Transcranial magnetic stimulation system

187698/2 γη mn

TRANSCRANSAL MAGNETIC STIMULATION

Applicant:

Brainsway, Inc.

1460-IL 1 187698/2

TRANSCRANIAL MAGNETIC STIMULATION

CROSS-REFERENCES TO RELATED APPLICATIONS

[001] This application claims priority from U.S. Patent App icaticn Serial 5 Number 11/153,905, filed on June 16, 2005, entitled “Transcranial Magnetic Stimulation System and Methods”, incorporated by reference herein in its entirety.

FIELD OF THE INVENTION

[002] The present invention relates to a system and methods for deep transcranial magnetic stimulation, and more particularly, to an improved system io and method for stimulating specific regions of the brain while minimizing pain and side effects.

BACKGROUND OF THE INVENTION

[003] Transcranial magnetic stimulation (TMS) is widely used as a 15 research tool to study aspects of the human brain and has been suggested as a diagnostic and therapeutic tool, especially in neurology and psychiatry.

[004] Biological tissue can be stimulated using magnetic fields produced by passing electrical currents through electrically conductive materials positioned adjacent to the tissue. The magnetic fields are intended to induce an 20 electric field in a tissue, provided that the tissue is a conductive medium. More specifically, magnetic stimulation can cause electric conduction in brain cells, and, as a consequence, generation of action potentials.

[005] The magnetic stimulation is delivered or generated by a TMS system, including a stimulation circuit and a coil positioned on the patient’s scalp, 25 inducing nerve stimulation within the brain. The TMS stimulation circuit generally includes a high voltage power supply which charges a capacitor or bank of capacitors, which are then rapidly discharged via an electronic switch into the TMS coil to produce a briefly changing magnetic field pulse. A typical circuit includes a transformer, such as a high-voltage transformer, JGBT transistor, or other device 30 used to transform low-voltage AC into high voltage DC. The switch, which may be, for example, a thyristor switch, must be able to traverse high current at short intervals (such as 50-250 ps). WO 2006/134598 PCT/1L2006/000694 2 (006J Current magnstie stimulation techniques and coils are suitable for superficial stimulation of the brain, whereas for some medical indications, deeper stimulation would he essential. For example, standard superficial stimulation does not induce effective stimulation directly in deep prefrontal cortex 5 areas (3-4 cm deep) and other reward and mood-related brain structures such as the nudeus accumbens (ventral striatum). Direct stimuiation of such deep regions may be more effective for the treatment of major depression than superficial cortical stimulation obtained with a standard TMS system. Stimulation of deep brain regions may be beneficial for many other deep-brain related disorders and io other psychiatric and neurological disorders such as autism, post-traumatic stress disorder (PTSD), addictive behaviors including smoking, overeating and drug addiction, schizophrenia, Parkinson’s disease, and others. Stimulation of deep brain regions requires a vory high intensity which cannot be reached by the magnetic stimulators available today, using standard circular or figure-eight coils, is Moreover, stimulators or coifs which may provide greater electromagnetic fields, if used for deep-brain stimulation, may cause undesirable side effects, such as, for example, opitaptic secures or other problems associated with over-stimulation of cortical regions.

[067] An attempt to solve thia problem is disclosed, for example, in U.S. 20 Patent Publication Number 2005/0228209. A method disclosed therein for TMS includes moving one or more (toils to a target area, and applying magnetic fields to the target from multiple locations oueh that at any given time, toe brain surface receives only p small amount of magnetic energy. However, toe method disclosed therein does not sddress to© physiological properties associated with 25 stimulating adieu potentials in neuronal structures, and does not include any discussion of temporal control of the timing of impulses from different sources.

[008] A novel approach to deep brain TMS with minimal surface stimulation has been previously described in International Publication Number WO 02/32504. Tit© device described therein inriudos a baa© and an extension portion, 30 the base having individual windings for individual paths of current flow, and the extension portion designed so as to misiimfeo unwanted stimulation of other regions ofthe brain. WO 2006/134598 FCT/HL2006/030694 3

SUMMARY OF THE tWENTiOR 1009] According to aspects of the present invention, toere is provided a method for TMS which includes activating a neuronal structure. The method indudes providing at feast one esil for delivery of electrical Impulses to a target area, toe coil having individual members designed to carry current in predetermined direntiors, and activating at Joust seme of toe individual members non-simultaneousiy. (0010] to some embodiments, muitip'n. ©site arc;· provided, and activating toe individual members indudes members from multiple coils non-simulteneously. In some ombodimorrts, some members from eno col! and members from multiple coils are activated non-rfrnuJtMneously, Some of to© members may also b© activated simultaneously.

[0011] In som® embodiments, foe activating involves first activating a first one of to© individual members and after a first pre-determined period of time activating a second one of too individual members, The predetermined period of time in some embodiments is within a range of CM000 microseconds, and in some embodiments in within a range of 5tMS© microseconds, in other embodiments, the pre-determined period of times te within a range of 1-100 milliseconds, and may be within a range of 1-10 milliseconds.. in some embodiments, the pre-determined period rf time may bo up to 1 second. The activating may further include after a second pre-determined period of time activating a third on© of toe individual members. The second pre determined period of time may b© to© same amount of time or a different amount of time tiian the first predetermined period rf time. The individual members may nneh bo connected to a separate control channel, wherein toe activating is done by activating tot? separate oonfrol channels. In another embodiment, the IndWWusl members may be connected to one control channel, and there may be provided a control system for controlling timing of to© activating of ft© individual members, in som© embodiments, too predetermined directions are too same direction for ouch of too individual members, while in other embodiments, too predetermined directions are a different direction for each of toe individual momhere, wherein each of too predetermined directions forms a path designed to mimie a neuronal structure. Activating may Endud© sequentially, WO 2006/534593 PCI /11200(:/000694 4 randomly, selectively or repeatedly activating each or some of toe individual members.

[0012] According to another aspect of toe present invention, there is provided a eoil for magnetic stimulation of a target area. The coil is positionable 5 on a body part, and includes o base portion having multiple spaced apart members for providing efcctncaf eutront tow in a direction tangential to the preferred direction for activation of the target area, the base portion positioned at a first level with respect to too target area, and a contacting return portion for carrying returning current in a direction opposite th© target area, the contacting io return portion in electrical communication with at least one member and positioned substantially in toe first love! and spaced at a distance from the target area.

[0013] In some embodiments, the coll may also include a protruding return portion for carrying returning current in a direction opposite the preferred direction, the protruding return portion in electrical communication with at least one is member and positioned at a second lovci with respect to toe target area, toe second level located at a distance above th© first level. Some of the iramfeers may be in ©techiest communication with to© protruding return portion ant oom© of toe members may b© In electrical communication with toe csntactiig return portion. In some embodiments, at least ©no member is positioned in a lateral- 20 medial direction and in some embodiments, at least on© member is positioned in an anterior-posterior direction. in some embodiments, th© multiple members are substantially parallel to on© another, in oom© embodiments, th© first level is the skull and to® second level is a distance obovo too skull. Th© distance may range from 4 -10 cm and may bo around 7 cm, A distance of th® contacting return portion 25 from the target area may to hi a range ef 7-10 cm. In some embodiments, the base portion hm a substantially areMike Gsnfiguraton which is complementary to toe body part, In some embodiments, toe body part is too head and the target area is a portion of a brain. Th© portion ©f th© brain targeted may be at least 3 cm deep. 30 [0014] Unless otherwise defined, ail technical and scientific terns; used herein have· too soms meaning es eorranOTiy uraicreteod by ona ©f ordinary skill in the art to which this invention belongs, Although methods and materia!© similar or WO 2006/134598 PC17JLIL2006/000694 5 equivalent to thuuo described herein eun bo uood in the practice or testing of the present invention, suitable methods and materials are described below. In case of conflict, the patent specification, including definitions, wifi control. In addition, the materials, methods, and examples ar© illustrative only and not intended to be limiting. ' BRIEF DESCRIPTION OF THE DRAWINGS [0015] The above and further advantages of the present invention may be better understood by referring to the fallowing description In conjunction with the accompanying drawings in which: FIG. 1A io a schematic illustrate of a system in aceordancr® with a preferred embodiment of the present Invention; FIG. IB is an illustration of a helmet from the system of FIG. 1 A; FIG. 2A is an illustration of a dovtoo including a frame and an electrically conductive coll having a base and an outwardly projecting extension portion; FIG. 2B is a schematic diagram illustrating conducting wires and current flow in the embodiment illustrated in FIG. 2A; FIG. 3A io an illustration of a devise including a frame and an electrically conductive ©oil having a base and an outwardly projecting extension portion with a plurality of radially elongated extension elements; FIG. 3B Is a schematic diagram illustrating conducting wires and current flow in the embodiment illustrated in FIG. 3A; FIG. 4 is an illustration of a coil for TMS in accordance with one preferred embodiment of tee present invention; FIG. 5 lo an illustration of a sni! for TMS in accordance with another preferred embodiment of tire present Invention; FIG. β is a htaek diagram illustration of a coaling system in accordance with a preferred embodiment of th© present invention; FIG. 7 is a block diagram illustration of externa! cooling unit from the cooling system depicted in FIG. 6; FIG. 8 is a block diagram Hiustration of a liquid dreufator from the cooling system depicted in FIG. 6; WO 2006/134398 PCT/SL2006/OC0694 6 FIG. 9 Is a schematic BlustratioR cf an internal system in contact with coils illustrated in FIGS. 4 and1 S, in accordance with on© preferred embodiment cf the present invention; FIG. 10 is a graphical illustration of a strengiMuration curve reflecting the average of four subjects, using eight different coils with inductance L of between 6 and 148 pH; FIG. 11 is a graphical illustration depicting pulses produced by TMS soils having inductances of 18 and 70 pH; FIG. 12 is a block diagram illustration of a multi-channel TMS system in accordance with embodiments ofthe present invention; FIG. 13 te a graphical illustration of electric field pulses induced in a deep brain region, a first cortical region,, and a second eortteaS region; FIG. 14 is a graphical illustration of electric field pulses induced in a deep brain region and three cortical regions; FIG. 15 te a graphical illustration of cleetrie field pulses induced in a deep brain region and three cortical regions, with different parameters than those shown in FIG. 14; FIG. 16 te an Illustration ef a coil designed to stimulate tbe right abductor poiltas brews in an experimental trial on humans; and FIG. 17 is a graphical illustration of the results of performing stimulation using the coi! of FIG. 16 as compared to a standard figure-8 soil.

[0016] It will be appreciated that for Qimpiidty and clarity of Blustration, elements shown in the drawings haw not necessarily boom drawn accurately or to scale. For example, th© dimensions of some of the elements may be exaggerated relative to other elements for clarify or eevera! physical components may be included in on© funefiortal block w dement Further, where considered appropriate, reference numerate may be repeated among the drawings to indicate corresponding or analogous elements. Moreover, son® of to© blocks depicted in the drawings may be combined into a single function. DETAIL® nLsempricm [0017] In th© following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. It will be understood by those of ordinary skill in the art that the present invention WO 2006/134538 PCT/1L2006/000694 7 may be practiced without these specific details, in other instances, weil-known methods, procedures, components and structures may not have been described in detail so as not to obscure th© present invention.

[0018] The present invention Is of a method for stimulating deep brain regions using TMS. Specifically, fire present invention can b© used to stimulate deep regions of the brain while maintaining a high percentage of field intensity as compared to superficial regions.

[0019] The principles and operation of a system and methods for transcranial magnetic stimulation according to toe present invention may be better understood with reference to th© drawings and accompanying descriptions.

[0020] Before explaining at least one embodiment of the invention in detail, it is to be undetutood fitui: (ire invention to ml limited in its application to the details of construction and tire arrangement of ft© components set forth in the following description or illustrated in too drawings, Th© invention is capable of other embodiments or ©f being praetieed or earned out in various ways. Also, it is to be understood that the phraseology and terminsfogy employed herein is for the purpose of doscriptcon and should not be regarded as limiting.

[00211 Reference Is now made to FIG. 1A, which is a schematic illustration of a system 80 in accordancu with a preferred embodiment of the present invention. System SO Includes a helmet 92 which holds roils for magnetic stimulation and is positionaW© around a head of a subject. Helmet 82 is adjustable via positioning portion 84. Positioning portion includes a stard 81 with an adjustable arm 83, a chair 8S with a rear head support 87, and an adaptor 89 between helmet 82 and adjustable arm 83. A stimulator 86 is in electrical communication with the coils of helmet 82, and is designed to provide electrical stimulation to ft© coifs. Stimulator 8Θ to a mirocrciaily available neurostimulator, such as any of ft© various models of magnetic stimulators produced by Medtronic, Inc. of Minneapolis, MN, USA (o.g., MagPro, MagLito Compact), or power supplies sold wife various models of magnetic stimulators produced by Magstim Company US, LLC, of New York, NY, USA (o.g., Magstim Model 200, Magstim Model 220, Magstim Model 250, BiStim, Magstim Rapid, Magstim QuadroPulse, Magstim Rapid2). Stimulator 88 is used to deliver electrical stimulation to the brain, and WO 2006/J34598 PC7It2005/000694 8 provides a eenfrolled output, frequonigy, and pulse duration, and may also indude an indication of coil temperature. A ceding system 88 is also in communication with th© coils of helmet 82, and is designed to maintain an ambient temperature in the coils during repetitive stimulation provided by stimulator 86. Cooling system 88 may be a system based on air cooling using a Freon system, or a thermoelectric cooler (TEC) system such as the TECs produced by Meteor Ltd, (Trenton, NJ, USA), with either open air pathways or dosed, two-direction air pathways, or ceding system 88 may be a liquid cooling system, A particular example of a cooling system 88, designed specifically tor use with the coils of the present invention, will bo described in further detail herein below with respect to FIGS. 6-9.

[0022] Reference is now made to FiG. 1B, which is a more detailed schematic illustration of helmet 82 in acsordanoe wife a preferred embodiment of the present invention. Helmet 82 indudes o rigid cover 90 and a flejtible cover 92. Flexible cover 92 to designed to provide flexibility over the head. An internal wall of helmet 82 is lined with a sponge for padding, tn ono embodiment, the liner is a 0.9 mm biocompatibto sponge with onesided gluo (3M Foam Medical Tape). Adaptor 89 is attached to an upper portion of stand 81 via an adjustment screw 94. Adjustment screw 94 enables adjustment of tho height or angle of helmet 82. Wires 96,98 run from stimulator 86 and cooling system 88 to helmet 82.

[0023] Positioned within helmet. 82 are coils for transcrania’ magnetic stimulation. Cate uro designed to penetrate deep regions of the brain, while minimizing adverse side effects. Tho basic prinapleo of operation of coils suitable for deep brain stimulation are as follows: [0024] 1. Proper orientation of stimulating eolls.

Coils must bo oriented such that they will produce a considerable field in a direction tangential to the surface, which should also bo the preferable direction to activate th© neurons under consideration, Thai is, wires of th© coils are directed in on© or more directions, which results in a preferred activation of neuronal structures orientated in these particular directions. In some eases, there is one preferred direction along the length or width axis, and in other cases, there are two WO 2006/134S38 FC1’ZIL2006/000694 9 or more preferred directions along both toe length and width axes. Thus, the placement and orientation of activating mils on the skull is important [00251 2. Minini’zation of non tengontis! mi! slomenfe.

Electrical field Intensity In the tissue to be stimulated and the rate of 5 decrease of electrical field as a function of distance from the coil depend on the orientation of to© coll elements relative to the tissue surface. It has been shown that coil elements which are perpendicular to th© surface Induce accumulation of surface charge, which leads to einecifafion of too perpendicular component of to© induced field at all pointe witoin the tissue, and in general to reduction of the io electrical field in all other directions in most pointe. Thus, too length of coil elements which are not tangential to Use brain tissue surface should be minimized. Furthermore, too noretangential coil ©torrents should be as small as poss ble and placed as far as possible from th© deep region to bo activated. The? combination of these two factor© helps to minimi?© accumulation of surface charge, is [0020J 3. Maximteaton of too field in too deop region as compared with the field at th© cortex. A major goal ef deep TMS is to maiam®© deep region stimulation without causing a large electrical fretd at surface areas of the brain. If to© electrical field at the surface areas is to© forge, it ran cause pain, spiteptic seizures, or other 20 complications. Thus, it is important to fry to majdmfe© deep region stimulation without causing a large electrical field to accumulate at surface areas. This can be accomplished by eurnmatfon of oteetircaS Impulse©, a concept which will be described further hereinbelow. In addition toe coil elements leatfing currents in a direction opposite to tha preferred direction (to© return paths), should bs located far 25 from toe desired brain region.

[Q027J For puraozez of tetter understanding ?h© present invention, as illustrated in Figures 4-10 of too drawings, reference is first mad® to to© construction and operation of previously described roils as lllusfrated in FIGS. 2A, 2B, 3A and 3S. Th© calo aro shown in two different configurations, which have 30 been previously diselosed in International Publication Number WO 02132504, entitled, "Gdl for magnetic stimulation and methods for using to© sam©," incorporated by reference herein in its entirety. WO 2006/134598 PCT/Π. 2096/000694 10 [00281 Referring now to FIG. 2A, a device 11 includes a frame and an electrically eonducSve coil hairing a base 12 and an outwardly projecting extension portion 14. In somo emhodimGnte, the frame iteotf io the electrically conductive coil, such as a frame composed of electrically conductive material. In other 5 embodiments, however, the frame is a flexible or malleable material, which may be configured to a desired shape for a specific application, and the electrically conductive coil comprises one or more windings of electrically conductive material associated with tho frame, such as being run alongside of, mounted lo, wound around, or placed inside th© frame. Tit© base 12 has a concave first side 19, io which is directed toward the body part of the subject, and a second side 20 opposite first side 19. The extension portion 14 extends outwardly from this second side and away from the base.

[0029] Device 11 can be placed in various orientations around the skull. However, device 11 effectively induces electric fields within the body of a subject is when the device 11 is placed with tho concave side 19 of the base 12 facing th© body of the subject [0030] The device 11 pictured in PIG. ?Λ has a partially torolda or ovate base 12 with a first end 22 and a second end 24. A tine extending between tries© two ends 22, 24 defines a length axis dong tri© length of the base 12. The base 20 12 has a substantially arcuate, semi-circular er semi-ovate shape along its length axis. The base 12 also has a width axis extending perpendicular to its length axis and this width axis has a substenfiaily arcuate, iiomi-clreuiar or semi-ovate shape. Thus, the base 12 pictured in FIG. 2A comprises an arch extending along its length axis and an arch extending along fe widte axis. Th© arch configurations 25 along both the length and width axes are complementary to the external shape of the body part wift whittfi the device is to be used. Tho device conforms to the side-to-side and front-tortjack arch shape of a subject’s skuil.

[0031] As shown in FIG. 2A, the base 12 includes n pair of substantially parallel, arcuate, elongate, tongitadinally-e^Bndlng, laterally spaced frame 30 members 21 and 23. Extending between and interconnecting longitudinal frame members 21 and 23 are ten elongate, arcuate, transverse frame mertbers 1,2,3, 4, 5, 6, 7, 8, 9, 10. Members 1-10 are spaced apart along th© lengths of WO 2006/134598 PCT/IL?,00( /000694 11 longitudinal frame members 21 and 23 and ar© coupled at their opposite ends to, and extend generally at right angles to, longitudinal frame members 21 and 23.

[0032] The extension 14 provides a path for the flow of oloistricity to and from the base 12. A surface charge can interfere with and reduce frn strength of 5 the electric Add produced by the coil portions in the base. Reduction in surface charge is accomplished by using a triangular, or upwardly converging, extension 14. The extension 14 comprises flint and cerartd efengutod elements 26,28. The elements have a first set of inner ends 30, 32 connected to the base 12 at positions spaced apart along tho length of the redo rf the fens© 12. The first io elongated element 28 has a first inner end 30 connected to th© base 12 adjacent to the first end 22 of the bass 12, and the second elongated element 28 has a first inner end 32 connected to the baso 12 adjacent to the second end 24 of th© base 12. The remainder portions 34,36 of these elements 26,28 extend away from the base 12 and converge toward each other. is [0033] RG. 2B is a schematic diagram illustrating conducting wires and

current flow in tho embodiment illusfrated in FIG. 2A In FIG. 2B, pointe labeled A-J and AA-JJ ate associated with the base, and pointe Q-V are associated with the extension portion. Pointe U and V correspond ta th© electrical inputs for the current produced by tho power supply (not shown). Using th© diagram of FIG. 2B 20 as a guide, on© can understand how a coil might b© constructed for the embodiment of FIG. 2A For oxampte, th© device 11 iiiustrated by FIG. 2A could comprise a ceil having ten windings numbered 1-10 extending in the arch width direction of tho base along tho ton elongate, areuato transverse from© mambers Ι-ΙΟ. Table 1 summarizes such a placement of windings. 25 Table 1

Winding No. Pathway 1 2 V-RU !+!!·! til· QU 3 V-R-iFUil-Q-U 4 5 V-R-F-FP-Q4J 6 V-T-frEBS-U WO 2006/134598 PCT/5L2906/000694 12

7 V-T-E-DW-EE-S-U 8 V-T-C-GG-S-U 9 V-T-C-B-BB-GC-S-U 10 V-T-C-B-A-AA-BB-CCS-U

[0034] A significant portion of too current flowing through the bane flows through the transverse strips of the coil and therefore, is orientec substantially along the reference ZQKfe shown in ΠΘ. 2A. The coil portions associated with the 5 base ar© complementary and tangential to toe surface of to© subject's skull. In particular embodiments, too total length ©f toe coil associated with the transverse frame elements 1-10 (i.e. substantially paralid to the width axis of toe base) exceeds toe remaining length of the coil associated with toe base (i.e. toe remaining length substantially parallel to too length axis of to© base). In these io embodiments, a majority ©f too current flowing through to® base is oriented

substantially along the referenced shown In FIG. 2A

[0035] An alternative embodiment of toe device disclosed in

International Publication Number WO 02(32504 is depleted in FIGS. 3A and 33. A device 11A has a base 12A and an extension portion 14A, where base 12A has a is first end 22A and a second end 24A, and a substantially areuat©, semi-dreuiar or semi-ovate shape along its length and width axea. However, in this embodiment, extension 14A includes a plurality of radially elongated extension elements 110, 112,114,...158,16Θ, rather than a minimal number ©f radially elongated elements 26, 28 shown in FIG. 2A. Th© embodiment shown In FIG. 3A includes Iwenty-six 20 radially extending elongated extension elements 110, 112, 114,...158, 16Q, although alternative embodiments may employ 0 different number of such elongated extension elements. As illustrated, toe radially elongated elements 110, 112, 114,...158,160 are eoflocted into four fen-tte groupings 170,172,174,176, and elongated elements 134 and 136 ere connected by lateral elements 180 and 25 182.

[0036] Simitar to base 12 illustrated in FIG. 2A, baso 12A illustrated :n FIG. 3A includes a pair of substantially pontile!, oreuato, elongate, longitudinally-extending, laterally spaced frame members 21A and 23A, Extending between and WO 2006/134598 FCT/I.2006/C00694 13 interconnecting longitudinal frame member© 21A and 23A ar© twenty-six elongate, arcuate transverse frame members 210,212,214,... 258,260. (0(137] The amount of surface charge, and the influence of fhst surface charge on the deeper tissues of tiro oubjotfo body that are stimulated, depends on 5 the overall lengths and locations of tiro etertrica! components which contain non-tangential components. In this embodiment, th© overall lengths of such non-tangential elements are reduced and their distances from the deep brain regions aimed for activation are increased, in otter werefo, to© rati© of to© total length of the coil extending radially from tiro base to Oto total ier^th of the eoil associated io with the base is less toon too corresponding ratio in th© previous embodiment, shown in FIG. 2A.

[0038] FIG. 39 fe »'« schematic illustration of current flow through the windings of the embodiment fllustrated in FIG. 3A, with reference numerals correlating these windings to certain structures fllusfrrted in FIG. 3A. FIG. 3B is is not a circuit diagram in too too oenso * - this illustrator simply shows how a aril for the device may be mad© from individual windings of the eoi!, wito each individual winding comprising a circuit, For too sake of clarity, only part of toe entire device is shown.

[0039] As illustrated in FIG. 30, th© direetten of etectoea! current flow is 20 the same in all of too twontyclx strips of too base 12A, flowing in a direction from the lateral frame member 23A to lateral frame member 21A. Generally, current to this portion <aftte aril rarives utZ, feavefe down to la, and tows through strips Ja-Ji, K?-Ki, L^M, and Ma-W Each strip (/Wh, has a return path through an elongated element 110, 112, 114, ..,158, 160 of one of to® fan-like 25 groupings 170,172,174,178. For «amp!©, ih© return path for strip J?-Ji may be elongated element 140 (not shown in FIG. 39). Th© amort flows to la then flows through strip Ha-Mi, and to h. From her®, too current flows up th® extension to W, then to X (toe line W-X representing toe Junction of two elongated elements 148 and 150), then to ©& then through ships 1 :a Τ’·ι, I;3,ί Vfh, Q? <h, B2Jh, Ag-Ai, 30 and returns to Ga. Each of strips I Vlί, )V!-V .¾ Ih, Ca-Ci, Ba=Bi, A? Ai, has a return path through on elongated element of farrtlko collection 178 composed of elongated elements 1Q0-160. The return paths of current flow ar© in toe opposite WO 2006/134398 PCT/IL20«(i/000694 14 directions of the strips. As in the first embodiment, shown in MG. 2A, extension portion 14A of this second embodiment places electrical currents flowing through the return paths away from too subject, to reduce their eteetrieal effect on th© body tissues of the subject 5 [0040] in the two previously described embodiments of a device for magnetic stimulation described above with reference to FiGS. 2A43 and 3A-B, return paths are placed away from the subject, to reduce their electrical effect on th© body tissues of to® shbjoct However, Increasing too distanoe from the skull requires longer non-tangential elements and causes an accumulation of surface io charges, which increases the decay in eleefrinn! field with depth. These conflicting principles are balanced as much as possible, so ao to minimize both unwanted electrical effects due to current flew in the retom paths and unwanted accumulation of surface charges.

[0041] In th© present application, a design to farther decrease the is lengths of non-tongcntial dements (ami thus minimizo unwanted surface charges at the area of stimulation) is disclosed. The embodiments described herein are particularly useful in cases yaher© too region to bo stimulated te not on a central line of the brain, such as prefrontal regions.

[0042] Reference te now made to FIG. 4, which is an illustration of a coil 20 300 for TMS in accordance with ope preferred embodiment of tho present invention. CoB 300 includes a base portion 312, a providing return portion 314, and a contacting return portion 315. Bose portion 312 is comprised of windings 317 of electrically conductive material. Base portion 312 has a concave first side 319, which is in direct contest wife te skull and is directed toward te body part of 25 the subject, and a second side 320 opposite first side 319. Protruding return portion 314 «tends outwardly from second old© 320 and away from base portion 312, and contesting return portion 31S is positioned a distance from base portion 312, but is in contact with to© skull. Thus, has© portion 312 can b© considered to be at a first height with respect to the target area. Protruding return portion 314 is 30 at a second height wherein tho first and second heights are defined with respect to the y-z plan© . Contacting return portion 310 Is at too first height, that is, is approximately on too cam© piano as base portion 312, but is at a planar distance WO 2006/1345%' PCT/iL20a6/e00694 15 (in the x-z plane) from the target area. Windings 317 are designed to be in contact with the skull, and may either bo preformed or malleable to accommodate foe curved anatomy of foe area on which it is to be placed. This design maximizes tangential stimulation, which is optimal for axonal depolarization. 5 [0043] The device 30Θ pictured In FIG. 4 has an arcuate base 312 with a first end 322 and a second end 324. Λ fine extending between these two ends 322, 324 defines a length axis along foe length of the base 312. The base 312 has a substantially arcuate, semi-circular or semi-ovate shape along its length axis. The base 312 also hoo a width asfo extending perpendicular to its length io axis and this width axis has substantially arcuate, semi-circular or semi-ovate shape. Thus, foe tee 312 pictured in FJQ. 4 comprises an arch extending along its length axis and an arch extending along Ito width axis. Th© arch configurations along both th© length and width axes are complementary to foe external shape of foe body pari with which foo dovfou is to to used. Trio device «informs to foe is side-to-sid© and fronMofoaek arch shape of a subject's skull.

[0044] Bass 312 includes windings 317, which arc comprised of a series of substantially parallel members 301-310. in foe embodiment depicted in FIG. 4, members 301-310 are oriented in a laieral-medlaS direction, making device 300 suitable tor activating structures in fo© prefrontal cortex and fibers connecting the 20 cingulate or prefrontal cortex with the nucleus aecymtons and ventral tegmental area. These are neuronal pathways related to 0« control of motivation, reward and pleasure. Each of rrantbers 301-310 carries an electrical current in th© lateral-medial direction (cvfetonfeliy parotid with foo length roao of base 312), with the direction of foe current being foe same in each ©f members 301-310. 25 Each of members 301-310 has a retom pate, extending through either protruding return portion 314 or through contacting retom portion 315. The members 301-310 are electrically connected to a power supply, such as by electrical leads 316, 318. In a preferred embodiment, each of members 301=310 is 14-22 cm in length. In on© embodiment, there is a separation of 0.5-4 .S cm between each of members 30 301-310. In n preferred embodiment, there ie a separation of 0.8 cm between each of members 301-310. Th© return paths 306,’-310" of members 306-310 are situated above th© head at a distance therefrom ns delineated by segments H I. WO 2006/134598 PCT/DLIWK,/008694 16

In one embodiment, the distance from the head to toe return paths 306”-310” of members 308=310 is between 4-10 cm. In a preferred embodiment to© distance from toe head to to® return paths 300" 310” of members 306-310 i§ approximate,y 7 cm. 5 (00451 Coil 300 may be composed ©f any electrically «inductive material, such as metel. Particular embodiments have coils comprising wire made of copper, aluminum or other electrically conductive material. In a preferred embodiment, toe coil is made of a double 14 AW6 insulated copper wire having a total length of 800 cm and winded into windings 317, connected in series. In io alternative embodiment too eoil fc mode ef 7 Shelamid 200 copper wires insulated by two polyester Sayers (68 pm insulation width), with 0.9 mm diameter of each wire, or any kind of multi-line wires. In another embodiment toe coil is mad© from a multiline wire composed of 40-60 lines of 3 mm cross section. In a preferred embodiment, coil elements are coated by a polyurethane resin type is Resinex 4 (Hamehabor Vohamkaoher Ltd., terod), for additional electrical insulation. In alternative embodiments coil elements are coated by a RNF-3000 heaVshrinfototo tube with 0.Q5 mm thickness (Rayehero Corp, Monte Park, CA, USA), for additional electrical insulation. In alternative embodiments, coil elements are coated by otter insulating materials, such as PVC, nr are sandwiched between 20 layers of insulating materials, ft should he readily apparent that too embodiments disclosed herein are examples only and should not bo regarded as limiting. The windings 317 are connected to an appropriate cable and connector, which is then connected to a stimulator. The stimulator may be any appropriate commercially available power supply, such as too power supplies avaitabte for use with otoer 25 magnetic coils. In preferred embodiments, the stimulator is one of various models of magnetic stimulators produced by Medtronic, toe. of Minneapolis, MN, USA (e.g., MagPra» MagtJto Compact), or power supplies sold with various models of magnetic stimulators produced by Magstim Company US, LLC, of New York, NY, USA (e.g., Magstim Model 200, Magstim Model 220, Magstim Mode! 250, BiStim, 30 Magstim Rapid, Magstim OuadroPutee Magstim Rapid2).

[0048] A power supply or stimulator (not shown) supplies current through lead 31® into on© of members 301=310. The stimulating current pulses WO 2006/134598 PCT/1L2006/000694 17 flow substantially in tho laterahmedial direction. Current then ascends through an ascending portion 311 extending upwards from base portion 312. At this point, current can take ono of two paths - either through protruding return portion 314 or through contacting return portion 315. If current runs through protruding return s portion 314, it runs from oseending portion 311, through protruding return port on (which runs substantially parallel to members of base portion 312), and back down to the level of th© skull at a descending portion 323. From there, current returns through lead 318 back into tho power supply. If current runs through contacting return portion 315, it runs from ascending portion 311, to a descending connector io 313, through confecting return portion 315 (which runs substantially parallel to members al base portion 312 and is positioned directly on th© skull, but at a distance from members 301-310 of base portion 312), to an ascending connector 321, and back down to th© level of the skull at descending portion 323. From there, current returns through lead 318 back into the power supply. In a preferred 15 embodiment, half of th© members run through protruding return portion 31 δ and half of them run through contacting return portion 314. However, the invention is not limited to this proportion, and any proportion of protruding return paths and contacting return paths is possible, so Jong as each return patii receives current from at least on© of the members. Current may be supplied simultaneously to all 20 members, or alternatively, may be supplied sequentially, In a random order, or selectively. In another embodiment, current is supplied to member 301, arid runs through a loop including each of tit© additional membero 301=310. It should also be readily apperent that altiiough the invention has been shown with reference to ten members, th© invention fe not in any way limited to thin number, end any 25 suitable number ©f members may be used, to additional embodiments, a single member may have a return path through both protruding return portion 314 and contacting return portion 315. In additional embodiments each member may have several wines connected in series, while the different members may be connected in parallel, and activated either sequentially, simultaneously, or in any sequence. 30 [0047] In th® preferred embodiment depicted in FIG. 4, current from each of members 391-310 runs through ascending portion 311 via pathways 3G1’-310'. At the top of ascending portion 311, current from members 301-305 runs WO 2006/134S98

FCTZIL200fr/0C069<S 18 through contacting return portion 31 δ via pathways 30T'-305" while current from members 308-310 runs through protracting return portion 314 via pathway» 306 '- 310". Specifically, members 301-303 traverse the path A-B^WS-F-G-H-FJ-Q-R- S-T-K-L-A. Member 304 traverses too path A-B-G-H-l-J-Q-R-S-T-K4.-A Member 5 305 traverse® th© path Λ Μ M U ·β Ο P··! H J «It δ Members 306-307 traverse to© path Members 308-309 traverse the path A-B-G-H-kJ4C“L-A. Member 310 trsvcrcco the path ArK-kMC-L-A. It should be readily apparent that other combinations and pathways are possible, and are within the scope of the present invention» io ¢0048] Protruding return portion 314 io spaced a distance from to© skull, as described above. Dy placing the return path at a distance from the skull, electrical stimulation of unwanted portions of toe brain Is minimized. However, surface charge accumulation at toe surface ©f too brain is increased. As such, some of too return paths are placed on too deoil itself, so as to reduce surface 15 charge accumulation. However, those return paths are placed a distant» from the site to be stimulated within th© brain so as to avoid conflicting signals in toe area of stimulation. In a preferred embodiment, 'too distance from too members to toe contacting return paths is al; least 5 cm. in name embodiments, the distance from toe members to too contacting return paths is in too range of 7-2C cm. In a 20 preferred embodiment, the distance is approximately 10 cm. Thus, ε balance is maintained between the need for reducing curtacc charge and to© conflicting need to avoid eleefrieat stimulation of unwanted portions of the brain. (0049] Reference is now mad© to FIG. 5, which is an illustration of a coil 400 for TMS in accordance with another preferred embodiment of th© present 25 invention, in this embodiment, members 401-414 ere oriented in an anterior-posterior direction, for activation of structures tit ti to profrontel cortex and fibers connecting the cingulate or prefrontal cortex with th© nucleus eccumbens and ventral tegmental area, with prefcreneo for too loft hemisphere These are neuronal pathways related to too control of motivation, reward and pleasure. Coil 30 400 includes a base portion 425, a prolrading return portion 440, and a contacting return portion 415. Base portion 425 is comprised of windings 417 of electrically conductive material. Base portion 425 has a concave first, or inner side 419, WO 2006/134S98

PCT/IL200ii/00065M 19 which is in direct contaet with the skull and is directed toward the body part of the subject, and a second, or outer side 420 opposite first side 419. Protrudirg return portion 440 extends outwardly from second side 420 and away from base portion 425, and contacting return portion 41§ is positioned a distance from bast) portion 5 425, but is in contact with the skull. Thus, base portion 425 can b® considered to be at a first level with respeet to too target area. Protruding return portion 440 is at a second level which is at a distance from toe first level in the y-direction. Contacting return portion 415 io at the first level, that is, is approximately on the same plane as base portion 425, but is at a planar distance (in toe x-z plane) from io toe target area. Windings 417 are designed to bo in contact with toe skull, and may either be pre-formed or malleable to accommodate too curved anatomy of toe area on which it is to be placed. This design maximizes tangential stimulation, which is optimal for axonal depolarization.

[0050] The device 400 pictured In FIQ. 5 has an arcuate base 425 with a is first end 422 and a second end 424. A fine extending between these two ends 422, 424 defines a length axis along ft© length of toe base 425. The base 425 has a substantially arcuate, nomi-dreular or comhovato shape along its length axis. The base 425 also has a width axis extending perpendicular to its length aids and tols width aids has substantially arcuate, semi-circular or semi-ovate 20 shape. Thus, to© base 425 pictured in FIG. 5 comprises an arch extending along its length ads and an arch extendtog along its width aids. The arch configurations along both tit© length und width axes arc emppiomontery to too external shape of toe body part with Which to© device is to b© used. The device conforms to toe side-toside and fronttobaek arch shape of a subject's skull. 25 [0051] Base 425 includes windings 417, which are comprised of a series of substantially parallel members 401-414. to the embodiment depicted to RG. 5, members 401-414 are oriontod in an anterior-posterior direction, making device 400 suitable for activating structures in the prefrontal cortex Each of members 401-414 carries an electrical current to the anterior-posterior direction 30 (substantially perpendicular with ft© length ads of base 425), with the direction of the current being too oamo in each of member© 401414. Each of members 401-414 has a return path, extending through either protruding return portion 440 or WO 2006/1345¾ PCT/BL2006/000694 20 through contacting return porta 41S. Tho mombcra 401-414 ar© elsdricelly connected to a power supply, such as by electrical leads 416,418. In a preferred embodiment, each of momfeora 461=414 has a length of 7-12 cm. The 14 members 401-414 are distributed above to© prefrontal cortex of the left 5 hemisphere. In one embodiment, there io a separation of 0.5-1.5 cm between each of members 401-414. in a preferred embodiment, there te a separation cf 1 cm between each of members 401-414. Three members 408-410 are elongated towards th© for©! inert, and their eontouateno pas© in to© Soft-right direct on along the orbitofrontal cortex to provide additional effect© in toot region, as delineated by io segments ! Λ Return path© 401”407" of memhero 401-407 arc attached to he head in th® right hemisphere, as delineated by segments D»E. In one embodiment, earii of the return paths 401M0?" te separated from one another by apprcwdmately 0,5-U cm, In a preferred embodiment, each of th© return paths 40Γ-407" is separated from on© another by approximately 0.8 cm. The return is paths 408" 414" of members 408-414 we «touted above th© head at r. distance therefrom as delineated by segments M-β. in ©ne embodiment, each of to® return paths 468M14" fe separated from ©no anotoor by QppraamateSy 6.1-6.7 cm. tn a preferred embodiment, each of to© return paths 401 Mi)/” is separated from one another by approramately 0.3 cm, In on© embodiment, to© distance from toe head 20 to the return paths 408M14" of members 408414 te between 4-16 cm. In a preferred embodiment, the distance from too head te ft© return paths 40BM14” of members 408414 is approximately 7 em.

[0052] Coil 466 may b© composod of any electrically conductive material, such as mefcri. Particular emhodimonte have coils comprising wire made 25 of copper, aluminum, silver, or ©titer etegSfeaily conductive material. In a preferred embodiment, th© coil is mad© of a double 14 AWG insulated capper wire having a total length of 750 cm and winded into windings 417, connected in series. In alternative embodiments to© oral is mad© of 7 Shelamid 200 copper wires insulated by two polyester tuyere ¢66 pin insulate width), with 0.0 mm diameter of 30 each wire, or any kind of multi-Rn© wires, in a preferred embodiment, coil elements are coated by a polyurethane rosin typo Reoinox 4 (Hamchaber Vehamkasher Ltd., Israel), for additional electrical insulation. In alternative WO 2006/134598 P€T/IL2(iC6/C00694 21 embodiments, coil elements are coated by other insulating materials, such as PVC, or are sandwiehed between layers of insulating materials. In alternative embodiments coil clsmsnte ore coated by a RNF3Q0O heat-shrinkable tab© with 0.65 mm thickness (Raychem Corp, Menlo Park, CA, USA), for additional 5 electrical insulation. It should be readily apparent that the embodiments disclosed herein are examples only and should not b© regarded as limiting. The windings 417 are connected to an appropriate cable and connector, which is than connected to a stimulator. The stimulator may bo any appropriate commercially available power supply, such as the power supplies available for use with other io magnetic coils. In prefcned embodiments, tho stimulator io on© of various models of magnetic stimulators produced by Modfrente, inc. of Minneapolis, MN, USA (e.g., MagPro, MagJJte Compact), or power supplies sold with various models of magnetic stimulators produced by Magstim Company US, LLC, of New York, NY, USA (e.g., Magstim Model 200, Magstim Model 220, Magstim Model 250, BiStim, is Magstim Rapid, Magstim Quadrattale©, Magstim Rapid2).

[0053] Tho stimulator or power supply (not shown) suppliers current through lead 41G into one of membcsis 4U1·414. The stimulating current pulocs flow substantially in the anterior-posterior direction. At this point, current can lake one of two paths - either through contesting return portion 415 or through an 20 ascending portion 421 extending upwards from bas© portion 425 and thei through protruding return portion 440. if current runs through contacting return portion 415, it runs from bas© portion 425 to contecting return portion 415 (which runs substantially parallel to members of base portion 425, and is positioned directly on the skull but at a distent» from members 401-414 of bas© portion 325) through an 25 asoending connector 427 and batik down to the love! of the skull via descending portion 423. From there, current returns torough lead 418 back into the power supply. If current runs through protruding return portion 440, it runs from ascending portion 421, through protruding return portion 440 (which runs substantially parallel to mombera of base portion 425), and back down to the love! 30 of the skull at a descending portion 423. From there, current returns through lead 418 back into the power supply. In a preferred embodiment, half of tho members run through protruding retom portion 440 and half of them run through contacting WO 2006/134598 PCT/DL2006/000694 22 return portion 415. However, too invention is not limited to this proportion, and any proportion of protruding return paths and contacting return paths is possible, so long as each retom path has current from at least one of tho members. Current may be supplied simultaneously to all members, or alternatively, may be supplied 5 sequentially, in a random sequenso, or seiestively. In another embodiment, current is supplied to member 401, and runs through a ioop including each of the additional members 401-414. It should also be readily apparent that although the invention has ton shown with rofcreneo to fourteen members, the invention 5s not in any way lirroted to this number, and any suitable number of members may be io used, in additional ombodimonte, a cingte member may haw a rotrrn path through both protruding return portion 440 and contacting return portion 415.

[0054] in the preferred embodiment depicted In FIG. current from each of members 401-407 runs through contacting return portion 415 via pathways 401M07" while current from members 408-414 runs through ascending 15 portion 421 and through protruding return portion 440 via pathways 408M14". Specifically, members 401-407 havers© th© path A-B-C-D-&F-G-H-A Members 408-410 traverse to© path Wlcntoero 411-414 traverse th© path A-N-L-JVM34+-A. It should be readily apparent toat other combinations and pathways are possible, and are within the scop® of to© present invention. 20 [0055] Protruding return portion 414 is spaced a distance from the skull.

In One embodiment, this distance is in a range of 4-10 cm, In a preferred embodiment, tois distent» is 7 cm. By placing tho return path at a distance from the skull, electrical stimulation of unwanted portions of th© brain is minimized. However, surface charge aoeumiiatton at too surface of too bran is increased. As 25 such, some of toe return paths are placed on the skull itself, so as to reduce surface charge accumulation. However, these return patos are placed n distance from toe site to be stimulated within toe brain so as to avoid conflicting signals in toe area of stimulation, In on© embodiment, to© distance from the central members (such as member 414, for example) to toe contacting return paths is in a 30 range of 7-15 era In a preferred embodiment, the distance from toe central members (such ao member 414, for oxamplo) to too contacting return paths is approximately 8 or 9 cm. Thus, a balance is maintained between the need for WO 2006/134598 FCT/H2006/000694 23 reducing surface charge and toe conflicting need to avoid electrical stimulation of unwanted portions of too brain.

[0056] In one embodiment, a screen may be applied to either of coils 300 or 400 to further reduce the magnetic field produced when electricity runs 5 through toe return portions. The serccri is comprised of a material wife high magnetic permeability, capable of inhibiting ©r diverting a magnetic field, such as mu metal, iron or stool. Alternatively too ocroon io comprised of a metal with high conductivity which can cause electric currertte or charge accumulation that may oppose the effect produced by the return portions. Any suitable screen or shield io capable of inhibiting magnetic fields tray be used. Th© screen may be any suitable size or shape, including but not limited to sheaths of mu metal surrounding one, some or all of too members of eoil 300 or 400, a flat disc of metal strategically placed, or an enclosure substantially enclosing toe return pate.

[0057] Reference is now made to RG. 0, which is n block diagram is illusfration ©f a cooling system 89, in accordance with on© embodiment of toe present invention. Altoough to© embodiment described herein refers to water or other liquids used for cooling, it is envisioned feat air cooling may bo used. The term "fluid” herein denotes liquid such as water, ©r gas such as a mixture of gases and more specifically, air. Cooling system 88 in designed for maintaining ambient 20 temperature in toe coils during repetitive operation. Cooling system 83 includes an external rooting unit SOT, a fluid dnaflator Sffi, and an internal system 504. Internal system 504 is connected to eoil 300 or 400. A’lows @00 represent the direction of cooling.

[6058] Rsfcrenc© is now mad© to FIG. 7, which is a block diagram 25 illustration of external cooling unit 500. ©derail cooling unit 500 includes a compressor 506, a condenser 608, an expansion vctfvo 510, arid a carburetor 512. Compressor 506 ts a commercially available compressor (available, fo’ example, from Electrolux, Thailand, Typo LS7TN), In a preferred embodiment, condenser 508 is made ©f 3/8 inch diameter pipe, and has 0.S horse power, a ventilator with 30 5-30W engine (EMI, Italy), and current of up to 0.20 A Expansion valve 510 is made of capillary pipe having approximately a 0.07 inch diameter and a length of 4 WO 2006/134393 PCT/Π,2006/000694 24 meters. Carburetor 512 is made of a 3/8 diameter spiral pipe having a total length of at least 4.7 meters.

[0059] Reference ie now nrado to FIG. 8, which la a block diagram illustration of fluid circulator 502. In th© embodiment described herein, fluid 5 circulator to a water circulator, and Includes a water tank 514 and a water pump 516. Water tank 514 te in contact with carburetor 512 of external coolir g unit 500. In a preferred embodiment, water tank 514 te a 10 liter iron tank coatee by a 1 cm layer of foamed polyurethane. Water pump 516 Is In fluid oommunieation with internal system 504, and is configured to deliver cooled water to radiate’s of io internal system 594. Water pump 51S is a oomrrtcrcislly avafinbto water pump available, for example, from Pentax, Italy (Typo CM50/01). Th© nominal working pressure used is 2 bar. The pressure is regulated by a manual feedback cock.

The excess of water returns to tho tank and creates circulation.

[0069] Cooling is aeGomplished as follows. Freon gas to corr pressed in is compressor 506, condensed in condenser 508, and expanded through expansion valve 510. The capillary In expansion valve 510 is connected to carburetor 512, where tee gas is evaporated again and returns to compressor 506. Carburetor 512 is immersed In water tank 514, thereby cooling te© water. The water is pumped out via water pump 516, and circulated through radiators of internal 20 system 504. In alternative embodiments, cooled air te circulated instead of water. In one embodiment, internal system 504 is a radiator system, Radiators sre in thermal conjunction with coil 300 or 400, aa will to described in greater cfetail hereinbelow with reference) to FIG. 9. The fluid circulation cools tee coil during pulse trains and stabilizes fc temperature nt mild temperatere range. In one 25 embodiment, temperature sensors are located at or near eoil 300 or 400, and information about temperature during a procedure can b© sent directly to cooling system 88. Automatic adjushnent of cooling can teen be don® based on the temperature information.

[0061] Reference ts now ntudo to FIG. 9, which is a schematic 30 illustration of internal system 504 in contact with coils 300 or 400, in accordance with one embodiment of tee present invention, fa teo embodiment shown heroin, internal system 504 indudes individual radiator unite 518 (shown partially cut), in WO 2006/134598 PCT/IL»»06/003694 25 close thermal contact and approximate geometric alignment with coils 300 or 400. Each of radiator unite 518 arc comprised of two parallel 1/4 inch pipes, and between them several capillary pipes of 0.07 inch diameter. In a preferred embodiment, the pipes are made of cropper and are coated by insulating lacquer 5 (John C. Dolph Company, New Jersey, USA). Radiator units 518 are sandwiched by layers of a thermal and electrieal insulator §20. Coil 300 or 400 is also sandwiched by layers of insulator 520. In a preferred embodiment, Insulator 520 is a semi-flexible polyurethane resin, preferably Resinex 4 available from Hamchaber and Hantasher Ltd., Cat Yam, Israel, in a preferred enfoodinrent, at toast two io layers of insulator §20 are situated on cither side of coil 300 or 400, and at least one layer of insulator 520 Io further situated between radiator unite 518 end helmet 82. An additional layer of Woeompatible foam medical tap® 522 (for example, Type 9776 available from 3M Center, St. Poul, MN, USA) attaches the entire system to th© head of foe subject The number of (radiator unite S18 depends on is the number of members or eoil units in th© coil. For example, for coil 300, six radiator unite are used, and for coil 400, seven radiator unite ar© used.

Methods of Operate: (0062( The basic method for operating system 80 of the present invention involves tho following stops: First, subjects are fitted with earplugs to 20 lessen any possible adverse effect on hearing. Th© subject is then seated on chair 85 with his/her heading resting on rear head support 87. Hdmet 8.2 with coil 300 or 400 and radiator unite 518 ar with any other suitable cooling system is positioned ever foe subjeefs head over tho prefrontal cortex, 5 cm anterior to th© hot spot for abductor polticis brevis (APB) muscle stimulation. Th© subject's motor 25 foreshdd te measured by delivering single stimulations to the motor cortex, by gradually increasing the intensity (using the single pulse mode, applying one pulse each time) and recording electrical activity in abductor polticis brevis (or any other muscle) using surface eleefrodes. Threshold le defined as foe lowest intensity of stimulation abl© to produce motor evoked potentials of at least 50pV in 5 of 10 30 trials. After defining foe motor threshold, eoH 300 or W0 is positioned on foe prefrontal cortex, and Ihe session is performed at 110% of foe motor threshold. WO 2006/134398 PCT/tt 2006/OC0694 26

Stimulator 86 is set to required power, frequency and duration values, as determined. Frequency can range from 1-50 Hz.

[0063] Each teutmont session Includes a predetermined lumber of trains, in some embodiments, a train of 1 to 100 pulses is administered. 5 Individual pulses measure from about 50 to 2000 microseconds, preferably in the 1000 microsecond range. In a preferred embodiment, the duration of each train is 1 second, with an inter-train interval of 20 seconds. Alternative durations and intervals are possible as well. Treatment plans aan include, for example, an increase in toe frequency used on different days. Pulses ran vary in frequency as io well as number. Certain embodiments use a frequency range of about 1 to 100

Hz.

[0064] In a preferred embodiment, each treatment session includes 42 trains. The duration of each train is 1 second and the inter-train interval is 20 seconds. Each subject undergoes three treatment sessions, on day 1, 3 and 5. is On day 1, stimulation b 1 Hz, on day 2, ctimuiatfon it; 10 Hz, and or day 3, stimulation is 20 Hz.

[0065] Tho basis prinap’os and opnratien of too system is based on summation ©f electrical impulses. Tho general concept of summation is that by providing several cuWhrashold impulses, if is possible to stimulate deop regions 20 of toe brain without unwanted stimulation or excessive electrical field applied at surface areas of the brain. In international Publication Number WO 02/32504, this concept was applied spatially by using several coil olemonte carrying current in a desired direction, each placed in o different location around toe head such that high electee field intensity is eoncerifrateri in c specific deep brain region, while 25 maintaining a high ratio of deep brain Gtecteenl field to surface electrical field. This type of spatial summation can bo termed one pair if spatial summation, since each of toe individual elements stimulates too same focused point.

[0066] While ©nrepnint spatial summation has been shown to be advantageous, other more specific methods could to useful in further increasing 30 toe depth penetration and spesfidty of to© treatment [0067] In one ornboclimcnt. of toe present invention, a different type of spatial summation is contemplated. Rather than focusing on a single point, WO 2006/134598 PCT/.IL2006/C00694 27 several points along a neuronal structure can be stimulated, rousing a net result depolarization at an even lower electrical field strength. This type of spatial summation can be termed morphological lino spatial summation. Th© points along the neuron at which the electric field Is produced may or may not be in a straight 5 line configuration. If, for exumpto, a path of a specific axonal bundle is known, such as for example th© medial fsrebrain bundle, th© coil can be designed in a configuration to produce significant electrical fields at several points along the bundle. Th© configuration of the eeii would approximate th© path of the bundle, which can be determined, for example, by a fiber tacking diffusion tensor MRI or io by other known imaging methods. This configuration may enable induction of an action potential In the bundle, white minimizing activation of other brain regions. Specifically, the coil can be activated at art Intensify which te sub-threshold and thus would not indue© an action potential atone specific brain region, but since it is being induced along a epedfie path, the summation of pointe in space would be is enough to induce th© action potential in the desired axonal bundle.

Tim® Suifimatteti Pi tnrSpto [0068] in general, TMS stimulators may produce a monophaslc or a biphasic pulse of electric current, During the discharge cycle, the TMS circuit 20 behaves like a RCL circuit, and the current I is given by: l(t) = 0Qexp(-at)sin(wt) (1) wt 25 where V is the maximal voltage, 0-R/2L, iapV((LC)“W), and R, C and L are the total values of foe resistance, capacitance and inductance, respectively, in foe circuit The inductance is mainly foe eoB inductance, but there is an additional contribution from foe cables, and foe resistance includes contributions from a switch (as described below) and foe noil.

[0069] Tiie total energy on tiie capacitor before discharging is given by: Wc=44CV2 (2) 30 WO 2006/134398 PCT/n.2006/030694 28 [0070] In prinrapte two related parameters may be relevant for neuronal activation: The electric fe'd strength, and too cpatisS derivative of the electric field. While the activation of peripteral nerves depends mainly on the derivative of the electric field along foe nerve fiber, for neuronal tissue with relatively short axons 5 with bends and branches, ouch ns th© brain, the absolute magnitude of the induced electric field is the biologically relevant parameter for neuronal stimulation. The induced electee field is proportional to foo rats of change of current (dl/dt). The brief strong current generates a timo-varylng magnetic field B. An electric field E is generated in a direction which is perpendicular to foe magnetic field, and io has an amplitude which is proportional to th© time-rate change of the vector potential A(r).

[0071] The vector potential A(r) in position r is related to the current in the txoil I by foe egression: A(r)=<f dr (3) 15 4π J iSn [0072] Where ujRteMO'7 Tm/A Ig foo permeability of fro© space, the integral of df is over tha wire path, and f is a vector indicating the position of the wire element The magnetic and electee fields are related to the vector potential 20 through the exprassfona'

Ba=VxA (4)

Ea=-^A (5) dt 25 [0073] The only quantity which changes with time is the current I. Hence the electric field Ea can be written as: Εα-"1Αο61 f dT. (G) 4xdt J k-r') 30 [0074] Sin® brain tissue has conducting properties, white foe air and skull are almost complete insulators, the vector potential will induce accumulation of electee charge at the brain surface. This charge is another source for electric field, which ran be expressed as: WO 2006/134598 PCT/IU006/C00694 29 Εφ = -νΦ (7)

Where Φ is the solar potential produced by the surface eleetrostatic charge.

The total field in the brain tissue E is th® vectorial sum of these two fields: 5 Ε=Εα+Εφ (8) [0075] The electrostatic field Ε» generally opposes the induced field Ea, which consequentiy reduces the tote! field E. Tho amount of surface charge produced and hence the magnitude of E&amp; depends strongly on coil configuration and orientation. io [0076] Referring back to Eq. 1, in most practical TMS circuits with accepted values of R, C and L, tho condition: a « w (9) is fulfilled. Since the electric field ia proportional to the time derivative of the 15 current, its time dependence ran be approximated by: E =Eoexp(><it)ajs(wt) (10) I0077J This electric field produces an action potential In excitable neuronal cells, which may result in activation of neuronal circuits if a particular threshold is reached. The neuronal response depends not only on toe electric field 20 strength, but also on toe ptfiss duration. Th© duration τ of one pulse cycle is about: t = 2tp/(LC) (11) [0078] The longer the pulse duration, th© smaller toe required electric field to reach neuronal threshold Emr. The dependence of on pulse duration is given by a strength-duration curve of ft© form: 25 Ebf= b(1+2dr) (12) where b is toe Rheobase, which corresponds to toe electric field required to induce neuronal activation at infinite duration, and e is the Chronaxie, related to toe time constant of neuronal membrane (as described, for example, In Bouriand JD, Nyenhuis JA, Noe WA, Schaefer JD, Foster KS, and Geddes LA, in Proc. Int Soc. 30 Magnetic Resonance in Median© Seientifie Meeting, Now York, 199S, p 1724). WO 201)6/134598 PCT/'X2((06/30()694 30 [0079] Reference fs now made to Pig. 10, which fe a strength-duration curve reflecting the average of four subjects, using eight differert coils with inductance L of between 6 and 148 pH.

[0080] As ran be seen from Eq. 11, the duration of a TMS pulse can be 5 extended in two ways: by Increasing the capacitance C, or by increasing the coil inductance L. In known stimulators, C is constant Increasing L leads to increased power and energy consumption. From Fq. 1 it can bo seen that the peak induced electric field Enas is proportional to:

EmaxOdl/dtoV/L (13) 10 [0081] The electric field required to reach neuronal threshold, Ethr, decreases with increasing L (Eqs. 11 and 12). Examining the ratio, r, between the induced peak elecfrte field and the required threshold, by combining Eqs. 1113, we obtain: 15 r = b(1-*-2cf(2m/(LG)) (MLC>^)/¥(LC)) MC)Lw/(i.) where Eo fe a pre-faetor depending on voriouo parameters including ecil geometry, configuration, inductance, number of turns etc, ai and aa were introduced in order 20 to emphasize the dependence on I, and C. it ran bo seen that too voltege required to reach neuronal activation threshold increases with L, and slowly decreases with G.

[0082] In order to ©Wain th© dependence of ft© required energy on L and C, wo substitute re1 in Eq. 14 and then substitute V in toe expression for toe 25 total capacitor energy (Eq. 2):

Wc = -t>2ata2V(LG) *a/) (W

Eo2 [0083] It can be seen that the required energy Increases quadratically with L and linearly with C. 30 [0084} Reference is now made to Fig. 11. which depicts pulses produced by TMS coils having inductances of 13 and 70 pH. The amplitudes represent th© threshold electric field according to pointe 1 and 2 in to© strength- WO 2006/134398 PCT/IL2006/(t00694 31 duration curve shown in Fig. W. Hie plots are for resistance and capacitance of R=0.1 Ohm and C- 16S pf, respectively.

[0085) tt can bo ecen that when the puts© duration is longer, too required threshold electric field is smaller.

[0086] !n regular TMS stimulators, too capacitor (or bank of capacitors) is discharged through a single switch to a single eoil, resulting in simultaneous current flow through al! coil elements, and thus simultaneous electric fields produced by ail coil elements. Thus, the electric field induced in cortical brain regions dose to roil elements wilt in general bs larger than to© field induced in deeper brain regions.

[0087] In one embodiment of too present Invention, each of toe various coil members can b© stimulated consecutively, resulting in temporal summation. Since neuronal activation threshold depends on both toe strength / intensity of the electric field and the stimulation duration, ihe threshold may be reduced by applying several puteoa wito short Intervals between them. Thus, it is possible to stimulate an action potential wito reduced stimulation intensity by increasing toe duration of too stimuiation. While increasing too duration Of a single pulse might be painful or detrimental to the surface areas of the brain, summing a series of individual pulses over a duration of time could have toe desired effect Moreover, the combination of timo and spatial summation may allow activation of neuronal pathways in deep brain regions, without activation of neurons in superficial regions. This is possible as the induced eleetoe field In a deep region may be considerable during too period of pulses coming from different members of toe coil, while th© induced fioid in a superfidai region dooor to a given coil element is higher during a short time fraction of the total period of pulses, but lower during activation of fhe other coil ©temmfe Far example, toe coil may be designed in a configuration! such that too various momboro ore scattered around a desired region or path, and may be stimulated consecutively so that at each time period only a certain clement or group of Clemente «9 activated, ihte way, a significant electrical field can to Induced nt to© desired region for all time periods, or with short inter-puiso Intervale that may atffl enable adivafen, whiio in too cortical region ofthe brain, only certain regions will experience a significant field at certain WO 2006/134398 PCT/fL,?,006/300694 32 periods, and the intervals between e^erienees of significant field vrill b© much longer.

[0088] This effect earn be aceomplishod by using more than on© stimulator, or by using a configuration of a stimulator which includes multiple 5 channels for stimulation. A multi-channel system may include multiple capacitors, each of which is discharged via an indhtidual channel, with different switches into different coils or portions of the coil, or to different portions of the coil which are connected in parallel. A control unit eart control the times of charging and discharging off each of the capacitors, and can aiso control delays between io operation times of sequential coils.

[0089] Reference is now made to FIG. 12, which is a block diagram illustration off a multi-charnel TMS system 700, in accordance wife embodiments of the present invention. System 700 includes a power supply 710, a control unit 720, and multiple channels 731-735. Although the example shown indudes five is individual channels, any suitable number of channels may b© used. In some embodiments, two or more channels are used. In some embodiments, 3-5 channels ar© used. in other embodimenta, maybe 10 channels may be used.

Power supply 710 is connected to oach of channels 731-735. Each channel 731-735 is further connected to a charger 740, one or more capacitors 750, a high 20 current fast switeh 760 through Which capacitors 750 are discharged, and a selected portion of fee TMS coil, or a separate coil. Gonhoi unit 720 is configured to control th© charging voltage and timing, th© discharge timing, delays between operation times of various coils or coil portions, and fee current poterity in each channel, and may be digital, analog, or a combination thereof. Control unit 720 25 may be comprised of a processor embedded within system 700, or attached thereto. For example, an external PC may bo connected to stimulator 710 end to each of channels 731-735. in the embodiment shown in FIQ. 12, each capacitor is discharged through a separate switch to individual ceils or portions off tiie coil.

[0090] Power supply 710 may Include any land off system which enables 30 charging of capacitors to a high voltogo. It may include a circuit which converts AC to DC, and amplifies the voitege. it may include εη AC to DC transformer, IGBT transistor, FLYBACK system, Buck boost circuit, or any other system which can WO 2006/134S98 PCT/IL2006/OC0694 33 charge capacitors to high volteg©. Power supply 710 may enable controlled charging of toe capacitors. In some embodiments, system 700 may further include accumulators and/or batteries which may supply too energy for charging the capacitors. System 700 may include any combination of part or all of the 5 mentioned components, and may bo able to operate ©n on© eiedric phase, three phases or both, on 220-230 V electricity mains, 110-115 V electricity mains, or any other electricity mains. System 700 may be specific to a certain typo a: electricity mains, or versatile and able to operate on two or more types of electric rets.

[0091] Tho maw'mui voltage on capacitor 759 may bo a few hundred io volte or more. Specific systems may be able to charge on© or more capacitors 750 to voltages of 500 V, 1000 V, 1200 V, 1500, V, 1800 V, 2000 V, 3000 V. 5000 V or more.

[0092] Capacitors 750 may have capacitonees from a few pf to hundreds of pf. In some embodimcnte, capacitors /60 may have capacitances of 40 to 60 pf. 15 In soma embodiments, capacitors 750 may have capadtenoes of 10 to 100 pf. In other embodiments, capacitors 750 may hare capacitances cf 10 to 300 pf. In other embodiments, capacitors 750 may have capacitances of 1 to 1000 jjf or more. In some ©rrtiodimente, capacitances in each of charnels 731-7.35 ar© the same. In ofeer embodiments some or all of th© channels 731-735 may have 20 different capacitances. In each channel there may bo a ©ingle capacitor 750, or an array of two or more capacitors 750 connected in parallel, to series or in any combination of parallel and series.

[0893] Switch 760 may bo a thyristor, a silicon controlled rectifier (SCR), an IGBT irarsistor, may include transistors, diodes, or any combination of both, 25 based on WIOSFET technology, TTL technology or any combination of both, yOS-gated thyristor, MOS controlled thyristor (MOT), or any switch that can pass high current in a short amount of time. Switch 700 should bo able to pass electric current at a rate of a few tens of amperes per microsecond or higher. In some embodiments, switch 769 may bs able to pass currents of up to 100 A/ps. In other 30 embodiments, switch 760 may to able to pass eumjnte of up to 120 A/ps, 150 A/ps, 200 A/ps, 500 A/ps or more. The peak current may b© 100 Amperes or more. In some embodiments, switnl1760 may be· abi© to pass peak curre nts of 200 WO 2006/134398 PCT/BL2006/000694 34

Amperes, 500 Amperes, 1000 Amperes, 2000 Amperes, 3000 Ampares, 5000 Amperes, 10000 Amperes or more. The pulse shape may b© monophasic, biphasic, polyphasic, or other, In principle two or more switches may bo connected to the same coil or element of coil. In somo embodiments one switch is connected 5 to each coil or element of coil, In some embodiments, a eoil or element of coil may be connected to more than ©no switch, and may bo activated in several periods by several channels.

[0094] In on© embodiment, multiple Individual stimulators may be used instead of a single stimulator induding multiple channels, with an overall coritrcl io unit for confrolling of tho timing of operation sf each stimulator. In yet another embodiment, a combination of multiple individual stimulators, and multi-channel stimulators may b© used.

[0095] In all of th© above embodiments, various coils or portions of coil may be operated sequentially, with delay times ranging from zero to several is milliseconds, with an overall resolution in the miereaeeoncte, tens of microseconds, or hundreds of microseconds range. In each operation one TMS cyclo is induced through a specific coil or portion of a cell. The cycle may be biphasic or monophasic, and the number of different coils or coil elements may vary. to some embodiments, tore© to five coils or portions of coil are operated consecutively. In 20 other embodiments, 10 or more coils or portions of coil are stimulated. In other embodiments, two coils ©r portions of coil are operated consecutively. In some cases, some of ihu coiia or portions of coil may bo operated simultaneously in a certain period. In some eases, each coil or portion of coil is stimulated once, ahd in other embodiments, each cell ©r portion of eoil fo stimulated multiple times. Delay 25 times ray be the same* for each stimulation, or may vary. Coils may bs positioned at various regions on the subject’s head, scattered around the deep brain region or several deep brain regions targeted for stimulation.

[0096] The following parameters are controllable by the operator of system 700: delay iirnas hoteon Emulation of different cote or portions of coil, 30 number of channels and coifs/eoti portions stimulated, number of times each coil/coil portion is activated, tinting of each activation, polarity of current in the coil, frequency of operation of each coil (i.e. number of pulses per second in each WO 2006/134398 PCT/Π 2006/000694 35 coil/coil portion), train duration of cash eoil, number of trains and inter-train intervals, and power output of operation for each coil. All these parameters may either be constant for different operations of a eoilfeoil portion, or may vary for different operations.

EXAMPLES

[0097] Reference is now mad© to FIG. 13, which is a graphical illustration of electric field pulses Induced in a deep brain region (curve 740), in a first cortical region (curve 742) anti a second cortical region (curve 744). The pulse of the second cortical region ©oil portion (curve 744) tags behind tie pulse of the first cortical region coil portion (curvo 742) by a foil cyrfo. In each roil portion, one puls© cycle is induced, and the switch is disconnected at the end of a cycle when the current is zero. In the example shown fn FIG. 13, th© field Intensity in the deep brain region is 60% of tho intensity induoad in the cortical region close to the coil portion adjacent to tiro first coital region, while the field intensity in this same cortical region during operation of tho eaii portion close to tire second cortical region is 5%. Thus, in the deep brain region a significant electric field is induced during two consecutive pulses, while in each of the cortical regions a significant field is induced only during on© cyclo. Thus, by alternating areas of cortical stimulation, different cortical regions get varying amounts of field intensity, while the deep brain region receives a consistent field intensity for the various periods of stimulation. £0099] Reforeno© is now mode to H©. 14, which Is a graphical illustration of electee field pulses induced in a deep brain region (curve 746) and three corticn’i regions (curves 747, 743, raid 749), where th© tim© delay between two consecutive pulses te half a cycle, and fit© current polarity in the second pulse is opposite te th© polarity in th© first and third pulses, In each coif or coil portion, one pulse cycle is induced, and tee switch is disconnected at te® end of cycle when the current Is zero. In thte example, the field intensity in tee deep brain region is 50% ofthe intensity induced in foe eertieal region dos© to th© equivalent coil, while th© field intensity in any on© of the cortical regions during operation of tee portion of coil cios© te another cortical region is 5%. In this eiemple there is an extension of tee duration at which th© deep brain region is exposed to WO 2006/134598 PCT/IL2006/00069&lt;3 36 significant field, and in addition there is an increase in intensity after each harf cycle. The absolute value of to© maximum at toe beginning of each pulse is higher than toe next maxima of too oamo pulao duo to too decay factor a=R/2L (Eq. 10), thus at toe beginning of too second pulse toe relationship between the field in the

5 deep region and the field in the first cortical region will b© higher with higher circuit resistance R, and with lower ooil inductance L

[0099] Reference is now mad© to FIG. 15, which is a graphical illustration of electric field pulses induced in a deep brain region (curve 750) and in three cortical regions (curves 752, 754, and 758), where the current polarities in io toe second and third poises ar© opposite to too polarity in tho first puls©, to© time delay between toe first and oocond pulse is approximately 3/4 cycle, and to© time delay between toe second and third pulse is about 1/8 of a cycle. In each coil one pulse cycle is induced, and too switch is disconnected at the end ofa cycle when toe current is zero. In this eommpte, to© field intensity in to© deep brain region is is 50% of the intensity induced in too certieoi region class to the coil portion adjacent to to© cortical region, while tho field intensity in any on© of to© cortical regions during operation of to© ceil dose to another cortical region fe 5%. in this example toere is extension of toe duration of tire positive half cyclo in too deep brain region, and increase of toe intensity. 20 [00100] ft should bo readily apparent that toe same principles as described above with reference to R6S. 13, 14 and 15 would apply to multiple coils or coil portions, and tout similar methods could be employed using several or all of toe coils or coil portions operating one© or multiple times. Also, more than one puls© may bo indunnd in part or all of tho wife, thus increasing toe time 25 duration at which to© deep brain region experiences significant inclunsd fields. The overall stimulator output required to activate neuronal structures may thus be lowered, and to© ability to activate deep brain regions with little or no activation of cortical regions may be improved.

[00101] A method of tenssaanial magnetic stimulation using temporal 30 summation in accordance with one embodiment of toe invention is as follows. A coil 300 or 400 such as too ono described show with reference to FIGS. 4 and 5 is placed on to© skull. In one embodiment, etectricai leads are connected to one WO 2006/134598 PCT/iL:>a«6/003694 37 power supply or stimulator with multiple channels. In another embodiment, additional leads are separately connected to two or more power supplies and to at least two members for providing electrical stimulation. Pulses are applied at a lower voltage and/or rato of ehang© of electric current, so that th© field induced at 5 cortical brain regions will bo suMhreshold ©r around the threshold level, but are applied to different members or groups of members at different times.

[00102] As one example, referring back to FIG. 5, elements Β-Ό 401-407 may be connected to one channel, elements A-N 411-414 may be connected to another channel, and elements frD 401‘MOT” may bo connected to different io channels. The current polarity (direction and phase of current) may be the same or different in th© separate channels. The windings connecting each element to the stimulator may be different from tho windings shown in FIG. 5. Th® operator may control the timing of operation and current polarity in each channel. Each channel may be operated once or multiple fimeu. For example one may operate elements 15 B-C 401-407 for one pulse cyclo, then elements ET3 401M07" for one pulse cycle with a delay of fell eyefe, half a cycle, quarter of o cyclo or any other delay time, followed by dements A-frt 411=414 for one puls© eyete with a delay rf frill cycle, half a cycle, a quarter ©f a cycle or any other delay time, and again followed by elements B-C 401-407 for ©no pulse cyclo with a delay of a frill cycle, half a cycle, 20 a quarter of a cycle or any other delay time, etc. In this way, one may achieve effective activation of deep brain region, with no or minimal activation of cortical regions, ft should b© noted that by usfng a multi-channel system, it is possible to control delay times and activation cycles, in order to frflly optimize toe strength/duration interplay for neuronal activation. 25 (00103] Various coils or elements of coll may be operated sequentially, with delay times of between zero and 1 ms or mor©, and specifically with delay times on toe order of microseconds, tens of microseconds and/or hundreds of microseconds.

In on© embodiment, different stimulations are applied at 100 microsecond 30 intervals. In other embodiments too different pulses are applied at between 10 to 1000 microsecond intervals, or even at intervals of several milliseconds. In one embodiment, members are activated in a sequential order. In another WO 2006/134598 PCT/Π,2006/000694 38 embodiment, only certain members are activated, or a random pattern is generated. In other embodiments, groups of members ar© activated In a certain order.

[00104] in standard TMS stimulators, toe operator may control the 5 following parameters: 1. Power output, which determines the peak current passed through the ceil and as a result toe strength of to© electee field induced. 2. Frequency, which determines tho number of pulses passed through th© coil each second. Accepted values may rang© from a single pulse up to 1 HZ, io 10 Hz, 20 Hz, 30 Hz, 50 Hz and oometimss 100 Hz. 3. Train duration - th© duration of a train sf pulses. The duration and toe frequency determine Ore number of pulses En a train. For example, in a train of 20 Hz with a duration of 2 seconds there are 40 pulses. 4. Inter-train interval -The intervals between consecutive trains. The intervals is may be from a few seconds to a few minutes. The intervals may be constant over a session of trains, or variable along to© session. 5. Number of trains in a session of trains.

[00105] In addition to all to© above, in a multi-channel system such as the one disclosed herein, too operator may centrni toe following parameters: 20 1, Th© timing of operation of each channel, and toe time delays between consecutive channels. Th© timo delays may bo from 0 (simultaneous operation of toe chunnols) up to several seconds, and may be 1 microsecond, several microseconds, tens of microseconds, hundreds of micrascconfta, milliseconds or more. Th© lima delays may bs to© same 25 between any consecutive channels, or there may be different time belays between different consecutive channel®. 2. Th© currant polarity in each channel, namely positive or negative current in toe first stroke of too triphasic cycle, ortho direction of a monophasic cycle. 3. The pulse shape in each channel, i.e. monophasic, triphasic, polyphasic, 30 one cycle, two cycles, three cycles or more. In specific embodiment» there may b© on© pulse cycle through each channel,, as is customary in standard TMS stimulators. WO 2006/134598 PCT/1L2C06/00(!694 39 4. The number of channels operated. 5. The order of operation of tiie diannels. In some cases one or more channels may be operated more then one®. For example a sequence of 10 operations may bo programmed, using 3 channels, in th© order: 1, 3,2,1, 3,2,1,3,2,1. Another example of a sequence of 15 operations using 5 channels: 1,5,3,4,2,1,5,3,4,2,1,5,3,4,2. In some applications two or more channels may be connected to toe same coil, so that this coil may be activated in several operations of different channels. 6. The power output, frequency, train duration, inter-train intervals, and number of trains for a session, in cadi channel. Part or all of toe above parameters may bo toe same for ail channels, or they may be different between part or all of too different channels.

[00106] In one embodiment, two or more of the various type® of summation are combined. For example, morphological line spatial summation can be used at a sublhreshold intonsiiy in combination with temporal summation. That is, different parte of an axonal bundle can be targeted selectively or sequentially, rather than simultaneously. Alternatively, one coil can include members for endpoint summation and for morphological line spatial summation. Each of the member types can b© simultaneously, sequentially or selectively stimulated.

[00107] A multi-channel TMS system such as to© on© described above may be used for activation of different body parte, i.o. different brain regions, with different power outputs, frequences, pulse shapes, train durations, inter-train intervals, and/or number of trains for n session. Tho different regions may be activated either simultaneously or with any time delay between them. The time delays may he in to© order of micrasesands, tens of microseconds, hundreds of microseconds, milliseconds, or any combination thereof. Different stimulation protocols may induce inhibitory or excitatory activation, it may thus be possible to study numerous interactions between different neuronal structures in different brain regions.

[00108] In one example, a possible application of to® multi-channel system may be activation of different body parts, i.e. different brain regions, with WO 2006/134598 PCT/IL200S/000634 40 different frequencies. Th© different regions may bo activated either simultaneously or with any time defay between them. As a non-Bmiting example, several studies found that high frequency repetitive TMS (rTMS) et 10 Hz or more directed to the left prefrontal cortex had anti-depressant effect in depression patients (Padberg P, 5 Zwanzger P, Thoma H, Kathmann N, Haag C, Greenberg BD, Hampel H, Mollor HJ. Repetitive transcrania! magnetic stimulation (rTMS) in pharmacolherapy-refractory major depression: comparative study of fast, slow and sham rTMS. Psychiatry Res 1099; 88:163=171). ft was also demonstrated that low frequency rTMS at 1 Hz directed to th© right prefrontal cortex had an anti-depressant effect io (Fitzgerald PB, Brown T, Marston HAU, Daskalarfe 74, Kulkami J. A double-blind placebo controlled trial of transeraniai magnetic stimulation in th© treatment of depression. Arch Gen Psychiatry 2003; 00:1002-1008; Klein E, Kreinin I, Chistyakov A, Keren D, Mecz U Mermur S, Ben-Shachar D, Feirrsod M. Therapeutic efficacy of right pre-frontal slow repetitive transcrania! magnetic is stimulation in majut depression: a double-blind controlled study. Arch Gen Psychiatry 199¾ 56:315-320; Fitzgerald PB, Benitez J, De Castalia A, Dasksdakis ZJ, Brown Tt, Kulkami ,1. A randomized controlled trial of sequential bilateral repetitive franscranial magnetic stimulation for treafrnent-resistant depression. Am J Psychiatry 2008; 183:88-94). Using a multi-channel TMS system, it may be 20 possible to activate left profrontel regions with high frequency rTMS, and right pre-frontal regions with tow frequency rTMS, either simultaneously or wito any time delay between them, thus possibly achieving enhanced therapeutic effect [00109] Another application may be connecting two, three or more capacitors in parallel (and/or in series) to on© channel through one switch, thus 25 controlling the puls© duration by ehangirty tit© total circuit capacitance (Eq. Γ). For example, one may connect three capacitors of §0 pf in paraltal, to obtain a total circuit capacitance of about 150 pf, thus extending to© pulse duration by about ^3. Extending puls© duration by increasing to© capacitance may provide savings In power consumption, energy, voltages and/or currents required for 30 neuronal stimulation. Th© ability to use different values of capacitance may give additional investigational tools for researchers, such as comparing effects of varying toe capacitance or toe like. WO 2006/134598 PCT/DL2006/000694 41 [00110] The abilities of multi-channel TMS systems as described here to stimulate several brain regions either simultaneously or with any time delay between them, and to obtain more focal activation of deep brain regions relative to standard one channel TMS stimulators may be beneficial in a large variety of applications. The system and methods of the present invention described herein may be used for research purposes, i.e. by activating any deep brain region with any set of operational parameters. In addition, they may be used to study er treat a neurophysiological condition. A "neurophysiological condition" may be a pathological neurophysiological condition or a neurophysiological disorder, such as, but not limited to: ©Meal depression, non-clinical depression, dysthemia, bipolar disorder, drug addiction, substance abuse, anxiety disorder, obsessive compulsive disorder, schizophrenia, Parkinson's disoase, Afzheirreris disease, post-traumatic stress disorder, addictions such as smoking and alcoholism, autism, eating disorders including obesity, bulimia and anorexia, and others.

EXAMPLE of TESTED COIL

[00111] Reference to now trade to the following example, which together with the above descriptions, illustrate th© invention in a non limiting fashion.

[00112] The biological efficacy of a cot! similar to toe ones described above with reference to FIGS. 4 and S was tested, using motor threshold as a measure of biological effect, ns described in Zangon ©t al., "Transcrarial magnetic stimulation of deep brain regions: evidence for efficacy of the H-coil”, Clinical Neurophysiology 116:775-779, 2005, it should be noted that although the experimental coil, a schematic of which is shown in FIG. 16, is used to stimulate the motor cortex, a region which Ig accessible and measurable, th© results ©an be appropriately compared to a ©oil designed to stimulate deep regions of foe brain (which is more difficult to measure). This comparison was mad© possible by increasing th© distance of the experimental col! from foe site of activation (namely foe motor cortex). Thus, a measure of foo rato of decrease of electric field as a function of distance was taken at different distances from the skull. These measurements were compared to measurements taken under foe same conditions using a standard figure-8 rail. WO 2006/134598 PCT/BL2006/000694 42 [00113] A coil 600 was designed to stimulate th© right abductor pollicis brevis (APB), as shown in FIG. 16. Th© coil 600 has 10 members 601-610 split into two groups, designated by A © and G-H in FIG. 16. The overage length of the members is 11 cm. The only coll elements having radial current components are 5 members 606-610, which are oonneeted to th© return paths shown in segments ΟΙ and J-F. The length of the radial connecting elements is approximately 8 cm. The return paths of the other five members 601-605 are placed on the heac at the contralateral hemisphere (segment O»E). The wires (segments B-C and F-A) connecting members 601-805 and return paths 60T-6Q5* are approximately 9 cm io long, on average. Coil 600 was compared to g standard oommereiaS Mngstim figure-8 coil with internal loop diameters of 7 em.

[00114] Subjects wore seated with th© right forearm and hand supported.

Motor evoked potentials of the right APB muscle wore recorded using silver-silver chloride surface eteettodes. Subjects were instructed to maintain muscle is relaxation throughout th© study. EM© amplitude was amplified using a conventional EMG machine (Counterpoint, Dantoc Electronics, Skovlunde,

Denmark) with bandpass between 10 and 2000 Sfe, The signal was digitized at a frequency of § kHz and fed into a laboratory computer.

[00115] A Magsllm Super Rapid stimulator (Th© Magstim Company New 20 York, NY) which produces a br-phaole puts©, coupled with either the figui3~8 ceil or the H-coil, was used. Preliminary studies showed the H-coil to have © loudness level of 1S dB when activated, similar to eoils 300 and 400 describee! above in accordance with preferred entelimente of the present invention. Subjects were fitted with foam ear plugs to attenuate the sound. 25 [00116] Coil 600 was placed on ttt© scalp over th© left motor cortex. The intersection of th© figure-8 coil was placed tangentially to the scalp with tire handle pointing backward and laterally at a 45 degree angle away from th© midiirte. Coils were held in a stable coil holder which could bo adjusted at different heights above the "hot spot" on the scalp. Resting motor threshold was determined for each coil 30 at different distances above th© scalp, ot increments of 0.5 cm.

[00117] Reference is now made to FIG. 17, which is a graphical illustration of foe results of foe example described above. The graph shows foe WO 20116/134598 PCTOL2036/OOO694 43 percentage of stimulator output needed to reach resting motor threshold as a fonction of distance of toe coil from to© "hot spot" on toe skull for both coil 600 and the standard figure-8 coil. As shown in FIG. 17, toe efficacy of coil 600 at large distances from to© scalp was significantly greater than for to® figure-8 coil. When using maximal stimulation power output, too tiguroS rail can be effective up to 2 cm away from the coil, while coil 600 can be effective at 5.6 cm away from the coil. Moreover, toe rate of deray of effectiveness as a function of the distance from the coil is much slower in coil 600 relative to the figured eoil.

[00118] It should be readily apparent toat the methods described herein may be applied to various types of TMS coils, end are not limited to to© specific embodiments of TMS coils disclosed In toe present application. (00119] It is appreciated toat certain features of to© invention, which are, for clarity, described in toe context of separate embodiments, may aiso be provided in combination in a single embodiment Conversely, various features of toe invention, which are, for brevity, described in th© context of a single errtoodiment, may also b© provided separately or in any suitable subcombination.

[00120} Although too invention hag boon described in conjunction with specific embodiments thereof, it is evident toat many alternatives, modifications and variations will be apparent to those skilled in the art Accordingly, it is intended to embrace all such alternatives, modification© and variations toat fall within th© spirit and broad ©eop© of th© appended claims. Ail publications, patents and patent applications mentioned in thia specification are herein incorporated in their entirety by reference into to© spesfieation, to too same extent as if each individual publication, patent or patent application wao specifically and individually indicated to be Incorporated herein by referene©. In addition, citation or identification of any referenso in this application shall not b© construed as an admission toat such reference is available as prior art to the present invention.

[00121} White certain features of to© present invention have been illustrated and described heroin, many mudifieaftm©» substitutions, changes, and equivalents may occur to those of ordinary sWli in Ore art It is, therefore to be understood toat too appended dote are intended to cover all such modifications and changes as fall within the tree spirit of the present invention. , crnxan rw:n ατα pnow pnizn irn nr “jaoa ,Ρ’ηη ηχΰ- naoana ma™ natrmaa np’ioz .zrtwan rwaa rnp’nn ρ-ίΛ oxnm ......r. Geodauer □ιηπη Pi?

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