# Patent

## Title
Transcranial magnetic stimulation for altering susceptibility of tissue to pharmaceuticals and radiation

## Abstract

Described herein are methods for modulating the susceptibility of one or more target or tissue regions, and particularly one or more brain regions, to a therapeutic agent such as a drug, immune agent, compound, radiation, etc. In particular, the methods and systems described herein may include magnetic stimulation (including transcranial magnetic stimulation) of target or non-target regions to modulate the susceptibility of the one or more target or tissue regions to a therapeutic agent.

## Background
CROSS REFERENCE TO RELATED APPLICATIONS
This patent application claims priority to provisional patent application Ser. No. 61/365,025, titled “TRANSCRANIAL MAGNETIC STIMULATION FOR ALTERING SUSCEPTIBILITY OF TISSUE TO PHARMACEUTICALS AND RADIATION,” filed on Jul. 16, 2010.
This patent application may be related to one or more of the following patents and pending patent applications (US and PCT applications), each of which is herein incorporated by reference in its entirety: U.S. Pat. No. 7,520,848, titled “ROBOTIC APPARATUS FOR TARGETING AND PRODUCING DEEP, FOCUSED TRANSCRANIAL MAGNETIC STIMULATION”, issued on Apr. 21, 2009; U.S. patent application Ser. No. 12/402,404, titled “ROBOTIC APPARATUS FOR TARGETING AND PRODUCING DEEP, FOCUSED TRANSCRANIAL MAGNETIC STIMULATION”, filed on Mar. 11, 2009; U.S. patent application Ser. No. 11/429,504, titled “TRAJECTORY-BASED DEEP-BRAIN STEREOTACTIC TRANSCRANIAL MAGNETIC STIMULATION”, filed on May 5, 2006; U.S. patent application Ser. No. 12/669,882, titled “DEVICE AND METHOD FOR TREATING HYPERTENSION VIA NON-INVASIVE NEUROMODULATION”, filed on Jan. 20, 2010; U.S. patent application Ser. No. 12/671,260, titled “GANTRY AND SWITCHES FOR POSITION-BASED TRIGGERING OF TMS PULSES IN MOVING COILS”, filed on Jan. 29, 2010; U.S. patent application Ser. No. 12/670,938, titled “FIRING PATTERNS FOR DEEP BRAIN TRANSCRANIAL MAGNETIC STIMULATION”, filed on Jan. 27, 2010; U.S. patent application Ser. No. 12/677,220, titled “FOCUSED MAGNETIC FIELDS”, filed on Mar. 9, 2010; PCT Application No. PCT/US2008/077851, titled “SYSTEMS AND METHODS FOR COOLING ELECTROMAGNETS FOR TRANSCRANIAL MAGNETIC STIMULATION”, filed on Sep. 26, 2008; PCT Application No. PCT/US2008/081048, titled “INTRA-SESSION CONTROL OF TRANSCRANIAL MAGNETIC STIMULATION”, filed on Oct. 24, 2008; U.S. patent application Ser. No. 12/324,227, titled “TRANSCRANIAL MAGNETIC STIMULATION OF DEEP BRAIN TARGETS”, filed on Nov. 26, 2008; PCT Application No. PCT/US2009/045109, titled “TRANSCRANIAL MAGNETIC STIMULATION BY ENHANCED MAGNETIC FIELD PERTURBATIONS”, filed on May 26, 2009; U.S. patent application Ser. No. 12/185,544, titled “MONOPHASIC MULTI-COIL ARRAYS FOR TRANSCRANIAL MAGNETIC STIMULATION”, filed on Aug. 4, 2008; U.S. patent application Ser. No. 12/701,395, titled “CONTROL AND COORDINATION OF TRANSCRANIAL MAGNETIC STIMULATION ELECTROMAGNETS FOR MODULATION OF DEEP BRAIN TARGETS”, filed on Feb. 5, 2010; and PCT Application No. PCT/US2010/020324, titled “SHAPED COILS FOR TRANSCRANIAL MAGNETIC STIMULATION”, filed on Jan. 7, 2010.


INCORPORATION BY REFERENCE
All publications, including patents and patent applications, mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.
FIELD OF THE INVENTION
Described herein are systems and methods for treating tissue, such as neuronal tissue and particularly brain tissue using Transcranial Magnetic Stimulation (TMS) to modulate the susceptibility of the target tissue to pharmaceutical and/or radiation treatment.
BACKGROUND OF THE INVENTION
Treatment of disease, pain and medical disorders using drugs and/or ionizing radiation (e.g., pharmacotherapy) may be more effective and may have fewer or less severe side-effects when that available of the drug/radiation treatment to a targeted tissue (for example a tumor or other diseased area of the body) is enhanced and/or where availability of the drug/radiation to non-targeted tissue is minimized. For example, radiation therapy and stereotactic radio surgery may be made more effective and less damaging to non-targeted tissues if targeted tissues such as tumors are radio sensitized prior to treatment, or when surrounding non-targeted tissue are radio protected.
The availability of a pharmaceutical to a given tissue in the body is determined by several factors including the concentration of the drug in the systemic circulation, plasma protein binding, the solubility of the drug within that organ, histological/anatomical barriers, the size of the tissue, and the blood flow or perfusion of that tissue. Specifically, the better perfused a tissue, the more drug is brought to a tissue per unit time. (e.g., Brunto et al, Moskowitz et al).
The sensitivity of a given tissue in the body to the effects of ionizing radiation is determined by several factors including the rate of cellular division, the state of differentiation of the cells, the degree of nourishment to those cells including blood perfusion, and the metabolic rate of that tissue (e.g., Rubin and Casarett). Better-nourished tumors are paradoxically more radiosensitive than those that are marginally nourished, although such tissue may also be better capable of carrying out repair to radiation-injured tissue. Most importantly, the higher the metabolic rate of a tissue, the more radiosensitive it is (Ueno 1971, Kimeldorf et al 1950, Smith et al 1951, Blount et al 1949, Rubin et al 1968).
Magnetic stimulation is a known method by which the perfusion of and the metabolic rate of targeted tissue may be alternatively increased or decreased (Zheng et al, Li et al, George et al, Speer et al).
The methods and systems described herein apply targeted magnetic stimulation to change the perfusion and metabolic rate of tissue, thereby making selected tissue more susceptible to the effects of a drug or ionizing radiation, and for making non-targeted tissue less susceptible to such effects.
References that my help provide context and background include, and may be referred to as indicated above include:
Ueno Y. Individual differences in radio sensitivity of mice correlated with their metabolic rate.
Acta Radiol Ther Phys Biol. 1971 August; 10(4):427-32. No abstract available.
Kimeldorf D J, Jones D C, Fishler M C. The effect of exercise upon the lethality of roentgen rays for rats. Science. 1950 Aug. 11; 112(2902):175-6.
Smith W W, Smith F. Effect of thyroid hormone on radiation lethality. Science. 1949 Jan. 28; 109(2822):83-4. Am J Physiol. 1951 June; 165(3):639-50.
Blount H C Jr, Smith W W. The Influence of Thyroid and Thiouracil on Mice Exposed to Roentgen Radiation. Science. 1949 Jan. 28; 109(2822):83-4.
Rubin P, Casarett G W. Clinical Radiation Pathology (Philadelphia: W B Saunders. 1968
Lemaire M, Pardridge W M, Chaudhuri G. Influence of blood components on the tissue uptake indices of cyclosporin in rats. J Pharmacol Exp Ther. 1988 February; 244(2):740-3.
Bodó A, Bakos E, Szeri F, Váradi A, Sarkadi B. The role of multidrug transporters in drug availability, metabolism and toxicity. Toxicol Lett. 2003 Apr. 11; 140-141:133-43. Review.
Wasan K M, Ramaswamy M, Wong W, Pritchard P H. Lipid transfer protein I facilitated transfer of cyclosporine from low- to high-density lipoproteins is only partially dependent on its cholesteryl ester transfer activity. J Pharmacol Exp Ther. 1998 February; 284(2):599-605.
Brunton L L, Lazo J S, Parker K L. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 11th Edition. 2006 McGraw-Hill Companies Inc.
Moskowitz M, Liao J, Omstead M N, Ron E. Increasing cerebral bioavailability of drugs. U.S. Pat. No. 6,818,669
George M S, Stallings L E, Speer A M, Nahas Z, Spicer K M, Vincent D J, Bohning D E, Cheng K T, Molloy, M, Teneback C C, Risch S C. Prefrontal Repetitive Transcranial Magnetic stiulation (rTMS) Changes Relative Perfusion Locally and Remotely. Human Psychopharmacol Clin Exp. 14, 161-170 (1999)
Speer A M, Kimbrell T A, Wassermann E M, D Repella J, Willis M W, Herscovitch P, Post R M. Opposite effects of high and low frequency rTMS on regional brain activity in depressed patients. Biol Psychiatry. 2000 Dec. 15; 48(12):1133-41.
Li C T, Wang S J, Hirvonen J, Hsieh J C, Bai Y M, Hong C J, Liou Y J, Su T P. Antidepressant mechanism of add-on repetitive transcranial magnetic stimulation in medication-resistant depression using cerebral glucose metabolism. J Affect Disord. 2010 Jul. 1.
Zheng H, Zhang L, Li L, Liu P, Gao J, Liu X, Zou J, Zhang Y, Liu J, Zhang Z, Li Z, Men W. High-frequency rTMS Treatment Increases Left Prefrontal Myo-Inositol in Young Patients with Treatment-Resistant Depression. Prog Neuropsychopharmacol Biol Psychiatry. 2010 Jun. 23.
SUMMARY OF THE INVENTION
Described herein are methods for enhancing or inhibiting (or a combination of both) susceptibility of a tissue (and particularly brain tissue) to pharmacological (drug) and/or radiation treatment by applying magnetic stimulation to up-regulate or down-regulate activity of one or more target tissue regions.
As described herein, magnetic stimulation, including transcranial magnetic stimulation (TMS), is applied used to alter the blood flow and metabolic rate of a portion of the body. In one embodiment, the diseased portion of the body slated for radiation or pharmacotherapy is up-regulated such that blood perfusion and metabolic rate of that tissue are increased thereby sensitizing this area to the effects of radiation and of drugs. In another embodiment, non-diseased portions of the body are down-regulated such that blood perfusion and metabolic rate of that tissue are decreased, thereby helping to protect those portions of the body from the effects of radiation and of drugs. In another embodiment, tissue that has been damaged from the effects of radiation and/or drugs may be up-regulated such that increased blood perfusion and metabolism may help with the cellular and tissue repair process.



BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 illustrates one example of treatment of a target tissue (in this example, brain tissue) using magnetic stimulation to alter the susceptibility of the tissue to treatment by a drug or radiotherapy.



DETAILED DESCRIPTION OF THE INVENTION
Included are systems and methods for modulating the susceptibility of one or more tissue regions to a pharmacological and/or radiation therapy. In general, a target tissue region may be made more susceptible to a pharmacological and/or radiation treatment by up-regulating the region through the application of magnetic energy. Similarly non-target tissue regions may be made less susceptible to a pharmacological and/or radiation therapy by down-regulating the region through the application of magnetic energy. The orientation and/or frequency of applied magnetic energy may result in selectively up-regulating and/or down regulating metabolic activity.
For example, transcranial magnetic stimulation (TMS) is known to modulate metabolic activity in targeted brain regions, which may be visualized using scanning techniques such as PET scans. There is a widespread belief that low-frequency stimulation of target brain regions causes down-regulation (e.g., inhibition) of the target brain regions, while up-regulation may be achieved using high-frequency (e.g., greater than 5 Hz) stimulation. Work in our lab has suggested that the orientation of the applied TMS may also contribute to determine if a region is up-regulated or down-regulated; in particular, preliminary studies suggest methods of achieving low-frequency TMS (e.g., less than 3 Hz) that results in up-regulation of target brain regions, particularly when the TMS coil(s) are oriented so that the induced current or the principle current at the apex of the TMS electromagnet is oriented transversely to the AP axis of a subject's head (e.g., the AP axis of the head, skull, brain, etc.).
In particular, described herein are methods of performing TMS at to up-regulate or down-regulate target regions (e.g., a target brain region) and thereby modulate the sensitivity of the target region to a therapy such as a pharmacological, immunological, or radiation therapy.
As used herein, low-frequency TMS may be used synonymously with slow rate or slow rTMS pulse rates, and may be between about 0.5 Hz to about 3 Hz. This low-frequency or slow rate rTMS pulse rates may be contrasted to traditionally “fast” rTMS pulse rates (e.g., between about 5-50 Hz). Thus, in some variations, low-frequency TMS may be less than about 5 Hz. As mentioned, low-frequency TMS is widely believed to result in inhibition of the target region, while high-frequency TMS is thought to result in up-regulation of the target region.
FIG. 1 illustrates one example of a method and system for modulating the susceptibility of a brain region to a pharmacological, immunological or radiation therapy. In FIG. 1, a target region 110 of a brain 100 is up-regulated with magnetic stimulation to increase the radio sensitivity of the tissue. Non-target regions 111 may be down-regulated by the selective application of TMS. In this example, a magnetic coil 120 is used to apply a magnetic stimulation process 121, immediately before, during or shortly after application of a drug 130 (e.g., using a drug delivery process 131 such as injection, oral, transcutaneous, etc.) and/or radiation treatment using a radiation treatment device 140 and an appropriate radiation delivery process 141. Thus a disorder may be treated by the overlapping application of a treatment modality (e.g., pharmacological treatment) with a magnetic stimulation that modulates the activity.
In some variations, the targeted tissue region is modulated simultaneous with the application of drug/immune agent/radiation, so that the applied magnetic field up- or down-regulates activity of the region resulting in a change in the perfusion rate of the target tissue and therefore either inhibiting or enhancing the susceptibility of the target region.
In another example, non-target brain regions may be made less sensitive to treatment (e.g., drug/radiation treatment) by magnetic stimulation. For example, down regulation of a targeted area by magnetic stimulation may be used to decreases radio-sensitivity of tissue. In some variation a target brain region may be up-regulated to enhance susceptibility to treatment while at the same time adjacent non-target brain regions may be made less sensitive by down-regulation. For example, a plurality of TMS coils may be used at different orientations and frequencies of stimulation to up-regulate some brain regions and to down-regulate others.
In one variation, magnetic stimulation may be used to improve tissue recovery at non-target region. For example, up-regulation of targeted areas by magnetic stimulation may increase blood flow and metabolic rate, thereby speeding healing processes. This may be performed in conjunction with the application of one or more drugs, compounds, therapeutic substances or the like, which may further enhance healing.
In some variations, magnetic stimulation may be applied to body region to increase drug availability at the target regions by increasing blood perfusion of that region, as mentioned above. Up-regulation of targeted area may increase local drug availability, aiding in targeting of the drug uptake and/or effect. Magnetic stimulation of a targeted tissue region may also decrease the availability of the drug at non-target regions by decreasing perfusion in these non-target regions. Down-regulation of non-targeted areas may lower local drug availability.
Although the examples provided herein describe primarily the use of magnetic energy (e.g., magnetic stimulation) to increase or decrease the susceptibility of tissue to a treatment such as drug, immuno-agent or radiation, any appropriate energy modality may be used. In particular, non-contact energy modalities may be used such as microwave, ultrasound, or the like. Further, the target tissue may be any appropriate tissue, and may not be limited to brain tissue or brain regions.
The various embodiments described above are provided by way of illustration only and should not be construed to limit the invention. Based on the above discussion and illustrations, those skilled in the art will readily recognize that various modifications and changes may be made to the present invention without strictly following the exemplary embodiments and applications illustrated and described herein. Such modifications and changes do not depart from the true spirit and scope of the present invention.

## Claims

1. A method of increasing the effect of a drug upon a targeted area of a patient's tissue by transcranial magnetic stimulation (TMS), the method comprising:
delivering a drug that reaches a target tissue via blood vessels to the patient;
steering a TMS electromagnet to deliver a first magnetic field energy to the target tissue, wherein the first magnetic field energy has a low frequency of 5 Hz or less, wherein the TMS electromagnet is oriented so that an induced current in the target tissue or a principle current at an apex of the TMS electromagnet is oriented transversely to an anterior to posterior (AP) axis of the patient's head; and
applying the first magnetic field energy to increase perfusion of the target tissue, so that availability of drug to the target tissue is increased.

2. The method of claim 1, further comprising applying a second magnetic field energy to a non-target tissue to decrease perfusion of the non-target tissue, so that availability of the drug to the non-target tissue is reduced.

3. The method of claim 1, wherein steering the TMS electromagnet further comprises steering a plurality of TMS coils to deliver the first magnetic field energy to the target tissue.

4. The method of claim 1, wherein applying the first magnetic energy further comprises applying the first magnetic energy at a low frequency between 0.5 Hz to 3 Hz.

5. The method of claim 1, wherein the target tissue is a deep brain tissue region.

6. The method of claim 1, wherein applying the first magnetic field energy is performed simultaneously with delivering the drug.

7. A method for increasing the effect of a drug upon a targeted area of a patient's tissue by transcranial magnetic stimulation (TMS), the method comprising:
delivering a drug that reaches a target tissue via blood vessels to the patient;
steering a TMS electromagnet to deliver a first magnetic field energy to the target tissue;
applying the first magnetic field energy to the target tissue to increase perfusion of the target tissue, so that availability of the drug to the target tissues is increased; and
applying a second magnetic field energy to a non-target tissue to decrease perfusion of the non-target tissue, so that availability of the drug to the non-target tissue is reduced,
wherein the first magnetic field energy has a low frequency of 5 Hz or less, wherein the TMS electromagnet is oriented so that an induced current from the TMS electromagnet is oriented transversely to an anterior to posterior (AP) axis of the patient's head.

8. The method of claim 7, wherein steering the TMS electromagnet further comprises steering a plurality of TMS coils to deliver the first magnetic field energy to the target tissue.

9. The method of claim 7, wherein the target tissue is a deep brain tissue region.

10. The method of claim 7, wherein applying the first magnetic field energy is performed simultaneously with delivering the drug.

11. A method of increasing the effect of a drug upon a targeted area of a patient's head by transcranial magnetic stimulation (TMS), the method comprising:
delivering a drug that reaches a target tissue via blood vessels to the patient;
steering a plurality of TMS electromagnets to deliver a first magnetic field energy to the target tissue, wherein the first magnetic field energy has a low frequency of 5 Hz or less, wherein the TMS electromagnet is oriented so that an induced current in the target tissue or a principle current at an apex of at least one of the TMS electromagnets is oriented transversely to an anterior to posterior (AP) axis of the patient's head; and
applying the first magnetic field energy to increase perfusion of the target tissue, so that availability of drug to the target tissue is increased.

12. A method of increasing the effect of a drug upon a targeted area of a patient's tissue by transcranial magnetic stimulation (TMS), the method comprising:
delivering a drug that reaches a target tissue via blood vessels to the patient;
steering a TMS electromagnet to deliver a first magnetic field energy to the target tissue, wherein the first magnetic field energy has a low frequency of 5 Hz or less, wherein the TMS electromagnet is oriented so that a current induced from the TMS electromagnet is oriented transversely to an anterior to posterior (AP) axis of the patient's head; and
applying the first magnetic field energy to increase perfusion of the target tissue, so that availability of drug to the target tissue is increased.

13. The method of claim 12, further comprising applying a second magnetic field energy to a non-target tissue to decrease perfusion of the non-target tissue, so that availability of the drug to the non-target tissue is reduced.

14. The method of claim 12, wherein steering the TMS electromagnet further comprises steering a plurality of TMS coils to deliver the first magnetic field energy to the target tissue.

15. The method of claim 12, wherein applying the first magnetic energy further comprises applying the first magnetic energy at a low frequency between 0.5 Hz to 3 Hz.

16. The method of claim 12, wherein the target tissue is a deep brain tissue region.

17. The method of claim 12, wherein applying the first magnetic field energy is performed simultaneously with delivering the drug.