated circuit, or ASIC, for example) or by an external controller which can remotely signal the implanted portion of the device.

[0072] The embodiments described briefly above are not a complete and exhaustive list, and other embodiments for the current invention are contemplated.

[0073] There could be any number of types of energy used in order to actuate the neuromodulation of the appropriate olfactory nerves. These energy types may include, but are not limited to, electrical stimulation, ultrasonic stimulation, electromagnetic stimulation, mechanical stimulation, biochemical stimulation, and optical (visible light) stimulation. Nonelectrical stimulation (e.g., ultrasound, magnetic, etc.) are of particular interest.

[0074] The devices described herein may operate by stimulation/modulation of the olfactory nerve(s). Olfaction, which may be related to the sense of smell, is a neurologically primitive system in most mammals, including humans, and is therefore potentially a powerful system for controlled neuromodulation, as described herein. Smell is the most important sense for most organisms. A wide variety of species use their sense of smell to locate prey, navigate, recognize and perhaps communicate with kin, and mark territory. The sense of smell differs from most other senses in its directness: we actually smell microscopic bits of a substance that have evaporated and made their way to the olfactory epithelium, a section of the mucus membrane in the roof of the olfactory cavity. The olfactory epithelium contains the smell-sensitive endings of the olfactory nerve cells, also known as the olfactory epithelial cells. These cells detect odors through receptor proteins on the cell surface that bind to odor-carrying molecules. A specific odorant docks with an olfactory receptor protein in much the same way as a key fits in a lock; this in turn excites the nerve cell, causing it to send a signal to the brain. This is known as the stereospecific theory of smell. [0075] Just as the sense of smell is direct in detecting fragments of the objects, it is also direct in the way the signal is transmitted to the brain. In most senses, such as vision, this task is accomplished in several steps: a receptor cell detects light and passes the signal to a nerve cell, which passes it onto another nerve cell in the central nervous system, which then relays it to the visual center of the brain. But in olfaction, all these jobs are performed by the olfactory nerve cell: in a very real sense, the olfactory epithelium is a direct outgrowth of the brain. The olfactory nerve cell takes the scent message directly to the nerve cells of the olfactory bulb of the brain (or, in insects and other invertebrates that lack true brains, the olfactory ganglia), where multiple signals from different olfactory cells with different odor sensitivities are organized and processed. In higher species the signal then goes to the brain's olfactory cortex, where higher functions such as memory and emotion are coordinated with the sense of smell. Because memory and emotion are coordinated with the sense of smell, it is possible to affect both memory and emotion by neuromodulation of this region via the nerves responsible for olfaction. This is just one embodiment of the invention.

[0076] Humans have about 40 million olfactory receptor neurons. In vertebrates, olfactory receptor neurons reside on the olfactory epithelium in the nasal cavity. These cells are bipolar neurons with a dendrite facing the interior space of the nasal cavity and an axon that travels along the olfactory nerve to the olfactory bulb. Many tiny hair-like cilia protrude from the olfactory receptor cell's dendrite into the mucus covering the surface of the olfactory epithelium. The surface of these cilia is covered with olfactory receptors, a type of G protein-coupled receptor. Each olfactory receptor cell expresses only one type of olfactory receptor, but many separate olfactory receptor cells express olfactory receptors which bind the same set of odors. The axons of olfactory receptor cells which bind the same odors converge to form glomeruli in the olfactory bulb.

[0077] A given olfactory receptor can bind to a variety of odor molecules with varying affinities. The activated olfactory receptor in turn activates the intracellular G-protein GOLF (GNAL), and adenylate cyclase and production of Cyclic AMP opens ion channels in the cell membrane, resulting in an influx of sodium and calcium ions into the cell. This influx of positive ions causes the neuron to depolarize, generating an action potential.

[0078] As mentioned, the sense of smell can be related to a number of neurological events. Some of these events are desirable and some are not desirable. The sense of smell can directly or indirectly impact neuronal activity in the brain. A person schooled in the art of neuromodulation or neurostimulation and the olfactory system of nerves could use a neuromodulation device to bring about a desired neurological result within the neurological circuitry of the brain by selectively modulating the activity of olfactory nerves with a neuromodulation device as described here. In some variations, the systems described herein may evoke a smell or may result in a perception of smell or odor.

[0079] There are a number of clinical indications which might be treated with a device as described by this patent. The target nerves can send many different kinds of signals to the brain. These signals can result in a wide variety of experiences within the brain and/or central nervous system. The results of neuromodulation of the target nerves could be used to treat any combination of physiological and or psychological conditions. Some of the clinical indications which could be treated by this technology include, but are not limited to: obesity, Parkinson's disease, migraine headache, depression, addiction, memory and mood disorders. [0080] The devices described here may be used to cause a specific pattern of

neuromodulation in the target nerves in order to treat any number of the above mentioned disorders. Below, a number of treatments for some specific disorders are described, as a representative sample, in order to demonstrate the breadth of use of this technology. The following list is not intended as a complete list of potential applications, but rather as a sample of the potential applications for this technology.

Example of an obesity treatment

[0081] The olfactory nerves are responsible for the sense of smell. The spectrum of smells that one can experience is very great. Some smells are pleasurable and others are not. If one were to use the invention in such a way as to neuromodulate the olfactory nerve and create a mild sensation of nausea or other discomfort, it could result in the suppression of appetite. The result could be a treatment for obesity.

[0082] In order to accomplish this, the controller could be preprogrammed to neuromodulate the olfactory nerve in specific patterns and at specific times of the day in order to suppress hunger. Alternatively, another embodiment would employ the use of an external portion of the device which could be controlled by the user or another individual and could be activated at the onset of hunger in order to suppress the sensation of hunger in the subject.

Example of a migraine treatment

[0083] It is true that smell sometimes create problem for the person particularly for the one suffering from migraine. It is also noteworthy that the symptoms of migraine include vomiting, headache, sensitivity towards light and smell and headache. Thus a smell in the case of migraine does not act as a boon rather it is considered as the main cause of problem. So for the patient of migraine sometimes it is advisable to remove smell which can lead to the attacks of migraine. In case the problematic smell is not removed in time, it leads to severe consequences.

[0084] The consequences of excessive smell are really very bad for the patient suffering from the problem of migraine. The headache stage which is considered as the third stage of migraine gets worse because of excessive smell. So, it is important to have the complete knowledge of the sense of smell to avoid problems for the patient of migraine.

[0085] In this embodiment, a clinician could program a medical device using this invention and have that device neuromodulate the olfactory nerves in such a way as to counteract the offending odor for the patient. In this way, the patient could, upon first onset of a migraine or the first sensation of the offending smell, use the device to counteract the offending smell and prevent the patient from moving towards a full blown migraine.

Example of a depression treatment

[0086] There is strong evidence that depression and the sense of smell are linked. Odors and emotions are both similarly processed along related circuitry in the brain. These regions include the orbitofrontal cortex and the amygdale. Odors can be and often are powerful emotional stimuli.

[0087] Evidence has been shown that the responsiveness to smells has been diminished in depressed patients. (Pause et. al. Psychophysiology, March 2003). These researchers targeted a dysfunctional state of the main olfactory bulb, a pea-sized structure located below the orbitofrontal cortex that receives sensory input, as potentially playing a pivotal role in depressed patients' reduced sense of smell, and well as "their intensified experience of sadness and fear," according to the study. [0088] A clinical specialist trained in the art of neuromodulation and the neuroanatomy of the target nerves could use the invention described herein to create a device which enables a patient, physician or other clinician to up-regulate activity in the olfactory system of the patient and possibly prevent the onset of depression or reduce the severity and impact of depression.

[0089] The advantages of the present invention include, without limitation, the ability to directly interact with nerves of the central nervous system, instead of sensory nerves external to the central nervous system. Another major benefit is that this method allows the user to perform neuromodulation without any invasive surgery. Yet another benefit of this invention would be that the use of the invention can easily performed under user control.

[0090] In broad embodiment, the invention is a device for performing neuromodulation by modulating the activity of the olfactory nerves or other nerves in the nasal cavity or sinus cavity.

[0091] While the foregoing written description of the invention enables one of ordinary skill to make and use what is considered presently to be the best mode thereof, those of ordinary skill will understand and appreciate the existence of variations, combinations, and equivalents of the specific embodiment, method, and examples herein. The invention should therefore not be limited by the above described embodiment, method, and examples, but by all embodiments and methods within the scope and spirit of the invention.

Claims

WHAT IS CLAIMED IS:

1. A neuromodulation device for treating obesity by stimulation of the olfactory nerve, the devices comprising:

a neuromodulation probe configured to delivery energy to the olfactory nerve, wherein the probe includes an actuator configured to convey energy to the olfactory nerve without substantial stimulation of adjacent, non-target nerves;

a power source coupled to the probe; and

a signal generator configured to modulate power from the power source to generate an applied signal to be delivered by the actuator to achieved a desired neuromodulatory effect by evoking a percept in the patient, wherein the percept is one or more of: nausea, satiety, hunger, thirst, pain, discomfort, exhaustion, tiredness, exhilaration, happiness, anxiety, restlessness, calmness, peacefulness, anger, disinterest, satisfaction, and aversion.

2. A method for suppressing or preventing pain, movement disorders, epilepsy,

cerebrovascular diseases, autoimmune diseases, sleep disorders, autonomic disorders, urinary bladder disorders, abnormal metabolic states, disorders of the muscular system, and neuropsychiatric disorders in a patient, the method comprising:

positioning at least one actuator probe of a neuromodulation device adjacent to or around at least one target site, said at least one target site selected from the group consisting of the patient's: superior sagittal sinus; confluence of sinuses; occipital sinus; sigmoid sinus; transverse sinus; straight sinus; inferior sagittal sinus; the dura adjacent the superior sagittal sinus, confluence of sinuses, occipital sinus, sigmoid sinus, transverse sinus, straight sinus, or inferior sagittal sinus; or falx cerebri; activating the at least one actuator probe to apply a signal to the at least one target site.

3. The method of claim 2 where the actuator probe delivers a non-electrical energy to the target site.

4. The method of claim 3 where the non-electrical energy is magnetic, or magnetic

induction.

5. The method of claim 3 where the non-electrical energy is ultrasonic.

6. The method of claim 3 where the non-electrical energy is chemical, biological, or

biochemical.

7. The method of claim 3 where the non-electrical energy is optical, low energy laser, or high energy laser.

8. The method of claim 3 where the non-electrical energy can be varied in duration,

intensity, and/or frequency.

9. The method of claim 3 where the actuator probe is part of a neuromodulation device left resident in the target site.

10. The method of claim 3 where the actuator probe is used in the target site but removed or disabled when not in use.

1 1. The method of claim 3 where the actuator probe is left resident in the target site with any one or more of the controller, the energy supply or other such components of the neuromodulation device external to the target site.

12. A method for suppressing, treating or preventing obesity or other metabolic disorders, and addictive disorders in a patient, the method comprising:

13. The method of claim 12 where the actuator probe delivers energy to the target site.

14. The method of claim 13 where the energy is magnetic, or magnetic induction.

15. The method of claim 13 where the energy is electrical.

16. The method of claim 13 where the energy is ultrasonic.

17. The method of claim 13 where the energy is chemical, biological, or biochemical.

18. The method of claim 13 where the energy is optical, low energy laser, or high energy laser.

19. The method of claim 13 where the energy can be varied in duration, intensity, and/or frequency.

20. The method of claim 13 where the actuator probe is part of a neuromodulation device left resident in the target site.

21. The method of claim 13 where the actuator probe is used in the target site but removed or disabled when not in use.

22. The method of claim 13 where the actuator probe is left resident in the target site with any one or more of the controller, the energy supply or other such components of the neuromodulation device external to the target site.

23. A method for suppressing, treating or preventing obesity or other metabolic disorders, eating disorders and addictive disorders in a patient, the method comprising:

positioning at least one actuator probe of a neuromodulation device adjacent to or around at least one target site, said at least one target site selected from the group consisting of the patient's: olfactory nerves, olfactory neuron receptors, olfactory epithelium, nasal cavity.

24. The method of claim 23 where the actuator probe delivers energy to the target site.

25. The method of claim 24 where the energy is magnetic, or magnetic induction.

26. The method of claim 24 where the energy is electrical.

27. The method of claim 24 where the energy is ultrasonic.

28. The method of claim 24 where the energy is chemical, biological, or biochemical.

29. The method of claim 24 where the energy is optical, low energy laser, or high energy laser.

30. The method of claim 24 where the energy can be varied in duration, intensity, and/or frequency.

31. The method of claim 24 where the actuator probe is part of a neuromodulation device left resident in the target site.

32. The method of claim 24 where the actuator probe is used in the target site but removed or disabled when not in use.

33. The method of claim 24 where the actuator probe is left resident in the target site with any one or more of the controller, the energy supply or other such components of the neuromodulation device external to the target site.

34. The method of claim 24 where the energy delivered to the target site induces the target site to modulate the olfactory neurons.

35. The method of claim 33 where the modulation of the olfactory neurons results in a

percept in the patient.

36. The method of claim 34 where the percept brings about a desired state of mind.

37. The method of claim 34 where the percept is one of a desired state chosen from: nausea, satiety, hunger, thirst, pain, discomfort, exhaustion, tiredness, exhilaration, happiness, anxiety, restlessness, calmness, peacefulness, anger, disinterest, satisfaction, aversion, or any combination of the above.

38. The method of claim 24 where the delivery of the energy is under active control by the patient.

39. The method of claim 24 where the delivery of the energy is under active control by a physician or clinician or other person other than the patient.

40. The method of claim 24 where the delivery of the energy is under control by a preprogrammed controller.

41. A method for suppressing, treating or preventing depression, anxiety or other mood

disorders, psychiatric disorders in a patient, the method comprising:

42. The method of claim 41 where the actuator probe delivers energy to the target site.

43. The method of claim 42 where the energy is magnetic, or magnetic induction.

44. The method of claim 42 where the energy is electrical.

45. The method of claim 42 where the energy is ultrasonic.

46. The method of claim 42 where the energy is chemical, biological, or biochemical.

47. The method of claim 42 where the energy is optical, low energy laser, or high energy laser.

48. The method of claim 42 where the energy can be varied in duration, intensity, and/or frequency.

49. The method of claim 42 where the actuator probe is part of a neuromodulation device left resident in the target site.

50. The method of claim 42 where the actuator probe is used in the target site but removed or disabled when not in use.

51. The method of claim 42 where the actuator probe is left resident in the target site with any one or more of the controller, the energy supply or other such components of the neuromodulation device external to the target site.

52. The method of claim 42 where the energy delivered to the target site induces the target site to modulate the olfactory neurons.

53. The method of claim 52 where the modulation of the olfactory neurons results in a

percept in the patient.

54. The method of claim 52 where the modulation of the olfactory neurons results in, or brings about a desired state of mind.

55. The method of claim 54 where the desired state of mind results in a lessening, mitigating, reduction of, therapy for, or otherwise considered treatment of depression, anxiety or other mood disorder.

56. The method of claim 42 where the delivery of the energy is under active control by the patient.

57. The method of claim 42 where the delivery of the energy is under active control by a physician or clinician or other person other than the patient.

58. The method of claim 42 where the delivery of the energy is under control by a preprogrammed controller.

59. A method for suppressing, treating or preventing pain, headache or migraine, or other physical disorders which cause physical discomfort in a patient, the method comprising: positioning at least one actuator probe of a neuromodulation device adjacent to or around at least one target site, said at least one target site selected from the group consisting of the patient's: olfactory nerves, olfactory neuron receptors, olfactory epithelium, nasal cavity.

60. The method of claim 59 where the actuator probe delivers energy to the target site.

61. The method of claim 60 where the energy is magnetic, or magnetic induction.

62. The method of claim 60 where the energy is electrical.

63. The method of claim 60 where the energy is ultrasonic.

64. The method of claim 60 where the energy is chemical, biological, or biochemical.

65. The method of claim 60 where the energy is optical, low energy laser, or high energy laser.

66. The method of claim 60 where the energy can be varied in duration, intensity, and/or frequency.

67. The method of claim 60 where the actuator probe is part of a neuromodulation device left resident in the target site.

68. The method of claim 60 where the actuator probe is used in the target site but removed or disabled when not in use.

69. The method of claim 60 where the actuator probe is left resident in the target site with any one or more of the controller, the energy supply or other such components of the neuromodulation device external to the target site.

70. The method of claim 60 where the energy delivered to the target site induces the target site to modulate the olfactory neurons.

71. The method of claim 70 where the modulation of the olfactory neurons results in a

percept in the patient.

72. The method of claim 71 where the percept brings about a desired state of mind.

73. The method of claim 71 where the percept is one of a lessening, reduction in, therapy of or otherwise considered treatment for pain, migraine, headache or other physical disorder which cause physical discomfort in the patient.

74. The method of claim 60 where the delivery of the energy is under active control by the patient.

75. The method of claim 60 where the delivery of the energy is under active control by a physician or clinician or other person other than the patient.

76. The method of claim 60 where the delivery of the energy is under control by a preprogrammed controller.