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Document Type and Number:
WIPO Patent Application WO/2000/023141
Kind Code:
This invention is an electrical stimulation of the vomeronasal organ (VNO) in humans to affect hypothalamic activity to influence autonomic function, to regulate hormone levels, particularly for contraception, and treatment of diseases including prostate cancer, reproductive disorders, and affective disorders. Electrical stimulation is by accomplished an apparatus consisting of a voltage source (32), a means for modulating the voltage (34), and an electrode (36). The signal is provided to the VNO through contact between VNO receptors and the electrode.

Application Number:
Publication Date:
April 27, 2000
Filing Date:
October 21, 1999
Export Citation:
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International Classes:
A61M31/00; C07J9/00; (IPC1-7): A61N1/00
Foreign References:
Attorney, Agent or Firm:
Alboszta, Marek (Suite 110 Santa Clara, CA, US)
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CLAIMS What is claimed is:
1. A method for affecting hypothalamic activity of a mammal having a vomeronasal organ (VNO). said method comprising the step of electrically stimulating said VNO.
2. The method of claim 1 wherein said hypothalamic activity comprises hormone level regulation in said mammal.
3. A method for affecting an autonomic function of a mammal having a vomeronasal organ (VNO). said method comprising the step of electrically stimulating said VNO.
PCT Patent Application entitled ELECTRICAL STIMULATION OF THE VOMERONASAL ORGAN for NOAM SOBEL CROSS-REFERENCE TO RELATED APPLICATIONS This application is based on Provisional application 60/105,053 filed 10/21/98, which is herein incorporated by reference.

FIELD OF THE INVENTION This invention relates generally to treatment and prevention of medical conditions by affecting hormone balance. More particularly, it relates to electrical stimulation of the vomeronasal organ (VNO) to affect activity of the hypothalamic-pituitary axis.

BACKGROUND ART Many human conditions and diseases are affected by bodily hormone levels. Some. including prostate and other cancers, affective disorders of all kinds, and reproductive disorders, are pathological results of hormone imbalances. A variety of non-pathological conditions. including mood states, are also strongly affected by hormone levels. Manipulation of hormone levels can also be used to generate desired outcomes, as is done with oral contraceptives. The ability to selectively control hormone levels, therefore, has the potential to provide enormous human benefit.

Hormone level regulation is accomplished by a complicated feedback system involving the hypothalamus and pituitary gland. The hypothalamus releases luteinizing hormone-releasing hormone (LHRH). which stimulates the pituitary gland to produce luteinizing hormone (LH) and other hormones. LH then travels to various organs throughout the body to stimulate release of hormones that act locally. When the local hormones reach a specific level in the bloodstream.

LHRH production is stopped in the hypothalamus. providing the feedback effect. Current methods for artificially altering hormone levels interfere with the feedback system in some way to trigger the desired production levels of the hormones of interest. Unfortunately. all existing treatments cause side effects that range from mildly irritating to life threatening.

For example. late-stage prostate cancer is often treated with hormone therapy, in an attempt to cause tumor regression and extend the patient's life. It has been known for the past half-century that the male sex hormone testosterone stimulates growth of the prostate and prostate cancer.

Since then. various treatment strategies aimed at depriving the body of male sex hormones.

called androgens, have emerged. Androgens are produced in the testes in response to stimulation by LH and follicle-stimulating hormone (FSH). also produced by the pituitary gland, and act on receptors in the prostate gland. All of the strategies are based on the disruption of the androgen hormone's pathway between the hypothalamus and prostate gland. with each one acting at different locations along the path. For example. some drugs lower testosterone production level, some inhibit release of LH. and some prevent androgen binding to prostate receptors. In general, treatment involves a combination of different types of drugs.

Side effects are common with all drug treatments of late-stage prostate cancer. Most therapies cause reduction in libido and sexual potency, breast enlargement, and fluid retention. all of which are directly related to decreased testosterone levels and cannot usually be avoided. Other side effects are caused by the drug administered. and include cardiovascular problems. damage to the spinal cord and other structures adjacent to the tumor, weakness, impotence, liver injury. gastrointestinal upset. rashes, dizziness. nausea. and diminished cortisone production. It is the latter type that will hopefully be avoided with improved therapies.

Currently, altering hormonal state chemically is the basis for a wide range of medical treatments.

These chemical treatments almost always have some side effects. What is needed is a method for altering hormone level regulation without introducing foreign chemicals into the body. so that side effects are minimized.

OBJECTS AND ADVANTAGES Accordingly. it is a primary object of the present invention to provide a method for altering hormone balance without the side effects produced by standard hormone therapy.

It is another object of the present invention to provide a method of hormone regulation that does not introduce a chemical imbalance into the hormonal system.

It is an additional object of the invention to provide a non-chemical. non-invasive method for affecting hypothalamic activity.

It is a further object of the invention to provide a safe method and apparatus for affecting hypothalamic activity by electrically stimulating the vomeronasal organ.

SUMMARY These objects and advantages are attained by a method for affecting hypothalamic activity of a mammal by electrically stimulating the vomeronasal organ (VNO). The VNO is a small organ located in the base of the nasal septum with pits that open into the nasal passage. Reception of certain chemicals. known as pheromones. by the VNO generates a bioelectric response that

triggers hypothalamic activity. Electrical stimulation mimics the bioelectric response induced by pheromone reception and is tailored to produce specific results. The method may be for hormone level regulation. contraception, or affecting an autonomic function.

Also provided is an apparatus for electrically stimulating the VNO. The apparatus includes a voltage source for providing a voltage. means for modulating the voltage to produce a modulated voltage with predetermined time-dependent parameters. and an electrode for applying the modulated voltage to the VNO. Preferably, the apparatus is implanted into the nose adjacent to the VNO, and consists of a battery. micro-chip and micro-electrode.

BRIEF DESCRIPTION OF THE FIGURES Fig. 1 is a schematic view of a human nasal passage showing the location of the human VNO as known in the prior art.

Fig. 2 is a schematic view of an apparatus of the present invention.

Fig. 3 is a cross-sectional view of an electrode for stimulating the VNO.

Fig. 4 is a side perspective view of a particular embodiment of the apparatus of Fig. 2.

Fig. 5 is a schematic view of the apparatus of Fig. 4 implanted into the nose.

DETAILED DESCRIPTION Although the following detailed description contains many specifics for the purposes of illustration, anyone of ordinary skill in the art will appreciate that many variations and alterations to the following details are within the scope of the invention. Accordingly, the following preferred embodiments of the invention are set forth without any loss of generality to. and without imposing limitations upon. the claimed invention.

The present invention provides a method for affecting hypothalamic activity by electrical stimulation of the vomeronasal organ (VNO). All non-human terrestrial mammals are known to have a VNO. also known as Jacobson's organ. a pit-shaped organ in the nasal passage that contains receptors for airborne chemicals known as pheromones. Pheromones emanate from the skin or bodily secretions of animals. and pheromone reception by the VNO of a member of the same species induces changes in activity of the hypothalamus. a region of the brain. These hypothalamic changes in turn affect activity in the pituitary gland. which modulates hormonal regulation. The changes ultimately induced by pheromone reception cause behavioral and physiological responses usually related to reproduction.

The function. and even existence. of the VNO in humans has been disputed since it was first observed in a human near the beginning of the 18"'century. Whether due to the"animal-like" connotations of the VNO. or to the general lack of scientific interest in chemical sensing in humans, the question of VNO presence in humans was not vigorously explored until very

recently. In the last decade, however, substantial evidence has been gathered to show unequivocally that the VNO is present in humans (see, for example, J. Garcia-Velasco and M. J.

Mondragon. J. Steroid Bochem. jlSol. Biol.. vol. 39* pp. 561-564. 1991).

A schematic diagram of a human nasal region 10 containing a vomeronasal organ (VNO) 12 is shown in Fig. 1. VNO 12 is located in the bottom of the septum, with a pit 14 opening into the nasal cavity. Pit 14 is between 0.2 and 2 mm in diameter, and is located approximately 2 cm into the nasal passage. Fig. 1 shows only pit 14 in the left nostril. but a similar pit opens into the right nostril. The olfactory nerves 16 are located in a separate region of the nasal passage. Olfactory nerves 16 and nerves associated with VNO 12 perform mutually exclusive functions: stimulating the VNO has no effect, therefore. on olfaction.

The function of both pheromones and the VNO in humans is yet to be determined conclusively, but evidence for the VNO's being functional is accruing. Recent studies. reported in K. Stern and M. K. McClintock,"Regulation of Ovulation by Human Pheromones atllreq vol. 392. pp.

177-179 (1998) show a classic pheromonal effect in women: a chemical in human sweat modulates the timing of menstruation. Currently, human VNO research focuses on chemical activation. Putative pheromones. steroid compounds believed to mimic the functionality of naturally-occurring pheromones. have recently been developed. These compounds have been used to test hypothalamic activity as a result of VNO reception. A number of putative pheromones are disclosed in U. S. patents issued to Berliner. Adams, and Jennings-White. For example. U. S. Patent No. 5,939. 570, issued to Berliner et al.. discusses some of these compounds and the behavioral and physiological responses they induce.

VNO structure in humans has not yet been determined. However. VNO structure in animals is well-established, and human structure is likely to be very similar. In animals. bipolar VNO receptor neurons have axons that carry electrical signals to the accessory olfactory bulb (AOB).

From the AOB. information travels to the amygdala and then directly to the hypothalamus. The references cited above detect autonomic responses induced by exposure of the VNO to putative pheromones. indicating that the neural pathways in other mammals exist in similar form in humans.

The present invention takes advantage of the close connection between the VNO and hypothalamus to control hypothalamic activity by electrically stimulating the VNO. Electrical stimulation of the VNO can mimic the effect of pheromones on VNO receptors. and this mimicking can be harnessed to alter hormonal state in a predetermined manner. The hypothalamus is responsible for regulating hormone levels in the bloodstream, and also controls autonomic functions. including pulse rate. blood pressure, and skin conductivity.

While electrical microstimulation of the human VNO has not yet been performed. it is well known that neurons may be stimulated electrically. and that electrical stimulation simulates bioelectric signal generation induced by neurotransmitters and other chemicals.

Microstimulation has been performed in other locations within the human nervous system under several different circumstances. Most commonly, microstimulation is used during neurosurgery in order to functionally characterize a brain region that is about to be excised or lesioned. It has also been used to generate sensation in phantom limbs. and visual sensations in the blind. In animals. it has been shown that microstimulation can be used to replicate neural activity representing sensory perceptions. For example, microstimulation of different locations on the cochlear nucleus in cats produces corresponding tonotopic responses in the inferior colliculus. and rats can discriminate among microstimulation of different locations on the olfactory bulb.

In addition, recent studies indicate that it will be possible to tailor the applied electrical signal to achieve a desired result. Putative pheromones have been applied to the VNO, and the induced electrical surface potentials have been measured. These studies are documented in L. Monti- Bloch and B. I. Grosser."Effect of Putative Pheromones on the Electrical Activity of the Human Vomeronasal Organ and Olfactory Epithelium."J. Steroid Biochem. Mol. Biol., vol. 39. pp. 573- 582 (1991) ; L. Monti-Bloch et al.."The Human Vomeronasal System." Psychoneuroendocrinology, vol. 19 (5-7), pp. 673-686 (1994) ; D. T. Moran et al.."Structure and Function of the Human Vomeronasal Organ."in R. L. Doty, editor, Handbook of Giistation and Olfaction. New York: Marcel Dekker, pp. 793-821 (1995) ; and in U. S. Patent No. 5*303703* issued to Monti-Bloch, which discloses a method and device for delivering pheromones to the VNO and recording its electrical response.

In the above studies. a brief depolarization of the VNO epithelium was recorded after introduction of the putative pheromone. A typical response to a stimulation of 30 pg (1 sec) of the stimulating chemical consists of a 100 msec latency followed by a sharp depolarization of about 4 mV that then exponentially returns to baseline within about 2.5 sec. As with most neurons, adaptation is seen quite rapidly, after about 1 second: even when the signal is maintained. the amplitude falls to the baseline. This effect is observed both with continuous pheromone streams and with repeated short-duration pulses. Pulse characterizations vary with the particular chemical and with dosage. Different putative pheromones in identical concentrations induce signals of different amplitude and recovery slopes, as do different doses of the same putative pheromones. Responses also differ dramatically between men and women.

The method of the present invention aims to induce similar responses by electrically stimulating the VNO with specific stimulation parameters. Parameters may be optimized and correlated with desired hypothalamic responses. In general, the following parameters are varied in the preferred ranges listed:

Amplitude: 40 usa-7.4 mA. and most preferably 40 lia-3 mA.

Frequency: 1-500 Hz. and most preferably 100-500 Hz.

* Pulse Duration: 100 us-1 s. and most preferably 200 us-500 u. s.

* Train Length: 0.5-10 s. and most preferably 2-10 s.

Inter-pulse Interval: 0-1 s.

Inter-train Interval: 0-10 s.

* Overall number of trains: 1-50.

Note that the preferred ranges are similar to those used in other animals and for other modalities.

Electrical stimulation of the VNO provides many benefits over both traditional hormonal therapy and chemical activation of the VNO. Even though chemical activation of the VNO using putative pheromones may reduce side effects found with traditional hormone therapy, introduction of a foreign substance into the body always brings a possibility of detrimental side effects. In addition. putative pheromones have been shown to produce effects at concentrations on the order of 10-'8 molar. It is virtually impossible to ensure that during administration of a nasal spray to one individual. these volatile compounds will not diffuse to the VNO of a different individual in sufficient concentration to have an effect. In contras electrical stimulation of the VNO of a patient obviously has no effect on other individuals. Electrical stimulation has the distinct advantage over existing methods for altering hormone balance that it does not introduce a chemical imbalance into the hormonal system. Rather, it"tricks''the nervous system into changing its own hormonal state. and therefore minimizes side effects.

The current method and apparatus may be used to affect any condition or behavior related to hypothalamic activity. Specific intended purposes for the present invention include contraception for both men and women, treatment of prostate cancer, and treatment of affective disorders. The following examples indicate how VNO stimulation may be used.

Prostate Cancer. Various types of hormone therapies are currently used for treating late-stage prostate cancer. The overarching goal is either to reduce androgen (primarily testosterone) levels in the bloodstream dramatically, or to block androgen receptors on the prostate. Many of these methods may be adapted to electrical stimulation of VNO: Estrogen and synthetic estrogen hormones act directly on the pituitary gland to inhibit LH release, which decreases androgen production by the testes. The same goal may be achieved bv stimulating the VNO to prevent release of LHRH by the hypothalamus.

LHRH agonists mimic LHRH. Initially. LH levels are increased. but, under constant stimulation from the LHRH-like drug, the pituitary gland becomes insensitive and eventually stops responding. By stimulating the VNO to cause increased LHRH release by the hypothalamus. the same effect can be achieved.

Progestins are a class of steroid hormones. including progesterone and its break-down products. that possess anti-androgen properties. They are produced in men in the adrenal glands and testes. and block both LH release from the pituitary gland and androgen receptors of the prostate gland. VNO stimulation can be tailored to stimulate progestin production at the testes indirectly.

Of course. these suggested uses for electrical stimulation of the VNO are based on existing therapies. and it is likely that further research will produce superior applications. VNO stimulation eliminates side effects caused by many drugs, and is also easier to tailor to a patient's specific needs and existing hormone levels. While many of the existing drug therapies have a lag time before testosterone levels are reduced. VNO stimulation should produce much more rapid hormone level changes. Currently. the only method for immediate suppression of testosterone levels. often needed to save a patient's life. is surgical castration.

Contraceptives. Both male and female contraception may be effected by electrical stimulation of the VNO.

In females, existing oral contraceptives provide a constant level of progestins. and sometimes also estrogen. in order to prevent ovulation. Since their introduction in the 1960's. oral contraceptives have been improved dramatically to decrease and optimize the dosage to minimize side effects. and a great deal of research has been performed to determine required hormone levels. Research on VNO electrical stimulation takes advantage of this work to determine parameters needed to produce the desired hormone levels. VNO stimulation triggers production of progestins by the ovaries by increasing LHRH and LH production. Because VNO stimulation triggers the nervous system to alter its own hormone levels, it can potentially be tailored to produce the optimal effects in each woman, thereby avoiding many of the common side effects.

Much less is known about hormonal contraception in males, and it is likely that VNO stimulation in men will not be met with as much interest. Follicle-stimulating hormone (FSH). released by the pituitary gland. stimulates sperm production in the testes. Release of FSH is induced by LHRH. and therefore activity of the hypothalamus may be influenced to prevent LHRH release.

The above examples are intended to illustrate how electrical stimulation of the VNO can be exploited to provide desired hormonal levels needed to treat conditions or diseases. Of course. electrical stimulation of the VNO may be used for any condition influenced bv the hypothalamus. or for any condition caused by hormone imbalance. Examples include other types of cancer. affective disorders of all kinds. and disorders related to reproduction. Hormone- related disorders are well known in the art. and the present invention may be used to treat these. as well as currently-unknown diseases. Non-pathological conditions, for example. mood levels and stress. may also be treated by electrically stimulating the VNO.

Fig. 2 shows a highly schematic diagram of an apparatus 20 used to carry out the method of the invention. Apparatus 20 contains a voltage source 22, means 24 for modulating the voltage to produce a signal with predetermined time-dependent parameters. and an electrode 26 for applying the signal to the VNO. The VNO receptors. accessed through the pit, are contacted with electrode 26. The apparatus may also be used for simultaneous recording of surface potentials induced by the stimulation. The predetermined time-dependent parameters are chosen specifically to produce the desired effect in the hypothalamus. An entire treatment schedule may be preprogrammed into modulator means 24, or the parameters may be changed during treatment.

There are two preferred embodiments of the apparatus. The first is an in-clinic form and is typically used by a physician or other healthcare provider. The in-clinic embodiment has few limitations on the particular components used. as long as the required signal can be generated.

The components are commonly known in the art. and any suitable components may be used. It is also well known in the art how to use the apparatus to generate the preferred electrical signal.

A particular example of the apparatus is an adaptation of those described in E. J. Tehovnik.

"Electrical Stimulation of Neural Tissue to Evoke Behavioral Responses,"J. Neurosci. Methods, vol. 65 (1), pp. 1-17 (1996) and in S. C. Gandevia and J. P. Hales."The Methodology and Scope of Human Microneurography. ''J. lVeurosci. Methods, vol. 74 (2), pp. 123-126 (1997), both of which are herein incorporated by reference. Note that these studies were not of VNO stimulation.

In this particular example. modulating means 24 includes amplifiers. filters. and other circuitry.

The main requirements for amplifiers used in the apparatus of the present invention is that they provide a high degree of electrical safety combined with high signal-to-noise ratio. In addition. if both stimulation and recording are performed. the apparatus must enable a rapid transition from stimulating to recording. Stimulation (and recording, if desired) is controlled from a main amplifier followed by a standard Neurolog device containing amplifiers and filters. The main amplifier contains an active bridge circuit as well as capacitance and resistance compensations.

A differential input artifact suppresser can be used to assure that the stimulating pulses do not contaminate the ensuing recording. Stimulation pulses and recordings are amplified to a speaker and viewed on an oscilloscope.

Electrode 26 must be small enough to fit into the VNO pit. which has an approximate diameter of between 0.2 and 2 mm. Preferably. electrode 26 is similar to microelectrodes described in Lenz et al.."Reorganization of Sensory Modalities Evoked by Microstimulation in Regions of the Thalamic Principal Sensorv Nucleus in Patients with Pain Due to Nervous System Injury."J.

Co1p../\eurol. vol. 39 (1). pp. 125-138 (1998). A preferred embodiment of an electrode 21 is

shown in Fig. 3. Electrode 21 is made of a platinum-iridium (70%-30%) wire 23 with a diameter 25 of 200 um that tapers to a tip 31 with a diameter 27 of 3-4 um. A coating layer of solder glass 28 surrounds wire 23, leaving an amount 29, about 5-10 um. of the end exposed. Electrode 21 can be fitted to a carrier tube at the tip of an arm connected to the main amplifier and controlled by a hydraulic drive. The electrode is then guided by the arm into the opening of the VNO pit. Electrode 21 is neither painful nor uncomfortable when inserted into the VNO pit.

Electrode 21 may be made by any suitable method. In particular, electrode 21 can be made by electrolytic etching of wire 23 by passing a current. preferably 12 V and 60 Hz. through wire 23 into a solution of sodium hydroxide (30%) and sodium cyanide (50%) using a graphite rod as the other electrode. The taper is achieved by attaching the wire eccentrically to the armature of an electric motor at 6 RMP, oriented such that the wire enters the etching solution at an oblique angle. Thus, as the motor rotates, the distal part of wire 23 is etched for longer than the proximal part. producing a uniform taper.

A treatment schedule is devised based on the patient's condition, and may range from a one-time application to an extended treatment over months or years. For example, a patient may receive treatments in the clinic once per week for a few months. The duration of each treatment will vary with the condition and desired effect. The in-clinic embodiment is best suited for treatments that are either sporadic or related to non-chronic conditions. and that require close physician supervision. For example, prostate cancer treatment is best performed with the in- clinic embodiment.

A second embodiment, an implantable apparatus 30, is illustrated schematically in Fig. 4.

Apparatus 30 is similar to apparatus 20, in that it contains a voltage source, in this case a battery 32; a modulating means. a chip 34 ; and an electrode 36. Apparatus 30 is small enough that it may be implanted in the nose so that electrode 36 is positioned to contact the VNO receptors.

Fig. 5 illustrates placement of apparatus 30 inside the septum. Implanted electrical devices are well-known in the art. and the present invention is similar to such devices. For example. pacemakers are small devices that are implanted in the chest for delivering electrical signals to the heart. Recently. vagus nerve stimulation was approved by the FDA for treating epilepsy. A small device is implanted in the chest. and an electrode is connected from the device to the vagus nerve in the side of the neck for delivering a small electrical current. It is obvious to one skilled in the art how to adapt such devices for use in the present invention.

Chip 34 contains a preprogrammed regimen for stimulating the VNO. Alternately. apparatus 30 may be controlled bv wireless means outside the body to change the regimen administered without removing the implanted device. Apparatus 30 may also be turned on and off by the

patient without removing the device. In general, any variations and features that are provided in pacemakers and other implanted signal-generating devices may be applied to apparatus 30.

Implantable apparatus 30 of the present invention is particularly well suited to applications requiring fairly constant stimulation of the VNO. For example, use of the apparatus for male and female contraception requires continual regulation of hormone levels, which is not well suited to clinic administration. Chronic conditions. such as affective disorders, are also best treated with the implanted device.

It will be clear to one skilled in the art that the above embodiment may be altered in many ways without departing from the scope of the invention. Accordingly, the scope of the invention should be determined by the following claims and their legal equivalents.