Common use of SCIENTIFIC BACKGROUND Clause in Contracts

SCIENTIFIC BACKGROUND. Clinical depression is one of the most common mental disorders. The condition is characterized mostly by a combination of a number of symptoms such as pessimism, loss of interest or pleasure, major weight change or change in appetite, fatigue or loss of energy, sleep disorder, loss of concentration, feelings of guilt, thoughts of death, etc. that last at least two weeks. In various studies, the average incidence of this disorder worldwide is between 5% and 15% annually. This situation adversely affects many areas of a person’s life, such as family, work and studies, quality of life and general health. It can be a considerable burden on the health services and at the same time can cause major functional damage, including loss of ability to work and alcoholism. The most accepted treatments in situations of depression are currently therapeutic treatment and psychotherapeutic treatment (on their own or in combination). However, there are cases in which these treatments do not lead to the desired results and to the patient’s remission (1-3). Between 20% and 40% of patients do not respond to the existing therapeutic treatment or to a combination of therapeutic treatment and psychotherapeutic treatment (4). In cases of persistent depression, patients who do not respond to the standard treatment occasionally switch to treatment with electro convulsive therapy. This treatment is considered the most effective (5) but is administered under general anesthetic, and apart from the risks of the anesthesia, it involves side effects, including a risk of developing cognitive disorders and permanent damage (6). Transcranial Magnetic Stimulation (TMS) is a non-invasive method in which the nerve cells in specific regions of the brain can be stimulated. This method, which has been in use for 20 years, works by means of a coil into which flows a pulsating electrical current. During pulsation, the current in the coil causes electromagnetic induction that permeates into the brain and creates an electrical field that arouses the nerve cells in the brain in the region at which the coil is directed. In the last few years, use has been made of Repetitive Transcranial Magentic Stimulation (rTMS) in the treatment of depression, whereby the TMS device is operated at a number of consecutive pulses at a certain frequency. This treatment is non-invasive, is administered when the patient is fully conscious, and has few side effects. In depressive patients with no psychotic component it is even as effective as the electro convulsive therapy (7). TMS has been approved by the FDA for major depressive disorder in patients who are not responsive to the standard treatment (8). The assumption is that in a state of depression there is an asymmetry in brain activity in the frontal lobe with resultant hypoactivity in the left Dorsolateral Prefrontal Cortex (DLPFC) and hyperactivity in the right DLPFC. The DLPFC is TMS sensitive and synaptically connected to the limbic system associated with the regulation of mood. The current most common protocols for treating depression using rTMS are: application of TMS to the left DLPFC at a high frequency of between 5-20Hz, a treatment that is thought to stimulate activity and on which the FDA (10-20Hz) protocol is based, or applying it at a lower frequency of 1Hz to the right DLPFC, a treatment that is thought to reduce activity. Two types of protocols have been found to be effective in the treatment of depression (9-10), however no advantage has been found in combining both options (11). The highest frequency protocol has a broader research base and has a better chance of being effective and was therefore chosen for this study. Meta-analyses have shown that the treatment with the highest frequency directed towards the left DLPFC is effective in the treatment of depression in comparison with sham stimulation (12-14). The medical center that administers TMS treatments has examined the first hundred subjects who received the treatment after it was approved by the FDA and showed that TMS was indeed effective in the treatment of depression (15). Another study also showed an improvement with the more intensive treatment of twice a day for a total duration of only two weeks (16). Another method for treating persistent depression is deep TMS in which the magnetic field created by the coil permeates deeper into the brain in comparison with the field created by the standard coils. The Israeli company Brainsway, which has developed a coil of this type, has shown that it is effective in the treatment of depression (17) and has also received FDA approval for the treatment of depression using this device (18). Another location for the treatment of depression is the medial prefrontal cortex (MPFC). The Brainsway H7 coil is designed to stimulate this region and has shown good results in depressive patients (19). However, the current application of TMS for research and treatment of brain disorders is still restricted by great differentiation, and it is difficult to obtain uniform brain reactions among the subjects. Recently conducted studies have shown that one of the reasons for this is the angular sensitivity of TMS. A new coil, the cloverleaf coil, has been developed by the Weizmann Institute and is specially adapted for the existing TMS system (20). This coil more effectively activates the region at which it is directed and thus improves the angular sensitivity of TMS. This improvement is made by rotating the magnetic field achieved by superposition of the fields of two coils in the common figure-of-eight configuration with a rotating field and a diameter of 79 mm located perpendicular to each other and operating with a phase time difference. Rotating field TMS facilitates the optimal location of the regions in the brain for which it is impossible to know the correct direction of the stimulation. The figure-of-eight coil used in most rTMS studies for the treatment of depression activates neurons with axons in only one specific direction parallel to the magnetic field, whereas the cloverleaf activates neurons with axons that go in all directions in a plane on which the magnetic field is exerted. A comparison can be seen in figure 1 from (20) between the angular sensitivity of both coils, expressed in a measurement of the thumb’s response after a pulse that activates it in the human motor cortex, which demonstrates the advantage the cloverleaf coil’s angular sensitivity has over the figure-of-eight coil (20). Unlike the deep TMS treatment that requires an original system, the cloverleaf coil can connect to standard TMS systems. As previously explained, in the standard TMS treatments of depression, patients vary in their response to the treatment which may be due to the angular sensitivity. In this study we will therefore examine if use of this new technology which has been found to be effective, can lead to a greater improvement in the treatment of depressive patients in comparison with treatment using the commonly used coil. In order to test this, the study will be double blind, so that only at the end of the follow up will it be possible to make a connection between the patient’s details and their serial number used in the trial. The cloverleaf coil may also be operated in the single configuration of figure-of-eight, so that both the subject and the person conducting the trial cannot know in which trial conditions they are. In addition and in parallel, the increased effect of rotating the magnetic field using a deep TMS device will be examined by expanding the configuration of the Brainsway H7 coil. The expansion of deep TMS into a rotating field is achieved in the identical fashion to the figure-of-eight coil, in other words a configuration of two coils perpendicular to each other and operated by a quarter turn of the power supply of one coil with respect to the H7 and Dual H7 devices independently. Improvement in the symptoms of depression after treatment with rTMS using the cloverleaf coil (or Dual H7). The treatment with the cloverleaf coil (or Dual H7) will be more effective than the treatment with the most commonly used coil, the figure-of-eight coil (or H7).