WO2008035344A2 - A device and method for deep brain stimulation as a new form of treating chronic depression - Google Patents

A device and method for deep brain stimulation as a new form of treating chronic depression Download PDF

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Publication number
WO2008035344A2
WO2008035344A2 PCT/IL2007/001160 IL2007001160W WO2008035344A2 WO 2008035344 A2 WO2008035344 A2 WO 2008035344A2 IL 2007001160 W IL2007001160 W IL 2007001160W WO 2008035344 A2 WO2008035344 A2 WO 2008035344A2
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stimulation
dbs
additionally
deep brain
therapy
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PCT/IL2007/001160
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French (fr)
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WO2008035344A3 (en
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Gal Yadid
Alexander Friedman
Moshe Abeles
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Bar-Ilan University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/3606—Implantable neurostimulators for stimulating central or peripheral nerve system adapted for a particular treatment
    • A61N1/36082—Cognitive or psychiatric applications, e.g. dementia or Alzheimer's disease

Definitions

  • the present invention generally pertains to deep brain stimulation of the ventral tegmental area as a new form of treatment for depression.
  • the neural activity in the brain can be influenced by electrical energy that is supplied from an external source outside of the body.
  • Various neural functions can thus be promoted or disrupted by applying an electrical current to the cortex or other region of the brain.
  • the quest for treating damage, disease and disorders in the brain have led to research directed toward using electricity or magnetism to control brain functions.
  • SSRIs Selective Serotonin Reuptake Inhibitors
  • Prozac® antidepressant many patients have been effectively treated with antidepressant medication.
  • New medications to treat depression are introduced almost every year, and research in this area is ongoing.
  • an estimated 10 to 30 percent of depressed patients taking an antidepressant are partially or totally resistant to the treatment.
  • Those who suffer from treatment-resistant depression have almost no alternatives.
  • Electroconvulsive Therapy is an extreme measure that is used today to treat such patients.
  • ECT Electroconvulsive Therapy
  • a low-frequency electrical signal is sent through the brain to induce a 30- to 60-second general seizure.
  • the side effects include memory loss and other types of cognitive dysfunction.
  • rTMS Repetitive Transcranial Magnetic Stimulation
  • Kirkcaldie et al. (1997) reported a greater than 50 percent response rate when applying rTMS to the left dorsolateral prefrontal cortex of 17 depressed patients.
  • a company headquartered in Houston, Tex. is currently exploring the application of vagus nerve stimulation to treatment-resistant depression; Rush, et al. (1999) report a success rate of 40-50 percent in a recent study of 30 patients.
  • DBS Deep Brain Stimulation
  • Several lines of evidence implicate the mesolimbic dopamine in the pathogenesis and treatment of depression (Ibid.).
  • DBS has also been applied to the treatment of central pain syndromes and movement disorders, and it is currently being explored as a therapy for epilepsy.
  • U.S. Pat. No. 6,016,449 to Fischell, et al. discloses 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.
  • Drevets (1997) reported that the ventral prefrontal cortex demonstrates increased activity in depressed patients, and further reported evidence that blood flow and metabolism are abnormally increased in the medial thalamus in patients with Major Depression and Bipolar Disorder as compared with controls. As also stated above, Bench reported abnormally increased blood flow in the cerebellar vermis in depressed patients with depression-related cognitive impairment. Abercrombie et al. (1998) reported that the metabolic rate in the right amygdala predicts negative affect in depressed patients (although no absolute difference was found between depressed and control subjects).
  • Low-frequency electrical stimulation i.e., less than 50-100 Hz
  • excitatory neurotransmitters, agonists thereof, and agents that act to increase levels of an excitatory neurotransmitter(s) have been demonstrated to excite neural tissue, leading to increased neural activity.
  • Inhibitory neurotransmitters have been demonstrated to inhibit neural tissue, leading to decreased neural activity; however, antagonists of inhibitory neurotransmitters and agents that act to decrease levels of an inhibitory neurotransmitter(s) have been demonstrated to excite neural tissue, leading to increased neural activity.
  • High-frequency electrical stimulation i.e., more than about 50-100 Hz is believed to have an inhibitory effect on neural tissue, leading to decreased neural activity.
  • inhibitory neurotransmitters, agonists thereof, and agents that act to increase levels of an inhibitory neurotransmitter(s) have an inhibitory effect on neural tissue, leading to decreased neural activity.
  • Excitatory neurotransmitters have been demonstrated to excite neural tissue, leading to increased neural activity; however, antagonists of excitatory neurotransmitters and agents that act to decrease levels of an excitatory neurotransmitter(s) inhibit neural tissue, leading to decreased neural activity.
  • Electrodes placed on the scalp.
  • Other devices require significant surgical procedures for placement of electrodes, catheters, leads, and/or processing units. These devices may also require an external apparatus that needs to be strapped or otherwise affixed to the skin.
  • DBS Deep Brain Stimulation
  • the method comprises steps selected inter alia from (a) obtaining a device as defined above; (b) implanting said lead in said targeted site region of the brain; (c) implanting said neurostimulator under the skin; (d) connecting said lead to said neurostimulator by said extension; (e) electrically stimulating said targeted site region; wherein said targeted site is the ventral tegmental area; further wherein said device is used especially for treating chronic depression in a patient.
  • FIG. 1 is a schematic drawing of the device.
  • FIG. 2 is graph displaying an analysis of VTA electrophysiology of Sprague-Dawley vs. FSL rats. SD. DBS functions to correct a specific electro-physiology form.
  • FIG. 3(A) is a graph displaying the effectiveness of antidepressants (paroxetine, mirtazapine, desipramine and nefazodone) as measured by immobility of FSL rats in a swim test.
  • antidepressants praroxetine, mirtazapine, desipramine and nefazodone
  • FIG. 3(B) is a graph displaying the effect on motivation (monitored by the swim test) vs. sham operated rats (placing the electrode by micro-surgery without applying the electrical current) and vs. a close-by (0.5 mm aside) stimulation in a non-relevant area of the brain.
  • FIG. 4 is a graph displaying the locomotors activity of the rats in swim test.
  • FIG. 5 is a graph displaying the effectiveness of AES on Anhedonia.
  • FIG. 6 is a graph displaying the effectiveness of AES on social interaction.
  • FIG. 7 is a graph displaying the effectiveness of AES on novelty exploration.
  • FIG. 8(A), 8(B) and 8(C) which are graphs displaying the results for applying DBS to cocaine addicted rats: extinction of the drug with reinforcement by light (A), relapse to cocaine usage after abstinence triggered by cocaine priming (20 mg/kg i.p.) (B) and same as B but after 30 additional days (C).
  • FIG 9 schematically represents in a flow diagram, the method (100) for Deep Brain
  • DBS Stimulation
  • the present invention provides a device for Deep Brain Stimulation (DBS) therapy in a targeted site region of the brain.
  • the targeted site region of the brain is the ventral tegmental area.
  • the device is used especially for treating chronic depression in a patient.
  • DBS Deep Brain Stimulation
  • the method comprises steps selected inter alia from (a) obtaining a device as defined above; (b) implanting the lead in the targeted site region of the brain; (c) implanting the neurostimulator under the skin; (d) connecting the lead to the neurostimulator by the extension; (e) electrically stimulating the targeted site region.
  • the targeted site is the ventral tegmental area.
  • the device is used especially for treating chronic depression in a patient.
  • DBS Deep brain stimulation
  • AES acute Electrical Stimulation
  • ECT Electro convulsive therapy
  • Electrohock refers hereinafter to a psychiatric treatment in which seizures are induced with electricity.
  • VTA Ventral Tegmental Area
  • DSM Diagnostic and Statistical Manual of Mental Disorders
  • depression refers hereinafter to any downturn in mood, which may be relatively transitory and perhaps due to something trivial.
  • depression can refer to the term clinical depression which is a state of intense sadness, melancholia or despair that has advanced to the point of being disruptive to an individual's social functioning and/or activities of daily living.
  • depression refers hereinafter to the definition according to the DSM-IV, a person who suffers from Major Depressive Disorder must either have a depressed mood or a loss of interest or pleasure in daily activities consistently for at least a two week period. This mood must represent a change from the person's normal mood; social, occupational, educational or other important functioning must also be negatively impaired by the change in mood.
  • Standard operated group refers hereinafter to a control of any operating procedure that was done on a laboratory animal to ensure that the consequential experimental result reflects those of the experiment and that the results are independent of the surgical procedure which the animal had undergone.
  • Neurostimulator refers hereinafter to a device which can provide power and electrical pulses for stimulation. It is usually a small sealed device similar to a cardiac pacemaker. The neurostimulator is implanted beneath the skin in the chest.
  • Electrode refers hereinafter to an electrical conductor used to make contact with a metallic part of a circuit.
  • Bipolar electrode refers hereinafter to an electrode that functions as the anode of one cell and the cathode of another cell.
  • Extension refers hereinafter to a thin, insulated wire that connects the electrode to the neurostimulator.
  • Neurological Test Stimulator refers hereinafter to an operation used to test the effectiveness of the Deep Brain Stimulation Therapy before the system is implanted.
  • FSL Flexible Sensitive Line
  • SD Sprague-Dawley
  • Anhedqnia refers hereinafter to the inability to gain pleasure from enjoyable experiences.
  • Anhedonia is unable to experience pleasure from normally pleasurable life events such as eating, exercise and social interaction.
  • Anhedonia can be used a measure of depressive-like behavior.
  • LMA Locomotor activity
  • Novelty exploration refers hereinafter to the test of Novelty (seeking) exploration behavior was measured in open field when rats do exploration to new object or arena.
  • onset time refers hereinafter to the time differences between the starting time of the treatment and the commencement time of the desired clinical effect.
  • the present invention provides a new method of intervention in depression based on Deep Brain Stimulation (DBS) of the ventral tegmental area (VTA), the origin of the dopaminergic neurons of the mesolimbic system. It is now disclosed that DBS of VTA is a novel application for treatment of chronic depression, especially for patients non-responsive to currently available antidepressant treatments.
  • DBS Deep Brain Stimulation
  • VTA ventral tegmental area
  • the present invention is based in part on the findings of therapeutic activity of DBS of the VTA in animal models of depression.
  • the present invention discloses the unexpected therapeutic effects obtained using implantation of a bipolar electrode to the VTA of Flinder sensitive line of rats (FSL).
  • an electrical stimulation targets different region of the brain such as ventral tegmental area (VTA), nucleolus accumbens, prefrontal cortex, habenula, arcuate nucleolus, subgenual cingulated gyrus - that control mood and motivation function.
  • VTA ventral tegmental area
  • the stimulation pattern is based on a specific programmed pattern.
  • FIG. 1 is schematic drawing of the device (100).
  • a lead (10) with tiny electrodes (20) is surgically implanted in the brain and connected by an extension (30) that lies under the skin to a neuro stimulator (or implanted pulse generator, IPG)(40) implanted near the collarbone.
  • the electrical stimulation can be non-invasively adjusted to meet each patient's individual needs.
  • the neurostimulator provides power and electrical pulses for stimulating the brain in order to interfere with neural activity at the target site. It is a small sealed device similar to a cardiac pacemaker. The neurostimulator is implanted beneath the skin in the chest.
  • the lead is a coiled wire and is placed in the brain.
  • the lead can have two designs: 1. concentric electrode with cone tip or 2. a thin insulated wire with few electrodes at the tip that is implanted in the brain.
  • the lead is connected to the extension (20), a thin, insulated wire that runs under the skin from the head, down the neck and into the upper chest and connected to the neurostimulator (40).
  • the lead is implanted by a functional stereotactic neurosurgeon, using a stereotactic head frame and imaging techniques such as magnetic resonance imaging (MRI) or computed tomography (CT) scanning to map the brain and localise the target within the brain.
  • MRI magnetic resonance imaging
  • CT computed tomography
  • the lead is inserted through a burr hole in the skull and implanted in the targeted site within the brain.
  • the patient's scalp is anaesthetized.
  • the burr hole is made and a test stimulation electrode is passed to the target in the brain.
  • the patient remains awake and alert so the neurosurgeon and a movement disorder neurologist can test the stimulation to maximise symptom suppression and minimise side effects before placement of the chronic stimulation lead.
  • the patient is put under general anaesthesia. Then, an extension is passed under the skin of the scalp, neck, and shoulder to connect the lead to the neurostimulator. Finally, a small incision is made near the clavicle, and the neurostimulator is implanted subcutaneously.
  • the patient After recovery from the surgery, the patient returns to the physician for reprogramming of the stimulation parameters to optimise symptom control and minimize side effect.
  • Fig. 2 is graph displaying an analysis of VTA electrophysiology of Sprague-Dawley vs. FSL rats. SD. DBS functions to correct a specific electro-physiology form. Accordingly a defined electrical template
  • VTA cell-firing As shown in Fig 2, normal Sprague Dawley rats' VTA has the ability to fire bursts with a large amount of spikes whereas FSLs rarely have this form. ⁇ but appear to compensate for this inability by an increased number of small bursts.
  • the inventors endeavored to mimic this exact pattern by applying DBS.
  • the electrode coordinates and placement play an important role.
  • two factors stimulation place and pattern play a critical role in depressive behavior correction.
  • DBS had a long-term effect (not as in Parkinson's and Tourette's (4)).
  • Fig. 3 a is a graph displaying the effectiveness of antidepressants (paroxetine, mirtazapine, desipramine and nefazodone) as measured by immobility of FSL rats in a swim test. Measurements were conducted 7, 9 and 14 days after treatment.
  • antidepressants praroxetine, mirtazapine, desipramine and nefazodone
  • FSL rats demonstrate characteristic depressive behavior: sleep and immune abnormalities, reduced appetite, general activity, anhedonia, loss of motivation and positive response to various clinically-used anti-depressant therapies and reduced psychomotor function (behavioral, neurochemical, and pharmacological features).
  • FSL rats exhibit changes consistent with cholinergic, serotonergic, dopaminergic, noradrenergic and GABAergic models of depression.
  • the FSL rat model for depression is useful for screening antidepressants and their efficiency in a controlled paradigm (Overstreet, D. H 1993, Overstreet, D. H 2005, Dremencov, E 2006).
  • Fig 3 a results of the AES treatment were compared to sham operated- and na ⁇ ve Sprague-Dawley rats (SD; ondepressive normal rats), na ⁇ ve FSL rats, and FSL rats treated with chemical antidepressants or electro-convulsive therapy (ECT).
  • SD ondepressive normal rats
  • na ⁇ ve FSL rats effects of antidepressants are currently confirmed after chronic (9-14 days) administration and by a behavioral (swim) test. This mimics the clinical observation that only chronic treatments are effective in humans.
  • Some antidepressant have faster onset of time (are effective after shorter time of administration).
  • These same medications have the same profile as in the present invention's model (have faster onset of time.
  • the present invention shows a superior method to achieve a faster and log lasting antidepressive effect by applying a programmed AES locally into the VTA.
  • behavioral tests were established: motivation behavior test (Fig. 3b), Locomotor activity test (Fig. 4), Anhedonia test (Fig 5), Social interaction test (Fig 6) and Novelty exploration (Fig. 7).
  • Fig. 3b is a graph displaying the effect on motivation (monitored by the swim test) vs. sham operated rats (placing the electrode by microsurgery without applying the electrical current) and vs. a close-by (0.5 mm aside) stimulation in a non-relevant area of the brain. Decrease in immobility is interpreted as improvement in motivation.
  • Fig 4. is a graph displaying the locomotors activity of the rats in swim test.
  • Fig. 4 Naive FSL rats have low locomotors activity then normal SD rats, treatment with AES don't change locomotors activity, i.e. FSL rats are less active than controls and that this difference is not changed after AES.
  • Fig. 4 AES has antidepressant function and not stimulant.
  • Fig. 5 is a graph displaying the effectiveness of AES on Anhedonia. Anhedonia was measured by sucrose self-administration test. Rats learn task in self-administration sucrose cages. As can be seen from Fig.
  • FSL rats have anhedonia that was measured by low number of press to active lever.
  • Fig. 5 displays that FSL rats very little interested in intake sucrose vs water in comparison with control, but after AES can gradually reach the same level of maintenance for sucrose self-administration.
  • Fig. 6 is a graph displaying the effectiveness of AES on social interaction. Social interaction was measured by dominant submissive test. As can be seen from the figure, FSL rats show submissive behavior to SD rats and after AES treatment was show inverse relationship.
  • FIG. 7 is a graph displaying the effectiveness of AES on novelty exploration. Novelty (seeking) exploration behavior was measured in open field when rats do exploration to new object.
  • FSL rats show low level of interest to new object when AES treatment normalized rats interest.
  • AES had an unexpectedly long-term effect on behavioral symptoms in the FSL rats (as opposed to continuous stimulation required in Parkinson's disease and Tourette's syndrome). This finding may be due to the bi- phasic nature of depression, in which the depressed individual alternates between normal and abnormal 'depressive' behavior stages. This pattern follows the dynamic fluctuation mode in the neuronal activity of the depressive brain. AES may restore neuronal dynamics to their stable, normal mode.
  • the present invention demonstrate that AES has several advantages, namely, fast onset (5-6 min after AES activation), selective effect within a specific brain site, and greater efficacy (Fig. 3-7) in correcting depressive behavior.
  • the present invention shows that AES exerts its effect immediately after one short treatment session, while antidepressants or ECT require between 7 to 14 treatment sessions.
  • the remedial effect of AES persists for up to one month after the single stimulation. Stimulation of FSL rat brain in a nonspecific region, the deep mesencephalic nucleus, resulted in no effect on depressive behavior, measured by a swim test conducted immediately after session of the stimulation (142 ⁇ 14.02 sec vs.
  • the present invention postulates that AES of the VTA is a novel application for treating chronic depression, particularly, but not only in patients that are non- responsive to conventional antidepressive treatments. It was show (Matsumoto et all 2007) that the primate lateral habenula is a major candidate for a source of negative reward-related signals in dopamine neurons.
  • the present invention tested a new method for intervention in depressive states based on DBS of the lateral habenula, in rat's addiction model. Concentric-bipolar electrode was implanted into the lateral habenula. Rats were trained to daily self- administer cocaine i.v.
  • Fig. 8a, 8b and 8c are graphs displaying the results for applying DBS to cocaine addicted rats: extinction of the drug with reinforcement by light (A), relapse to cocaine usage after abstinence triggered by cocaine priming (20 mg/kg i.p.) (B) and same as B but after 30 additional days (C).
  • lateral habenula is a major candidate for a source of negative reward-related signals in dopamine neurons. Rats were trained to self-administration cocaine. After cauterization (10 days), rats were daily transferred into the operant condoning chambers for 60 min sessions, during their dark cycle. During the infusion (i.v.
  • Fig 9 is schematically represents in a flow diagram, the method (100) for Deep Brain Stimulation (DBS) therapy in a targeted site region of the brain.
  • DBS Deep Brain Stimulation
  • a device for DBS is obtain.
  • the lead is implanted in a targeted site region of the brain.
  • the neurostimulator is implanted under the skin.
  • the lead and the neurostimulator are connected.
  • the targeted site region is electrically stimulated.
  • FSL Flinders Sensitive Line
  • Electrode construction and Surgery procedures Animals were anesthetized with ketamine hydrochloride (100 mg/kg, i.p.) and xylazine (10 mg/kg, i.p.) prior to stereotaxic surgery.
  • a bipolar stimulating electrode (Stanly-steel, diametr-0.5 mm with cathode and anode isolation) was inserted into the VTA (anterior 5.3, lateral 0.5, ventral 8.1 mm from bregma). Implantation was secured to the skull with screws and dental acrylic cement. Post-surgery rimadyl (2 mg/kg, i.p.) was injected.
  • Depressive-like behavior was measured by immobility time using a version of Porsolt forced swim test (See e.g., Dremencov and Overstreet ).
  • a swim test Cylindrical tank (40 cm high and 18 cm in diameter) contained enough water (2 0 C higher then room temperature) that rat could touch the bottom with its hind tail. A rat was considered to have stopped swimming when both back paws were immobile. Test duration is 5 minutes. Histology- At the completion of the experiment, animals were anesthetized, transcardially perfused with PBSxI followed by 4% paraformaldehyde.
  • FSL Flinders Sensitive Line
  • Rats were anesthetized with chloral hydrate (400 mg/kg, i.p.) and a recording
  • ketamine hydrochloride 100 mg/kg, i.p.
  • xylazine 50 mg/kg, i.p.
  • a bipolar stimulating electrode stainless steel, 0.01 mm diameter with cathode and anode isolation
  • the site-specificity was tested by stimulation in another region (Deep mesencephalic nucleus) that is near the VTA (anterior 5.3, lateral 1.5, ventral 6.6 mm from bregma).
  • the implantation was secured to the skull with screws and dental acrylic cement. Post-surgery rimadyl (2 mg/kg, i.p.) was injected.
  • Stimulation procedure The calculated pattern of bursts in SD rats was applied to the VTA of FSL rats, using DBS (300 micro-amperes; 2 bursts/second with a 180 msec pause after each burst; total of 10 HZ stimulation). Stimulation was produced once in each rat, for a period of 20 minutes.
  • a microdialysis probe (2 mm in length, 20 IcD cutoff value; CMA/10; Carnegie Medicine; Swiss, Sweden) was surgically implanted into the shell of the nucleus accumbens (1.4 mm anterior and 1.2 mm lateral to bregma; 7.6 mm ventral to the dura) of each rat using a stereotaxic apparatus (David-Kopf Instruments; Tujunga, CA) and cemented to the skull. After surgery, rats were habituated for 22-24 h to a cylindrical microdialysis chamber (35 cm diameter x 40 cm high). Teflon microdialysis tubing (MF-5164; Bioanalytical Systems; W.
  • the dialysates were collected during 30 min intervals into polyethylene tubes containing 15 ⁇ l of a 0.02% EDTA and 1% ethanol solution, and stored at -70 0 C until subjected to HPLC for monoamine analysis.
  • the aCSF was switched to aCSF containing 10 ⁇ M of GBR 12909, a selective DA reuptake inhibitor, for 3 h (6 samples).
  • the mean DA levels in the nucleus accumbens which were calculated as a percentage of the basal DA levels, were used to assess DA release in the nucleus accumbens.
  • Depressive-like behavior was measured by calculation of immobility time using a modified version of the Porsolt forced swim test (Dremencov et all Overslreet et all 2005 Overstreet 1993) . It should be pointed out that the swim test is not used to induce depressive behavior as in other models for depression. Rather, it serves as a test to examine the efficacy of various depressive treatments.
  • a cylindrical tank (40 cm high and 18 cm in diameter) contained enough water (at 2°C higher than room temperature) to allow rats to touch the bottom with their hind tail. Rats were considered to have stopped swimming when both back paws were immobile. Test duration is 5 minutes.
  • Locomotors activity test :
  • Rats were initially habituated to an open field, a plastic polymer box (90 x 90 x 30 cm), for 5 min/day for 14 days. AU experiments were performed between 8:00 and 14:00 in red light. A camera was placed above the box. The video and computer equipment were situated in a separate room, in which all video and observation analysis was done. On day 15, each rat was filmed in the open field for 5 min, so that naive behavioral parameters could be measured. Rats were filmed 14 days after surgery (operated), after AES (FSL rats were treated by AES) and once per week till month after AES. (Strekalova et all 2004, Kazlauckas et all 2005 and Malkesman 2007, Janssen I960).
  • the behavior testing apparatus see Pinhasov A, Ilyin SE, Crooke J, Amato FA, Vaidya AH, Rosenthal D, Brenneman DE, Malatynska E: Different levels of gamma- synuclein mRNA in the cerebral cortex of dominant, neutral and submissive rats selected in the competition test. Genes Brain Behav 2005;4(l):60-4, and in Pinhasov A, Crooke J, Rosenthal D, Brenneman D, Malatynska E: Reduction of Submissive Behavior Model for antidepressant drug activity testing: study using a video-tracking system.
  • Dominant-submissive relationship testing began with the random assignment of rats into pairs. These pairs were brought together once a day, during a testing period. Otherwise, they were housed separately with other animals in groups of there. Each member of a pair was placed in opposite chambers of the testing apparatus. The time spent on the feeder (milk with 20% sucrose) by each animal was recorded during a 5- min testing period. Then, the animals were separated, returned to their home. During the first 2 week (12 days) of testing rats were initially habituated. Rats were tested before surgery (naive rats), 10 days after surgery (operated rats), after AES (FSL rats were treated by AES) and once per week till month after AES. Important that animals have free access to water and eat, it means that test measure only submissive behavior.
  • Rats were trained to self- administration sucrose (10% sucrose solution; 0.13 ml/infusion) delivered into a liquid drop receptacle for oral consumption. Rats were daily transferred into the operant condoning chambers (Med-Associates, Inc.; St Albans Vermont) for 30 min sessions, during their dark cycle. During the infusion, a light located above the active lever was lit 20 s. During the 20 s intervals of sucrose infusion, active lever presses were recorded, but no additional sucrose reinforcement was provided. Presses on inactive lever were recorded, but did not activate the infusion pump and light. Rats were returned to home cages at the end of the daily session. It should be pointed out that the animals had free access to water and eat, therefore the test measure only anhedonic behavior. Novelty interest test
  • New object exploration test Rats were allowed to explore a new object for 5 min in a plastic polymer box (90 x 90 x 30 cm). Illumination intensity was 5 Ix. The object, with a complex texture surface (artificial camel, 15 x 6 x 5 cm), was fixed to the near side of exploration area. The total duration of time spent exploring the object was scored. (Strekalova et all 2004, Kazlauckas et all 2005)
  • Antidepressants were prepared and administered daily for 7, 9 or 14 days to FSL rats as previously described (Dremencov et al, 2006). AU behavioral measurements were conducted one day after the last administration.

Abstract

The present invention discloses a device for Deep Brain Stimulation (DBS) therapy in a targeted site region of the brain. The targeted site region of the brain is the ventral tegmental area. Moreover, the device is used especially for treating chronic depression in a patient. The present invention also discloses a method for Deep Brain Stimulation (DBS) therapy in a targeted site region of the brain. The method comprises steps selected inter alia from (a) obtaining a device as defined above; (b) implanting the lead in the targeted site region of the brain; (c) implanting the neurostimulator under the skin; (d) connecting the lead to the neurostimulator by the extension; (e) electrically stimulating the targeted site region.

Description

A DEVICE AND METHOD FOR DEEP BRAIN STIMULATION AS A NEW FORM OF TREATING CHRONIC DEPRESSION
FIELD OF THE INVENTION
The present invention generally pertains to deep brain stimulation of the ventral tegmental area as a new form of treatment for depression.
BACKGROUND
The neural activity in the brain can be influenced by electrical energy that is supplied from an external source outside of the body. Various neural functions can thus be promoted or disrupted by applying an electrical current to the cortex or other region of the brain. As a result, the quest for treating damage, disease and disorders in the brain have led to research directed toward using electricity or magnetism to control brain functions.
Recent estimates indicate that more than 19 million Americans over the age of 18 years experience a depressive illness each year. Over 45%. of patients, even if they respond to available treatments, relapse. The American Psychiatric Association recognizes several types of clinical depression, including Mild Depression (Dysthymia), 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. Approximately 9.2 million Americans suffer from Major Depression, and approximately 15 percent of all people who suffer from Major Depression take their own lives. Bipolar Disorder involves major depressive episodes alternating with high-energy periods of rash behavior, poor judgment, and grand delusions. An estimated one percent of the American population experiences Bipolar Disorder annually.
Generally antidepressants require several weeks to exert clinical effects. In the last half-century there has been little or no revolutionary progress in the pharmacology of antidepressant development (See Gershon, A. A., Vishne, T. & Grunhaus, L. Dopamine D2-like receptors and the antidepressant response. Biol Psychiatry 61, 145- 53 ,2007).
Significant advances in the treatment of depression have been made in the past decade. Since the introduction of Selective Serotonin Reuptake Inhibitors (SSRIs), e.g., Prozac® antidepressant, many patients have been effectively treated with antidepressant medication. New medications to treat depression are introduced almost every year, and research in this area is ongoing. However, an estimated 10 to 30 percent of depressed patients taking an antidepressant are partially or totally resistant to the treatment. Those who suffer from treatment-resistant depression have almost no alternatives.
Electroconvulsive Therapy (ECT) is an extreme measure that is used today to treat such patients. In ECT, a low-frequency electrical signal is sent through the brain to induce a 30- to 60-second general seizure. The side effects include memory loss and other types of cognitive dysfunction.
Repetitive Transcranial Magnetic Stimulation (rTMS) is currently being explored as another therapy for depression. Kirkcaldie et al. (1997) reported a greater than 50 percent response rate when applying rTMS to the left dorsolateral prefrontal cortex of 17 depressed patients. In addition, a company headquartered in Houston, Tex. is currently exploring the application of vagus nerve stimulation to treatment-resistant depression; Rush, et al. (1999) report a success rate of 40-50 percent in a recent study of 30 patients.
Deep Brain Stimulation (DBS) is a useful technique in a number of neurological illnesses (such as Parkinson's Disease and Tourette's Syndrome (See WS Anderson, FA Lenz.. Nat Clin Pract Neurol. 2(6):310-20, 2006). Several lines of evidence implicate the mesolimbic dopamine in the pathogenesis and treatment of depression (Ibid.). DBS has also 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 to Fischell, et al. discloses 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. However, Fischell et al. do not teach or suggest the use of such a system for the treatment of mood disorders, such as depression. As was recently reported by Bejjani, et al. (1999), a patient responded to DBS of an area near the thalamus during the therapeutic placement of a stimulator for tremor, by lapsing into a sudden and marked depressive episode. The depression ceased within a couple of minutes after stimulation was halted, and the patient demonstrated a rebound ebullience. This phenomenon was repeated in the same patient several weeks later for purposes of verification.
Drevets (1997) reported that the ventral prefrontal cortex demonstrates increased activity in depressed patients, and further reported evidence that blood flow and metabolism are abnormally increased in the medial thalamus in patients with Major Depression and Bipolar Disorder as compared with controls. As also stated above, Bench reported abnormally increased blood flow in the cerebellar vermis in depressed patients with depression-related cognitive impairment. Abercrombie et al. (1998) reported that the metabolic rate in the right amygdala predicts negative affect in depressed patients (although no absolute difference was found between depressed and control subjects).
Studies of neurotransmitter receptors in the brains of patients with depression also suggest possible sites of the brain that are abnormal in depression. Stockmeier et al. (1997) reported an increased number of serotonin receptors in the dorsal raphe nucleus of suicide victims with major depression as compared with psychiatrically normal controls. Similarly, Yavari et al. (1993) reported decreased activity in the dorsal raphe nucleus in a rat model of endogenous depression. Klimek et al. (1997) reported reduced levels of norepinephrine transporters in the locus coeruleus in major depression. These findings corroborate existing anatomical evidence regarding the functions of these areas.
Recent studies have found a fundamental role of the dopaminergic system in an animal model of depression namely the Flinder sensitive line (FSL) of rats, normalized by various clinically-used antidepressants (see Dremencov, Y. Weizmann, N. Kinor , I. Gispan-Herman, G. Yadid, Curr Drug Targets. 7(2), 165 (2006); and D.H. Overstreet , E. Friedman , A.A. Mathe , G. Yadid, Neiirosci Biobehav Rev. 29(4- 5), 739 (2005) Epub).
Low-frequency electrical stimulation (i.e., less than 50-100 Hz), has been demonstrated to excite neural tissue, leading to increased neural activity. Similarly, excitatory neurotransmitters, agonists thereof, and agents that act to increase levels of an excitatory neurotransmitter(s) have been demonstrated to excite neural tissue, leading to increased neural activity. Inhibitory neurotransmitters have been demonstrated to inhibit neural tissue, leading to decreased neural activity; however, antagonists of inhibitory neurotransmitters and agents that act to decrease levels of an inhibitory neurotransmitter(s) have been demonstrated to excite neural tissue, leading to increased neural activity.
High-frequency electrical stimulation (i.e., more than about 50-100 Hz) is believed to have an inhibitory effect on neural tissue, leading to decreased neural activity.
Similarly, inhibitory neurotransmitters, agonists thereof, and agents that act to increase levels of an inhibitory neurotransmitter(s) have an inhibitory effect on neural tissue, leading to decreased neural activity. Excitatory neurotransmitters have been demonstrated to excite neural tissue, leading to increased neural activity; however, antagonists of excitatory neurotransmitters and agents that act to decrease levels of an excitatory neurotransmitter(s) inhibit neural tissue, leading to decreased neural activity.
Various electrical stimulation and/or drug infusion devices have been proposed for treating neurological disorders. Some devices stimulate through the skin, such as electrodes placed on the scalp. Other devices require significant surgical procedures for placement of electrodes, catheters, leads, and/or processing units. These devices may also require an external apparatus that needs to be strapped or otherwise affixed to the skin.
Examples of patents that teach drug infusion and/or electrical stimulation for treatment of neurological disorders are U.S. Pat. No. 5,092,835; 5,299,569; 5,540,734;
5,975,085; 6,128,537; and 6,167,311.
In U.S. Pat. No. 6,128,537 and 6,167,311 the electrical signal generator is implanted in the body of the patient, but not in the patient's head.
Thus, there is still a long felt need for a simple, effective electrical stimulation treatment for neurological disorders.
SUMMARY OF THE INVENTION
It is one object of the invention to disclose a device for Deep Brain Stimulation (DBS) therapy in a targeted site region of the brain; wherein said targeted site region of the brain is the ventral tegmental area; farther wherein said device is used especially for treating chronic depression in a patient.
It is also an object of the invention to disclose the device for DBS therapy as defined above, wherein said device comprising (a) at least one lead; said lead having at least one electrode at said lead's tip; (b) at least one neurostimulator; said neurostimulator is adapted to provide electrical pulses; and (c) an extension; said extension connecting said lead to said neurostimulator.
It is also an object of the invention to disclose the device for DBS therapy as defined above, wherein said DBS restores the normal activity of the nervous system; further wherein said device provides relief to said chronic depression symptoms' after one treatment session; further wherein said relief is greater than a relief obtained by anti- depressive drugs.
It is also an object of the invention to disclose the device for DBS therapy as defined above, wherein said device is adapted to provide a therapeutic pattern of 5 spikes/burst with 80-160 msec intervals between said spikes, the pulse amplitude ranges from approximately 300 micro Ampere, the pulse frequency ranges from approximately 10 Hertz.
It is also an object of the invention to disclose the device for DBS therapy as defined above, additionally comprising controlling means; wherein said controlling means are adapted to attune the pattern of said stimulation.
It is also an object of the invention to disclose the device for DBS therapy as defined above, additionally comprising (a) a memory storage module; said memory storage module stores said stimulation pattern's parameters; and (b) a controller in communication with said memory storage module adapted to control said stimulation pattern based upon said parameters.
It is also an object of the invention to disclose the device for DBS therapy as defined above, wherein said parameters are selected from a group comprising of spikes/burst ratio, intervals between spikes, pulse amplitude, pulse width, pulse frequency, on- time and off-time, output current, output voltage and stimulation time. It is also an object of the invention to disclose the device for DBS therapy as defined above, wherein said stimulation time is higher than 1 minute and lower than 20 minutes. It is also an object of the invention to disclose the device for DBS therapy as defined above, wherein the onset time of said device is higher 5 minutes and lower than 4 weeks.
It is also an object of the invention to disclose the device for DBS therapy as defined above, wherein said targeted site region of the brain is selected from a group comprising nucleolus accumbens, prefrontal cortex, habenula, arcuate nucleolus,
Subgenual cingulated gyrus.
It is also an object of the invention to disclose the device for DBS therapy as defined above, especially used for drug addiction, epilepsy, Parkinson's disease, bulemia, anxiety/obsessive compulsive disorders, Alzheimer's disease, autism, and neurogenic pain, post traumatic stress disorder.
It is also an object of the invention to disclose the device for DBS therapy as defined above, additionally comprising a patient controller; said patient controller having means to enable said patient to adjust said therapy.
It is also an object of the invention to disclose the device for DBS therapy as defined above, additionally comprising a portable programmer; said portable programmer is adapted to monitor said neurostimulator functions.
It is also an object of the invention to disclose the device for DBS therapy as defined above, wherein said portable programmer is not invasive.
It is also an object of the invention to disclose a method for Deep Brain Stimulation
(DBS) therapy in a targeted site region of the brain. The method comprises steps selected inter alia from (a) obtaining a device as defined above; (b) implanting said lead in said targeted site region of the brain; (c) implanting said neurostimulator under the skin; (d) connecting said lead to said neurostimulator by said extension; (e) electrically stimulating said targeted site region; wherein said targeted site is the ventral tegmental area; further wherein said device is used especially for treating chronic depression in a patient.
It is also an object of the invention to disclose the method as defined above, additionally comprising the step of restoring the normal activity of the nervous system.
It is also an object of the invention to disclose the method as defined above, additionally comprising the step of attenuating the pattern of said therapy to 5 spikes/burst with 80-160 msec intervals between said spikes, adjusting the pulse amplitude to about 300 micro Ampere, adjusting the pulse frequency to about 10 Hertz.
It is also an object of the invention to disclose the method as defined above, additionally comprising the step of electrically re-stimulating said targeted site region according to a predetermined medical needs.
It is also an object of the invention to disclose the method as defined above, additionally comprising the step of controlling and attenuating the pattern of said therapy.
It is also an object of the invention to disclose the method as defined above, additionally comprising the step of selecting parameters of said stimulation's pattern from a group comprising spikes/burst ratio, intervals between spikes, pulse amplitude, pulse width, pulse frequency, on-time and off-time, output current, output voltage and stimulation time.
It is also an object of the invention to disclose the method as defined above, additionally comprising the steps of (a) storing said parameters in a memory storage module; and (b) controlling said stimulation's pattern based upon said parameters.
It is also an object of the invention to disclose the method as defined above, additionally comprising the step of adjusting said stimulation time to be higher that 1 minute and lower than 20 minutes.
It is also an object of the invention to disclose the method as defined above, additionally comprising the step of adjusting the onset time of said device to be higher 5 minutes and lower than 4 weeks.
It is also an object of the invention to disclose the method as defined above, additionally comprising the step of selecting said targeted site region of the brain from a group comprising nucleolus accumbens, prefrontal cortex, habenula, arcuate nucleolus, Subgenual cingulated gyrus.
It is also an object of the invention to disclose the method as defined above, especially used for drug addiction, epilepsy, Parkinson's disease, bulemia, anxiety/obsessive compulsive disorders, Alzheimer's disease, autism, and neurogenic pain, post traumatic stress disorder.
It is still an object of the invention to disclose the method as defined above, additionally comprising the step of controlling said stimulation by means of enabling the adjustment of said therapy by said patient.
It is lastly an object of the invention to disclose the method as defined above, additionally comprising the step of programming said neurostimulator functions.
BRIEF DESCRIPTION OF THE DRAWINGS
In order to understand the invention and to see how it may be implemented in practice, and by way of non-limiting example only, with reference to the accompanying drawing, in which:
FIG. 1 is a schematic drawing of the device.
FIG. 2 is graph displaying an analysis of VTA electrophysiology of Sprague-Dawley vs. FSL rats. SD. DBS functions to correct a specific electro-physiology form.
FIG. 3(A) is a graph displaying the effectiveness of antidepressants (paroxetine, mirtazapine, desipramine and nefazodone) as measured by immobility of FSL rats in a swim test.
FIG. 3(B) is a graph displaying the effect on motivation (monitored by the swim test) vs. sham operated rats (placing the electrode by micro-surgery without applying the electrical current) and vs. a close-by (0.5 mm aside) stimulation in a non-relevant area of the brain.
FIG. 4 is a graph displaying the locomotors activity of the rats in swim test.
FIG. 5 is a graph displaying the effectiveness of AES on Anhedonia.
FIG. 6 is a graph displaying the effectiveness of AES on social interaction.
FIG. 7 is a graph displaying the effectiveness of AES on novelty exploration.
FIG. 8(A), 8(B) and 8(C) which are graphs displaying the results for applying DBS to cocaine addicted rats: extinction of the drug with reinforcement by light (A), relapse to cocaine usage after abstinence triggered by cocaine priming (20 mg/kg i.p.) (B) and same as B but after 30 additional days (C).
FIG 9 schematically represents in a flow diagram, the method (100) for Deep Brain
Stimulation (DBS) therapy in a targeted site region of the brain.
DETAIL DESCRIPTION OF THE SPECIFIC EMBODIMENTS
The following description is provided, alongside all chapters of the present invention, so as to enable any person skilled in the art to make use of said invention and sets forth the best modes contemplated by the inventor of carrying out this invention. Various modifications, however, is adapted to remain apparent to those skilled in the art, since the generic principles of the present invention have been defined specifically to provide a new method and a device for treating especially depression by deep brain stimulation, especially of the ventral tegmental area.
The present invention provides a device for Deep Brain Stimulation (DBS) therapy in a targeted site region of the brain. The targeted site region of the brain is the ventral tegmental area. Moreover, the device is used especially for treating chronic depression in a patient.
It is also an object of the invention to disclose a method for Deep Brain Stimulation (DBS) therapy in a targeted site region of the brain. The method comprises steps selected inter alia from (a) obtaining a device as defined above; (b) implanting the lead in the targeted site region of the brain; (c) implanting the neurostimulator under the skin; (d) connecting the lead to the neurostimulator by the extension; (e) electrically stimulating the targeted site region. The targeted site is the ventral tegmental area. The device is used especially for treating chronic depression in a patient.
The term "Deep brain stimulation (DBS)" refers hereinafter to a surgical treatment involving the implantation of a medical device, which sends electrical impulses to specific parts of the brain during lifetime.
The term "Acute Electrical Stimulation (AES)" refers hereinafter to the procedure in which an electrical stimulation targets different region in the brain; stimulation is acute in a time scale.
The term "Electro convulsive therapy (ECT)", "Electroshock" refers hereinafter to a psychiatric treatment in which seizures are induced with electricity.
The term "Ventral Tegmental Area (VTA)" refers hereinafter to a part of the midbrain, lying close to the substantia nigra and the red nucleus.
The term "Diagnostic and Statistical Manual of Mental Disorders (DSM)" is a handbook for mental health professionals that lists different categories of mental disorder and the criteria for diagnosing them, according to the publishing organization the American Psychiatric Association.
The term "depression" refers hereinafter to any downturn in mood, which may be relatively transitory and perhaps due to something trivial. Moreover the term depression can refer to the term clinical depression which is a state of intense sadness, melancholia or despair that has advanced to the point of being disruptive to an individual's social functioning and/or activities of daily living. Furthermore the term depression refers hereinafter to the definition according to the DSM-IV, a person who suffers from Major Depressive Disorder must either have a depressed mood or a loss of interest or pleasure in daily activities consistently for at least a two week period. This mood must represent a change from the person's normal mood; social, occupational, educational or other important functioning must also be negatively impaired by the change in mood.
The term "Sham operated group" refers hereinafter to a control of any operating procedure that was done on a laboratory animal to ensure that the consequential experimental result reflects those of the experiment and that the results are independent of the surgical procedure which the animal had undergone.
The term "Neurostimulator" refers hereinafter to a device which can provide power and electrical pulses for stimulation. It is usually a small sealed device similar to a cardiac pacemaker. The neurostimulator is implanted beneath the skin in the chest.
The term "Electrode" refers hereinafter to an electrical conductor used to make contact with a metallic part of a circuit.
The term "Bipolar electrode" refers hereinafter to an electrode that functions as the anode of one cell and the cathode of another cell.
The term "Extension" refers hereinafter to a thin, insulated wire that connects the electrode to the neurostimulator.
The term "Neurological Test Stimulator" refers hereinafter to an operation used to test the effectiveness of the Deep Brain Stimulation Therapy before the system is implanted.
The term "Flinder's Sensitive Line (FSL)" refers hereinafter to a special kind of rats which are considered to be a genetic model of depression.
The term "Sprague-Dawley (SD)" refers hereinafter to an outbred strain of albino laboratory rats belonging to the species Rattus norvegicus. They are used widely for experimental purposes because of their calmness and ease of handling.
The term "Anhedqnia" refers hereinafter to the inability to gain pleasure from enjoyable experiences. Anyone who suffers from Anhedonia is unable to experience pleasure from normally pleasurable life events such as eating, exercise and social interaction. Anhedonia can be used a measure of depressive-like behavior.
The term "Locomotor activity (LMA)" refers hereinafter to the movement from place to place. In psychopharmacology, locomotor activity of lab animals is often monitored to assess the behavioral effects of these drugs.
The term "Novelty exploration" refers hereinafter to the test of Novelty (seeking) exploration behavior was measured in open field when rats do exploration to new object or arena.
The term "onset time" refers hereinafter to the time differences between the starting time of the treatment and the commencement time of the desired clinical effect.
The term "long term" refers hereinafter to the time differences between the commencement time of the desired clinical effect and the next treatment.
Before explaining the figures, it should be understood that the invention is not limited in its application to the details of construction and the arrangement of the components set forth in the following description or illustrated in the drawings. The invention can be carried out in various ways.
The present invention provides a new method of intervention in depression based on Deep Brain Stimulation (DBS) of the ventral tegmental area (VTA), the origin of the dopaminergic neurons of the mesolimbic system. It is now disclosed that DBS of VTA is a novel application for treatment of chronic depression, especially for patients non-responsive to currently available antidepressant treatments.
The present invention is based in part on the findings of therapeutic activity of DBS of the VTA in animal models of depression. The present invention discloses the unexpected therapeutic effects obtained using implantation of a bipolar electrode to the VTA of Flinder sensitive line of rats (FSL).
In DBS an electrical stimulation targets different region of the brain such as ventral tegmental area (VTA), nucleolus accumbens, prefrontal cortex, habenula, arcuate nucleolus, subgenual cingulated gyrus - that control mood and motivation function.
The stimulation pattern is based on a specific programmed pattern.
Reference is now made to Fig. 1 which is schematic drawing of the device (100). A lead (10) with tiny electrodes (20) is surgically implanted in the brain and connected by an extension (30) that lies under the skin to a neuro stimulator (or implanted pulse generator, IPG)(40) implanted near the collarbone. The electrical stimulation can be non-invasively adjusted to meet each patient's individual needs.
The neurostimulator provides power and electrical pulses for stimulating the brain in order to interfere with neural activity at the target site. It is a small sealed device similar to a cardiac pacemaker. The neurostimulator is implanted beneath the skin in the chest.
The lead is a coiled wire and is placed in the brain. The lead can have two designs: 1. concentric electrode with cone tip or 2. a thin insulated wire with few electrodes at the tip that is implanted in the brain.
The lead is connected to the extension (20), a thin, insulated wire that runs under the skin from the head, down the neck and into the upper chest and connected to the neurostimulator (40).
The lead is implanted by a functional stereotactic neurosurgeon, using a stereotactic head frame and imaging techniques such as magnetic resonance imaging (MRI) or computed tomography (CT) scanning to map the brain and localise the target within the brain. The lead is inserted through a burr hole in the skull and implanted in the targeted site within the brain.
Before the lead implant procedure, the patient's scalp is anaesthetized. The burr hole is made and a test stimulation electrode is passed to the target in the brain. The patient remains awake and alert so the neurosurgeon and a movement disorder neurologist can test the stimulation to maximise symptom suppression and minimise side effects before placement of the chronic stimulation lead.
Once the chronic stimulation lead is properly placed, the patient is put under general anaesthesia. Then, an extension is passed under the skin of the scalp, neck, and shoulder to connect the lead to the neurostimulator. Finally, a small incision is made near the clavicle, and the neurostimulator is implanted subcutaneously.
After recovery from the surgery, the patient returns to the physician for reprogramming of the stimulation parameters to optimise symptom control and minimize side effect.
Reference is now made to Fig. 2 which is graph displaying an analysis of VTA electrophysiology of Sprague-Dawley vs. FSL rats. SD. DBS functions to correct a specific electro-physiology form. Accordingly a defined electrical template
(stimulation pattern) was applied constructed from the recorded and analyzed FSL
VTA cell-firing. As shown in Fig 2, normal Sprague Dawley rats' VTA has the ability to fire bursts with a large amount of spikes whereas FSLs rarely have this form.^ but appear to compensate for this inability by an increased number of small bursts.
The inventors endeavored to mimic this exact pattern by applying DBS.
Understanding that VTA projections influence many mesolimbic areas, the electrode coordinates and placement play an important role. According to the present invention two factors (stimulation place and pattern) play a critical role in depressive behavior correction.
Unexpectedly, DBS had a long-term effect (not as in Parkinson's and Tourette's (4)).
This may be due to a bi-phasic nature of depression. Flipping from normal to abnormal 'depressive' behavior stage of the depressed individual follows his modes of dynamic fluctuation of neuronal activity. DBS changed (transport) neuronal dynamics to the stable normal mode.
Reference is now to Fig. 3 a which is a graph displaying the effectiveness of antidepressants (paroxetine, mirtazapine, desipramine and nefazodone) as measured by immobility of FSL rats in a swim test. Measurements were conducted 7, 9 and 14 days after treatment.
FSL rats demonstrate characteristic depressive behavior: sleep and immune abnormalities, reduced appetite, general activity, anhedonia, loss of motivation and positive response to various clinically-used anti-depressant therapies and reduced psychomotor function (behavioral, neurochemical, and pharmacological features). In neurochemical and pharmacological studies, FSL rats exhibit changes consistent with cholinergic, serotonergic, dopaminergic, noradrenergic and GABAergic models of depression. Thus, the FSL rat model for depression is useful for screening antidepressants and their efficiency in a controlled paradigm (Overstreet, D. H 1993, Overstreet, D. H 2005, Dremencov, E 2006).
In Fig 3 a results of the AES treatment were compared to sham operated- and naϊve Sprague-Dawley rats (SD; ondepressive normal rats), naϊve FSL rats, and FSL rats treated with chemical antidepressants or electro-convulsive therapy (ECT). As can be seen from Fig 3 a, with FSL rats, effects of antidepressants are currently confirmed after chronic (9-14 days) administration and by a behavioral (swim) test. This mimics the clinical observation that only chronic treatments are effective in humans. Some antidepressant have faster onset of time (are effective after shorter time of administration). These same medications have the same profile as in the present invention's model (have faster onset of time. However, although shorter it still need at least 7 days of application (in the rat model). Herein the present invention shows a superior method to achieve a faster and log lasting antidepressive effect by applying a programmed AES locally into the VTA. To test the antidepressive efficacy 5 behavioral tests were established: motivation behavior test (Fig. 3b), Locomotor activity test (Fig. 4), Anhedonia test (Fig 5), Social interaction test (Fig 6) and Novelty exploration (Fig. 7).
Reference is now to Fig. 3b which is a graph displaying the effect on motivation (monitored by the swim test) vs. sham operated rats (placing the electrode by microsurgery without applying the electrical current) and vs. a close-by (0.5 mm aside) stimulation in a non-relevant area of the brain. Decrease in immobility is interpreted as improvement in motivation.
Decreasing levels of immobility can be explained by two reasons: AES in VTA play antidepressant role or AES has stimulant features as, for example, amphetamine. To rule-out the possibility that increasing swimming/ exploration is not due to nonspecific psychostimulation but rather a correction of motivation deficit, locomotion activity in the open field was tested.
Reference is now made to Fig 4. which is a graph displaying the locomotors activity of the rats in swim test. As shown if Fig. 4 Naive FSL rats have low locomotors activity then normal SD rats, treatment with AES don't change locomotors activity, i.e. FSL rats are less active than controls and that this difference is not changed after AES. According to fig. 4 AES has antidepressant function and not stimulant. Reference is now made to Fig. 5 which is a graph displaying the effectiveness of AES on Anhedonia. Anhedonia was measured by sucrose self-administration test. Rats learn task in self-administration sucrose cages. As can be seen from Fig. 5, FSL rats have anhedonia that was measured by low number of press to active lever. Fig. 5 displays that FSL rats very little interested in intake sucrose vs water in comparison with control, but after AES can gradually reach the same level of maintenance for sucrose self-administration.
Reference is now made to Fig. 6 which is a graph displaying the effectiveness of AES on social interaction. Social interaction was measured by dominant submissive test. As can be seen from the figure, FSL rats show submissive behavior to SD rats and after AES treatment was show inverse relationship.
Reference is now made to Fig. 7 which is a graph displaying the effectiveness of AES on novelty exploration. Novelty (seeking) exploration behavior was measured in open field when rats do exploration to new object. As can be seen from the figure FSL rats show low level of interest to new object when AES treatment normalized rats interest. According to the present invention AES had an unexpectedly long-term effect on behavioral symptoms in the FSL rats (as opposed to continuous stimulation required in Parkinson's disease and Tourette's syndrome). This finding may be due to the bi- phasic nature of depression, in which the depressed individual alternates between normal and abnormal 'depressive' behavior stages. This pattern follows the dynamic fluctuation mode in the neuronal activity of the depressive brain. AES may restore neuronal dynamics to their stable, normal mode. When comparing acute electrical stimulation treatment to other pharmacological treatments, the present invention demonstrate that AES has several advantages, namely, fast onset (5-6 min after AES activation), selective effect within a specific brain site, and greater efficacy (Fig. 3-7) in correcting depressive behavior. The present invention shows that AES exerts its effect immediately after one short treatment session, while antidepressants or ECT require between 7 to 14 treatment sessions. The remedial effect of AES persists for up to one month after the single stimulation. Stimulation of FSL rat brain in a nonspecific region, the deep mesencephalic nucleus, resulted in no effect on depressive behavior, measured by a swim test conducted immediately after session of the stimulation (142 ± 14.02 sec vs. 162.2 ± 13.24 sec in FSL-sham operated rats). No effect was seen even 7 days after stimulation (144.78 ± 14.18 sec vs. 153.6 ± 9.49 sec in FSL-sham operated rats). Furthermore, it is important to note that specific parameters of electrical stimulation which have very limited influence of no more than 700-800 μm from the tip of the electrode were used (Roger Lemon "Methods for neuronal recording in conscious animals" page 40 fig 2.11).
The present invention postulates that AES of the VTA is a novel application for treating chronic depression, particularly, but not only in patients that are non- responsive to conventional antidepressive treatments. It was show (Matsumoto et all 2007) that the primate lateral habenula is a major candidate for a source of negative reward-related signals in dopamine neurons. The present invention tested a new method for intervention in depressive states based on DBS of the lateral habenula, in rat's addiction model. Concentric-bipolar electrode was implanted into the lateral habenula. Rats were trained to daily self- administer cocaine i.v. (FRl according to Green-Sadan T, Kinor N, Roth-Deri I, Geffen-Aricha R, Schindler CJ, Yadid G: Transplantation of glial cell line-derived neurotrophic factor-expressing cells into the striatum and nucleus accumbens attenuates acquisition of cocaine self-administration in rats. Eur J Neurosci 2003;18(7):2093-8). After maintenance stabilization rats were treated by DBS. Level of cocaine usage was measured daily up 2 month after DBS treatment. Treatment with acute-electricalstimulation (AES) to the lateral habenula demonstrates greatly enhanced effectiveness both in its onset time and longitudinal effect (see Fig 8).
Reference is now made to Fig. 8a, 8b and 8c which are graphs displaying the results for applying DBS to cocaine addicted rats: extinction of the drug with reinforcement by light (A), relapse to cocaine usage after abstinence triggered by cocaine priming (20 mg/kg i.p.) (B) and same as B but after 30 additional days (C). As can be seen the figures, lateral habenula is a major candidate for a source of negative reward-related signals in dopamine neurons. Rats were trained to self-administration cocaine. After cauterization (10 days), rats were daily transferred into the operant condoning chambers for 60 min sessions, during their dark cycle. During the infusion (i.v. 0.13 ml/infusion 1.5mg/kg/5s), a light located above the active lever, was lit 5 s. During the 20 s intervals of cocaine infusion, active lever presses were recorded, but no additional cocaine reinforcement was provided. Rats were trained until stable maintenance levels were attained (at least 3 days of 7-10 active lever presses). Presses on inactive lever were recorded, but did not activate the infusion pump and light. Rats were returned to home cages at the end of the daily session. Extinction used as measure of animal craving to cocaine. Addicted animals demonstrated great number of press to active level in extinction time. In the first day of extinction DBS treated rats receive DBS treatment after press to cocaine pedal (2-5 DBS sessions of 3 sec). Number of press to active pedal was measured in each day of extinction. After DBS in lateral abenula addicted animals don't press to active pedal, this demonstrated low level of craving. To the fifth day of experiment there is no significant difference between all groups. In the 7 day of experiment rats has reinforcement by cocaine and light. Incubation after long time separation from cocaine was measured in 31 day of the experiment. A social interaction behavior testing apparatus can be found in Pinhasov A, Ilyin SE, Crooke J, Amato FA, Vaidya AH, Rosenthal D, Brenneman DE, Malatynska E: Different levels of gamma-synuclein mRNA in the cerebral cortex of dominant, neutral and submissive rats selected in the competition test. Genes Brain Behav 2005;4(l):60-4, and in Pinhasov A, Crooke J, Rosenthal D, Brenneman D, Malatynska E: Reduction of Submissive Behavior Model for antidepressant drug activity testing: study using a video-tracking system. Behav Pharmacol 2005; 16(8):657-64.
Reference is now made to Fig 9 which is schematically represents in a flow diagram, the method (100) for Deep Brain Stimulation (DBS) therapy in a targeted site region of the brain. At the first stage (10) a device for DBS is obtain. Next (20) the lead is implanted in a targeted site region of the brain. At the next step (30) the neurostimulator is implanted under the skin. Next (40), the lead and the neurostimulator are connected. Finally (50) the targeted site region is electrically stimulated. EXAMPLES
FSL Model- The Flinders Sensitive Line (FSL) is partially resembles depressed individuals. It exhibits sleep and immune abnormalities, reduced appetite and psychomotor function (behavioral, neurochemical, and pharmacological features) that are observed in depressed individuals. Neurochemical and pharmacological evidence suggests that FSL exhibits changes consistent with the cholinergic, serotonergic, dopaminergic, noradrenergic and GABAergic models of depression. This model is useful as a screen for antidepressants and their efficiency. Male FSL rats (250-300 g) were used under conditions of constant temperature (250C) and humidity (50%), with a 12:12 h light/dark cycle, with free access to food and water.
Electrode construction and Surgery procedures- Animals were anesthetized with ketamine hydrochloride (100 mg/kg, i.p.) and xylazine (10 mg/kg, i.p.) prior to stereotaxic surgery. A bipolar stimulating electrode (Stanly-steel, diametr-0.5 mm with cathode and anode isolation) was inserted into the VTA (anterior 5.3, lateral 0.5, ventral 8.1 mm from bregma). Implantation was secured to the skull with screws and dental acrylic cement. Post-surgery rimadyl (2 mg/kg, i.p.) was injected.
Stimulation procedure- Prior studies found that SD's VTA has the ability to fire bursts with great amount of spikes when FSLs rare this form^ but compensate this inability by increased number of small bursts. Normal (SD) averaged firing was estimated as 5 spikes/ burst with 80 msec interval between spikes. Here we applied that SD calculated bursts' form/pattern to FSL's VTA (70-200 micro-amperes; 2 bursts/ second with 180 msec pause after each burst; total of 10 HZ stimulation). Stimulation was produced once in each rat for 20 minutes period.
Monitoring depressive-like behavior - Depressive-like behavior was measured by immobility time using a version of Porsolt forced swim test (See e.g., Dremencov and Overstreet ). A swim test Cylindrical tank (40 cm high and 18 cm in diameter) contained enough water (20C higher then room temperature) that rat could touch the bottom with its hind tail. A rat was considered to have stopped swimming when both back paws were immobile. Test duration is 5 minutes. Histology- At the completion of the experiment, animals were anesthetized, transcardially perfused with PBSxI followed by 4% paraformaldehyde. Their brains were removed and post-fixed in 4% formaldehyde, and thereafter with phosphate buffer 30% sucrose, and sliced (40 μm sections) frozen using a cryostat microtome. Sections were mounted on glass slides (coated with 2% gelatin) and stained with Cresyl violet and subsequently examined under a microscope to verify the placement of the electrode. Only data sets recorded from verified VTA were analyzed.
Experimental Procedures
Animals- The Flinders Sensitive Line (FSL) partially resembles depressed individuals. These rats exhibit sleep and immune abnormalities, reduced appetite and psychomotor function features that are observed in depressed individuals. Neurochemical and pharmacological evidence suggests that FSL rats exhibit changes consistent with the cholinergic, serotonergic, dopaminergic, noradrenergic and GABAergic models of depression. Therefore this model is useful as a screen for antidepressants and their efficiency ( Overstreet et al., 2005). Male (250-300 g) FSL rats as well as Sprague Dawley (as controls) were maintained under conditions of
unvarying temperature (25°C) and humidity (50%), in a 12:12 h light/dark cycle and
with free access to food and water.
In vivo electrophysiology
Rats were anesthetized with chloral hydrate (400 mg/kg, i.p.) and a recording
electrode (tungsten, 5 MΩ) was stereotaxically inserted into a tract in the VTA
(anterior 5.3, lateral 0.5, ventral 8.1 mm from bregma). The level of anesthesia was kept constant and a slow heart rate (300 beats/min) was maintained monitoring continuous electrocardiogram recordings. Single unit recordings from VTA neurons of Sprague-Dawley and FSL rats, (n=12 per each group, number of cells equal to rats number), respectively, were performed using amplitude discrimination. After the last recording from each animal, the location of the electrode tip was determined by electrolytic lesioning (0.5 mA of DC current, 15 sec). After transcardially perfusing the rats, their brains were removed and post-fixed in 10% formaldehyde. Frozen sections (50 μm) were cut and examined under a microscope. Only data sets recorded from the VT A- verified placement of the electrode tip were analyzed.
Electrode construction and Surgery procedures.
For AES- Animals were anesthetized with ketamine hydrochloride (100 mg/kg, i.p.) and xylazine (50 mg/kg, i.p.) prior to stereotaxic surgery. A bipolar stimulating electrode (stainless steel, 0.01 mm diameter with cathode and anode isolation) was inserted into the VTA (anterior 5.3, lateral 0.5, ventral 8.1 mm from bregma). The site-specificity was tested by stimulation in another region (Deep mesencephalic nucleus) that is near the VTA (anterior 5.3, lateral 1.5, ventral 6.6 mm from bregma). The implantation was secured to the skull with screws and dental acrylic cement. Post-surgery rimadyl (2 mg/kg, i.p.) was injected.
Stimulation procedure - The calculated pattern of bursts in SD rats was applied to the VTA of FSL rats, using DBS (300 micro-amperes; 2 bursts/second with a 180 msec pause after each burst; total of 10 HZ stimulation). Stimulation was produced once in each rat, for a period of 20 minutes.
Measurements of dopamine release
Sprague-Dawley (n=10), FSL (n=10), desipramine-treated FSL rats (n=10) and AES in VTA treated FSL rats (n=10) were anesthetized with chloral hydrate (400 mg/kg, Lp.; Merck Chemicals Ltd.; Darmstadt, Germany). A microdialysis probe (2 mm in length, 20 IcD cutoff value; CMA/10; Carnegie Medicine; Stockholm, Sweden) was surgically implanted into the shell of the nucleus accumbens (1.4 mm anterior and 1.2 mm lateral to bregma; 7.6 mm ventral to the dura) of each rat using a stereotaxic apparatus (David-Kopf Instruments; Tujunga, CA) and cemented to the skull. After surgery, rats were habituated for 22-24 h to a cylindrical microdialysis chamber (35 cm diameter x 40 cm high). Teflon microdialysis tubing (MF-5164; Bioanalytical Systems; W. Lafayette, IN), protected with a metal spring (30 cm in length), was then passed from the perfusion pump to the microdialysis probe via a swivel (Instech; Plymouth Meeting, PA) and positioned above the center of the cage to allow free movement of the rat. Artificial CSF (aCSF; 145 mM NaCl, 1.2 mM CaCl2, 2.7 mM KCl, 1.0 mM MgCl2, pH 7.4) was pumped continuously (1 μl/min) through the dialysis probe using a microinjection pump (CMA 100; Carnegie Medicine), starting upon the insertion of the probe into the brain. Microdialysis samples were collected from non-anesthetized, freely-moving rats. The dialysates were collected during 30 min intervals into polyethylene tubes containing 15 μl of a 0.02% EDTA and 1% ethanol solution, and stored at -700C until subjected to HPLC for monoamine analysis. After collecting samples for determination of baseline levels (mean of the first four fractions), the aCSF was switched to aCSF containing 10 μM of GBR 12909, a selective DA reuptake inhibitor, for 3 h (6 samples). The mean DA levels in the nucleus accumbens, which were calculated as a percentage of the basal DA levels, were used to assess DA release in the nucleus accumbens. Monitoring depressive-like behavior Swim test
Depressive-like behavior was measured by calculation of immobility time using a modified version of the Porsolt forced swim test (Dremencov et all Overslreet et all 2005 Overstreet 1993) . It should be pointed out that the swim test is not used to induce depressive behavior as in other models for depression. Rather, it serves as a test to examine the efficacy of various depressive treatments. A cylindrical tank (40 cm high and 18 cm in diameter) contained enough water (at 2°C higher than room temperature) to allow rats to touch the bottom with their hind tail. Rats were considered to have stopped swimming when both back paws were immobile. Test duration is 5 minutes. Locomotors activity test:
Rats were initially habituated to an open field, a plastic polymer box (90 x 90 x 30 cm), for 5 min/day for 14 days. AU experiments were performed between 8:00 and 14:00 in red light. A camera was placed above the box. The video and computer equipment were situated in a separate room, in which all video and observation analysis was done. On day 15, each rat was filmed in the open field for 5 min, so that naive behavioral parameters could be measured. Rats were filmed 14 days after surgery (operated), after AES (FSL rats were treated by AES) and once per week till month after AES. (Strekalova et all 2004, Kazlauckas et all 2005 and Malkesman 2007, Janssen I960).
Social Behavior test
The behavior testing apparatus (see Pinhasov A, Ilyin SE, Crooke J, Amato FA, Vaidya AH, Rosenthal D, Brenneman DE, Malatynska E: Different levels of gamma- synuclein mRNA in the cerebral cortex of dominant, neutral and submissive rats selected in the competition test. Genes Brain Behav 2005;4(l):60-4, and in Pinhasov A, Crooke J, Rosenthal D, Brenneman D, Malatynska E: Reduction of Submissive Behavior Model for antidepressant drug activity testing: study using a video-tracking system. Behav Pharmacol 2005;16(8):657-64) was based on a design by Malatynska and Kostowski (1984) and constructed at Johnson & Johnson PRD, Spring House, PA. The apparatus and procedure have been described elsewhere (Knapp et al. 2002; Malatynska et al. 2002a). The same procedure, with modifications of the criteria for the selection of dominant- submissive pairs of rats, was used in the studies described in (A. Pinhasov et all 2004 , and A. Pinhasov et all 2005).
Dominant-submissive relationship testing began with the random assignment of rats into pairs. These pairs were brought together once a day, during a testing period. Otherwise, they were housed separately with other animals in groups of there. Each member of a pair was placed in opposite chambers of the testing apparatus. The time spent on the feeder (milk with 20% sucrose) by each animal was recorded during a 5- min testing period. Then, the animals were separated, returned to their home. During the first 2 week (12 days) of testing rats were initially habituated. Rats were tested before surgery (naive rats), 10 days after surgery (operated rats), after AES (FSL rats were treated by AES) and once per week till month after AES. Important that animals have free access to water and eat, it means that test measure only submissive behavior.
Anhedonia test (sucrose self-administration)
Experiment was designed to test whether AES increase basic reward behavior (De La Garza et al., 2004 and De La Garza et al., 2005). Rats were trained to self- administration sucrose (10% sucrose solution; 0.13 ml/infusion) delivered into a liquid drop receptacle for oral consumption. Rats were daily transferred into the operant condoning chambers (Med-Associates, Inc.; St Albans Vermont) for 30 min sessions, during their dark cycle. During the infusion, a light located above the active lever was lit 20 s. During the 20 s intervals of sucrose infusion, active lever presses were recorded, but no additional sucrose reinforcement was provided. Presses on inactive lever were recorded, but did not activate the infusion pump and light. Rats were returned to home cages at the end of the daily session. It should be pointed out that the animals had free access to water and eat, therefore the test measure only anhedonic behavior. Novelty interest test
New object exploration test. Rats were allowed to explore a new object for 5 min in a plastic polymer box (90 x 90 x 30 cm). Illumination intensity was 5 Ix. The object, with a complex texture surface (artificial camel, 15 x 6 x 5 cm), was fixed to the near side of exploration area. The total duration of time spent exploring the object was scored. (Strekalova et all 2004, Kazlauckas et all 2005)
Antidepressants administration
Antidepressants were prepared and administered daily for 7, 9 or 14 days to FSL rats as previously described (Dremencov et al, 2006). AU behavioral measurements were conducted one day after the last administration.
Histology
Animals were anesthetized and transcardially perfuse with PBSxI followed by 4% paraformaldehyde. The brains were removed and immersed in 4% paraformaldehyde for 24 hrs, and then in phosphate buffer with 30% sucrose for 48 hrs. The brains were then frozen on dry ice and sliced (40 μm sections) using a cryostat microtome. Sections were mounted on glass slides (coated with 2% gelatin), stained with Cresyl violet and subsequently examined under a microscope to verify the placement of the electrode.

Claims

1. A device for Deep Brain Stimulation (DBS) therapy in a targeted site region of the brain; wherein said targeted site region of the brain is the ventral tegmental area; further wherein said device is used especially for treating chronic depression in a patient.
2. The device for DBS therapy according to claim 1, wherein said device comprising: a. at least one lead; said lead having at least one electrode at said lead's tip; b. at least one neurostimulator; said neurostimulator is adapted to provide electrical pulses; c. an extension; said extension connecting said lead to said neurostimulator.
3. The device for DBS therapy according to claim 1, wherein said DBS restores the normal activity of the nervous system; further wherein said device provides relief to said chronic depression symptoms' after one treatment session; further wherein said relief is greater than a relief obtained by anti-depressive drugs.
4. The device for DBS therapy according to claim 1, wherein said device is adapted to provide a therapeutic pattern of 5 spikes/burst with 80-160 msec intervals between said spikes, the pulse amplitude ranges from approximately 300 micro Ampere, the pulse frequency ranges from approximately 10 Hertz.
5. The device for DBS therapy according to claim 1, additionally comprising controlling means; wherein said controlling means are adapted to attune the pattern of said stimulation.
6. The device for DBS therapy according to claim 1, additionally comprising (a) a memory storage module; said memory storage module stores said stimulation pattern's parameters; and (b) a controller in communication with said memory storage module adapted to control said stimulation pattern based upon said parameters.
7. The device for DBS therapy according to claim 6, wherein said parameters are selected from a group comprising of spikes/burst ratio, intervals between spikes, pulse amplitude, pulse width, pulse frequency, on-time and off-time, output current, output voltage and stimulation time.
8. The device for DBS therapy according to claim 7, wherein said stimulation time is higher than 1 minute and lower than 20 minutes.
9. The device for DBS therapy according to claim 1, wherein the onset time of said device is higher 5 minutes and lower than 4 weeks.
10. The device for DBS therapy according to claim 1, wherein said targeted site region of the brain is selected from a group comprising nucleolus accumbens, prefrontal cortex, habenula, arcuate nucleolus, Subgenual cingulated gyrus.
11. The device for DBS therapy according to claim 1, especially used for drug addiction, epilepsy, Parkinson's disease, bulemia, anxiety/obsessive compulsive disorders, Alzheimer's disease, autism, and neurogenic pain, post traumatic stress disorder.
12. The device for DBS therapy according to claim 1, additionally comprising a patient controller; said patient controller having means to enable said patient to adjust said therapy.
13. The device for DBS therapy according to claim 2, additionally compr,ising a portable programmer; said portable programmer is adapted to monitor said neurostimulator functions.
14. The device for DBS therapy according to claim 14, wherein said portable programmer is not invasive.
15. A method for Deep Brain Stimulation (DBS) therapy in a targeted site region of the brain; said method comprising the steps: a. obtaining a device as defined in claim 2; b. implanting said lead in said targeted site region of the brain; c. implanting said neurostimulator under the skin; d. connecting said lead to said neurostimulator by said extension; e. electrically stimulating said targeted site region; wherein said targeted site is the ventral tegmental area; further wherein said device is used especially for treating chronic depression in a patient.
16. The method for deep brain stimulation according to claim 16, additionally comprising the step of restoring the normal activity of the nervous system.
17. The method for deep brain stimulation according to claim 16, additionally comprising the step of attenuating the pattern of said therapy to 5 spikes/burst with 80-160 msec intervals between said spikes, adjusting the pulse amplitude to about 300 micro Ampere, adjusting the pulse frequency to about 10 Hertz.
18. The method for deep brain stimulation according to claim 15, additionally comprising the step of electrically re-stimulating said targeted site region according to a predetermined medical needs.
19. The method for deep brain stimulation according to claim 15, additionally comprising the step of controlling and attenuating the pattern of said therapy.
20. The method for deep brain stimulation according to claim 15, additionally comprising the step of selecting parameters of said stimulation's pattern from a group comprising spikes/burst ratio, intervals between spikes, pulse amplitude, pulse width, pulse frequency, on-time and off-time, output current, output voltage and stimulation time.
21. The method for deep brain stimulation according to claim 20, additionally comprising the steps of (a) storing said parameters in a memory storage module; and (b) controlling said stimulation's pattern based upon said parameters.
22. The method for deep brain stimulation according to claim 20, additionally comprising the step of adjusting said stimulation time to be higher that 1 minute and lower than 20 minutes.
23. The method for deep brain stimulation according to claim 15, additionally comprising the step of adjusting the onset time of said device to be higher 5 minutes and lower than 4 weeks.
24. The method for deep brain stimulation according to claim 15, additionally comprising the step of selecting said targeted site region of the brain from a group comprising nucleolus accumbens, prefrontal cortex, habenula, arcuate nucleolus, Subgenual cingulated gyrus.
25. The method for deep brain stimulation according to claim 15, especially used for drug addiction, epilepsy, Parkinson's disease, bulemia, anxiety/obsessive compulsive disorders, Alzheimer's disease, autism, and neurogenic pain, post traumatic stress disorder.
26. The method for deep brain stimulation according to claim 15, additionally comprising the step of controlling said stimulation by means of enabling the adjustment of said therapy by said patient.
27. The method for deep brain stimulation according to claim 15, additionally comprising the step of programming said neurostimulator functions.
PCT/IL2007/001160 2006-09-22 2007-09-20 A device and method for deep brain stimulation as a new form of treating chronic depression WO2008035344A2 (en)

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