WO2008003318A1

WO2008003318A1 - A research model system and a method for using electrical stimulation and/ chemical stimulation to induce depressive illness in research animals

Info

Publication number: WO2008003318A1
Application number: PCT/DK2007/000338
Authority: WO
Inventors: Jens Christian Hedemann SØRENSEN; Carsten Reidies Bjarkam
Original assignee: Aarhus Universitet; Region Midtjylland
Priority date: 2006-07-05
Filing date: 2007-07-04
Publication date: 2008-01-10

Abstract

The present invention concerns a research model system for causing a depressive illness in an animal subject other than a human being, said system comprising a probe having a stimulation portion in communication with the subcallosal area; and a device to stimulate the probe thereby activating the subcallosal area and causing the depressive illness. By a research model system and method according to the invention, there is provided a research system allowing for causing an increase of activity in the predetermined areas so that test of depressive illness treatment methods can be performed in this research model.

Description

A research model system and a method for using electrical stimulation and/or chemical stimulation to induce depressive illness in research animals

TECHNICAL FIELD

This invention relates to nervous tissue stimulation for inducing a condition resembling depressive illness in research animals by modulating the function of the nervous tissue at a predetermined stimulation site in the brain.

BACKGROUND OF THE INVENTION

Each year several people experience a depressive illness. The types of depressive illness may be clinical depression, including Mild Depression (Dysthymia) and the spectrum of anxiety disorders, Major Depression, and Bipolar Disorder (Manic-Depression). Major Depression is defined by a constellation of chronic symptoms that include sleep problems, appetite problems, anhedonia or lack of energy, feelings of worthlessness or hopelessness, difficulty concentrating, and suicidal thoughts. Bipolar Disorder involves major depressive episodes alternating with high-energy periods of rash behaviour, poor judgment, and grand delusions.

Significant advances in the treatment of depression have been made in the past decade. Since the introduction of selective serotonin reuptake inhibitors (SSRIs), i.e., Prozac(R), many subjects have been effectively treated with anti-depressant medication. However, an estimated 10 to 30 percent of depressed subjects taking an anti-depressant are partially or totally resistant to the treatment. Those who suffer from treatment-resistant depression have almost no alternatives. Thus, there is a need to develop research models of depressive illness that may lead to new treatments for these subjects.

The use of electrical stimulation for treating neurological and psychiatric diseases, such as movement disorders, chronic pain, obsessive compulsive disorder, depression and epilepsy, has been widely discussed in the literature. It has been recognized that electrical stimulation holds significant advantages over lesioning since lesioning destroys the nervous system tissue. In many instances, the preferred effect is to modulate neuronal activity. Electrical stimulation permits such modulation of the target neural structures and, equally importantly, does not require the destruction of nervous tissue. Such electrical stimulation procedures include deep brain stimulation (DBS), electroconvulsive therapy (ECT), repetitive transcranial (rTMS) magnetic stimulation and vagal nerve stimulation (VNS).

Efforts have been made to treat psychiatric disorders with peripheral/cranial nerve stimulation. Recently, partial benefits with vagus nerve stimulation in subjects with depression have been described in U.S. Pat. No. 5,299,569. Another example of electrical stimulation to treat depression is described in U.S. Pat. No. 5,470,846, which discloses the use of transcranial pulsed magnetic fields to treat depression. Yet further, U.S. Pat. No. 5,263,480 describes that stimulation of the vagus nerve may control depression and compulsive eating disorders and U.S. Pat. No. 5,540,734 teaches stimulation of the trigeminal or glossopharyngeal nerves for psychiatric illness, such as depression.

Deep brain stimulation (DBS) has been applied to the treatment of central pain syndromes and movement disorders, and it is currently being explored as a therapy for epilepsy. For instance, U.S. Pat. No. 6,016,449 and U.S. Pat. No. 6,176,242 disclose a system for the electrical stimulation of areas in the brain for the treatment of certain neurological diseases such as epilepsy, migraine headaches and Parkinson's disease. From US 2005/033379, which is incorporated by reference, there is known a further method and system using electrical stimulation and/or chemical stimulation to treat depression.

To improve methods of treating depressive illnesses, and particularly to test the effectiveness of such methods and its potential side effects, extensive research is being performed. However, research on human subjects with depressive illness is complicated by the severeness of the disease and the inaccessible brain tissue. There is, accordingly, a need for research animals which display human like depressive illness in order to provide improved research facilities for achieving comparative test results to evaluate established and future treatments of depressive illness.

SUMMARY OF THE INVENTION

By the invention, it is realised that in order to improve methods of depressive illness treatment there is realised a need to improve research facilities by providing a research model system for causing depressive illness in an animal subject other than a human being.

Accordingly, the invention concerns a research model system for causing depressive illness in an animal subject other than a human being, said system comprising a probe having a stimulation portion in communication with the subcallosal area, and a device to stimulate the probe thereby activating the subcallosal area and causing the depressive illness. Moreover, the invention concerns a research system for causing subjects with depressive illness in an animal subject other than a human being, said system comprising an electrical stimulation lead that is implanted into the subject's brain, said lead comprising at least one electrode that is in communication with an area homologous to Brodmann area 25 in humans and delivers an electrical signal to the homolog Brodmann area 25; and a signal generator that generates the electrical signal for transmission to the at least one electrode of the lead resulting in delivery of the electrical signals to the homolog Brodmann area 25 thereby causing the depressive illness.

In a further aspect of the invention, there is provided a research system for causing subjects with depressive illness in an animal subject other than a human being, said system comprising a catheter that is implanted into a subject's brain, said catheter having a proximal end coupled to a pump and a discharge portion for infusing a dosage of a pharmaceutical by the catheter into the subcallosal area; and a pump to discharge the pharmaceutical through the discharge portion of the catheter into the predetermined site thereby chemically stimulating the subcallosal area and causing the depressive illness.

The invention furthermore relates to a method for causing subjects with depressive illness in an animal subject other than a human being. The invention also relates to the use of the system for causing subjects with depressive illness in an animal subject other than human beings, where said subject is a research animal selected from the group comprising mammals e.g. primates, pigs, cats, dogs and research mice or research rats. The invention also relates to the use of the system for causing subjects with depressive illness in an animal subject other than human beings, where said subject is a genetically modified research animal developed by genetical engineering e.g. knock out, knock in, iRNA or siRNA techniques from the animal group comprising mammals e.g. primates, pigs, cats, dogs and research mice or research rats.

In certain embodiments, the invention uses electrical stimulation and/or chemical stimulation, i.e. one or more pharmaceuticals, to cause depressive illness. In addition to electrical and/or chemical stimulation, magnetic stimulation can also be used, such as transcranial magnetic stimulation ("TMS"). According to one embodiment of the invention, the stimulation modulates areas of the brain that exhibit altered activity in subjects relative to psychiatrically normal control subjects, thereby causing depressive illness. Such stimulation is likely to be produced by electrical stimulation, an excitatory neurotransmitter or agonist(s) thereof, an inhibitory neurotransmitter of antagonist(s) thereof, and/or a medication that increases the level of an excitatory neurotransmitter or decreases the level of an inhibitory neurotransmitter. Another embodiment of the invention uses genetic techniques to stimulate the areas of the brain that exhibit altered activity in subjects relative to psychiatrically normal control subjects, thereby causing depressive illness. Such stimulation is likely to be produced the injection of stem cells, iRNA, siRNA, viral vectors, genetically modified stem cells or encapsulated cells resulting in increase activity in the targeted brain area and thus causing depressive illness.

One embodiment of the present invention utilizes neurosurgical intervention to modulate the pathological activity of the subcallosal area in subjects to cause depressive illness. Such interventions include applying electrical stimulation, herein termed "deep brain stimulation" or DBS, as is currently practiced to treat a number of disorders like Parkinson's disease. Other stimulations can include chemical stimulation such as through the use of pharmaceutical or drug pumps, for example local delivery of neuroactive substances or genetically engineered substances to cause the pathological activity stemming from or coursing through this area. It is envisioned that such stimulation (i.e., electrical, magnetic, chemical or genetic) modulates the grey matter and white matter tracts in a subcallosal area, as well as the white matter tracts that are associated with the subcallosal area (such as the white matter tracts that lead to and from the subcallosal area or that are adjacent to the subcallosal area), which in turn modulates the limbic system. Still further, other stimulations may comprise magnetic stimulation and/or transplantation of cells or genetic manipulation based on iRNA and siRNA techniques. Such simulations can be verified by a research model system according to the invention.

According to one embodiment of the invention, it is realised that the electrical activation for causing mood and/or anxiety disorder may be provided by applying a low frequency signal, such as a frequency below approx. 120 Hz and more preferably below 60 Hz. When applying a high frequency, e.g. above 120 Hz, a treatment of the depression is achieved. However, according to this embodiment of the invention it is realised that by applying a low frequency in the above-mentioned ranges, the reverse simulation effect may be achieved resulting in depressive illness. This provides an effective research animal tool for studying the effectiveness of both the known treatments of depressive illness and developing new and improved treatments.

Certain embodiments of the present invention involve a method that comprises surgically implanting a device or research stimulation system in communication with a predetermined site, for example the subcallosal area, in the subject's brain. The device or stimulation system is operated to stimulate the predetermined site thereby causing the depressive illness. The device or stimulation system may include a probe, for example, an electrode assembly (i.e., electrical stimulation lead), pharmaceutical-delivery assembly (i.e., catheters or encapsulated cell devices) or combinations of these (i.e., a catheter having at least one electrical stimulation lead) and/or a signal generator or signal source (i.e., electrical signal source, chemical signal source (i.e., pharmaceutical delivery pump) or magnetic signal source). The probe may be coupled to the electrical signal source, pharmaceutical delivery pump, or both which, in turn, is operated to stimulate the predetermined treatment site. Yet further, the probe and the signal generator or source can be incorporated together, wherein the signal generator and probe are formed into a unitary or single unit, such unit may comprise, one, two or more electrodes. These devices are known in the art as microstimulators, for example, Bion(TM) which is manufactured by Advanced Bionics Corporation.

It is envisioned that the predetermined site is the subcallosal area. The subcallosal area includes, but is not limited to the subgenual cingulate area, subcallosal gyrus area, ventral/medial prefrontal cortex area, ventral/medial white matter, Brodmann area 24,

Brodmann area 25, and/or Brodmann area 10. More specifically, the predetermined site is a subgenual cingulate area, more preferably Brodmann area 25, Brodmann area 24 or Brodmann area 10. When referring to the Brodmann areas and other areas throughout this specification, homolog areas in the brain of the animal subject other than human beings are meant. By a research model system and method according to the invention, there is provided a research system allowing for causing an increase of activity in the predetermined areas so that test of depressive illness treatment methods can be performed in this research model.

Stimulation of the subcallosal area includes stimulation of the grey matter and white matter tracts associated with the subcallosal area that result in the depressive illness. Associated white matter tracts includes the surrounding or adjacent white matter tracts leading to or from the subcallosal area or white matter tracts that are contiguous with the subcallosal area. Modulating the subcallosal area via electrical and/or chemical stimulation (i.e., pharmaceutical or gentical) and/or magnetic stimulation can result in increasing, decreasing, masking, altering or overriding neuronal activity resulting in the depressive illness. Yet further, stimulation of the subcallosal area may result in modulation of neuronal activity of other areas of the brain, for example, Brodmann area 24, Brodmann area 25, Brodmann area 10, Brodmann area 9, the hypothalamus and the brain stem.

Another embodiment of the present invention comprises a method of causing the depressive illness comprising the steps of: surgically implanting an electrical stimulation lead having a proximal end and a stimulation portion, wherein after implantation the stimulation portion is in communication with a predetermined site; the stimulation lead is coupled to or in communication with a signal generator; and an electrical signal is generated using the signal generator to modulate the predetermined site thereby causing the depressive illness.

In further embodiments, the method can comprise the steps of: surgically implanting a catheter having a proximal end coupled to a pump and a discharge portion for infusing a dosage of a pharmaceutical or genetically engineered substance, wherein after implantation the discharge portion of the catheter is in communication with the predetermined stimulation site; and operating the pump to discharge the pharmaceutical through the discharge portion of the catheter into the stimulation site thereby causing the depressive illness. The pharmaceutical is selected from the group consisting of excitatory neurotransmitter and agonists thereof, an inhibitory neurotransmitter and antagonist thereof, an agent that decreases the level of an inhibitory neurotransmitter, an agent that increase the level of an excitatory neurotransmitter. The genetically engineered substance is selected from the group consisting of injection of stem cells, iRNA, siRNA, viral vectors, genetically modified stem cells or encapsulated cells. It is envisioned that chemical stimulation or infusion of pharmaceuticals or genetically engineered substances can be performed independently of electrical stimulation and/or in combination with electrical stimulation.

Another embodiment of the present invention is a method of causing depressive illness comprising the steps of: surgically implanting an electrical stimulation lead having a proximal end and a stimulation portion, wherein after implantation the stimulation portion is in communication with a predetermined site; surgically implanting a catheter having a proximal end coupled to a pump and a discharge portion for infusing a dosage of a pharmaceutical and/or genetically engineered substance, wherein after implantation the discharge portion of the catheter is in communication with a predetermined infusion site; and coupling the proximal end of the lead to a signal generator; generating an electrical signal with the signal generator to modulate the predetermined site; and operating the pump to discharge the pharmaceutical and/or the genetically engineered substance through the discharge portion of the catheter into the infusion site thereby causing the depressive illness.

Other embodiments of the present invention include a system for causing subjects with depressive illness. The therapeutic research system comprises an electrical stimulation lead that is implanted into the subject's brain. The electrical stimulation lead comprises at least one electrode that is in communication with a predetermined site and delivers electrical signals to the predetermined site; and a signal generator that generates signals for transmission to the electrodes of the lead resulting in delivery of electrical signals to predetermined site thereby causing the depressive illness. The electrical stimulation lead may comprise one electrode or a plurality of electrodes in or around the target area. Still further, the signal generator is implanted in the subject's body.

Another example of a therapeutic research model system includes a catheter having a proximal end coupled to a pump and a discharge portion for infusing a dosage of a pharmaceutical and/or genetically engineered substance, wherein after implantation the discharge portion of the catheter is in communication with a predetermined stimulation site; and a pump to discharge the pharmaceutical and/or genetically engineered substance through the discharge portion of the catheter into the predetermined stimulation site thereby causing the depressive illness.

Still further, another therapeutic research model system comprises a device that is surgically implanted into the subject such that the device is in communication with a predetermined site, for example the subcallosal area. An exemplary device includes a microstimulator (i.e., Bion(TM) manufactured by Advanced Bionics Corporation) in which the device contains a generating portion and at least one electrode in a single unit. In further embodiments, a lead assembly is associated with at least one electrode of the microstimulator such that the lead can stimulate the predetermined site not in direct contact with the microstimulator.

Other therapeutic research model systems according to the invention may include a probe that is in communication with the predetermined site and a device that stimulates the probe thereby causing the depressive illness. The probe can be, for example, an electrode assembly (i.e., electrical stimulation lead), pharmaceutical and/or genetically engineered substance-delivery assembly (i.e., catheters) or combinations of these (i.e., a catheter having at least one electrical stimulation lead). The probe is coupled to the device, for example, electrical signal source, pharmaceutical and/or genetically engineered substance delivery pump, or both which, in turn, is operated to stimulate the predetermined treatment site.

The foregoing has outlined rather broadly the features and technical advantages of the present invention in order that the detailed description of the invention that follows may be better understood. Additional features and advantages of the invention will be described hereinafter which form the subject of the claims of the invention. It should be appreciated that the conception and specific embodiment disclosed may be readily utilized as a basis for modifying or designing other structures for carrying out the same purposes of the present invention. It should also be realized that such equivalent constructions do not depart from the invention as set forth in the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a schematic diagram showing the resulting effect of electrical stimulation on the brain tissue nerve cells depending on the frequency input.

DETAILED DESCRIPTION OF THE INVENTION

It is readily apparent to one skilled in the art that various embodiments and modifications can be made to the invention disclosed in this Application without departing from the scope and spirit of the invention.

Electrical Stimulation Devices that can be used for causing a depression state in a subject are described in US2005/033379.

While not being bound by the description of a particular procedure, subjects who are to have an electrical stimulation lead or electrode implanted into the brain, generally, first have a stereotactic head frame, such as the Leksell, CRW, or Compass, mounted to the subject's skull by fixed screws. A stereotactic headframe for quadrupeds are disclosed in WO

2004/058085 A1. However, frameless techniques may also be used. Subsequent to the mounting of the frame, the patient typically undergoes a series of magnetic resonance imaging (MRI) sessions, during which a series of two dimensional slice images of the patient's brain are built up into a quasi-three dimensional map in virtual space. This map is then correlated to the three dimensional stereotactic frame of reference in the real surgical field. In order to align these two coordinate frames, both the instruments and the patient must be situated in correspondence to the virtual map. The current way to do this is to rigidly mount the head frame to the surgical table. Subsequently, a series of reference points are established to relative aspects of the frame and the patient's skull, so that either a person or a computer software system can adjust and calculate the correlation between the real world of the patient's head and the virtual space model of the subject's MRI scans. The surgeon is able to target any region within the stereotactic space of the brain with precision (i.e., within 1 mm). Initial anatomical target localization is achieved either directly using the MRI images, or indirectly using interactive anatomical atlas programs that map the atlas image onto the stereotactic image of the brain. As is described in greater detail below, the anatomical targets may be stimulated directly or affected through stimulation in another region of the brain. The anatomical target for causing a depressive state is described in US2005/033379. The stimulation lead, and stimulation source implantation is also described in US2005/033379. In quadrupeds the stimulation source implantation can in addition take place in the neck and back region.

Initially, there is an impetus to model or create psychiatric disorders in an experimental animal with direct modulation of activity in that portion of the brain causing the pathological behaviour. In this regard, there have been a large number of anatomical studies that have helped to identify the neural structures and their precise connections implicated in psychiatric activity/disorders. These are the structures that are functioning abnormally and manifesting in psychiatric/behavioural/addiction disorders. Numerous anatomical studies from autopsies, animal studies, and imaging such as computerized tomography (CT) scans, and magnetic resonance imaging (MRI) scans have demonstrated the role of these structures and their connections in psychiatric activity/disorders. In addition to these anatomical studies, a number of physiological techniques and diagnostic tools are used to determine the physiological aberrations underlying these disorders. This includes electrical methods such as electroencephalography (EEG), magnetoencephalography (MEG), as well as metabolic and blood flow studies such as functional magnetic resonance imaging (fMRI), and positron emission tomography (PET). The combination of the anatomical and physiological studies have provided increased insight into our understanding of the structures which are involved in the normal functioning or activity of the brain and the abnormal functioning manifesting in psychiatric, behavioural and addiction disorders.

The present invention finds utility in its application to model human psychological or psychiatric activity/disorders in an animal subject other than human beings, e.g. mammals such as a pig or a primate, as it is appreciated that the present invention is applicable to all experimental animals or genetic modifications thereof. This may include, for example, rodents, pigs, primates, canines, felines, ruminants etc. Utilizing the various embodiments of the present invention, one skilled in the art may be able to modulate the functional outcome of the brain to achieve a depression like state in the subject.

One technique that offers the ability to affect neuronal function is the delivery of electrical, chemical and/or genetically engineered substance, and/or magnetic stimulation for neuromodulation directly to target tissues via an implanted device having a probe. The probe can be a stimulation lead or electrode assembly or drug and/or genetically engineered substance -delivery catheter, or any combination thereof. The electrode assembly may be one electrode, multiple electrodes, or an array of electrodes in or around the target area. The proximal end of the probe can be coupled to a device, such as an electrical signal source, pharmaceutical delivery pump, or both which, in turn, is operated to stimulate the predetermined treatment site. In certain embodiments, the probe can be incorporated into the device such that the probe and the signal generating device are a single unit.

Certain embodiments of the present invention involve a method of causing a depressive illness comprising the steps of: surgically implanting an electrical stimulation lead having a proximal end and a stimulation portion, wherein after implantation the stimulation portion is in communication with a predetermined site; coupling the proximal end of the lead to a signal generator; and generating an electrical signal with the signal generator to modulate the predetermined site thereby causing the depressive illness.

In further embodiments, neuromodulation of the predetermined site of the present invention can be achieved using magnetic stimulation. One such system that can be employed and that is well known in the art is described in U.S. Pat. No. 6,425,852, which is incorporated herein by reference.

The disease modulating system or deep brain stimulation system of the present invention is surgically implanted as described in the above sections. One of skill in the art is cognizant that a variety of electrodes or electrical stimulation leads may be utilized in the present invention. It is desirable to use an electrode or lead which contacts or conforms to the target site for optimal delivery of electrical stimulation. One such example is a single multi-contact electrode with eight contacts separated by 2-2.5 mm each contact having a span of approximately 2 mm. Another example is an electrode with two 1 cm contacts with a 2 mm intervening gap. Yet further, another example of an electrode that can be used in the present invention is a 2 or 3 branched electrode/catheter to cover the predetermined site or target site. Each one of these three pronged catheters/electrodes have four contacts 1-2 mm contacts with a centre to centre separation of 2 of 2.5 mm and a span of 1.5 mm. Similar designs with catheters to infuse drugs and/or genetically engineered substances with single outlet pore at the extremities of these types of catheters or along their shaft may also be designed and used in the present invention. Still further, the present invention extends to methods of transplanting cells into a predetermined site to cause depressive illness. It is envisioned that the transplanted cells can deliver a biologically active molecule to the predetermined site or to induce a condition and/or modulate existing neuronal cells. Such transplantation methods are described in U.S. Application No. US 2004/0092010, which is incorporated herein by reference.

The predetermined site or target area is the subcallosal area, more preferably, the subgenual cingulate area, and more preferably the homolog Brodmann area 25/Brodmann area 24. Stimulation of the subcallosal area (i.e., subgenual cingulate area or Brodmann area 25/Brodmann area 24) and/or the surrounding or adjacent white matter tracts leading to or from the subcallosal area or white matter tracts that are contiguous with the subcallosal area results in changes that cause or induce the depressive illness in the subject. It is contemplated that modulating the subcallosal area, more particularly a subgenual cingulate area, can result in the depressive illness. Yet further stimulation of a subgenual cingulate area, more particularly Brodmann area 25, results in modulation of neuronal activity of other areas of the brain, for example, Brodmann area 9, Brodmann area 10, Brodmann area 24, the hypothalamus, and the brain stem.

Using the disease modulating stimulation system of the present invention, the predetermined site or target area is stimulated in an effective amount or effective stimulation regimen to increase, modulate or induce the depressive illness.

As shown in the diagram in figure 1 , it is realised by the invention that a low frequency, such as a frequency below approx. 60-120 Hz, will cause an increase in activity in the homolog Brodmann 25 area whereby a depression is caused, whereas a high frequency, such as a frequency above 120 Hz will result in an inhibitation of the Brodmann 25 area, and thereby treat the depression. Accordingly, in a research model system according to the invention a low frequency causing an increase in the activity in the subcallosal area and thereby causing a depressive illness in the subject.

According to one embodiment of the present invention, the target site is stimulated using stimulation parameters such as, pulse width of about 1 to about 500 microseconds, more preferable, about 1 to about 90 microseconds; frequency of about 1 to about 120 Hz, more preferably, about 1 to about 60 Hz; and voltage of about 0.5 to about 10 volts, more preferably about 1 to about 10 volts. It is known in the art that the range for the stimulation parameters may be greater or smaller depending on the particular patient needs and can be determined by the physician. Other parameters that can be considered may include the type of stimulation for example, but not limited to acute stimulation, subacute stimulation, and/or chronic stimulation.

It is envisioned that stimulation of the subcallosal area and/or the adjacent white matter modulates other targets in the limbic-cortical circuit or pathway thereby stimulating limbic- cortical circuits resulting in depression and/or anxiety in the subjects.

In order to increase the effectiveness of the electrical activation method of the present invention, it may be desirable to combine electrical activation with chemical and/or genetical activation to cause the depressive illness. In one preferred embodiment, an implantable signal generator and electrical stimulating lead and an implantable pump and catheter(s) are used to deliver electrical stimulation and/or one or more stimulating drugs and/or genetically active substances to the above mentioned areas to cause depressive illness.

Herein, stimulating drugs comprise medications, anaesthetic agents, synthetic or natural peptides or hormones, neurotransmitters, cytokines and other intracellular and intercellular chemical signals and messengers, and the like. In addition, certain neurotransmitters, hormones, and other drugs are excitatory for some tissues, yet are inhibitory to other tissues. Therefore, where, herein, a drug is referred to as an "excitatory" drug, this means that the drug is acting in an excitatory manner, although it may act in an inhibitory manner in other circumstances and/or locations. Similarly, where an "inhibitory" drug is mentioned, this drug is acting in an inhibitory manner, although in other circumstances and/or locations, it may be an "excitatory" drug. In addition, stimulation of an area herein includes stimulation of cell bodies and axons in the area.

Similarly, excitatory neurotransmitter agonists (i.e., norepinephrine, epinephrine, glutamate, acetylcholine, serotonin, dopamine), agonists thereof, and agents that act to increase levels of an excitatory neurotransmitter(s) (i.e., edrophonium; Mestinon; trazodone; SSRIs (i.e., flouxetine, paroxetine, sertraline, citalopram and fluvoxamine); tricyclic antidepressants (i.e., imipramine, amitriptyline, doxepin, desipramine, trimipramine and nortriptyline), monoamine oxidase inhibitors (i.e., phenelzine, tranylcypromine, isocarboxasid)), generally have an excitatory effect on neural tissue, while inhibitory neurotransmitters (i.e., dopamine, glycine, and gamma-aminobutyric acid (GABA)), agonists thereof, and agents that act to increase levels of an inhibitory neurotransmitter(s) generally have an inhibitory effect. (Dopamine acts as an excitatory neurotransmitter in some locations and circumstances, and as an inhibitory neurotransmitter in other locations and circumstances.) However, antagonists of inhibitory neurotransmitters (i.e., bicuculline) and agents that act to decrease levels of an inhibitory neurotransmitter(s) have been demonstrated to excite neural tissue, leading to increased neural activity. Similarly, excitatory neurotransmitter antagonists (i.e., prazosin, and metoprolol) and agents that decrease levels of excitatory neurotransmitters may inhibit neural activity. Yet further, lithium salts and anaesthetics (i.e., lidocane) may also be used in combination with electrical stimulation.

Genetically active substances such as injection of stem cells, iRNA, siRNA, viral vectors, genetically modified stem cells or encapsulated cells may likewise be placed in the predetermined site in order to increase brain activity and thereby cause depressive illness. Although the present invention and its advantages have been described in detail, it should be understood that various changes, substitutions and alterations can be made herein without departing from the invention as defined by the appended claims.

Claims

Claims:

1. A research model system for causing a depressive illness in an animal subject other than a human being, said system comprising: a probe having a stimulation portion in communication with the subcallosal area; and a device to stimulate the probe thereby activating the subcallosal area and causing depressive illness.

2. A research model system according to claim 1, wherein the probe is coupled to the device.

3. A research model system according to claim 1 , wherein the probe is incorporated within the device.

4. A research model system according to any of claims 1 to 3, wherein the activation is electrical.

5. A research model system according to claim 4, wherein the electrical activation is provided by applying a low frequency signal, such as a frequency below approx. 120 HZ and more preferably below 60 Hz.

6. A research model system according to any of claims 4 or 5, wherein the probe is an electrical stimulation lead.

7. A research model system according to claim 6, wherein the lead comprises a plurality of electrodes.

8. A research model system according to any of claims 1 to 3, wherein the activation is chemical or caused by a genetically engineered substance.

9. A research model system according to any of claims 1 to 3, wherein the activation is magnetic.

10. A research model system according to any of the preceding claims, wherein the probe is a pharmaceutical or genetically engineered substance catheter.

11. A research model system according to claim 10, wherein the catheter comprises at least one electrode.

12. A research model system according to any of the preceding claims, wherein the device is a combination of an electrical signal source and a pharmaceutical and/or genetically engineered substance delivery pump.

13. A research model system according to any of to any of the preceding claims, wherein the probe comprises an electrical stimulation lead having a stimulation portion in communication with the subcallosal area; and an electrical signal generating portion to stimulate the probe thereby stimulating the subcallosal area and causing the depressive illness, wherein the lead and the generating portion are combined in one unit.

14. A research model system according to claim 13, wherein the generating portion further comprising a pharmaceutical and/or genetically engineered substance delivery pump.

15. A research model system according to claim 13 or 14, wherein the lead comprises a plurality of electrodes.

16. A research model system according to any of claims 13 to 15, wherein the lead further comprises a catheter.

17. A research system for causing subjects with depressive illness in an animal subject other than a human being, said system comprising: an electrical stimulation lead that is implanted into the subject's brain, the lead comprises at least one electrode that is in communication with the subcallosal area and delivers an electrical signal to the subcallosal area in response to the received signal; and a signal generator that generates the electrical signal for transmission to the at least one electrode of the lead resulting in delivery of the electrical signals to the subcallosal area thereby causing the depressive illness.

18. A research model system according to claim 17, wherein the lead comprises a plurality of electrodes.

19. A research model system according to claim 17, wherein the signal generator is implanted in the subject's body.

20. A research model system according to claim 17 further comprising: a catheter that is implanted into a subject's brain, the catheter having a proximal end coupled to a pump and a discharge portion for infusing a dosage of a pharmaceutical and/or genetically engineered substance is in communication with the subcallosal area and a pump to discharge the pharmaceutical and/or genetically engineered substance through the discharge portion of the catheter into the predetermined site thereby chemically stimulating the subcallosal area and causing the depressive illness.

21. A research system for causing subjects with depressive illness in an animal subject other than a human being, said system comprising: an electrical stimulation lead that is implanted into the subject's brain, said lead comprising at least one electrode that is in communication with an area homologous to Brodmann area 25 in human and delivers an electrical signal to the homolog Brodmann area 25; and a signal generator that generates the electrical signal for transmission to the at least one electrode of the lead resulting in delivery of the electrical signals to the homolog Brodmann area 25 thereby causing the depressive illness.

22. A research system for causing subjects with depressive illness in an animal subject other than a human being, said system comprising: a catheter that is implanted into a subject's brain, said catheter having a proximal end coupled to a pump and a discharge portion for infusing a dosage of a pharmaceutical and/or genetically engineered substances is in communication with the subcallosal area; and a pump to discharge the pharmaceutical and/or genetically engineered substance through the discharge portion of the catheter into the predetermined site thereby chemically stimulating the subcallosal area and causing the depressive illness.

23. A research model system according to claim 22, wherein the catheter further comprises an electrical stimulation lead having at least one electrode.

24. A research model system according to claim 23 further comprising a signal generator that generates signals for transmission to the electrode of the lead resulting in delivery of electrical signals to the subcallosal thereby causing the depressive illness.

26. A research model system according to claim 25, wherein the lead comprises a plurality of electrodes.

27. A research model system according to claim 25, wherein the signal generator is implanted in the subject's body.

28. A research model system according to claim 25, wherein the pump is implanted in the subject's body.

29. A method for causing a depressive illness in an animal subject other than a human being, said method including the steps of: activating the subcallosal area in the brain of said animal subject by a probe having a stimulation portion in communication with said subcallosal area; and stimulating the probe by a device thereby activating the subcallosal area and causing the depressive illness.

30. A method for causing subjects with depressive illness in an animal subject other than a human being, said method including the steps of: implanting an electrical stimulation lead into the subject's brain, said lead comprising at least one electrode that is in communication with an area homologous to Brodmann area 25 in human and delivers an electrical signal to the homolog Brodmann area 25; and generating the electrical signal in a signal generator and transmitting said electrical signal to the at least one electrode of the lead resulting in delivery of the electrical signals to the homolog Brodmann area 25 thereby causing the depressive illness.

31. A method for causing subjects with depressive illness in an animal subject other than a human being, said method including the steps of: implanting a catheter into a subject's brain, said catheter having a proximal end coupled to a pump and a discharge portion for infusing a dosage of a pharmaceutical and/or genetically engineered substance is in communication with the subcallosal area; and releasing the pharmaceutical and/or genetically engineered substance through the discharge portion of the catheter into the predetermined site thereby chemically stimulating the subcallosal area and causing the depressive illness.

32. A use of a research system according to any of claims 1 to 28 for performing a method of any of claims 29 to 31 in an animal subject other than human beings, where said subject is a research animal selected from the mammalian animal group or genetic manipulated derivates thereof.