WO2015153868A1

WO2015153868A1 - Methods and systems for controlling magnetic fields and magnetic field induced current

Info

Publication number: WO2015153868A1
Application number: PCT/US2015/024054
Authority: WO
Inventors: Liyi Elliott HONG; Fow-Sen Choa
Original assignee: University Of Maryland, Baltimore; University Of Maryland, Baltimore County
Priority date: 2014-04-02
Filing date: 2015-04-02
Publication date: 2015-10-08
Also published as: EP3125986A1; EP3125986B1; WO2015153868A8; US10518098B2; EP3125986A4; US20170021187A1

Abstract

The present invention discloses methods and systems to control magnetic fields and magnetic field induced currents, and more particularly to provide stimulations within a patient's body, such as deep brain stimulation, in a non-invasive manner and with greater focus and control than has been afforded by prior known methods and systems. In accordance with certain aspects of an embodiment, an array of magnetic coils is provided and positionable about a portion of a patient's body. During operation, at least some of the magnetic coils function as DC coil pairs configured to generate a DC magnetic field, while at least some of the other magnetic coils function as transient magnetic field generators to generate an induced current within a portion of the patient's body, such as in a region of the patient's brain. The system is configured such that the DC magnetic fields may be used to manipulate the transient magnetic fields, in turn allowing significantly improved control and focus of the induced current within a specifically desired volume of interest within a patient's body.

Description

METHODS AND SYSTEMS FOR CONTROLLING MAGNETIC FIELDS AND MAGNETIC FIELD INDUCED CURRENT

CROSS REFERENCE TO RELATED APPLICATIONS

This application is based upon and claims priority from United States Provisional Patent Application No. 61/973,944, titled "Methods and Systems for Controlling Magnetic Fields and Magnetic Field Induced Current" and filed on April 2, 2014 by the inventors herein, which is hereby incorporated by reference for all purposes as if fully set forth herein.

FIELD OF THE INVENTION

The present invention relates generally to the control of magnetic fields, and more particularly to methods and systems for controlling a transient magnetic field using one or more DC magnetic fields to provide magnetic stimulation to a patient's body.

BACKGROUND

In recent years, deep brain stimulation (DBS) has shown a great potential as an effective treatment for many neurological and neurodegenerative diseases. DBS is already FDA-approved as a treatment for diseases like essential tremor, Parkinson's disease, and dystonia. DBS has also been tested or proposed as a remedy for disorders like chronic pain, major depression, obsessive- compulsive disorder, dementia and schizophrenia (Schlaepfer, T. E., B. Bewernick, S. Kayser and D. Lenz (2011), "Modulating affect, cognition, and behavior - prospects of deep brain stimulation for treatment-resistant psychiatric disorders," Front Integr Neurosci 5: 29; Hoffman, R. E., R. Gueorguieva, K. A. Hawkins, M. Varanko, N. N. Boutros, Y. T. Wu, K. Carroll and J. H. Krystal (2005), "Temporoparietal transcranial magnetic stimulation for auditory

hallucinations: safety, efficacy and moderators in a fifty patient sample," Biol Psychiatry 58(2): 97-104; Jin, Y., S. G. Potkin, A. S. Kemp, S. T. Huerta, G. Alva, T. M. Thai, D. Carreon and W. E. Bunney, Jr. (2006), "Therapeutic effects of individualized alpha frequency transcranial magnetic stimulation (alphaTMS) on the negative symptoms of schizophrenia," Schizophr Bull 32(3): 556-561 ; and Kuhn, J., M. Bodatsch, V. Sturm, D. Lenartz, J. Klosterkotter, P. J. Uhlhaas, C. Winter and T. O. Grundler (2011), "[Deep brain stimulation in schizophrenia]," Fortschr Neurol Psychiatr 79(11): 632-641). In many cases, DBS treatment seems to be able to stop or slow the disease process and improve symptoms and functioning for patients. Although DBS is so promising, it is still an invasive method and requires brain surgery through the skull and insertion of electrodes into deep brain regions. The surgery can potentially damage existing functional brain cells and is usually performed as a last resort. The situation has not only restricted the number of patients treated, but has also limited the opportunity to explore the full potential of the technique.

Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation method. TMS uses transient pulse field induced currents to cause neuronal depolarization and

hyperpolarization in brain cortices. It induces a small electrical current, which stimulates nerve cells including their branches and allows for the study of brain functions and the development of new treatments for brain disorders. Currently there are many coil designs with a few of them on the market and many on the drawing board, all of which struggle with the inability to stimulate the brain with focus and depth at the same time. Commonly used coils, including the circular coil shown in Fig. 1(a), and the so-called figure 8 coils shown in Fig. 1 (b), can only stimulate superficial areas of the brain (Roth, Y., A. Amir, Y. Levkovitz and A. Zangen (2007), "Three- dimensional distribution of the electric field induced in the brain by transcranial magnetic stimulation using figure-8 and deep H-coils," J Clin Neurophysiol 24(1): 31-38; Deng, Z. D., S. H. Lisanby and A. V. Peterchev (2013), "Coil design considerations for deep transcranial magnetic stimulation," Clin Neurophysiol; and Roth, Y., G. S. Pell and A. Zangen (2013), "Commentary on: Deng et al., Electric field depth- focality tradeoff in transcranial magnetic stimulation: simulation comparison of 50 coil designs," Brain Stimul 6(1): 14-15).

The only approved and commercially available coil that is promoted as a deep brain TMS, is the H-coil TMS, as shown by Fig. 1(c), by Brainsway of Jerusalem, Israel. However, the H-coil still generates currents that are mostly circulating around the outer region of the brain, causing some increased depth of stimulation through summation but also affecting much wider cortical regions of the brain (Roth et al. 2007). Loss of focality is a trade-off for depth in H-coils as in all other coils currently available or conceived (Denget al. 2013; Roth et al. 2013; Roth et al. 2007). Another limitation of some of these coils is that they require factory -wired configurations and can only target one predetermined area per coil. The hardware-to-brain inflexibility limits research and clinical applications, which often require testing of different anatomic locations, or personalized localization in different patients to achieve maximum benefit. Thus far, the figure-8 coil has the best combination of focality and depth. Its focality is achieved by summing one clockwise and one counter-clockwise circular field at the middle, making the focality of the induced currents more predictable. However, the resolution is modest and the stimulation does not go very deep.

In light of the foregoing limitations, there is a need for methods and systems that provide noninvasive controllable DBS, and also stimulations that are capable of operating effectively deep within the body. However, achieving the above purposes and/or benefits is not a necessary feature to each of the exemplary embodiments and claims may recite subject matter that does not achieve the above stated purpose. SUMMARY OF THE INVENTION

Disclosed herein are methods and systems to control magnetic fields and magnetic field induced currents, and more particularly to provide stimulations within a patient's body, such as deep brain stimulation, in a non-invasive manner and with greater focus and control than has been afforded by prior known methods and systems. In accordance with certain aspects of an embodiment, an array of magnetic coils is provided and positionable about a portion of a patient's body. During operation, at least some of the magnetic coils function as DC coil pairs configured to generate a DC magnetic field, while at least some of the other magnetic coils function as transient magnetic field generators to generate an induced current within a portion of the patient's body, such as in a region of the patient's brain. The system is configured such that the DC magnetic fields may be used to manipulate the transient magnetic fields, in turn allowing significantly improved control and focus of the induced current within a specifically desired volume of interest within a patient's body.

BRIEF DESCRIPTION OF THE DRAWINGS

The above and other aspects, features and advantages of the disclosed exemplary embodiments will be more apparent from the following detailed description taken in conjunction with the accompanying drawings in which:

Figs. 1 (a) to (c) show a schematic view of prior art devices.

Fig. 2 shows a schematic view of a magnetic stimulator system according to an exemplary embodiment of the invention.

Fig. 3 shows a schematic view of a two coil system disposed on a magnetic core according to an exemplary embodiment of the invention. Figs. 4 (a) and (b) show schematically a horizontal and a vertical cross-section through a magnetic stimulator system according to an exemplary embodiment of the invention.

Fig. 5 shows a schematic view of a target volume inside a brain of a treatment subject according to an exemplary embodiment of the invention.

Fig. 6 shows schematically the distributions of the DC magnetic field, the conductivity, and the current density along the line "L" in Fig. 5 passing through the brain of a subject and through the target volume according to an exemplary embodiment of the invention.

Fig. 7 shows schematically the distributions of the magnetic field generated by the magnetic stimulator system during a first time period according to an exemplary embodiment of the invention.

Fig. 8 shows schematically the distributions of the magnetic field generated by the magnetic stimulator system during another time period according to an exemplary embodiment of the invention.

Figs. 9(a) to (d) show schematically four neuron stimulations circumstances according to an exemplary embodiment of the invention.

Fig. 10 shows a schematic view of a magnetic stimulator system and a method for running such system according to an exemplary embodiment of the invention.

Figs. 1 1 (a) to (c) show a schematic view of simulation results for the configuration of the magnetic field for a two-dimensional system according to an exemplary embodiment of the invention.

Figs. 12 (a) to (d) show a schematic view of simulation results for the configuration of the magnetic field in a magnetic system according to an exemplary embodiment of the invention. Figs. 13 (a) and (b) show a schematic view of simulation results for the configuration of the magnetic field in a coils system according to another exemplary embodiment of the invention.

Figs. 14(a) and (b) show a magnetic stimulation system including magnetic shields and the effects of magnetic shields on an externally applied magnetic field according to another exemplary embodiment of the invention.

Fig. 15 shows a schematic view of a method of applying the DC current to coils of the stimulator system according to an exemplary embodiment of the invention.

Fig. 16 shows a schematic view of a control system according to an exemplary embodiment of the invention.

DETAILED DESCRIPTION

The following detailed description is provided to gain a comprehensive understanding of the methods, apparatuses and/or systems described herein. Various changes, modifications, and equivalents of the systems, apparatuses and/or methods described herein will suggest themselves to those of ordinary skill in the art. Descriptions of well-known functions and structures are omitted to enhance clarity and conciseness.

The invention is described with reference to the drawings in which like references are labeled with like numerals. The relationship and functioning between the various elements are better understood by reference to the figures. However, the embodiments described herein are examples only and the invention is not limited to those specifically described or depicted in the figures. It should also be understood that the figures are not drawn to scale and in some instances details that are not necessary for the understanding of the present invention are omitted such as common methods of manufacturing. Furthermore, it should be understood that the invention described herein is generally described in terms of a deep brain stimulation system and method. However, it should be understood that that the systems and methods of the present invention may be used for a wide range of uses including to stimulate other areas of the brain and body. One having ordinary skill in the art would recognize minor changes that would be necessary to adapt the system for different uses. These modifications should be considered part of the invention because they do not deviate from its overall spirit. The drawings are two-dimensional, although the invention is for both two-dimensional and three-dimensional designs for coil arrangement. The drawings are based on a few coils in one configuration, although the invention is to provide dozens, hundreds, or thousands of coils in combination within one configuration.

(A). The configuration of the system for controlling magnetic fields.

Referring now to the figures, FIG. 2 illustrates one potential configuration of a magnetic stimulator system 100. System 100 comprises a plurality of magnetic coils configured to generate magnetic fields in a region of interest, the coils being arranged in arrays; power supply 150; and a control system 160 configured to control the currents in the coils, thereby controlling the magnetic fields generated by the coils. The coil-array comprises an external housing 120 that has a central cavity 115 which is sized to fit a living animal's head, torso, or limb. The housing may be domed shaped, as shown in Fig. 4(b), if it is specifically configured for a head or it may be generally cylindrical with openings on either end. More generally, the physical structure of the array can be in the shape of a helmet, a dome, a donut or other shapes conforming to specific body parts. It can also be several separate arrays each containing multiple coils, and the arrays may be arranged in various spatial locations. Fig. 4(a) and (b) show schematically a horizontal and a vertical cross-section through a magnetic stimulator system 100 according to an exemplary embodiment. Four or more magnetic coils (poles), 130, are located on the inner wall of the housing. At least two poles are used to generate the DC magnetic field (e.g. DC coils 410 and 41 1 in Fig. 4(a)) and at least two poles are used to generate the transient magnetic field (e.g. transient coils 420 and 421 in Fig. 4(a)). During the course of a procedure, a pole may be used as both a DC field generator and a transient magnetic field generator at different times. The coils may be driven in pairs (as shown in Fig 4(a)) such that one coil corresponds to a north pole and the other to a south pole (e.g. coils 420 and 421).

A useful construct for expressing the behavior of the magnetic fields induced by the coils is the magnetic field "beam" or "beams" associated with the magnetic field. Generally, a beam is defined by a path of higher intensity or higher amplitude regions of a vector field distribution. For example, while a laser output intensity distribution spreads from minus infinity to positive infinity, the skilled artisans refer to the fact that the laser has a finite beam spot size. There are a multiple ways of defining the "beam spot size" of a laser field (and other vector fields). An often used way of defining the beam is by the "full wave half maximum (FWHM)", where the half power points are taken as the diameter of the beam. Anything inside the radius is called laser beam covered area while outside the radius regions is often neglected. Other ways of defining the beam is by taking the points having power equal to 1/10 of the peak power as the beam diameter or by taking the points having power of 1/e of the peak power. The invention is not limited by the particular way a beam can be defined.

In an exemplary embodiment of the invention the magnetic coil poles may be disposed on a magnetic core as shown in Fig. 3. The magnetic core may comprise an iron core (having magnetic permeability about 200,000 times larger than the air) or other magnetic materials known to have high magnetic permeability. The magnetic system may be designed so as to ensure that the magnetic field flux generated by the coils is kept as much as possible inside of the high permeability core material. Keeping the magnetic flux in high permeability region makes possible the generation of high magnetic fields by relatively small electrical currents into the coils. However, all magnetic stimulators will need to have a region passing through nonmagnetic materials. Minimizing this region will minimize the driving electrical current. Thus, using more iron core along the magnetic path reduces magnetic resistance. In turn, smaller magnetic resistance enables the use of low driving currents to achieve high magnetic fields. This will help to reduce power consumption and minimize heating problems.

The housing 120 may be made of iron core material, or other high permeability materials, such as to reduce magnetic resistance. To obtain higher magnetic fields, superconducting materials which can achieve high dynamic ranges of control may be used to reduce the risk of heating and mechanical stress. If iron core is used, a nonmetallic inner liner 140, may be welded inside to provide additional strength. The inner liner and external housing may contain ventilation, temperature control, noise and/or heat reduction apparatus, and access holes for monitoring a human participant, recording additional information, and increasing safety and patient comfort.

The magnetic coil poles may be positioned on the magnetic system 100 to create a two or three dimensional field. When generating a three dimensional field, the magnetic coil array may be stationary and variation of the field will be controlled by the poles. The precise positioning between the array and the human subject can be obtained by moving the subject using a controlled stretcher, chair, or a similar device, or by moving the array with respect to the subject. If a two dimensional field is used, the magnetic coil array may be moved along the z axis, allowing for targeting within a volume. Securing mechanisms (not depicted), such as straps or braces, will be located within or around the magnetic coil array to keep the target area in place during treatment.

(B). Stimulating brain cells by electric currents induced by short pulses of transient magnetic fields (achieving neural firing threshold).

Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation method. TMS uses transient field induced currents to cause neuronal depolarization and hyperpolarization in brain cortices. It induces a small electrical current, which stimulates nerve cells including their branches and allows for the study of brain functions and the development of new treatments for brain disorders.

When a perturbation of the neuronal cell membrane takes place, the voltage across the membrane will change. When the change is making the potential inside the cell less negative, this is called a depolarization process. In a depolarization process, when the potential difference is close to -55mV (exact number varies from cell to cell), a depolarization chain reaction process occurs where the potential inside a cell will become less negative, then fully depolarized to even positive, and then go back to negative values becoming polarized again. This process is called neuron firing or action potential generation. In a conductive material, like tissue or nerve cell body, an electrical field will create a current J = σΕ and part of the current will charge the membrane capacitor to change the ~ -70m V polarization voltage to a more positive value. When the polarization voltage is close to ~ -55mV the action potential chain reaction starts to take place. This -55mV polarization voltage is called action potential threshold or neuronal firing threshold. Among others, the purpose of the systems and methods herein is to generate currents capable of causing neuronal depolarization and hyperpolarization (or causing neuronal firing and pulse action potential) only into a certain (possibly small) target volume of the brain.

(C). Methods of operating the magnetic system to obtain neuronal firing only or primarily in a target volume and confining the induced currents into the target area.

One of the shortcomings of prior art devices shown in Fig. 1 comes from the fact that the transient magnetic fields employed by such systems generate above threshold electric currents (causing neuronal firing) over large regions of the brain and especially in the regions close to the skull. In many situations, for treatment purposes, it is desirable to cause neuronal firing (i.e. achieve neuronal firing threshold) only in a certain relatively small volume deep into the brain (hereinafter referred as target volume) as shown by the target volume in Fig. 5. As explained herein, the magnetic stimulation system 100 may be used to cause neuronal firing / stimulation only (or primarily) in the target volume.

Using the methods set forth herein, the magnetic stimulation system may be operated such that the induced currents in the target volume are larger than the currents outside the target volume. Likewise, and again using the methods set forth herein, the magnetic stimulation system may be operated such that, in the target volume, currents induced by a sequence of pulses (generated from multiple pairs of coils) add up to reach the neuronal firing threshold whereas the currents generated by the same pulses outside the target volume do not add up to the neuronal firing threshold. The magnetic stimulation system may be operated so as to achieve both the first and second situations mentioned above, thereby ensuring that neuron firing is achieved primarily in the target volume. The combination above may enable one to focus the neuronal firing in a small target volume. The various methods (e.g. methods for achieving stimulation in a target volume) disclosed in this application may be used separately, simultaneously, or in various combinations such as to achieve the desired stimulation of the brain.

(D). Adjusting the conductivity of the brain material by the DC magnetic field.

The magneto-resistance phenomenon may be employed to adjust the conductivity of various regions of the brain tissue as desired. A DC magnetic field may be used to restrict the motion of charged particles and to restrict the induced currents produced by transient fields via the magneto-resistance effect. By controlling the DC magnetic field profile in space, it is possible to control the spatial distribution of the induced currents and achieve focused stimulation. Thus, the magneto-resistance effect may be used to obtain the desired stimulation location and to control the size of the stimulated region by changing the DC field distribution. Further, by adjusting the DC field distribution it is possible to reduce the spot size and to protect high field regions near the transient coils.

For example, with respect to Fig. 5, the distribution of the DC magnetic field may be controlled such that the transient magnetic field TF generates effective currents within the target volume "V" while the transient magnetic field TF generates significantly smaller currents in the region "S" right under the skull.

The magneto-resistance phenomenon and field dependence of magneto-conductance is shortly presented hereinafter. The ions and electrons (e.g. ions inside the brain) obey the Lorentz force equation shown below:

In the above equation "m" is the mass of the ionic particle, "v" is its velocity, "τ" is the collision mean free time. When the DC magnetic field (B) is along the z-direction, and the electric field (E), induced by the transient magnetic field (BT), is along the x-direction then the current density related to the velocity of the particles is provided by equations:

/* = "^w¾ sndjy = -*»¾._# /_jf = _¾Α e d /_y = o_fSE_s

Where:

In the above equations co_c is the cyclotron frequency and σ₀ is the tissue conductivity without magnetic field. When the DC magnetic field increases, the tissue conductivity decreases following a 1/B² dependence when B field is high. Thus, if the magnetic field is double for some regions, the conductivity will drop to 1/4 times (25%). For example, with respect to Fig. 5, the distribution of the DC magnetic field may be controlled such that the DC field in the "S" volume situated right under the skull is twice as larger as the DC field in the "target volume." Thus, the magneto-conductivity of the brain material in the "S" region will be about 4 times larger than the magnetic conductivity in the target volume V. As a result, the electric currents generated by a transient magnetic field TF into the "S" region are suppressed by the low conductivity in that region whereas the electric currents generated by the transient magnetic field TF into the target volume V are significantly less suppressed because the conductivity in the "V" region is 4 times higher.

Thus, the coils of the magnetic stimulation system 100 may be operated such that a first set of coils generate a DC magnetic field having a configuration such as to adjust the conductivity of various regions of the brain tissue as desired. For example, the currents through the first set of coils may be set such that the DC magnetic field in a target volume (V) has a first value BV whereas the DC magnetic field in the regions outside the target volume is larger than BV. As a result, the conductivity of the brain matter inside the target volume (V) is smaller than the conductivity of the brain matter outside the target volume.

Further, at the same time with the first set of coils generating the above mentioned DC field, transient currents are driven through a second set of coils of the magnetic stimulator 100 such as to generate transient magnetic fields TF into the brain. The transient magnetic fields TF induce currents into the brain matter (by magnetic induction: VxE = - dB/dT). The induced currents depend both on the electromagnetic induction and on the conductivity of the particular brain region. The conductivity of the brain regions is adjusted by the DC field configuration such that the currents induced by the transient magnetic fields inside the target volume "V" are large enough to reach neuronal firing threshold (thereby causing neuronal firing) whereas the currents induced outside the volume are not large enough to reach neuronal firing threshold (thereby not causing neuronal firing).

The above described behavior of brain conductivities and induced currents as function of the DC fields applied is explained with reference to Fig. 6 of the drawings. Fig. 6 shows schematically the distributions of the DC magnetic field, the conductivity, and the current density along the line "L" in Fig. 5 passing through the brain of a subject and through the target volume. As seen in Fig. 6, the brain conductivities and the induced currents are higher in the region where the DC field is low, such as inside the target volume V. Conversely, the brain conductivities and the induced currents are smaller in the region where the DC field is high, such as in the regions outside of the target volume V. The configuration of the DC and transient magnetic fields may be changed (e.g.

continuously) during the treatment, which in turn changes the conductivity distribution and the pattern of induced currents in the brain, thereby changing the stimulated brain region. For example, during a first time period, a first DC and transient field may be applied (e.g. as shown in Fig. 7) which may induce the desired currents in the target volume VI and restrict the induced currents outside the volume VI. During a second period, a second DC and transient field may be applied (e.g. as shown in Fig. 8) which may induce the desired current in another target volume V2 but will restrict currents to be induced by transient field outside the volume V2. During the treatment period, both the DC and transient fields configurations can be adjusted (e.g. together or separately) such that the target volume is moved inside the brain thereby moving the brain region to which magnetic stimulation treatment is applied. This way the target volume to which treatment is delivered can be moved from one region to another inside the brain without moving the patient.

The DC and transient fields may be adjusted such that the target volume "V" may have a diameter as small as 5 mm. The DC fields and the transient fields may be adjusted such that the target volume "V" may have a diameter smaller than 5mm, or smaller than 10mm, or smaller than 15 mm, or smaller than 20 mm, or smaller than 30mm. The target volume may be smaller than 5% of the brain volume, smaller than 10% of the brain volume, smaller than 20% of the brain volume, or smaller than 30% of the brain volume. The DC fields and the transient fields may be adjusted such that the target volume "V" may be as deep as 10mm, 20mm, 30mm, 50mm, 60mm or 100mm under the surface of the brain. The DC magnetic field in the target volume "V" may be from about 0.001 Tesla to about 0.5 Tesla. The DC magnetic field at the surface of the head (in the air just outside of the surface of the magnet core) may be from about 1 Tesla to about 7 Tesla.

The transient magnetic fields may have the following characteristics. The transient magnetic fields may be such that, in the target volume, dB/dt is between 10⁴ and 10⁵ Tesla per second . The transient magnetic fields may be such that, at the surface of the head, dB/dt is between 2xl0⁴ and 2xl0⁵ The transient fields may come as pulses or sequences of pulses. The pulses may last between a few microseconds and 0.5ms. The pulses sequences may include pulses spaced apart at less than 0.1ms, or less than 0.05ms, or less than 0.02ms, or about 0.01ms.

The number of coils (poles) can range from a few coils to several hundreds to even thousands of coils. It is likely that coils numbering within the range of dozens to 200 will be suitable for use with the current technology. The ranges of values for the DC ramp up peak current is -100-lOOOA and the pulse peak current is ~ 200-4000 A, although higher and lower values can be used. The transient field coils of the stimulator system 100 may be driven in pairs such that one coil corresponds to a north pole and the other to a south pole.

(E). Summation of the effects of sequences of magnetic pulses and magnetic field beams.

Experimental studies performed by the inventors herein have shown a summation effect of sub-threshold behavior for the Transcranial Magnetic Stimulation applied to the human motor cortex for generating motor response. The above experimental studies have been described in detail in the article "Neural Summation in Human Motor Cortex by Subthreshold Transcranial Magnetic Stimulations" (Xiaoming Du , Fow-Sen Choa , Ann Summerfelt , Malle A. Tagamets, Laura M. Rowland, Peter Kochunov, Paul Shepard, L. Elliot Hong; published in Experimental Brain Research, DOI 10.1007/s00221-014-4146-z, Nov. 2014) incorporated hereinafter in its entirety as if fully set forth herein.

Sub-threshold stimulation is a stimulation that is not strong enough to generate action potential or motor response. The inventors showed that when two sub-threshold stimuli are fired in close temporal proximity, a motor response can be generated only when each sub-threshold stimulation is at 60% or more of the threshold strength. Therefore, it is possible to use subthreshold firing to avoid neuromodulation taking place outside of desired regions. Only when multiple sub-threshold stimulations converge at the desired region will an action potential or above threshold firing of the neural tissue at that location take place.

Some aspects of the invention include the summation of two or more sub-threshold stimulations in order to achieve neuron firing. Stimulation summation may be achieved by exposing the target to two or more sub-threshold stimulations. The sub-threshold stimulations may be released within a certain window of time (temporal), FIG. 9(b), or they may occur at the same time but reach the neuron from a different path (spatial), FIG. 9(c). Inhibitory postsynaptic potentials (IPSP) may also be combined with excitatory postsynaptic potentials (EPSP) to prevent neuron firing, FIG. 9(d). The membrane potential of a neuron weakens over time so subthreshold stimulations must be released within a certain period of time when using temporal summation, FIG. 9(a). By sequentially sending transient pulses with different spatial paths, at different times, the time summation effect achieves neuron activation in a very small target region while tissues outside the highest overlapping area are well protected and remain below stimulation activation. Table 1

Table 1 depicts experimental results on temporal summation for pulses that are 10% and 20% below the threshold intensity. The table shows time constant neurons can hold subthreshold stimulation in the range of milliseconds to tens of milliseconds which is well within the range of the present invention. The sample two-dimensional unit described above confirmed that summation does occur.

Neural firing threshold can be achieved directly, that is by generating pulses of current above the threshold. Neural firing threshold can also be achieved indirectly by the summation of multiple sub-threshold field stimulations (and the induced voltages and currents) ordered in time. Neural stimulation/firing can be achieved by sequentially generating multiple lines of induced currents and only allowing the cross point of these lines to accumulate sufficient charge on the cell membrane.

For example, assume that a sequence of time-ordered magnetic field pulses PI to P10 is applied to a neuron cell in the brain. Each of the PI to PI 0 generates an induced current that leads to an increase of the membrane voltage by AV=C*AQ, where C is membrane capacitance, thereby inducing a charge AQ on the membrane. The voltage AV and the charge AQ generated by a single pulse, out of the pulses PI to PI 0, is not enough to depolarize the membrane, reach action potential threshold, or reach neural firing threshold. However, if the pulses in the sequence are spaced apart such as to allow cross-point summation between the pulses, the voltages generated by each of the pulses may add up in time such that, after a number of pulses, AV of the membrane will be large enough to depolarize the membrane and reach action potential thresholds. Thus firing threshold can be obtained by the summation of multiple sub-threshold stimulations.

As explained in the following with reference to Fig. 10, by using a sequence of time- ordered sub-threshold pulses it is possible to achieve targeted neural stimulation in a small volume at any desired depth into the brain.

The magnetic stimulation system 100, as shown in Fig. 10, may be operated such that, in the target volume, currents induced by a sequence of pulses (generated from multiple pairs of coils) add up to reach neural firing threshold whereas the currents generated by the same pulses outside the target volume do not add up to the neural firing threshold. The coils may be driven in pairs such that one coil corresponds to a north pole and the other to a south pole.

For example, a sequence of transient magnetic pulses may be fired from pair of coils of the stimulation system 100, as shown in Fig. 10, as follows: a first transient pulse PI is fired from the pair of coils CI at the time tl ; a second transient pulse P2 is fired from the pair of coils C2 at the time t2 = tl+dT; and a third transient pulse P3 is fired from the pair of coils C3 at the time t3 = tl+2*dT. The pulses PI, P2 and P3 have a sub-threshold strength which is 60% or more of the threshold strength.

Pulse PI generates a magnetic field Bl having a specific distribution Bl(x, y, z). The distribution Bl(x, y, z) is such as to form a beam SI for which the magnetic field B l is larger in the region of the beam SI and smaller in the regions outside the beam SI (e.g. the field strength outside the region S I is less than 60% of the strength necessary to achieve threshold strength whereas the field inside region SI is larger than 60% but less than 100% of the field necessary to achieve threshold strength). Similarly, pulse P2 generates a magnetic field B2 having a specific distribution B2(x, y, z). The distribution B2(x, y, z) is such as to form a beam S2 for which the magnetic field B2 is larger in the region of the beam S2 and smaller in the regions outside the beam S2 (e.g. the field strength outside the region S2 is less than 60% of the strength necessary to achieve threshold strength whereas the field inside region S2 is larger than 60% but less than 100% of the field necessary to achieve threshold strength). Further, pulse P3 generates a magnetic field B3 having a specific distribution B3(x, y, z). The distribution B3(x, y, z) is such as to form a beam S3 for which the magnetic field B3 is larger in the region of the beam S3 and smaller in the regions outside the beam S3 (e.g. the field strength outside the region S3 is less than 60% of the strength necessary to achieve threshold strength whereas the field inside region S3 is larger than 60% but less than 100% of the field necessary to achieve threshold strength). In this application the term "field strength" has a general meaning including the magnetic field absolute value, the rate at which the magnetic field changes with time (e.g. the rate dB(x,y,z)/dt at various positions (x, y, z) inside the brain), or other meanings that the skilled artisans would use.

The stimulator system 100 may be positioned and/or moved such that the target volume V is at the intersection of the beams SI, S2, and S3.

The brain material situated at the intersection of beams SI, S2, and S3 (inside the target volume V) receives a sequence of three pulses (i.e. PI, P2 and P3) each having a strength larger 60% of the threshold strength. Thus, as explained in the article, even though none of the three pulses has enough strength to cause stimulation, the effects of the pulses PI, P2, and P3 (all of them being above the 60% threshold strength) may add up such as to cause neuron firing. At the same time, the brain material outside the intersection of beams SI, S2, and S3 (e.g. the region "U" outside of the target volume), is applied a sequence of magnetic pulses

(corresponding to the three pulses PI, P2, and P3) but the magnetic field generated by the pulses PI, P2, and P3 in this outside region "U" is less than 60% (or at least one of the pulses has a strength less than 60%) of the threshold strength. As a result, in the region outside V (e.g. in region U), the magnetic fields corresponding to the three pulses do not add up to a composite strength above the threshold and, consequently, the neurons outside of the volume V will not fire.

In other words, the nerve cells along the transient magnetic field path (but not situated at the intersection of beams SI to S3) will never be able to accumulate sufficient charge to depolarize their membrane and reach action potential threshold. However, the nerve cells at the cross point (situated at the intersection of beams Si, S2, and S3) can accumulate shots from different paths and eventually accumulate sufficient charges to depolarize the membrane and reach action potential. By doing so, equivalent magnetic focusing is achieved through superposition of coil arrays and summation of different paths.

While the above example has been explained with respect to a sequence of three pulses having strengths larger than 60%, the skilled artisan would understand that a sequence of pulses including any number of pulses may be used (e.g. 5, 10, 15, 20 pulses) and the pulse strengths may have various values (e.g. 70%, 80% of the threshold strength). Further, the time spacing (dT), the pulse length (tp) of the pulse sequences, and the pulse shapes may be adjusted such as to trigger neuronal firing in the desired target volume while at the same time preventing the triggering of neuronal firing in other brain regions. (F). Focusing the pulsed transient magnetic fields into the target volume by superposition of magnetic fields generated by a plurality of pairs of coils.

As mentioned above, the magnetic stimulation system 100 includes a plurality of coils that may be run such as to generate a pulsed transient magnetic field by driving a transient current through the coils. The coils may be driven in pairs such that one coil corresponds to a north pole and the other to a south pole.

The inventors herein have discovered that the transient magnetic field in a certain volume inside the coil system 100 may be focused by superimposing the magnetic fields of various coil pairs of the system 100. Further, the inventors herein have discovered a near-field effect in the sense that the composite field profile becomes smaller with decreasing the coil diameter and the field spot size is reduced when the coil diameter is reduced. The smaller the diameter of the coils and the smaller the inter-coils spacing (and the larger the density of coils in the array) the smaller the field spot size and the composite field profile. Moreover, the inventors herein have discovered that the field spot size can be reduced by using diagonal superposition of pulsed magnetic fields from array pairs and near-field geometric effects.

All of the above enable the operator of the magnetic stimulator to obtain a highly focused magnetic field with a spot size smaller than a few mm in diameter.

FIGS. 11(a) - (c) show simulation results of a two-dimensional design. Fig. 11(a) shows that the relative magnetic field spreads everywhere when the left and right DC control field is not turned on. Fig. 11(b) shows a case when the left and right DC magnetic fields are turned on and, as a result, the pulsed field becomes focused and can only pass through the middle part of the region. The focal point of the field may be moved from one location to another by adjusting the DC magnetic fields of the surrounding coil pairs. This way the focal point may be shifted left and right or forward and backwards as shown in Fig. 11(c). In the 3-D case a similar method may be used to adjust the location of the focal point. Alternatively, the whole two dimensional unit may be moved up and down to adjust the focal point in the z-direction. Because more DC coils may be distributed in a 3-D space, multiple field paths may be obtained and the paths may be nonlinear, thus further increasing the ability to localize and to focus.

Fig. 12 shows that the required DC current to achieve focusing may be reduced by increasing the coil/pole number, reducing the pole diameter of the coils, and operating on diagonal poles (shut off the rest). In the example setup depicted in FIG. 11, the required DC current is over 1 kA in order to achieve focusing. In the FIG 12 setup, the required DC current is reduced down to 400A.

To greatly reduce the focal spot size, the pole diameter may be reduced and the pole number may be increased as shown in FIGS. 12 (c) and (d). By sequentially turning on the transient field in cross diagonal paths, the cross point volume can be very small. The volume of the above threshold region may be further reduced down to theoretically infinitely small by appropriately adjusting the transient field strength of each path.

Figs. 13 (a) and (b) shows computer simulation result for the magnetic field shape generated by a system of eight pairs of coils. Fig. 13(a) shows the distribution of the magnetic field lines. Fig. 13(b) shows the magnitude of the magnetic field as function of position along the line "S" in Fig. 13(a). As seen in Fig. 13(b) the value of the magnetic field exhibits a pronounced peak (relatively small FWHM) in the central region which proves the focusing effect of the multi-coil system in Fig. 13(a).

Fig. 14(a) shows a magnetic stimulation system 100 according to another exemplary embodiment of the invention. The magnetic stimulation system 100 may further include magnetic shields (e.g. the shields 145 in Fig. 14(a)) to further adjust the magnetic field distribution generated by the stimulation system (e.g. inside the brain of the patient) thereby improving the focus/shape of the transient or DC magnetic fields as shown by Fig. 14(a).

Magnetic shields include nonmagnetic materials having high electrical conductivity (e.g.

graphene, silver, copper, etc.).

Fig. 14(b) shows exemplary embodiments of the magnetic shields (e.g. 141 and 142) and their effect on an applied external magnetic field. The two magnetic shields 141 and 142 may have a ring or disk shape. The induced eddy currents into the shields may provide a counter magnetic field in opposite direction to the externally applied forward magnetic field. The summation of the forward and counter magnetic fields creates a total field distribution which redistributes the externally applied field to a distorted but more focused field distribution (as shown in the left side of Fig. 14(b)). The shape of the total final field may be determined by treating the inserted high conductivity shield material as boundary conditions for the original field source and by solving the field equation with these boundary conditions. The solution of such an equation shows a more focused field distribution as shown by the field in the left panel of Fig. 14(b).

(G) Reducing the duty cycle for the DC current.

The equivalent DC current may be further reduced by reducing its duty cycle, as depicted in FIG. 15. This method employs a slow DC field ramp up 601, followed by multiple transient AC pulses, 602, followed by a ramp down of the DC current back to the original stage, 603. This process will reduce heat and magnetic stress of the operation.

(H) . Configuration of the control system. FIG. 16 illustrates an example control system 160. The control system comprises a processor 202, memory 204, storage device 208, bus 210, input device 212, display 214, and communications interface 270. Control system 160 may be an individual system, as shown in FIG. 16, or it may be integrated into another medical system or computer.

Input device 212 allows for patient specific treatment plans to be uploaded into the system. In some instances, the input device includes a keyboard, mouse, touchscreen, or other interface to allow for operator control. The input device may include the algorithms to calculate treatment plan. These interfaces, along with display 214, allow the operator to enter or perform calculation of a treatment plan or make changes to an uploaded plan. Preplanned patient specific treatment plans may also be uploaded through communications interface 270. Files may be uploaded from the internet 284 via network link 2, 274 or from a local network via network link 1, 272. Communications interface 270 also communicates with magnetic coil array 282.

Instructions are sent to the magnetic coil arrays to execute the treatment plan. Input device 212 can generate individualized, computer-generated treatment plans. The treatment plan can then be executed through the computerized controls for the DC coils and transient coils using computer assisted algorithms.

The controls can include turning on and off particular configurations on the number of coils, the spatial locations of the coils, the different intensities among the coils, and the different timing and patterns of the individual coils. The computerized treatment solutions can be anatomically guided by the actual images of the structure of the body parts of the patient or participant. The anatomic images can be from magnetic resonance imaging or other recording devices. The anatomic images are input into the computers. The computer will then calculate and output the DC fields and path needed for the treatment plan, and create the sequence for turning on and oil particular configurations on the number of coils, the spatial locations of the coils, the different intensities among the coils, and the different timing and patterns of the individual coils. Similarly, the device can output and execute the precise locations and strength of the magnetic fields.

The above methods for stimulating the brain may be used separately, simultaneously, or in various spatial and temporal combinations such as to achieve the desired brain stimulation. Methods of performing transcranial brain stimulation disclosed herein may include any combination of the above disclosed methods and apparatuses. For example, a method of performing transcranial brain stimulation may employ any one or any combination of the following: focusing the pulsed transient magnetic fields into the target volume by superposition of magnetic fields generated by a plurality of pairs of coils; summation of the effects of sequences of magnetic pulses and magnetic field beams; adjusting the conductivity of the brain material by DC magnetic fields; and reducing the duty cycle for the DC current.

While the exemplary embodiments have been shown and described, it will be understood by those skilled in the art that various changes in form and details may be made thereto without departing from the spirit and scope of the present disclosure as defined by the appended claims.

In addition, many modifications can be made to adapt a particular situation or material to the teachings of the present disclosure without departing from the essential scope thereof.

Therefore, it is intended that the present disclosure not be limited to the particular exemplary embodiments disclosed as the best mode contemplated for carrying out the present disclosure, but that the present disclosure will include all embodiments falling within the scope of the appended claims.

Claims

What is claimed is:

1. A system for controlling magnetic fields and induced currents in a target volume inside a brain of a human or animal, the system comprising:

(a) , an array of magnetic coils disposed on an external housing, the array comprising: a first set of coils configured to generate a DC magnetic field in the brain; and a second set of coils configured to generate transient magnetic fields inducing a plurality of currents in the brain matter;

(b) . a power source; and

(c) . a control system;

wherein the target volume is smaller than 20% of the brain volume and is disposed at least 2cm deep under the brain surface;

wherein the currents induced in the target volume are large enough such as to trigger neuronal firing in more than 75% of the target volume;

wherein the currents induced outside the target volume are small enough such as not to trigger neuronal firing in more than 5% of the brain matter outside the target volume.

2. The system of claim 1, wherein the average DC magnetic field inside the target volume is less than 50% of the average DC magnetic field on the surface of the brain.

3. The system of claim 1, wherein the average DC magnetic field inside the target volume is less than 75% of the average DC magnetic field on the surface of the brain.

4. The system of claim 1, wherein the first set of coils comprises more than 10 pairs of DC coils arranged substantially around the brain, or wherein the second set of coils comprises more than 10 pairs of transient coils arranged substantially around the brain.

5. The system of claim 1, wherein the system comprises more than 20 coils arranged on a dome shaped housing and disposed such as to be distributed substantially uniformly on the interior surface of the dome.

6. The system of claim 1, wherein the coils comprise a magnetic core material disposed inside the coils and connecting pairs of coils with each other such as to confine the magnetic field inside the magnetic core material.

7. The system of claim 1 further comprising one or more magnetic shields configured to focus the magnetic field.

8. The system of claim 1, wherein the second set of coils are configured to generate a sequence of transient magnetic field pulses generating a corresponding sequence of magnetic field beams inside the brain;

wherein, for each of the beams, the transient magnetic fields of the beam do not have the strength necessary for achieving neuronal firing threshold;

wherein at least two beams paths, corresponding to at least two consecutive pulses, intersect inside the target volume; wherein the shapes of the magnetic field pulses and the time-spacing between the consecutive pulses are such that the corresponding effects of the beams on the brain region at the intersection of the beams add up such as to cause neuronal firing;

wherein, in the regions outside the intersection of the beams, the beams of the sequence do not cause significant neuronal firing.

9. The system of claim 8 wherein the time-spacing between two consecutive pulses is less than 0.02ms.

10. The system of claim 1, wherein the array of coils is disposed on a dome shaped housing such as to accommodate a human head and such that the distance between the coils and the head is less than 5 cm.

11. The system of claim 1, wherein the diameter of the target volume is less than 30mm.

12. The system of claim 1, wherein the diameter of the target volume is less than 10mm.

13. The system of claim, wherein the target volume is disposed at least 4cm under the brain surface.

14. A method of operating the system of claim 1, the method comprising:

generating a sequence of transient magnetic field pulses, the sequence of pulses generating a corresponding sequence of magnetic field beams inside the brain; wherein, for each of the beams, the transient magnetic fields of the beam do not have the strength necessary for achieving neuronal firing threshold;

wherein at least two beams paths, corresponding to at least two consecutive pulses, intersect inside the target volume;

wherein the shapes of the magnetic field pulses and the time-spacing between the consecutive pulses are such that the corresponding effects of the beams on the brain region at the intersection of the beams add up such as to cause neuronal firing;

15. The method of claim 14 wherein each of the beams have a magnetic field distribution such that the field strength outside the beam is less than 60% of the field necessary to achieve firing threshold strength whereas the field strength inside beam region is larger than 60% but less than 100% of the field necessary to achieve threshold strength

16. The method of claim 14 wherein each of the pulses being transmitted primarily via a pair of coils.

17. The method of claim 14 wherein the time-spacing between two consecutive pulses is less than 0.02ms.

18. The method of claim 14 further comprising: generating a DC field, via the first set of coils, such that the average DC field in the target volume is less than 50% of the average DC field on the surface of the brain.

19. The method of claim 14 further comprising:

generating a DC field, via the first set of coils, such that the average DC field in the target volume is less than 75% of the average DC field on the surface of the brain.

20. A method of operating the system of claim 1, the method comprising:

generating a DC field, via the first set of coils, such that the average DC field in the target volume is less than 50% of the average DC field on the surface of the brain.