Microtesla magnetic therapy

Abstract

Methods and apparatuses for treating a patient by manipulating mitochondrial reactive oxygen species (ROS). These methods and apparatuses may be used to treat a variety of therapeutic indications, including, but not limited to, reducing or eliminating inflammation and / or for treating an inflammatory disorder, and / or for treating a disorder by applying a modulated time-varying magnetic field in which one or more pulse parameters, such as burst width and / or burst duration, are modulated during the treatment period within a defined range to cause a significant changes in ROS.

Description

MICROTESLA MAGNETIC THERAPYCLAIM OF PRIORITY

[0001] This application claims priority to U.S. provisional patent application no. 63 / 575,186, titled “TREATMENT OF INFLAMMATION,” filed on April 5, 2024; U.S. patent provisional application no. 63 / 638,407, titled “LOW ENERGY INDUCTIVE FIELD THERAPY TO TREAT INFLAMMATION,” filed on April 24, 2024; and U.S. provisional patent application no. 63 / 719,103, titled “MICROTESLA MAGNETIC THERAPY TO TREAT INFLAMMATION,” filed on November 11, 2024, each of which is herein incorporated by reference in its entirety.BACKGROUND

[0002] Reactive oxygen species (ROS) play vital roles in many cellular signaling pathways under both physiological and pathological conditions. ROS are a series of highly active radicals, irons and molecules that have a single unpaired electron in their outer shell, including free oxygen radicals, such as superoxide anion, hydroxyl radical, and single oxygen, and non-radical ROS, for instance, hydrogen peroxide, organic hydroperoxides, and hypochloric acid. The intracellular ROS levels are dependent on the dynamic balance between ROS generation and elimination. ROS at low levels can act as second messengers and activate signaling cascades in response to gene expression, cell proliferation, apoptosis, and other intracellular pathways. On the other hand, excessive ROS could attack membrane phospholipids, impair mitochondrial function, and damage proteins, lipids, DNA, RNA, and sugar to disrupt normal cellular processes.

[0003] To date, there is no clear understanding of the effect of magnetic fields on ROS levels. Published literature provides conflicting evidence that magnetic fields, e.g., static magnetic fields (SMFs), extremely low frequency electromagnetic fields (ELF-EMFs), and radio frequency electromagnetic radiations (RF-EMRs) may increase ROS levels in multiple types of human, mouse, and rat cells, as well as in various mice and rat tissues. However some reports show no change ROS levels due to such magnetic fields.

[0004] What is needed are methods and apparatuses for robustly and repeatably manipulating ROS, and mitochondrial ROS in particular, in order to treat disorders such as, but not limited to, inflammation, including but not limited to neuroinflammation. The methods and apparatuses described herein may address these needs.SUMMARY OF THE DISCLOSURE

[0005] Described herein are methods and apparatuses for treating a patient by manipulating mitochondrial reactive oxygen species (ROS). These methods and apparatuses may be used to treat a variety of therapeutic indications, including, but not limited to, reducing or eliminating inflammation, and / or for treating a disorder (such as, but not limited to, an inflammatory disorder) by applying a modulated time-varying magnetic field in which one or more pulse parameters, such as burst width and / or burst duration, are modulated during the treatment period within a defined range to cause a significant changes in ROS.

[0006] The methods and apparatuses described herein may be used to mitigate oxidate stress and its associated damage. In addition to treating inflammation (and diseases and disorders associated with inflammation), these method and apparatuses may be used to treat diseases, diabetes, and cancer. For example, these methods and apparatuses may be used to treat diabetic cardiomyopathy to reduce adverse cardiac changes and improve myocardial function. These methods and apparatuses may be used to treat ischemia-reperfusion injury, including to protect against cardiac ischemia-reperfusion injury. These methods and apparatuses may be used to treat atherosclerosis, e.g., by inhibiting proinflammatory cytokine production and, in turn, atherosclerosis. These methods and apparatuses may be used as a cardioprotective therapy. In some cases, these methods and apparatuses may be used to treat diabetes and / or other metabolic disorders: mitochondrial dysfunction and oxidative stress are implicated in metabolic disorders like diabetes, obesity, and stroke. The methods and apparatuses described herein may also or additionally be used to treat cancer.

[0007] In particular, the methods and apparatuses described herein may be used to treat inflammation and inflammatory disorders. For example, these methods and apparatuses may be used to decrease inflammation, either locally and / or systemically. In general, the methods and apparatus described herein are configured to apply a modulated magnetic field to the tissue (or cells) to be treated. The specific modulation of the applied magnetic field, which is described in greater detail below, is surprisingly effective; outside of the parameter ranges described herein, significantly little, or no, effect is seen. The parameter ranges may include both the application of the magnetic field, (e.g., the time-varying modulation of the applied field, which may be determined by controlling the applied energy, including varying of the pulse burst width, and / or the burst repetition rate) as well as the period between the application of the magnetic field (e.g., the off-time, or the period during which a time-varying field is not being applied). The application of the modulated time-varying magnetic field may be applied from one or more applicators locally (e.g., to head, eyes, neck, shoulder, chest, torso, arm, upper arm, elbow, forearm, wrist, hand, groin, leg, upper leg, lower leg, knee,ankle, foot, etc.) or systemically. The application may be performed externally, including non-contact (e.g., at a fixed distance from the body surface) or contact (held against the body surface). In some examples an applicator may be implanted into the body.

[0008] For example, the method and apparatuses described herein may be used to treat a neurological disorder and / or a neuropsychological disorder, including but not limited to: Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington’s disease, spinocerebellar ataxia (SCA), multiple sclerosis (MS), epilepsy, cerebral ischemic- reperfusion, diabetic neuropathy, Long Covid, traumatic brain injury, post-concussion syndrome, chronic Lyme disease, schizophrenia, bipolar disorder, ischemic stroke, hemorrhagic stroke, etc.

[0009] For example, the method and apparatuses described herein may be used to enhance athletic performance and / or to recover from injury (including surgical injury), for physical therapy, etc.

[0010] The time-varying magnetic fields referred to herein may be more specifically referred to as modulated time-varying magnetic fields, in which the time-varying magnetic field is modulated so that the rate of change of the magnetic field is changing. The modulated time-varying magnetic field may be modulated by modulating one or more of: the pulse burst width (e.g., between about 1 msec and 100 msec) and / or the burst repetition rate (e.g., between about 0.1 Hz and about 100 Hz) of the energy applied to generate the magnetic field (e.g., applied to the magnetic field applicator. The applied magnetic field may be between about 0.2 and 0.5 Gauss, and the duty cycle may be about 2% or greater (e.g., 3% or greater, 4% or greater, etc.).

[0011] In any of these methods and apparatuses the application of a treatment (e.g., a dose) may be limited to no more than once per 24 hours or longer (e.g., no more than once per 30 hours, once per 36 hours, etc. including any time between 24 hours and 48 hours).

[0012] The methods and apparatuses described herein may modulate mitochondrial biology, e.g., by modulating the release of ROS. In some cases, these methods and apparatuses are configured to modulate the release of ROS with a controlled range that may maximize the efficacy, e.g., to reduce inflammation, which may be detected by a reduction in pro-inflammatory molecules (e.g., IL-lb and TNFa). Surprisingly the enhanced efficacy and reliably resulting from these treatments are specific to the ranges and parameters described herein, as outside of these ranges the decrease in inflammation is not seen or is greatly diminished and / or highly variable.

[0013] For example, described herein are methods, including methods of treating a subject (e.g., a patient). These methods may include treating inflammation and / or methods oftreating an inflammatory disorder. Also described herein are apparatuses (including systems and devices) for performing any of these methods. For example, descried herein are methods comprising: applying a dose of a modulated time-varying magnetic field to a tissue or cells from an applicator for a duration period, wherein the applicator emits a magnetic field driven by a modulated pulse train comprising a plurality of burst of pulses, wherein the modulated pulse train is modulated by varying one or more pulse parameter; and preventing the application of a subsequent dose to the tissue or cells to greater than 24 hours to decrease the level of, e.g., one or more inflammatory molecules.

[0014] The modulated pulse train may be modulated by varying one or more pulse parameter selected from the group of: pulse burst width and burst repetition rate. For example, the pulse burst width during the treatment period may be increased or decreased by between 1 msec and 100 msec in a stepwise manner during the treatment. In some examples the pulse repetition rate during the treatment period is increased or decreased by between 0.1 Hz and about 100 Hz in a stepwise manner. In some examples varying the pulse burst width during the treatment period comprises increasing or decreasing the pulse burst width by between 5-50 msec every 1-10 minutes of the duration period. In some examples varying the pulse burst width during the treatment period comprises increasing or decreasing the pulse burst width by between 10-50 msec every 3-10 minutes of the duration period. In some examples, the burst repetition rate comprises increasing or decreasing the burst repetition rate by between about 0.1-100 Hz every 1-10 minutes of the duration period. For example, varying the burst repetition rate may comprise increasing or decreasing the burst repetition rate by between about 10-100 Hz every 3-10 minutes of the duration period.

[0015] In any of these apparatuses, the modulated pulse train may be modulated by varying both a pulse burst width and a burst repetition rate during the treatment period. The dose period may be between 1 minute and 60 minutes. For example, the dose period may be between 10 minutes and 30 minutes.

[0016] In any of these methods, preventing the application of the subsequent dose to the tissue or cells may comprise preventing the application of a subsequent dose until after 36 hours of a prior dose.

[0017] Any of these methods may include positioning the applicator against the tissue or cells. These methods and apparatuses may be configured for non-invasive application. In some variations the apparatus may be used as an implant.

[0018] Any appropriate ‘carrier’ train of pulses may be used. For example, the plurality of burst of pulses may have a frequency of greater than 1 MHz (e.g., 5 MHz or greater, 10 MHz or greater, etc.); optionally the frequency may be less than 1GHz (e.g., 1 GHz or less,500 MHz or less, 150 MHz or 100 MHz or less, between 1 MHz and 500 MHz, between 1 MHz and 250 MHz, between 10 MHz and 50 MHz, etc.). The plurality of bursts of pulses may have a frequency of about 27.12 MHz

[0019] In any of these methods, the method may reduce the level of one or more inflammatory molecule by at least 10% (e.g., at least 15% at least 20%, at least 35%, at least 40%, at least 50%, etc.). For example, preventing the application of a subsequent dose to decrease the level of one or more inflammatory molecules may comprise reducing the level of one or both of TNFa and IL lb by at least 10%. Any of these methods may include confirming the decrease in the level of inflammation, including measuring or detecting a decrease in the level of a pro-inflammatory molecule. The decrease in inflammation may be detected by other means as well, including a decrease in swelling, and / or a decrease in in one or more protein markers for inflammation, such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), etc.

[0020] These methods may be methods of treating inflammation or an inflammatory diseases. For example, a method may include: applying a dose of a modulated time-varying magnetic field to a tissue or cells from an applicator for a duration period, wherein the applicator emits a magnetic field driven by a modulated pulse train comprising a plurality of burst of pulses, wherein the modulated pulse train is modulated by one or more of: varying a pulse burst width during the treatment period between 1 msec and 50 msec in a stepwise manner and / or varying a burst repetition rate during the treatment period between 0.1 Hz and about 100 Hz in a stepwise manner; and preventing the application of a subsequent dose to the tissue or cells to greater than 24 hours to decrease the level of one or more inflammatory molecules.

[0021] Varying the pulse burst width during the treatment period may comprise increasing or decreasing the pulse burst width by between 5-40 msec every 1-10 minutes of the duration period. For example, varying the pulse burst width during the treatment period may comprise increasing or decreasing the pulse burst width by between 5-25 msec every 3- 10 minutes of the duration period. Varying the burst repetition rate may comprise increasing or decreasing the burst repetition rate by between about 0.1-100 Hz every 1-10 minutes of the duration period. In some examples varying the burst repetition rate comprises increasing or decreasing the burst repetition rate by between about 10-100 Hz every 3-10 minutes of the duration period. The modulated pulse train may be modulated by varying both the pulse burst width and the burst repetition rate during the treatment period.

[0022] As mentioned, the dose period may be between 1 minute and 60 minutes. The dose period may be between 10 minutes and 30 minutes (e.g., between 10 minutes and 20minutes, etc.). Preventing the application of the subsequent dose to the tissue or cells may comprise preventing the application of a subsequent dose until after about 24 hours (e.g., after about 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 37 hours, 38 hours, 39 hours, 40 hours, 41 hours, 42 hours, 43 hours, 44 hours, 45 hours, 46 hours, 47 hours, 48 hours, etc.).

[0023] The plurality of burst of pulses may have a frequency of greater than 1 MHz (e.g., greater than 2 MHz, 2 MHz, 3 MHz, 4 MHz, 5 MHz, 6 MHz, 7.5 MHz, 10 MHz, 12.5 MHz, 15 MHz, etc., such between about 1MHz and about 100 MHz, between about 5 MHz and 60 MHz, between about 10 MHz and about 50 MHz, etc.). For example, the plurality of bursts of pulses may have a frequency of about 27.12 MHz

[0024] Also described herein are apparatuses for performing any of these methods, including systems and device (e.g., hardware, software and / or firmware). For example, an apparatus may include: one or more magnetic field applicators configured to apply a magnetic field; a signal generator coupled to the one or more magnetic field applicators to apply a dose of a modulated time-varying magnetic field during a treatment period; and a controller comprising one or more processors and control circuity coupled to the signal generator and configured to drive the signal generator to emit a modulated pulse train comprising a plurality of burst of pulses, wherein the modulated pulse train is modulated by automatically varying one or more pulse parameter to decrease the level of one or more inflammatory molecules, further wherein the controller is configured to prevent the application of a subsequent dose within 24 hours of a previous dose.

[0025] The controller may be configured to module the modulated pulse train by varying one or more of: a pulse burst width and / or a burst repetition rate. The controller may be configured to module the modulated pulse train in a stepwise manner during the treatment once every 3-10 minutes. The controller may be configured to modulate the pulse train by increasing or decreasing a pulse burst width during the treatment period by between 1 msec and 100 msec in a stepwise manner during the treatment. The controller may be configured to modulate the time-varying pulse train by increasing or decreasing a burst repetition rate during the treatment period by between 0.1 Hz and about 100 Hz in a stepwise manner. The controller may be configured to modulate the time-varying pulse train by increasing or decreasing a burst width during the treatment period comprises increasing or decreasing the pulse burst width by between 5-50 msec every 1-10 minutes of the duration period. The controller may be configured to modulate the time-varying pulse train by increasing or decreasing a burst width during the treatment period, for example, by increasing or decreasing the pulse burst width by between 10-50 msec every 3-10 minutes of the durationperiod. The controller may be configured to modulate the time-varying pulse train by increasing or decreasing a burst repetition rate by between about 0.1-100 Hz every 1-10 minutes of the duration period. The controller may be configured to modulate the timevarying pulse train by increasing or decreasing a burst repetition rate by between about 10- 100 Hz every 3-10 minutes of the duration period. The controller may be configured to modulate the time-varying pulse train by varying both the pulse burst width in a stepwise manner and the burst repetition rate in a stepwise manner during the treatment period.

[0026] The controller may be configured so that the dose period is set to between about 1 minute and about 60 minutes, e.g., between about 10 minutes and about 20 minutes.

[0027] The controller may be configured to prevent the application of the subsequent dose to the tissue or cells until after greater than 24 hours (e.g., after 30 hours, after 36 hours, etc.) of a prior dose to a particular patient. Any of these apparatuses may be configured so that the plurality of burst of pulses have a frequency (e.g., a carrier frequency) of greater than 1 MHz (e.g., between 1 MHz and 100 MHz, between 10 MHz and 50 MHz, etc.). The plurality of bursts of pulses may have a frequency of about 27.12 MHz

[0028] For example, an apparatus may include: one or more magnetic field applicators configured to apply a magnetic field; a signal generator coupled to the one or more magnetic field applicators to apply a dose of a modulated time-varying magnetic field during a treatment period; and a controller comprising one or more processors and control circuity coupled to the signal generator and configured to drive the signal generator to emit a modulated pulse train comprising a plurality of burst of pulses, wherein the modulated pulse train is modulated by one or more of varying a pulse burst width during the treatment period between 1 msec and 50 msec in a stepwise manner; and / or varying a burst repetition rate during the treatment period between 0.1 Hz and about 100 Hz in a stepwise manner; and wherein the controller is further configured to prevent the application of a subsequent dose to the tissue or cells within 24 hours of a prior dose.

[0029] All of the methods and apparatuses described herein, in any combination, are herein contemplated and can be used to achieve the benefits as described herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0030] A better understanding of the features and advantages of the methods and apparatuses described herein will be obtained by reference to the following detailed description that sets forth illustrative embodiments, and the accompanying drawings of which:

[0031] FIGS. 1A-1B are graphs illustrating the effect of low energy magnetic field stimulation on IL-lb (FIG. 1 A) and TNFa (FIG. IB) using a variety of parameters, including varying burst width, to modulate inhibition of inflammation.

[0032] FIGS. 2A-2B are graphs illustrating the effect of low energy magnetic field stimulation on IL-lb (FIG. 2A) and TNFa (FIG. 2B) using a variety of different parameters, including different burst widths, to modulate inhibition of inflammation.

[0033] FIGS. 3A-3B are graphs illustrating the effect of low energy magnetic field stimulation on IL-lb (FIG. 3 A) and TNFa (FIG. 3B) using a variety of parameters, including varying the repetition rate of the bursts of pulses, to modulate inhibition of inflammation.

[0034] FIG. 4 is a graph illustrating the effect of low energy magnetic field stimulation on IL-lb using a variety of parameters, including increasing burst duration and more frequent changes in the repetition rate.

[0035] FIGS. 5A-5B are graphs illustrating the effect of low energy magnetic field stimulation on IL-lb (FIG. 5 A) and TNFa (FIG. 5B) when repeating the treatment more than once every 24 hours.

[0036] FIGS. 6A-6C are graphs illustrating the effect of low energy magnetic field on microglial cell number, surface area and percent area (FIGS. 6A-6C, respectively) when treatment periods are repeated every 24 hours or every 48 hours.

[0037] FIG. 7 is a graph showing a comparison between sham treated and low energy magnetic field treatment brain lesions and microglia.

[0038] FIGS. 8A-8C illustrate one example of the effect of low energy magnetic field treatment as described herein on mitochondrial ROS from human donor cells one hour post treatment (FIG. 8 A), the effect of low energy magnetic field treatment six hours post treatment on IL-lb gene expression (FIG. 8B), and the effect of low energy magnetic field treatment 24 hours post treatment on IL-lb protein (FIG. 8C).

[0039] FIG. 9 schematically illustrates one example of a possible molecular pathway for the low energy magnetic field treatment described herein, including modulation of mitochondrial ROS.

[0040] FIG. 10 schematically illustrates an example of a noninvasive MMT device that is configured to target inflammatory brain disorders with low energy magnetic field treatment as described herein.

[0041] FIG. 11 is a graph showing that MMT promotes mitochondrial recycling and renewal within 48 hours of treatment.

[0042] FIGS. 12A-12D illustrate the results of a Scenith assay in THP1 cells. FIGS. 12A and 12B show an example image (FIG. 12A) and mask (FIG. 12B) for measuring single cells.FIG. 12C is a graph of the frequency vs. population response analysis. FIG. 12D is a graph summarizing the Scenith results.

[0043] FIG. 13 is a graph illustrating the difference in carrier frequency vs. induced electrical field and SAR (specific absorption rate).

[0044] FIG. 14 illustrates one example of a modulated pulse train comprising a plurality of burst of pulses for a modulated waveform configured to generate a modulated timevarying magnetic field.DETAILED DESCRIPTION

[0045] As will be illustrated in detail herein, the inventors have developed methods and apparatuses to treat a subject based on their surprising finding that varying the rate that energy that is applied by a pulsed magnetic field over time (e.g., during a continuous treatment period), may result in a profound modulation of reactive oxygen species. Surprisingly, this or similar specifically-modulated pulsed magnetic fields may result in a significant and measurable reduction in inflammation, particularly as compared to reductions seen by applying a pulsed magnetic field applied at a constant rate (including time-varying with a constant frequency) and / or by a constant magnetic field. Moreover, this effect appears to be dose-dependent, and applying a second dose again before a defined time period hours (e.g., at 20 hours, 24 hours, 30 hours, 36 hours, etc.) may abolish this effect. This effect is specific to the application of modulated, pulsed, low-energy magnetic fields within a particular range of parameter values, and outside of these particular ranges the reduction either does not occur at all, or is substantially diminished. Furthermore, the method and apparatuses may result in a significantly more reliable (e.g., less variable) reduction in inflammation. The pulsed magnetic field treatments described herein may be referred to as microtesla magnetic therapy (MMT) and the apparatuses configured to deliver this energy may be referred to as MMT applicators. In some cases MMT may be referred to (or may include) as a new and specific type of low energy inductive field therapy (LEIT).

[0046] These methods and apparatuses described herein may modulate the production of inflammatory molecules (e.g., cytokines) in the tissue or cells, such as, but not limited to pro- inflammatory proteins, including but not limited to interleukin 1 beta (H- lb) and Tumor necrosis factor (TNFa). Other pro-inflammatory molecules may include inflammatory cytokines such as IL-6, IL-8, IL-12, IFN-y, IL-18, and IL-la. These effects may be due, at least in part, to a change in the level of reactive oxygen species (ROS), which may modulate inflammation, when applying a time varying magnetic field as described herein. Thus, the methods and apparatuses described herein may significantly decrease the level of pro-inflammatory molecules by the application of low-energy, modulated time-varying magnetic fields.

[0047] In general, the methods and apparatuses described herein vary an applied modulated time-varying magnetic field that is applied to a tissue or cells to reduce inflammation in the tissue / cells. The reduction in inflammation achieved may include be observed as a significant decrease in pro-inflammatory molecules (e.g., Il- lb, TNFa, etc.), which may be assayed directly or indirectly from the tissue / cells. For example, these methods and apparatuses may result in a reduction in pro-inflammatory molecules of greater than 10% (e.g., greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, etc. This reduction may be relative to baseline tissue / cells, and / or relative to an inflammatory response of the tissue / cell, including, but not limited to, relative to the inflammatory response following a challenge to the tissue / cells by an inflammatory agent.

[0048] As used herein, varying the modulated time-varying magnetic field may include varying one, or in some cases more than one, pulse parameter (e.g., pulse width, burst width, pulse frequency, pulse amplitude, etc.). In some examples these method and apparatuses may vary both burst width and pulse frequency during the treatment period. A traditional time- vary magnetic field may be applied at a constant repetition rate (also referred to as burst frequency, e.g., the frequency of pulses and / or bursts of pulses), such as, e.g., 1 Hz, and a constant burst width, e.g., 40 msec, during a treatment period. In contrast, these methods and apparatuses may vary parameters, such as the burst width and the repetition rate, resulting in significantly greater reduction in inflammation as compared with tissue / cells treated by the application of magnetic field energy using a traditional time-varying magnetic field. For example the burst width during a treatment period may be varied between 1 msec and 100 msec (e.g., between about 1 msec and 50 sec, between about 1 msec and about 80 msec, between about 1 msec and about 60 msec, between about 1 msec and about 40 msec, between about 1 msec and about 20 msec, between about 1 msec and 10 msec, between about 1.5 msec and 10 msec, between about 1.5 msec and 8 msec, between about 1.5 msec and 6 msec, etc.) at a repetition rate of between about 2 millihertz and about 20 millihertz (e.g., about every 1 min, every 2 min, every 3 min, every 4 min, every 5 minutes, etc.).

[0049] For example, the apparatus or method may vary the burst width and / or burst repetition rate during a treatment period. A treatment period may be the duration of treatment from the start of the application of the pulsed magnetic field energy to the stop of the application of pulsed magnetic field energy, after which the pulsed magnetic field energy is no longer applied. The treatment period may be from about 5 minutes or longer, e.g., about 6minutes or longer, about 7 minutes or longer, about 8 minutes or longer, about 9 minutes or longer, about 10 minutes or longer, about 12 minutes or longer, about 13 minutes or longer, about 15 minutes or longer, about 17 minutes or longer about 20 minutes or longer, about 25 minutes or longer, about 30 minutes or longer, about 35 minutes or longer about 40 minutes or longer, about 1 hour longer, about 1.5 hours or longer, about 2 hours or longer, about 2.5 hours or longer, about 3 hours or longer, etc., including between about 5 minutes and 4 hours, about 5 minutes and 3 hours, between about 5 minutes and 2 hours, between about 5 minutes and 1 hour, about 5 minutes and 50 minutes, about 5 minutes and 45 minutes, about 5 minutes and 40 minutes, about 5 minutes and 35 minutes, about 5 minutes and 30 minutes, about 5 minutes and 25 minutes, about 5 minutes and 20 minutes, about 5 minutes and 15 minutes, about 5 minutes and, etc. In some cases the treatment period may be between about 10-50 minutes.

[0050] In any of these methods and apparatuses, the burst width may vary during the treatment period. The burst width may be varied in a continuous manner or in a discrete manner. As mentioned, the burst width may be varied between about 1 msec and about 200 msec. In some cases the burst width may be varied between about 10 msec and 200 msec in a stepwise manner, e.g., increasing or decreasing by x msec (where x is about 1 msec, about 2 msec, about 3 msec, about 5 msec, about 10 msec, about 15 msec, about 20 msec, about 25 msec, about 30 msec, about 40 msec, about 50 msec, about 60 msec, about 70 msec, about 80 msec, etc.) every y seconds / minutes during the treatment period (e.g., every 1 second, every 2 seconds, every 5 seconds, every 10 seconds, every 30 seconds, every 1 minute, every 1.5 minutes, every 2 minutes, every 2.5 minutes, every 3 minutes, every 5 minute, etc.). For example, the pulse width may be increased or decreased by between about 5-50 msec every 1-10 minutes.

[0051] In any of these methods and apparatuses, the burst repetition rate (burst frequency) may be varied during the treatment period. The burst repetition rate may be varied in a continuous manner or a discrete manner. For example, the burst repetition rate may be varied between about 0.1 Hz and about 100 Hz. In some cases the burst repetition rate may be varied between 0.1 Hz and about 100 Hz in a stepwise manner, e.g., increasing or decreasing by x Hz (where x is about 1 Hz, about 2 Hz, about 3 Hz, about 4 Hz, about 5 Hz, about 7 Hz, about 10 Hz, about 15 Hz, about 20 Hz, about 25 Hz, about 30 Hz, about 35 Hz, about 40 Hz, about 45 Hz, about 50 Hz, about 55 Hz, about 60 Hz, about 65 Hz, about 70 Hz, about 80 Hz, about 90 Hz, about 100 Hz, etc.) every y seconds / minutes during the treatment period (e.g., every 1 second, every 2 seconds, every 5 seconds, every 10 seconds, every 30 seconds, every 1 minute, every 1.5 minutes, every 2 minutes, every 2.5 minutes, every 3 minutes, every 5minute, etc.). For example, the burst repetition rate may be increased or decreased by between about 0.1-100 Hz every 1-10 minutes.

[0052] In some examples, both the burst width and the burst repetition rate may be varied, either independently of each other or concurrently. For example, the burst width and the burst repetition rate may be independently varied, including changing during the treatment period at different times, and by different amounts / percentages. Alternatively in some cases the burst repetition rate and burst width may be changed during the treatment period at the same time.

[0053] Any of these methods and apparatuses may also limit the application of the dose of energy so that additional doses are not applied more often than every 36 hours. For example, the treatment periods may be limited to being repeated only after a 30-36 hour delay or quiescent period. This is consistent with the theory that the effect is mediated by ROS that may be released at a relatively low, protective level during or after the treatment period in which the time varying magnetic field is varied as descried herein, but additional applied magnetic fields may result in an excess of ROS that cannot be dealt with by the tissue / cells. EXAMPLES Example 1

[0054] In a first example, peripheral blood mononuclear cells were isolated from blood collected from healthy human donors. 500k cells per well were plated in six well plates and stimulated with 100 ng / ml of either LPS or vehicle. Plates were treated with either active electromagnetic fields (EMFs) or sham for 15 minutes and then placed in a culture incubator for 24 hours before supernatants were collected, and inflammatory proteins measured via ELISA.

[0055] The graphs shown in FIGS. 1 A and IB illustrate the results of these experiments. FIG. 1A shows the normalized level of ILlb, while FIG. IB shows the normalized level of TNFa. Treatment with 15 minutes of pulsed magnetic fields, e.g., EMF, with a 40 msec burst width at 1 Hz (“40 msec 1 Hz + LPS”) resulted in a very modest reduction in inflammatory proteins (an approximately 9% decrease in IL-lb, and an approximately 17% decrease TNFa). Varying the burst width from 10 msec to 20 msec to 40 msec every 5 minutes at 1 Hz pulse burst repetition rate / frequency during the treatment period improved the effect (e.g., resulting in a decrease of 30% of IL-lb, and a decrease in 38% of TNFa). Remarkably, using a 2 msec burst and varying the burst repetition rate (frequency) from 10 Hz to 20 Hz to 40 Hz for 5 minutes each yields a large effect (a decrease of 65% in IL-lb, and a decrease of 69% in TNFa).

[0056] As shown in FIGS. 1 A and IB, long bursts (e.g., 40 msec bursts) at 1 Hz reduced inflammation modestly, while changing the burst width multiple times (e.g. at least three times during times during a 15 minute continuous treatment period) nearly doubled the effect, while keeping the burst width constant and varying the repetition rate multiple times during treatment (e.g., at least three time during the 15 minute treatment period) had the greatest anti-inflammatory effect. Thus, varying the waveform parameters during treatment appears to be an important feature for driving anti-inflammatory effects.Example 2

[0057] In a second example size of the burst width used when changing the burst repetition rate was examined. These results, illustrated in FIGS. 2A-2B, suggest that the burst width may preferably be greater than 1.5 msec (e.g., between about 1.5 msec and about 10 msec, between 1.5 msec and 8 msec, between 1.5 msec and 6 msec, between 1.5 msec and 5 msec, between 2 msec and 10 msec, between 2 msec and 8 msec, etc.).

[0058] The graph in FIG. 2 A shows the effect of varying parameters including pulse length and / or burst repetition rate on ILlb. The graph in FIG. 2B shows the effect on TNFa. In Figs. 2A and 2B, 15 minutes of treatment (treatment period) with a 2 msec burst width at 40 Hz had a modest effect (e.g., decrease of 17% in IL-1B, and a decrease of 20% in TNFa). When a short (e.g., 1 msec) burst width of pulses was applied with a varying burst repetition rate, e.g., switching from 10 Hz to 20 Hz to 40 Hz after every five minutes (“10 / 20 / 40”), a modest decrease was seen (e.g., a decrease of 17% in IL-lb, -3% TNFa). In contrast, when the burst width was increased to 2 msec or 4 msec for the 10 / 20 / 40 Hz regime (e.g., changing the burst repetition rate / frequency every five minutes from 10 to 20 to 40 Hz) a much more robust effect was seen. For example, with a 2 msec burst width, a decrease of 31% of IL-lb and 66% of TNFa was seen. With a 4 msec burst width, a decrease of 60% of IL-lb and 43% of TNFa was seen.

[0059] There also does not seem to be a significant benefit to changing the burst repetition rate / frequency more often than every 4-5 minutes, at least at lower burst widths (e.g., 2 msec). For example, changing the repetition rate of a 2 msec burst 5 times, changing the burst repetition rate / frequency every three minutes from 5 Hz to 10 Hz to 20 Hz to 30 Hz to 40Hz (e.g. “5 / 10 / 20 / 30 / 40”), slightly lessened the effect for TNFa. Similarly, increasing the magnitude of the change in burst repetition rate / frequency slightly lessened the effect, e.g., changing the burst repetition rate / frequency of a 2 msec bursts from 20 Hz to 40 Hz to 80 Hz or (20 / 40 / 80) or from 40 Hz to 80 Hz to 160 Hz (“40 / 80 / 160”). Thus, in general, pulsing with a 2 msec burst width at 40 Hz was not as effective as changing the repetition rate 3 times (e.g., every 5 minutes of a 15 minute treatment period) during the treatment. Using a1 msec burst width and varying the repetition rate 3 times (during a 15 minute treatment period) was not as effective as using a 2 msec burst width and also changing the repetition rate three times for a 15 minute treatment period. However, using a burst rate of 2 msec or greater (e.g., 4 msec burst width) and varying the repetition rate 3 times during a 15 minute treatment period appears to have the greatest effect. Making more frequent changes of the repetition rate (changing the repetition rate give times over a 15 minute treatment period instead of changing the repetition rate three times) also slightly lessened the effect on inflammation. Similarly using a 2 msec burst width and varying the repetition rate 3 times at larger magnitudes (20 / 40 / 80 Hz and 40 / 80 / 160 Hz) also slightly lessened the effect compared to (10 / 20 / 40 Hz). Thus, using a burst width of greater than 1.5 msec (e.g., 2 msec, 4 msec, etc.) and changing the repetition rate between about 1 Hz to 80 Hz (e.g., 10 / 20 / 40 Hz) provides an effective pulsing strategy. In some cases, it may be beneficial to set the burst width to greater than 1 msec (e.g., 1.5 msec or greater, 2 msec or greater, etc., between 1.5 msec and 10 msec, between 1.5 msec and 8 msec, between 1.5 msec and 6 msec, between 1.5 msec and 6 msec, etc.).Example 3

[0060] The order of the change in burst repetition rate / frequency of the pulses did not affect the reduction in inflammation. FIGS. 3A-3B illustrate an example comparing the differences in reduction of ILlb and TNFa, respectively, when the repetition rate of the bursts of pulses is changed every five minutes, but to different levels (e.g., between 10, 20 and 40 Hz). FIGS. 3A-3B include a 2 msec or 4 msec burst width for 10 / 20 / 40 Hz repetition rate (five minutes in a 15 min treatment period) both of which were nearly equivalently effective at reducing the IL-lb and TNFa inflammatory markers (2 msec: -30% IL-lb, -59% TNFa; 4 msec: -33% IL-lb, -54% TNFa). Using a 2 msec burst width and varying the order of the change in repetition rate had a modest effect on IL-1 beta levels but was meaningfully less effective at reducing TNFa levels (2 msec 40 / 20 / 10 Hz: -31% ILl-b, -35% TNFa; 2 msec 10 / 40 / 10 Hz; -28% ILl-b, -27% TNFa). Thus, changing the order of the repetition rate changes (40 / 20 / 10 and 10 / 40 / 10) did not meaningfully impact IL-lb levels and had a slight reduction of TNFa. Thus, in some variations, it may be beneficial to use ascending repetition rate changes (e.g., 10 / 20 / 40).Example 4

[0061] In some cases, changing the number of times that the burst repetition rate (e.g., frequency) of the bursts changes may be beneficial. For example, the graph shown in FIG. 4 shows a decrease in inflammation (show by the decreasing level of IL-lb) with increasing burst duration and more frequent changes in the repetition rate. In FIG. 4, a 2 msec burstwidth is used with a 10 / 20 / 40 Hz repetition rate (e.g., five minutes each of 10 Hz then 20 Hz, then 40 Hz) reduced IL- lb by 68%. In the same experiment a 4 msec burst width for a 10 / 20 / 40 Hz repetition rate (e.g., five minutes each of 10, 20 and 40 Hz) reduced IL-lb by 49%. A 2 msec burst width for 10 / 20 / 30 / 40 / 50 Hz repetition rate (e.g., three minutes each of 10, 20, 30, 40 and 50 Hz) also reduced the level of IL-lb by about 50%. This is similar, but slightly more effective than the use of five 3 -minute changes in repetition rate shown in FIG. 2A. Thus, in general, changing the burst width two or more times may be effective for reducing inflammation (and pro-inflammatory molecules). For IL-lb in particular, longer burst width and more frequent changes to the repetition rate during a period of treatment may increase efficacy of treatment.Example 5

[0062] In general, it may be particularly helpful to prevent repeating the treatment (e.g., delivery of a dose as part of a treatment period) from repeating to soon after completing the prior dose.

[0063] FIGS. 5 A and 5B show the effect of a treatment during a 15 minute treatment period in which the burst width is 2 msec and the repetition rate is 10 / 20 / 40 Hz (e.g., five minutes each of 10 Hz, 20 Hz, and 40 Hz) applied twice (2x) in a 24 hour period abolished the anti-inflammatory effect and yielded an increase in ILl-b of 18% and TNFa of 25%.

[0064] As shown FIGS. 5 A and 5B, applying the treatment more frequently than once in24 hours may reverse the beneficial effect observed in a single dose (e.g., singe treatment period).Example 6

[0065] As mentioned, it may be particularly helpful to prevent repeating the treatment (e.g., delivery of a dose as part of a treatment period) from repeating to soon after completing the prior dose. In particular any of these methods and apparatuses may be configured to prevent the application of a second dose (e.g., a second treatment period) until a quiescent period has elapsed. In general, the quiescent period may be between 24 and 48 hours, such as25 hours or longer, 26 hours or longer, 27 hours or longer, 28 hours or longer, 29 hours or longer, 30 hours or longer, 31 hours or longer, 32 hours or longer, 33 hours or longer, 34 hours or longer, 35 hours or longer, 36 hours or longer, etc.).

[0066] In some examples, Sprague-Dawley rats were stereotactically injected with 2 microliters of LPS into the substantia nigra of the brain. They were subsequently restrained, and a coil was positioned around the circumference of the cranium centered over the brain lesion. Animals were then treated with either sham (inert coil) daily, active (low energy inductive therapy, or LEIT / MMT) daily, or active (MMT) every 48 hours for 7 days. MMTspecification was 2 msec burst width applied with a 10 Hz repetition rate for 5 minutes, 20 Hz repetition rate for 5 minutes, and 40 Hz repetition rate for 5 minutes (10 / 20 / 40 Hz), totaling 15 minutes of treatment. After 7 days of treatment, animals were euthanized, and brains work collected for histological evaluation.

[0067] As shown in FIGS. 6A-6C, animals that were treated with MMT (2 msec burst width at 10 / 20 / 40 Hz for 15 min) every 48 hours had less microglial inflammation compared to sham-treated animals. When stimulated daily (every 24 hours) for seven days, treated rat brains showed little difference in (or actually increased) microglial cell number (FIG. 6A), microglial surface area (FIG. 6B) and microglial percent area (FIG. 6C). In contrast, when limiting the application of LIET to every 48 hours, a significant decrease in microglial cell number (FIG. 6A), microglial surface area (FIG. 6B) and microglial percent area (FIG. 6C) was seen.

[0068] This result was apparent in whole brain sections, as shown in FIG. 7, resulting in visibly smaller brain lesions from tissue sections using anti-IBAl stain for microglia indicated. Comparing sham treatment to MMT treatment every 48 hours resulted in significantly less microglial cell infiltration, surface area positive for microglial marker, and percent area positive for microglial marker. MMT treatment every 24 hours was no different from sham treatment.

[0069] Thus, applying one or more MMT treatments to human immune cells every 24 hours abolished the anti-inflammatory effect of the therapy. These rodent data suggest that the optimal treatment dosing for MMT is greater than one treatment every 24 hours (e.g., once every 25 hours or longer, 26 hours or longer, 27 hours or longer, 28 hours or longer, 29 hours or longer, 30 hours or longer, 31 hours or longer, 32 hours or longer, 33 hours or longer, 34 hours or longer, 35 hours or longer, 36 hours or longer, etc.). Thus, any of these methods or apparatuses may include a strict quiescent period (“off period”) of 24 hours or longer (e.g., 25 hours or longer, 26 hours or longer, 27 hours or longer, 28 hours or longer, 29 hours or longer, 30 hours or longer, 31 hours or longer, 32 hours or longer, 33 hours or longer, 34 hours or longer, 35 hours or longer, 36 hours or longer, etc.) before a second treatment period may be applied.Example 7

[0070] The methods and apparatuses also show a dramatic effect on inflammation. FIGS. 8A-8C illustrate data from human donor tissue treated with MMT as described herein, for a single treatment. After 1 hour post-treatment (FIG. 8 A), the application of MMT increased mitochondrial ROS (assayed with MitoPYl MFI) in immune cells from human donors, following an immune challenge (e.g., application of LPS). After 6 hours post-treatment,MMT significantly reduced inflammatory gene expression (e.g., IL-lb mRNA). This resulted in a dramatic decrease in inflammatory protein secretion (e.g., IL-lb) as shown in FIG. 8C.

[0071] Without being bound by any particular theory of operation, these results may be the result of modulation of mitochondrial response for ROS. This is schematically illustrated in FIG.9, illustrating mitohormesis, in which the application of the MMT results in a stressdefense transcription that, at appropriate levels reduces inflammation, reduces cell death and increases the lifespan of the organism. This may help explain the dose sensitivity seen in these results for the first time, in which either too little or too much pulsed electromagnetic (e.g., pulsed magnetic field) energy, as well as the dramatic improvements seen when varying the rate that energy is applied by a pulsed magnetic field over time, e.g., varying the timevarying magnetic field including varying one, or in some cases more than one, pulse parameter such as (but not limited to) the pulse width (e.g., between 1.5 msec or more, e.g., between 1.5 msec and 10 msec), and / or burst frequency.

[0072] In general, the low energy magnetic field (MMT) methods and apparatuses described herein are sufficiently low energy that they are sub-threshold for triggering a neuromuscular contraction response. Thus, they do not trigger contraction of muscle fibers and / or sensory neurons. This may advantageously allow application of therapeutic MMT energy to be applied and specifically modulated as described herein with a high degree of patient tolerance, while retaining efficacy. In addition, the energy applied by the therapy is non-thermal, and does not result in direct ablation or destruction of tissue or cells based on the applied electromagnetic (e.g., magnetic field) energy.

[0073] Surprisingly, the methods and apparatuses described herein may also modulate mitochondrial turnover. This is illustrated in FIG. 11. In this example, human Peripheral blood mononuclear cells (PBMCs) are treated with an MMT apparatus (as described herein) for 15 minutes and then cells are stained with mitotracker, an agent that binds to mitochondria and is used to quantify the number of mitochondria per cell. Stained cells were analyzed via flow cytometry to allow quantification of mitochondrial content on a cell by cell basis.

[0074] At 24 hours we observe a reduction in mitotracker signaling which is consistent with recycling of mitochondria that are damaged or dysfunctional, aka mitophagy. By 48h the treated cells have similar mitochondrial content to control suggesting new healthy mitochondria are created. The methods and apparatuses described herein may therefore modulate turnover (e.g., recycling) of mitochondria in humans. Thus, these methods and apparatuses may promote healing, slowing disease progression, and combating aging.

[0075] In general, any appropriate apparatus may be used to apply the low energy magnetic fields described herein, and may include control circuitry for modulating one or more stimulation parameters (e.g., burst width, burst repetition rate, quiescent period, etc.). For example, an apparatus as described herein may include one or more magnetic field generating devices, which may be coupled or coupled to an energy source (e.g., battery, wall power, etc.), the magnetic field generating device may be optimized to apply the energies described herein. The magnetic field generating device (magnetic field pulse generator) may be controlled by a dedicated controller and / or may be controlled by a separate controller. The apparatus may also include one or more applicators (emitters). For example, the applicator may generally be part of a magnetic treatment device that may be part of an applicator for being held against or near (including adjacent to) the tissue to be treated. An applicator may be configured to include one or more magnetic field delivery components, e.g., coils, which are configured to apply the controlled magnetic fields described herein. In some cases the applicator(s) may be configured to be held against the body of the patient, including against the skin of the body for non-invasive energy application. The applicator(s) may be adapted to apply energy to any or more body part, including the head, face, neck, shoulder, arms, hands, wrists, chest, back, buttocks, stomach, groin, leg, thigh, angle, foot, etc.

[0076] These applicators and the magnetic field generators may be configured to deliver pulsed magnetic fields using a carrier signal, e.g., of between about 1 and 100 MHz. In some cases, the carrier signal frequency may be derived from a 27.12 MHz continuous sine (or square) wave. Any appropriate carrier frequency may be used (e.g., having a puling frequency of greater than 1 MHz, greater than 5 MHz, greater than 10 MHz, greater than 20 MHz, greater than 25 MHz, etc.), such as between 1 MHz and 100 MHz (e.g., between about 5 MHz and 80 MHz, between about 10 MHz and 50 MHz, etc.). The individual pulses may be monopolar or bipolar. The pulses may be transmitted as bursts of carrier pulses having a carrier frequency, and the bursts of pulses may have a burst width of between about 1 msec and about 100 msec (e.g., between about 1.5 msec and 50 msec, between about 1.5 msec and 25 msec, between about 1.5 msec and 12 msec, between about 1.5 and 10 msec, between about 1.5 msec and 8 msec, etc.). In some, non-limiting, examples the pulsed magnetic field generator may delivery pulse burst envelopes of mono- or bi-polar rectangular or sinusoidal pulses. The resulting pulsed magnetic field may induce a peak electric fields between 106and 1 volts per centimeter (V / cm).

[0077] If the carrier frequency is outsider of these ranges (e.g., less than 1 MHz, and / or greater than 100 MHz, the effects of the applied magnetic field may be reduced. In particular, for earner frequencies > 100MHz, die magnetic field may not penetrate as needed.

[0078] Thus, the modulated pulsed magnetic fields described herein may be applied by a pulsed EMF generator and emitter / applicator (e.g. coil, including but not limited to a Helmholtz coli) that is pulsing a train of pulses in bursts having a fixed or varying, and in particular, stepwise varying, burst duration. The individual pulses may be at any appropriate frequency.

[0079] For example, FIG. 10 illustrates one example of an apparatus configured to apply a low energy magnetic field to tissue / cells in which the modulated time-varying magnetic field is modulated by increasing or decreasing the pulse width every 1-10 minutes during a treatment period and / or changing the burst repetition rate by increasing or decreasing the pulse burst rate every 1-10 minutes during the treatment period. The apparatus may be configured to limit the application of the treatment so that there is a quiescent period of at least 24 hours between consecutive treatment periods.

[0080] For example, the controller of the apparatus may be configured to vary the modulated time-varying magnetic field by increasing or decreasing the pulse width by between about 5-50 msec every 1-10 minutes during a treatment period (lasting between 1- 180 minutes or more, e.g., lasting between 1-60 minutes, between 1-45 minutes, between 1- 30 minutes, between 1-20 minutes, between 1-15 minutes, etc.). In some examples the controller of the apparatus may be configured to vary the burst repetition rate by increasing or decreasing the pulse burst rate every 1-10 minutes during the treatment period by between about 0.1-100 Hz (e.g., by about 10 Hz, by about 15 Hz, by about 20 Hz, by about 25 Hz, by about 30 Hz, by about 40 Hz, etc.). In some cases, the burst rate may be limited to between about 0.1 Hz and 500 Hz (e.g., between 1 Hz and 400 Hz, between 2 Hz and 300 Hz, between 5 Hz and 250 Hz, between 10 Hz and 200 Hz, etc.).

[0081] In FIG. 10 the apparatus includes an applicator 1005 integrated into a wearable apparatus (e.g., headset) 1006. The applicator may include one or more coils for delivering a magnetic field. The magnetic field is configured as a headset in this example and may include a frame holding the applicator coils. Any appropriate applicator may be used. The applicator may be integrated into a garment or other wearable apparatus, or it may be configured as a device to be held near or against the body for the treatment duration. In FIG. 10, the apparatus also includes a base 1007 having a housing that may enclose the control circuity, including a magnetic field generator and control circuitry configured to control operation of the apparatus, as described herein. The applicator may be connected to the magnetic field generator by one or more cables or wires, as shown in FIG. 10. In some examples the applicator may be integrated with the base and control circuitry (and / or power source or power control circuitry).

[0082] As described in FIG. 11, the methods and apparatuses described herein may modulate mitochondria directly or through ROS. The modulation may be sensitive to the recovery time from stimulation, e.g., requiring an “off” period before the next significant dose is applied. Similar effects, e.g., showing metabolic adaptations likely due to mitochondrial treatment, were seen using a Scenith assay, which is a flow-cytometry assay that examines metabolic responses in multiple cells / cell types. In this example THP1 cells were used for either treated (MMT) or untreated (control / sham). FIGS. 12A and 12B show an example image and mask for measuring single cells as part of a Scenith assay. The results are shown in FIG. 12D. FIG. 12C shows the results of 4 image analysis. FIG. 12D shows the Scenith assay results. Control / sham treatment showed a clear loss of fluorescence in response to Oligomycin A, indicating Thpl cells are very sensitive to Oxphos inhibition, but not as much to glycolysis inhibition with 2DG. However, 48 hours after MMT treatment, cells are resistant to both glycolysis and mitochondrial inhibitors. Thus, MMT treatment (the application of modulated pulsed / time-varying magnetic fields) resulted in a significant enhancement of mitochondrial activity as compared with control. This effect may result in clinical improvement and outcomes for therapies including treating inflammation or inflammatory disorders, enhancing recover from trauma (including surgical trauma), improving physical therapy, reducing cardiovascular risk, improving exercise recovery, etc. as described above.

[0083] As discussed above, the carrier frequency may be between about 1MHz and 100 MHz, including between about 1 and 75 MHz, or between about 1 and 50MHz. In general, the magnetic (B) field increases linearly with the frequency up to a certain point, but may be constrained by inductive losses and near- field effects. The magnetic field may be stronger at higher frequencies but does not directly induce charge movement like the electric (E) field. In contrast, the electric field may increase quadratically with frequency, meaning that higher frequencies generate significantly stronger electric fields; below about 1 MHz, the induced E- field is relatively weak, while between 10 MHz and 40 MHz, the E-field reaches strong biologically active levels while still maintaining reasonable tissue penetration. Above about 100 MHz, the E-field becomes very strong but is rapidly absorbed in superficial tissues, limiting deep penetration. Thus, in some cases it may be desirable to limit the frequency range to about 10 MHz to 40 MHz. This may balance the electrical field strength, penetration, SAR, and safety and my enable effective electron transport chain (ETC) modulation in mitochondria while avoiding excessive dielectric absorption and tissue heating.

[0084] Frequencies above 50 MHz may see an increase in SAR (see, e.g., FIG. 13), leading to excessive power absorption and tissue heating. Tissue conductivity may risesharply, reducing penetration depth and more energy may be absorbed at the skin and skull, preventing effective deep-brain stimulation. For frequencies below 10 MHz a significantly reduced SAR and less heating may be seen, but there may be weaker E-field induction, which may not provide sufficient charge movement for mitochondrial modulation.

[0085] Any appropriate waveform may be used to drive the applied magnetic field as described herein. As described above, the magnetic field may be delivered as a modulated time-varying magnetic field to a tissue or cells from an applicator for a duration period (dose). The applicator generally emits a magnetic field driven by a modulated pulse train comprising a plurality of bursts of pulses. The modulated pulse train is modulated by one or more of: varying a pulse burst width during the treatment period and / or varying a burst repetition rate during the treatment period. The pulse burst width may be modulated between about 1 msec and 50 msec in a stepwise manner. The burst repetition rate may be modulated between about 0.1 Hz and about 100 Hz in a stepwise manner. The term “stepwise manner” may refer to periodically increasing or decreasing the pulse burst width and / or burst repetition rate from a first rate to a second rate in a period of steps or increments. For example, the first rate may be held for a first period of time, then increased or decreased quickly or instantaneously to second rate for a second period of time, then increased or decreased to a third rate for a third period of time, etc.

[0086] FIG. 14 illustrates one example of a modulated pulse train using a 27.12 MHz carrier wave showing a plurality of bursts that have a first burst repetition rate (e.g., 10 Hz) initially, and after a first time period of 5 min, the burst repetition rate is increased to a second burst repetition rate of 20 Hz for a second time period of 5 minutes, and then the burst repetition rate is again increased to 40 Hz for a third time period, which may be maintained for a third time period (e.g., 5 minutes). In this example the amplitude is approximately 0.3 Gauss (G). The apparatuses and methods described herein may apply between about 0.1 and 0.8 G (e.g., about 0.2 and 0.6 G, about 0.2 and 0.5 G, etc.), having a duty cycle of about 2% or greater (e.g., 3% or greater, 4% or gerater,5% or greater, 6% or greater, 7% or greater, 8% or greater, 9% or greater, 10% or greater, 11% or greater, 15% or greater, 20% or greater, 25% or greater, 30% or greater, etc.).

[0087] All publications and patent applications mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. Furthermore, it should be appreciated that all combinations of the foregoing concepts and additional concepts discussed in greater detail below (provided such conceptsare not mutually inconsistent) are contemplated as being part of the inventive subject matter disclosed herein and may be used to achieve the benefits described herein.

[0088] Any of the methods (including user interfaces) described herein may be implemented as software, hardware or firmware, and may be described as a non-transitory computer-readable storage medium storing a set of instructions capable of being executed by a processor (e.g., computer, tablet, smartphone, etc.), that when executed by the processor causes the processor to control perform any of the steps, including but not limited to: displaying, communicating with the user, analyzing, modifying parameters (including timing, frequency, intensity, etc.), determining, alerting, or the like. For example, any of the methods described herein may be performed, at least in part, by an apparatus including one or more processors having a memory storing a non-transitory computer-readable storage medium storing a set of instructions for the processes(s) of the method.

[0089] While various embodiments have been described and / or illustrated herein in the context of fully functional computing systems, one or more of these example embodiments may be distributed as a program product in a variety of forms, regardless of the particular type of computer-readable media used to actually carry out the distribution. The embodiments disclosed herein may also be implemented using software modules that perform certain tasks. These software modules may include script, batch, or other executable files that may be stored on a computer-readable storage medium or in a computing system. In some embodiments, these software modules may configure a computing system to perform one or more of the example embodiments disclosed herein.

[0090] As described herein, the computing devices and systems described and / or illustrated herein broadly represent any type or form of computing device or system capable of executing computer-readable instructions, such as those contained within the modules described herein. In their most basic configuration, these computing device(s) may each comprise at least one memory device and at least one physical processor.

[0091] The term “memory” or “memory device,” as used herein, generally represents any type or form of volatile or non-volatile storage device or medium capable of storing data and / or computer-readable instructions. In one example, a memory device may store, load, and / or maintain one or more of the modules described herein. Examples of memory devices comprise, without limitation, Random Access Memory (RAM), Read Only Memory (ROM), flash memory, Hard Disk Drives (HDDs), Solid-State Drives (SSDs), optical disk drives, caches, variations or combinations of one or more of the same, or any other suitable storage memory.

[0092] In addition, the term “processor” or “physical processor,” as used herein, generally refers to any type or form of hardware-implemented processing unit capable of interpreting and / or executing computer-readable instructions. In one example, a physical processor may access and / or modify one or more modules stored in the above-described memory device. Examples of physical processors comprise, without limitation, microprocessors, microcontrollers, Central Processing Units (CPUs), Field-Programmable Gate Arrays (FPGAs) that implement softcore processors, Application-Specific Integrated Circuits (ASICs), portions of one or more of the same, variations or combinations of one or more of the same, or any other suitable physical processor.

[0093] Although illustrated as separate elements, the method steps described and / or illustrated herein may represent portions of a single application. In addition, in some embodiments one or more of these steps may represent or correspond to one or more software applications or programs that, when executed by a computing device, may cause the computing device to perform one or more tasks, such as the method step.

[0094] In addition, one or more of the devices described herein may transform data, physical devices, and / or representations of physical devices from one form to another. Additionally or alternatively, one or more of the modules recited herein may transform a processor, volatile memory, non-volatile memory, and / or any other portion of a physical computing device from one form of computing device to another form of computing device by executing on the computing device, storing data on the computing device, and / or otherwise interacting with the computing device.

[0095] The term “computer-readable medium,” as used herein, generally refers to any form of device, carrier, or medium capable of storing or carrying computer-readable instructions. Examples of computer-readable media comprise, without limitation, transmission-type media, such as carrier waves, and non-transitory-type media, such as magnetic-storage media (e.g., hard disk drives, tape drives, and floppy disks), optical-storage media (e.g., Compact Disks (CDs), Digital Video Disks (DVDs), and BLU-RAY disks), electronic-storage media (e.g., solid-state drives and flash media), and other distribution systems.

[0096] A person of ordinary skill in the art will recognize that any process or method disclosed herein can be modified in many ways. The process parameters and sequence of the steps described and / or illustrated herein are given by way of example only and can be varied as desired. For example, while the steps illustrated and / or described herein may be shown or discussed in a particular order, these steps do not necessarily need to be performed in the order illustrated or discussed.

[0097] The various exemplary methods described and / or illustrated herein may also omit one or more of the steps described or illustrated herein or comprise additional steps in addition to those disclosed. Further, a step of any method as disclosed herein can be combined with any one or more steps of any other method as disclosed herein.

[0098] The processor as described herein can be configured to perform one or more steps of any method disclosed herein. Alternatively or in combination, the processor can be configured to combine one or more steps of one or more methods as disclosed herein.

[0099] When a feature or element is herein referred to as being "on" another feature or element, it can be directly on the other feature or element or intervening features and / or elements may also be present. In contrast, when a feature or element is referred to as being "directly on" another feature or element, there are no intervening features or elements present. It will also be understood that, when a feature or element is referred to as being "connected", "attached" or "coupled" to another feature or element, it can be directly connected, attached or coupled to the other feature or element or intervening features or elements may be present. In contrast, when a feature or element is referred to as being "directly connected", "directly attached" or "directly coupled" to another feature or element, there are no intervening features or elements present. Although described or shown with respect to one embodiment, the features and elements so described or shown can apply to other embodiments. It will also be appreciated by those of skill in the art that references to a structure or feature that is disposed "adjacent" another feature may have portions that overlap or underlie the adjacent feature.

[0100] Terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. For example, as used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms "comprises" and / or "comprising," when used in this specification, specify the presence of stated features, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, steps, operations, elements, components, and / or groups thereof. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items and may be abbreviated as " / ".

[0101] Spatially relative terms, such as "under", "below", "lower", "over", "upper" and the like, may be used herein for ease of description to describe one element or feature's relationship to another element(s) or feature(s) as illustrated in the figures. It will be understood that the spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if a device in the figures is inverted, elements described as "under”, or "beneath"other elements or features would then be oriented "over" the other elements or features. Thus, the exemplary term "under" can encompass both an orientation of over and under. The device may be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly. Similarly, the terms "upwardly", "downwardly", "vertical", "horizontal" and the like are used herein for the purpose of explanation only unless specifically indicated otherwise.

[0102] Although the terms “first” and “second” may be used herein to describe various features / elements (including steps), these features / elements should not be limited by these terms, unless the context indicates otherwise. These terms may be used to distinguish one feature / element from another feature / element. Thus, a first feature / element discussed below could be termed a second feature / element, and similarly, a second feature / element discussed below could be termed a first feature / element without departing from the teachings of the present invention.

[0103] In general, any of the apparatuses and methods described herein should be understood to be inclusive, but all or a sub-set of the components and / or steps may alternatively be exclusive and may be expressed as “consisting of’ or alternatively “consisting essentially of’ the various components, steps, sub-components or sub-steps.

[0104] As used herein in the specification and claims, including as used in the examples and unless otherwise expressly specified, all numbers may be read as if prefaced by the word "about" or “approximately,” even if the term does not expressly appear. The phrase “about” or “approximately” may be used when describing magnitude and / or position to indicate that the value and / or position described is within a reasonable expected range of values and / or positions. For example, a numeric value may have a value that is + / - 0.1% of the stated value (or range of values), + / - 1% of the stated value (or range of values), + / - 2% of the stated value (or range of values), + / - 5% of the stated value (or range of values), + / - 10% of the stated value (or range of values), etc. Any numerical values given herein should also be understood to include about or approximately that value, unless the context indicates otherwise. For example, if the value " 10" is disclosed, then "about 10" is also disclosed. Any numerical range recited herein is intended to include all sub-ranges subsumed therein. It is also understood that when a value is disclosed that "less than or equal to" the value, "greater than or equal to the value" and possible ranges between values are also disclosed, as appropriately understood by the skilled artisan. For example, if the value "X" is disclosed the "less than or equal to X" as well as "greater than or equal to X" (e.g., where X is a numerical value) is also disclosed. It is also understood that the throughout the application, data is provided in a number of different formats, and that this data, represents endpoints and starting points, andranges for any combination of the data points. For example, if a particular data point “10” and a particular data point “15” are disclosed, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as well as between 10 and 15. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0105] Although various illustrative embodiments are described above, any of a number of changes may be made to various embodiments without departing from the scope of the invention as described by the claims. Optional features of various device and system embodiments may be included in some embodiments and not in others. Therefore, the foregoing description is provided primarily for exemplary purposes and should not be interpreted to limit the scope of the invention as it is set forth in the claims.

[0106] The examples and illustrations included herein show, by way of illustration and not of limitation, specific embodiments in which the subject matter may be practiced. As mentioned, other embodiments may be utilized and derived there from, such that structural and logical substitutions and changes may be made without departing from the scope of this disclosure. Such embodiments of the inventive subject matter may be referred to herein individually or collectively by the term “invention” merely for convenience and without intending to voluntarily limit the scope of this application to any single invention or inventive concept, if more than one is, in fact, disclosed. Thus, although specific embodiments have been illustrated and described herein, any arrangement calculated to achieve the same purpose may be substituted for the specific embodiments shown. This disclosure is intended to cover any and all adaptations or variations of various embodiments. Combinations of the above embodiments, and other embodiments not specifically described herein, will be apparent to those of skill in the art upon reviewing the above description.

Claims

CLAIMSWhat is claimed is:

1. An apparatus, the apparatus comprising: one or more magnetic field applicators configured to apply a magnetic field; a signal generator coupled to the one or more magnetic field applicators to apply a dose of a modulated time-varying magnetic field during a treatment period; and a controller comprising one or more processors and control circuity coupled to the signal generator and configured to drive the signal generator to emit a modulated pulse train comprising a plurality of burst of pulses, wherein the modulated pulse train is modulated by one or more of: varying a pulse burst width during the treatment period between 1 msec and 100 msec in a stepwise manner; and / or varying a burst repetition rate during the treatment period between 0.1 Hz and about 100 Hz in a stepwise manner.

2. The apparatus of claim 1, wherein the one or more magnetic field applicators are configured to apply the magnetic field outside of a patient’s body.

3. The apparatus of claim 1, wherein the controller is further configured to prevent the application of a subsequent dose to the same patient within 24 hours of a prior dose.

4. The apparatus of claim 1, wherein the controller is configured to vary both the burst width and burst repetition rate during the treatment period.

5. The apparatus of claim 1, wherein the controller is configured to module the modulated pulse train in a stepwise manner during the treatment once every 3-10 minutes.

6. The apparatus of claim 1, wherein the controller is configured to module the modulated pulse train by increasing or decreasing a pulse burst width during the treatment period by between 1 msec and 50 msec in a stepwise manner during the treatment.

7. The apparatus of claim 1, wherein the controller is configured to modulate the modulated pulse train by increasing or decreasing a burst width during the treatmentperiod comprises increasing or decreasing the pulse burst width by between 5-50 msec every 1-10 minutes of the duration period.

8. The apparatus of claim 1, wherein the controller is configured to modulate the modulated pulse train by increasing or decreasing a burst width during the treatment period comprises increasing or decreasing the pulse burst width by between 10-50 msec every 3-10 minutes of the duration period.

9. The apparatus of claim 1, wherein the controller is configured to modulate the modulated pulse train by increasing or decreasing a burst repetition rate by between about 0.1-100 Hz every 1-10 minutes of the duration period.

10. The apparatus of claim 1, wherein the controller is configured to modulate the modulated pulse train by increasing or decreasing a burst repetition rate by between about 10-100 Hz every 3-10 minutes of the duration period.

11. The apparatus of claim 1, wherein the dose period is between 1 minute and 60 minutes.

12. The apparatus of claim 1, wherein the dose period is between 10 minutes and 20 minutes.

13. The apparatus of claim 1, wherein the controller is configured to prevent the application of the subsequent dose to the tissue or cells until after 36 hours of a prior dose.

14. The apparatus of claim 1, wherein the plurality of burst of pulses have a frequency of between than 1 MHz and 50 MHz.

15. The apparatus of any of claims 1-14, wherein the plurality of bursts of pulses have a frequency of about 27.12 MHz.

16. An apparatus, the apparatus comprising: one or more magnetic field applicators configured to apply a magnetic field; a signal generator coupled to the one or more magnetic field applicators to apply a dose of a modulated time-varying magnetic field during a treatment period; anda controller comprising one or more processors and control circuity coupled to the signal generator and configured to drive the signal generator to emit a modulated pulse train comprising a plurality of burst of pulses, wherein the modulated pulse train is modulated by automatically varying one or more pulse parameter to decrease the level of one or more inflammatory molecules.

17. The apparatus of claim 16, wherein the controller is configured to prevent the application of a subsequent dose to the same patient within 24 hours of a previous dose.

18. The apparatus of any of claims 16-17, wherein the controller is configured to module the modulated pulse train by varying one or more of a pulse burst width and / or a burst repetition rate.

19. The apparatus of any of claims 16-18, wherein the controller is configured to module the modulated pulse train in a stepwise manner during the treatment once every 3-10 minutes.

20. The apparatus of any of claims 16-19, wherein the controller is configured to module the modulated pulse train by increasing or decreasing a pulse burst width during the treatment period by between 1 msec and 100 msec in a stepwise manner during the treatment.

21. The apparatus any of claims 16-20, wherein the controller is configured to module the modulated pulse train by increasing or decreasing a burst repetition rate during the treatment period by between 0.1 Hz and about 100 Hz in a stepwise manner.

22. The apparatus of any of claims 16-21, wherein the controller is configured to modulate the modulated pulse train by increasing or decreasing a burst width during the treatment period comprises increasing or decreasing the pulse burst width by between 5-50 msec every 1-10 minutes of the duration period.

23. The apparatus of any of claims 16-22, wherein the controller is configured to modulate the modulated pulse train by increasing or decreasing a burst width during the treatment period comprises increasing or decreasing the pulse burst width by between 10-50 msec every 3-10 minutes of the duration period.

24. The apparatus of claim 23, wherein the controller is configured to modulate the modulated pulse train by increasing or decreasing a burst repetition rate by between about 0.1-100 Hz every 1-10 minutes of the duration period.

25. The apparatus of claim 16, wherein the controller is configured to modulate the modulated pulse train by increasing or decreasing a burst repetition rate by between about 10-100 Hz every 3-10 minutes of the duration period.

26. The apparatus of claim 16, wherein the controller is configured to modulate the pulse train by varying both the pulse burst width in a stepwise manner and the burst repetition rate in a stepwise manner during the treatment period.

27. The apparatus of any of claims 16-26, wherein the dose period is between 1 minute and 60 minutes.

28. The apparatus of any of claims 16-27, wherein the dose period is between 10 minutes and 20 minutes.

29. The apparatus of any of claims 16-28, wherein the controller is configured to prevent the application of the subsequent dose to the tissue or cells until after 36 hours of a prior dose.

30. The apparatus of any of claims 16-29, wherein the plurality of burst of pulses have a frequency of between 1 MHz and 1 GHz.

31. The apparatus of any of claims 16-30, wherein the plurality of bursts of pulses have a frequency of about 27.12 MHz.

32. A method, the method comprising: applying a dose of a modulated time-varying magnetic field to a tissue or cells from an applicator for a duration period, wherein the applicator emits a magnetic field driven by a modulated pulse train comprising a plurality of bursts of pulses, wherein the modulated pulse train is modulated by one or more of: varying a pulse burst width during the treatment period between 1 msec and 50 msec in a stepwise manner; and / or varying a burst repetition rate during the treatment period between 0.1 Hz and about 100 Hz in a stepwise manner; andpreventing the application of a subsequent dose to the tissue or cells to greater than 24 hours to decrease the level of one or more inflammatory molecules.

33. The method of claim 32, wherein varying the pulse burst width during the treatment period comprises increasing or decreasing the pulse burst width by between 5-40 msec every 1-10 minutes of the duration period.

34. The method of claim 32, wherein varying the pulse burst width during the treatment period comprises increasing or decreasing the pulse burst width by between 5-25 msec every 3-10 minutes of the duration period.

35. The method of claim 32, wherein varying the burst repetition rate comprises increasing or decreasing the burst repetition rate by between about 0.1-100 Hz every 1-10 minutes of the duration period.

36. The method of claim 32, wherein varying the burst repetition rate comprises increasing or decreasing the burst repetition rate by between about 10-100 Hz every 3-10 minutes of the duration period.

37. The method of claim 32, the modulated pulse train is modulated by varying both the pulse burst width and the burst repetition rate during the treatment period.

38. The method of claim 32, wherein the dose period is between 1 minute and 60 minutes.

39. The method of claim 32, wherein the dose period is between 10 minutes and 30 minutes.

40. The method of claim 32, wherein preventing the application of the subsequent dose to the tissue or cells comprises preventing the application of a subsequent dose until after 36 hours.

41. The method of claim 32, further comprising positioning the applicator against the tissue or cells.

42. The method of claim 32, wherein the plurality of burst of pulses have a frequency of greater than 1 MHz.

43. The method of claim 32, wherein the plurality of bursts of pulses have a frequency of about 27.12 MHz.

44. The method of claim 32, wherein preventing the application of a subsequent dose to decrease the level of one or more inflammatory molecules comprises reducing the level of one or both of TNFa and IL lb by at least 10%.

45. A method, the method comprising: applying a dose of a modulated time-varying magnetic field to a tissue or cells from an applicator for a duration period, wherein the applicator emits a magnetic field driven by a modulated pulse train comprising a plurality of burst of pulses, wherein the modulated pulse train is modulated by varying one or more pulse parameter.

46. The method of claim 45, further comprising preventing the application of a subsequent dose to the tissue or cells to greater than 24 hours to decrease the level of one or more inflammatory molecules.

47. The method of any of claims 45-46, wherein the modulated pulse train is modulated by varying one or more pulse parameter selected from the group of: pulse burst width and burst repetition rate.

48. The method of claim 47, wherein the pulse burst width during the treatment period is increased or decreased by between 1 msec and 100 msec in a stepwise manner during the treatment.

49. The method of claim 47, wherein the pulse repetition rate during the treatment period is increased or decreased by between 0.1 Hz and about 100 Hz in a stepwise manner.

50. The method of claim 47, wherein varying the pulse burst width during the treatment period comprises increasing or decreasing the pulse burst width by between 5-50 msec every 1-10 minutes of the duration period.

51. The method of claim 47, wherein varying the pulse burst width during the treatment period comprises increasing or decreasing the pulse burst width by between 10-50 msec every 3-10 minutes of the duration period.

52. The method of claim 47, wherein varying the burst repetition rate comprises increasing or decreasing the burst repetition rate by between about 0.1-100 Hz every 1-10 minutes of the duration period.

53. The method of claim 47, wherein varying the burst repetition rate comprises increasing or decreasing the burst repetition rate by between about 10-100 Hz every 3-10 minutes of the duration period.

54. The method of any of claims 45-53, wherein the modulated pulse train is modulated by varying both a pulse burst width and a burst repetition rate during the treatment period.

55. The method of any of claims 45-54, wherein the dose period is between 45 minute and 60 minutes.

56. The method of any of claims 45-55, wherein the dose period is between 450 minutes and 30 minutes.

57. The method of any of claims 45-56, wherein preventing the application of the subsequent dose to the tissue or cells comprises preventing the application of a subsequent dose until after 36 hours.

58. The method of any of claims 45-57, further comprising positioning the applicator against the tissue or cells.

59. The method of any of claims 45-58, wherein the plurality of burst of pulses have a frequency of greater than 45 MHz.

60. The method of any of claims 45-59, wherein the plurality of bursts of pulses have a frequency of about 27.452 MHz.

61. The method of any of claims 45-60, wherein preventing the application of a subsequent dose to decrease the level of one or more inflammatory molecules comprises reducing the level of one or both of TNFa and ILlb by at least 10%.

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