US20100210893A1

US20100210893A1 - Apparatus and method for electromagnetic treatment of plant, animal, and human tissue, organs, cells, and molecules

Info

Publication number: US20100210893A1
Application number: US12/771,954
Authority: US
Inventors: Arthur A. Pilla
Original assignee: IVIVI TECHNOLOGIES Inc; IVIVI TECHNOLOGIES LLC; Ivivi Health Sciences LLC
Current assignee: IVIVI TECHNOLOGIES Inc; IVIVI TECHNOLOGIES LLC; Rio Grande Neurosciences Inc
Priority date: 2003-12-05
Filing date: 2010-04-30
Publication date: 2010-08-19
Also published as: BRPI0417129A; CA2548270A1; US20050197522A1; WO2005056111A2; NZ548283A; JP2007524476A; US20170266458A1; IL176126A0; US20140046117A1; US20140046115A1; AU2004296198A1; WO2005056111A3; EP1694409A2; US7744524B2; US20100222631A1

Abstract

An apparatus and method for electromagnetic treatment of plants, animals, and humans comprising: configuring at least one waveform according to a mathematical model having at least one waveform parameter, said at least one waveform to be coupled to a target pathway structure; choosing a value of said at least one waveform parameter so that said at least waveform is configured to be detectable in said target pathway structure above background activity in said target pathway structure; generating an electromagnetic signal from said configured at least one waveform; and coupling said electromagnetic signal to said target pathway structure using a coupling device.

Description

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No. 11/003,108, filed Dec. 3, 2004 entitled “APPARATUS AND METHOD FOR ELECTROMAGNETIC TREATMENT OF PLANT, ANIMAL, AND HUMAN TISSUE, ORGANS, CELLS, AND MOLECULES which claims the benefit under 35 U.S.C. §119 of U.S. Provisional Patent Application No. 60/527,327, filed Dec. 5, 2003, titled “APPARATUS AND METHOD FOR ELECTROMAGNETIC TREATMENT OF PLANT, ANIMAL, AND HUMAN TISSUE, ORGANS, CELLS AND MOLECULES”.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention
This invention pertains generally to an apparatus and a method for in vitro and in vivo therapeutic and prophylactic treatment of plant, animal, and human tissue, organs, cells and molecules. In particular, an embodiment according to the present invention pertains to use of non-thermal time-varying magnetic fields configured for optimal coupling to target pathway structures such as molecules, cells, tissue, and organs, using power and amplitude comparison analysis to evaluate a signal to thermal noise ratio (“SNR”) in the target pathway structure. Another embodiment according to the present invention pertains to application of bursts of arbitrary waveform electromagnetic signals to target pathway structures such as molecules, cells, tissues, and organs using ultra lightweight portable coupling devices such as inductors and electrodes, and driver circuitry that can be incorporated into a positioning device such as knee, elbow, lower back, shoulder, foot, and other anatomical wraps, as well as apparel such as garments, footware, and fashion accessories.
Yet another embodiment according to the present invention pertains to application of steady state periodic signals of arbitrary waveform electromagnetic signals to target pathway structures such as molecules, cells, tissues, and organs. Examples of therapeutic and prophylactic applications of the present invention are musculoskeletal pain relief, edema reduction, increased local blood flow, microvascular blood perfusion, wound repair, bone repair, osteoporosis treatment and prevention, angiogenesis, neovascularization, enhanced immune response, tissue repair, enhanced transudation, and enhanced effectiveness of pharmacological agents. An embodiment according to the present invention can also be used in conjunction with other therapeutic and prophylactic procedures and modalities such as heat, cold, ultrasound, vacuum assisted wound closure, wound dressing, orthopedic fixation devices, and surgical interventions.
2. Discussion of Related Art
It is now well established that application of weak non-thermal electromagnetic fields (“EMF”) can result in physiologically meaningful in vivo and in vitro bioeffects. Time-varying electromagnetic fields, comprising rectangular waveforms such as pulsing electromagnetic fields (“PEMF”), and sinusoidal waveforms such as pulsed radio frequency fields (“PRF”) ranging from several Hertz to an about 15 to an about 40 MHz range, are clinically beneficial when used as an adjunctive therapy for a variety of musculoskeletal injuries and conditions.
Beginning in the 1960′s, development of modern therapeutic and prophylactic devices was stimulated by clinical problems associated with non-union and delayed union bone fractures. Early work showed that an electrical pathway can be a means through which bone adaptively responds to mechanical input. Early therapeutic devices used implanted and semi-invasive electrodes delivering direct current (“DC”) to a fracture site. Non-invasive technologies were subsequently developed using electrical and electromagnetic fields. These modalities were originally created to provide a non-invasive “no-touch” means of inducing an electrical/mechanical waveform at a cell/tissue level. Clinical applications of these technologies in orthopaedics have led to approved applications by regulatory bodies worldwide for treatment of fractures such as non-unions and fresh fractures, as well as spine fusion. Presently several EMF devices constitute the standard armamentarium of orthopaedic clinical practice for treatment of difficult to heal fractures. The success rate for these devices has been very high. The database for this indication is large enough to enable its recommended use as a safe, non-surgical, non-invasive alternative to a first bone graft. Additional clinical indications for these technologies have been reported in double blind studies for treatment of avascular necrosis, tendinitis, osteoarthritis, wound repair, blood circulation and pain from arthritis as well as other musculoskeletal injuries.
Cellular studies have addressed effects of weak low frequency electromagnetic fields on both signal transduction pathways and growth factor synthesis. It can be shown that EMF stimulates secretion of growth factors after a short, trigger-like duration. Ion/ligand binding processes at a cell membrane are generally considered an initial EMF target pathway structure. The clinical relevance to treatments for example of bone repair, is upregulation such as modulation, of growth factor production as part of normal molecular regulation of bone repair. Cellular level studies have shown effects on calcium ion transport, cell proliferation, Insulin Growth Factor (“IGF-II”) release, and IGF-II receptor expression in osteoblasts. Effects on Insulin Growth Factor-I (“IGF-I”) and IGF-II have also been demonstrated in rat fracture callus. Stimulation of transforming growth factor beta (“TGF-β”) messenger RNA (“mRNA”) with PEMF in a bone induction model in a rat has been shown. Studies have also demonstrated upregulation of TGF-β mRNA by PEMF in human osteoblast-like cell line designated MG-63, wherein there were increases in TGF-β1, collagen, and osteocalcin synthesis. PEMF stimulated an increase in TGF-β1 in both hypertrophic and atrophic cells from human non-union tissue. Further studies demonstrated an increase in both TGF-β1 mRNA and protein in osteoblast cultures resulting from a direct effect of EMF on a calcium/calmodulin-dependent pathway. Cartilage cell studies have shown similar increases in TGF-β1 mRNA and protein synthesis from EMF, demonstrating a therapeutic application to joint repair. U.S. Pat. No. 4,315,503 (1982) to Ryaby and U.S. Pat. No. 5,723,001 (1998) to Pilla typify the research conducted in this field.
However, prior art in this field applies unnecessarily high amplitude and power to a target pathway structure, requires unnecessarily long treatment time, and is not portable.
Therefore, a need exists for an apparatus and a method that more effectively modulates biochemical processes that regulate tissue growth and repair, shortens treatment times, and incorporates miniaturized circuitry and light weight applicators thus allowing the apparatus to be portable and if desired disposable. A further need exists for an apparatus and method that more effectively modulates biochemical processes that regulate tissue growth and repair, shortens treatment times, and incorporates miniaturized circuitry and light weight applicators that can be constructed to be implantable.

SUMMARY OF THE INVENTION

An apparatus and a method for delivering electromagnetic signals to human, animal and plant target pathway structures such as molecules, cells, tissue and organs for therapeutic and prophylactic purposes. A preferred embodiment according to the present invention utilizes a Power Signal to Noise Ratio (“Power SNR”) approach to configure bioeffective waveforms and incorporates miniaturized circuitry and lightweight flexible coils. This advantageously allows a device that utilizes a Power SNR approach, miniaturized circuitry, and lightweight flexible coils, to be completely portable and if desired to be constructed as disposable and if further desired to be constructed as implantable.
Specifically, broad spectral density bursts of electromagnetic waveforms, configured to achieve maximum signal power within a bandpass of a biological target, are selectively applied to target pathway structures such as living organs, tissues, cells and molecules. Waveforms are selected using a unique amplitude/power comparison with that of thermal noise in a target pathway structure. Signals comprise bursts of at least one of sinusoidal, rectangular, chaotic and random wave shapes, have frequency content in a range of about 0.01 Hz to about 100 MHz at about 1 to about 100,000 bursts per second, and have a burst repetition rate from about 0.01 to about 1000 bursts/second. Peak signal amplitude at a target pathway structure such as tissue, lies in a range of about 1 μV/cm to about 100 mV/cm. Each signal burst envelope may be a random function providing a means to accommodate different electromagnetic characteristics of healing tissue. A preferred embodiment according to the present comprises a 20 millisecond pulse burst comprising about 5 to about 20 microsecond symmetrical or asymmetrical pulses repeating at about 1 to about 100 kilohertz within the burst. The burst envelope is a modified 1/f function and is applied at random repetition rates. A resulting waveform can be delivered via inductive or capacitive coupling.
It is an object of the present invention to configure a power spectrum of a waveform by mathematical simulation by using signal to noise ratio (“SNR”) analysis to configure an optimized, bioeffective waveform then coupling the configured waveform using a generating device such as ultra lightweight wire coils that are powered by a waveform configuration device such as miniaturized electronic circuitry.
It is another object of the present invention to evaluate Power SNR for any target pathway structure such as molecules, cells, tissues and organs of plants, animals and humans using any input waveform, even if the electrical equivalents are non-linear as in a Hodgkin-Huxley membrane model.
It is another object of the present invention to provide a method and apparatus for treating plants, animals and humans using electromagnetic fields selected by optimizing a power spectrum of a waveform to be applied to a chosen biochemical target pathway structure such as a molecule, cell, tissue and organ of a plant, animal, and human.
It is another object of the present invention to employ significantly lower peak amplitudes and shorter pulse duration. This can be accomplished by matching via Power SNR, a frequency range in a signal to frequency response and sensitivity of a target pathway structure such as a molecule, cell, tissue, and organ, of plants, animals and humans.
The above and yet other objects and advantages of the present invention will become apparent from the hereinafter set forth Brief Description of the Drawings, Detailed Description of the Invention, and Claims appended herewith.

BRIEF DESCRIPTION OF THE DRAWINGS

Preferred embodiments of the present invention will be described below in more detail, with reference to the accompanying drawings:

FIG. 1 is a flow diagram of a method for electromagnetic treatment of plant, animal, and human target pathway structures such as tissue, organs, cells, and molecules according to an embodiment of the present invention;

FIG. 2 is a view of control circuitry and electrical coils applied to a knee joint according to a preferred embodiment of the present invention;

FIG. 3 is a block diagram of miniaturized circuitry according to a preferred embodiment of the present invention;

FIG. 4A is a line drawing of a wire coil such as an inductor according to a preferred embodiment of the present invention;

FIG. 4B is a line drawing of a flexible magnetic wire according to a preferred embodiment of the present invention;

FIG. 5 depicts a waveform delivered to a target pathway structure such as a molecule, cell, tissue or organ according to a preferred embodiment of the present invention;

FIG. 6 is a view of a positioning device such as a wrist support according to a preferred embodiment of the present invention;

FIG. 7 is a graph illustrating maximally increased myosin phosphorylation for a PMRF signal configured according to an embodiment of the present invention; and

FIG. 8 is a graph illustrating a power consumption comparison between a 60 Hz signal and a PEMF signal configured according to an embodiment of the present invention.

DETAILED DESCRIPTION

Induced time-varying currents from PEMF or PRF devices flow in a target pathway structure such as a molecule, cell, tissue, and organ, and it is these currents that are a stimulus to which cells and tissues can react in a physiologically meaningful manner. The electrical properties of a target pathway structure affect levels and distributions of induced current. Molecules, cells, tissue, and organs are all in an induced current pathway such as cells in a gap junction contact. Ion or ligand interactions at binding sites on macromolecules that may reside on a membrane surface are voltage dependent processes, that is electrochemical, that can respond to an induced electromagnetic field (“E”). Induced current arrives at these sites via a surrounding ionic medium. The presence of cells in a current pathway causes an induced current (“J”) to decay more rapidly with time (“J(t)”). This is due to an added electrical impedance of cells from membrane capacitance and time constants of binding and other voltage sensitive membrane processes such as membrane transport.
Equivalent electrical circuit models representing various membrane and charged interface configurations have been derived. For example, in Calcium (“Ca²⁺”) binding, the change in concentration of bound Ca²⁺ at a binding site due to induced E may be described in a frequency domain by an impedance expression such as:
$Z_{b} (ω) = R_{ion} + \frac{1}{{ωC}_{ion}}$
which has the form of a series resistance-capacitance electrical equivalent circuit. Where ω is angular frequency defined as 2πf, where f is frequency, i=−1^1/2, Z_b(ω) is the binding impedance, and R_ionand C_ionare equivalent binding resistance and capacitance of an ion binding pathway. The value of the equivalent binding time constant, τ_ion=R_ionC_ion, is related to a ion binding rate constant, k_b, via τ_ion=R_ionC_ion=1/k_b. Thus, the characteristic time constant of this pathway is determined by ion binding kinetics.
Induced E from a PEMF or PRF signal can cause current to flow into an ion binding pathway and affect the number of Ca²⁻ ions bound per unit time. An electrical equivalent of this is a change in voltage across the equivalent binding capacitance C_ion, which is a direct measure of the change in electrical charge stored by C_ion. Electrical charge is directly proportional to a surface concentration of Ca²⁺ ions in the binding site, that is storage of charge is equivalent to storage of ions or other charged species on cell surfaces and junctions. Electrical impedance measurements, as well as direct kinetic analyses of binding rate constants, provide values for time constants necessary for configuration of a PMF waveform to match a bandpass of target pathway structures. This allows for a required range of frequencies for any given induced E waveform for optimal coupling to target impedance, such as bandpass.
Ion binding to regulatory molecules is a frequent EMF target, for example Ca²⁻ binding to calmodulin (“CaM”). Use of this pathway is based upon acceleration of wound repair, for example bone repair, that involves modulation of growth factors released in various stages of repair. Growth factors such as platelet derived growth factor (“PDGF”), fibroblast growth factor (“FGF”), and epidermal growth factor (“EGF”) are all involved at an appropriate stage of healing. Angiogenesis is also integral to wound repair and modulated by PMF. All of these factors are Ca/CaM-dependent.
Utilizing a Ca/CaM pathway a waveform can be configured for which induced power is sufficiently above background thermal noise power. Under correct physiological conditions, this waveform can have a physiologically significant bioeffect.
Application of a Power SNR model to Ca/CaM requires knowledge of electrical equivalents of Ca²⁺ binding kinetics at CaM. Within first order binding kinetics, changes in concentration of bound Ca²⁺ at CaM binding sites over time may be characterized in a frequency domain by an equivalent binding time constant, τ_ion=R_ionC_ion, where R_ionand C_ionare equivalent binding resistance and capacitance of the ion binding pathway. τ_ionis related to a ion binding rate constant, k_b, via τ_ion=R_ionC_ion=1/k_b. Published values for k_bcan then be employed in a cell array model to evaluate SNR by comparing voltage induced by a PRF signal to thermal fluctuations in voltage at a CaM binding site. Employing numerical values for PMF response, such as V_max=6.5×10⁻⁷sec⁻¹, [Ca²⁺]=2.5 μM, K_D=30 μM, [Ca²⁺CaM]=K_D([Ca²⁺]+[CaM]), yields k_b=665 sec⁻¹(τ_ion=1.5 msec). Such a value for τ_ioncan be employed in an electrical equivalent circuit for ion binding while power SNR analysis can be performed for any waveform structure.
According to an embodiment of the present invention a mathematical model can be configured to assimilate that thermal noise is present in all voltage dependent processes and represents a minimum threshold requirement to establish adequate SNR. Power spectral density, S_n(ω), of thermal noise can be expressed as:
S _n(ω)=4kT Re[Z _M(x, ω)]
where Z_M(x, ω) is electrical impedance of a target pathway structure, x is a dimension of a target pathway structure and Re denotes a real part of impedance of a target pathway structure. Z_M(x, ω) can be expressed as:
$Z_{M} (x, ω) = [\frac{R_{e} + R_{i} + R_{g}}{y}] \tanh (yx)$
This equation clearly shows that electrical impedance of the target pathway structure, and contributions from extracellular fluid resistance (“R_e”), intracellular fluid resistance (“R_i”) and intermembrane resistance (“R_g”) which are electrically connected to a target pathway structure, all contribute to noise filtering.
A typical approach to evaluation of SNR uses a single value of a root mean square (RMS) noise voltage. This is calculated by taking a square root of an integration of S_n(ω)=4kT Re [Z_M(x, ω)] over all frequencies relevant to either complete membrane response, or to bandwidth of a target pathway structure. SNR can be expressed by a ratio:
$S N R = \frac{\langle V_{M} (ω) \rangle}{R M S}$
where |V_M(ω)| is maximum amplitude of voltage at each frequency as delivered by a chosen waveform to the target pathway structure.
Referring to FIG. 1, wherein FIG. 1 is a flow diagram of a method for delivering electromagnetic signals to target pathway structures such as molecules, cells, tissue and organs of plants, animals, and humans for therapeutic and prophylactic purposes according to an embodiment of the present invention. A mathematical model having at least one waveform parameter is applied to configure at least one waveform to be coupled to a target pathway structure such as a molecule, cell, tissue, and organ (Step 101). The configured waveform satisfies a SNR or Power SNR model so that for a given and known target pathway structure it is possible to choose at least one waveform parameter so that a waveform is detectable in the target pathway structure above its background activity (Step 102) such as baseline thermal fluctuations in voltage and electrical impedance at a target pathway structure that depend upon a state of a cell and tissue, that is whether the state is at least one of resting, growing, replacing, and responding to injury. A preferred embodiment of a generated electromagnetic signal is comprised of a burst of arbitrary waveforms having at least one waveform parameter that includes a plurality of frequency components ranging from about 0.01 Hz to about 100 MHz wherein the plurality of frequency components satisfies a Power SNR model (Step 102). A repetitive electromagnetic signal can be generated for example inductively or capacitively, from said configured at least one waveform (Step 103). The electromagnetic signal is coupled to a target pathway structure such as a molecule, cell, tissue, and organ by output of a coupling device such as an electrode or an inductor, placed in close proximity to the target pathway structure (Step 104). The coupling enhances a stimulus to which cells and tissues react in a physiologically meaningful manner.
FIG. 2 illustrates a preferred embodiment of an apparatus according to the present invention. A miniature control circuit 201 is coupled to an end of at least one connector 202 such as wire. The opposite end of the at least one connector is coupled to a generating device such as a pair of electrical coils 203. The miniature control circuit 201 is constructed in a manner that applies a mathematical model that is used to configure waveforms. The configured waveforms have to satisfy a SNR or Power SNR model so that for a given and known target pathway structure, it is possible to choose waveform parameters that satisfy SNR or Power SNR so that a waveform is detectable in the target pathway structure above its background activity. A preferred embodiment according to the present invention applies a mathematical model to induce a time-varying magnetic field and a time-varying electric field in a target pathway structure such as a molecule, cell, tissue, and organ, comprising about 10 to about 100 msec bursts of about 1 to about 100 microsecond rectangular pulses repeating at about 0.1 to about 10 pulses per second. Peak amplitude of the induced electric field is between about 1 uV/cm and about 100 mV/cm, varied according to a modified 1/f function where f=frequency. A waveform configured using a preferred embodiment according to the present invention may be applied to a target pathway structure such as a molecule, cell, tissue, and organ for a preferred total exposure time of under 1 minute to 240 minutes daily. However other exposure times can be used. Waveforms configured by the miniature control circuit 201 are directed to a generating device 203 such as electrical coils via connector 202. The generating device 203 delivers a pulsing magnetic field configured according to a mathematical model, that can be used to provide treatment to a target pathway structure such as knee joint 204. The miniature control circuit applies a pulsing magnetic field for a prescribed time and can automatically repeat applying the pulsing magnetic field for as many applications as are needed in a given time period, for example 10 times a day. A preferred embodiment according to the present invention can be positioned to treat the knee joint 204 by a positioning device. The positioning device can be portable such as an anatomical support, and is further described below with reference to FIG. 6. Coupling a pulsing magnetic field to a target pathway structure such as a molecule, cell, tissue, and organ, therapeutically and prophylactically reduces inflammation thereby reducing pain and promotes healing. When electrical coils are used as the generating device 203, the electrical coils can be powered with a time varying magnetic field that induces a time varying electric field in a target pathway structure according to Faraday's law. An electromagnetic signal generated by the generating device 203 can also be applied using electrochemical coupling, wherein electrodes are in direct contact with skin or another outer electrically conductive boundary of a target pathway structure. Yet in another embodiment according to the present invention, the electromagnetic signal generated by the generating device 203 can also be applied using electrostatic coupling wherein an air gap exists between a generating device 203 such as an electrode and a target pathway structure such as a molecule, cell, tissue, and organ. An advantage of the preferred embodiment according to the present invention is that its ultra lightweight coils and miniaturized circuitry allow for use with common physical therapy treatment modalities and at any body location for which pain relief and healing is desired. An advantageous result of application of the preferred embodiment according to the present invention is that a living organism's wellbeing can be maintained and enhanced.
FIG. 3 depicts a block diagram of a preferred embodiment according to the present invention of a miniature control circuit 300. The miniature control circuit 300 produces waveforms that drive a generating device such as wire coils described above in FIG. 2. The miniature control circuit can be activated by any activation means such as an on/off switch. The miniature control circuit 300 has a power source such as a lithium battery 301. A preferred embodiment of the power source has an output voltage of 3.3 V but other voltages can be used. In another embodiment according to the present invention the power source can be an external power source such as an electric current outlet such as an AC/DC outlet, coupled to the present invention for example by a plug and wire. A switching power supply 302 controls voltage to a micro-controller 303. A preferred embodiment of the micro-controller 303 uses an 8 bit 4 MHz micro-controller 303 but other bit MHz combination micro-controllers may be used. The switching power supply 302 also delivers current to storage capacitors 304. A preferred embodiment of the present invention uses storage capacitors having a 220 uF output but other outputs can be used. The storage capacitors 304 allow high frequency pulses to be delivered to a coupling device such as inductors (Not Shown). The micro-controller 303 also controls a pulse shaper 305 and a pulse phase timing control 306. The pulse shaper 305 and pulse phase timing control 306 determine pulse shape, burst width, burst envelope shape, and burst repetition rate. An integral waveform generator, such as a sine wave or arbitrary number generator can also be incorporated to provide specific waveforms. A voltage level conversion sub-circuit 308 controls an induced field delivered to a target pathway structure. A switching Hexfet 308 allows pulses of randomized amplitude to be delivered to output 309 that routes a waveform to at least one coupling device such as an inductor. The micro-controller 303 can also control total exposure time of a single treatment of a target pathway structure such as a molecule, cell, tissue, and organ. The miniature control circuit 300 can be constructed to apply a pulsing magnetic field for a prescribed time and to automatically repeat applying the pulsing magnetic field for as many applications as are needed in a given time period, for example 10 times a day. A preferred embodiment according to the present invention uses treatments times of about 10 minutes to about 30 minutes.
Referring to FIGS. 4A and 4B a preferred embodiment according to the present invention of a coupling device 400 such as an inductor is shown. The coupling device 400 can be an electric coil 401 wound with multistrand flexible magnetic wire 402. The multistrand flexible magnetic wire 402 enables the electric coil 401 to conform to specific anatomical configurations such as a limb or joint of a human or animal. A preferred embodiment of the electric coil 401 comprises about 10 to about 50 turns of about 0.01 mm to about 0.1 mm diameter multistrand magnet wire wound on an initially circular form having an outer diameter between about 2.5 cm and about 50 cm but other numbers of turns and wire diameters can be used. A preferred embodiment of the electric coil 401 can be encased with a non-toxic PVC mould 403 but other non-toxic moulds can also be used.
Referring to FIG. 5 an embodiment according to the present invention of a waveform 500 is illustrated. A pulse 501 is repeated within a burst 502 that has a finite duration 503. The duration 503 is such that a duty cycle which can be defined as a ratio of burst duration to signal period is between about 1 to about 10⁻⁵. A preferred embodiment according to the present invention utilizes pseudo rectangular 10 microsecond pulses for pulse 501 applied in a burst 502 for about 10 to about 50 msec having a modified 1/f amplitude envelope 504 and with a finite duration 503 corresponding to a burst period of between about 0.1 and about 10 seconds.
FIG. 6 illustrates a preferred embodiment according to the present invention of a positioning device such as a wrist support. A positioning device 600 such as a wrist support 601 is worn on a human wrist 602. The positioning device can be constructed to be portable, can be constructed to be disposable, and can be constructed to be implantable. The positioning device can be used in combination with the present invention in a plurality of ways, for example incorporating the present invention into the positioning device for example by stitching, affixing the present invention onto the positioning device for example by Velcro®, and holding the present invention in place by constructing the positioning device to be elastic.
In another embodiment according to the present invention, the present invention can be constructed as a stand-alone device of any size with or without a positioning device, to be used anywhere for example at home, at a clinic, at a treatment center, and outdoors. The wrist support 601 can be made with any anatomical and support material, such as neoprene. Coils 603 are integrated into the wrist support 601 such that a signal configured according to the present invention, for example the waveform depicted in FIG. 5, is applied from a dorsal portion that is the top of the wrist to a plantar portion that is the bottom of the wrist. Micro-circuitry 604 is attached to the exterior of the wrist support 601 using a fastening device such as Velcro® (Not Shown). The micro-circuitry is coupled to one end of at least one connecting device such as a flexible wire 605. The other end of the at least one connecting device is coupled to the coils 603. Other embodiments according to the present invention of the positioning device include knee, elbow, lower back, shoulder, other anatomical wraps, and apparel such as garments, fashion accessories, and footware.

Example 1

The Power SNR approach for PMF signal configuration has been tested experimentally on calcium dependent myosin phosphorylation in a standard enzyme assay. The cell-free reaction mixture was chosen for phosphorylation rate to be linear in time for several minutes, and for sub-saturation Ca²⁻ concentration. This opens the biological window for Ca²⁺/CaM to be EMF-sensitive. This system is not responsive to PMF at levels utilized in this study if Ca²⁺ is at saturation levels with respect to CaM, and reaction is not slowed to a minute time range. Experiments were performed using myosin light chain (“MLC”) and myosin light chain kinase (“MLCK”) isolated from turkey gizzard. A reaction mixture consisted of a basic solution containing 40 mM Hepes buffer, pH 7.0; 0.5 mM magnesium acetate; 1 mg/ml bovine serum albumin, 0.1% (w/v) Tween 80; and 1 mM EGTAl2. Free Ca²⁺ was varied in the 1-7 μM range. Once Ca²⁺ buffering was established, freshly prepared 70 nM CaM, 160 nM MLC and 2 nM MLCK were added to the basic solution to form a final reaction mixture. The low MLC/MLCK ratio allowed linear time behavior in the minute time range. This provided reproducible enzyme activities and minimized pipetting time errors.
The reaction mixture was freshly prepared daily for each series of experiments and was aliquoted in 100 μL portions into 1.5 ml Eppendorf tubes. All Eppendorf tubes containing reaction mixture were kept at 0° C. then transferred to a specially designed water bath maintained at 37±0.1° C. by constant perfusion of water prewarmed by passage through a Fisher Scientific model 900 heat exchanger. Temperature was monitored with a thermistor probe such as a Cole-Parmer model 8110-20, immersed in one Eppendorf tube during all experiments. Reaction was initiated with 2.5 μM 32P ATP, and was stopped with Laemmli Sample Buffer solution containing 30 μM EDTA. A minimum of five blank samples were counted in each experiment. Blanks comprised a total assay mixture minus one of the active components Ca²⁺, CaM, MLC or MLCK. Experiments for which blank counts were higher than 300 cpm were rejected. Phosphorylation was allowed to proceed for 5 min and was evaluated by counting 32P incorporated in MLC using a TM Analytic model 5303 Mark V liquid scintillation counter.
The signal comprised repetitive bursts of a high frequency waveform. Amplitude was maintained constant at 0.2 G and repetition rate was 1 burst/sec for all exposures. Burst duration varied from 65 μsec to 1000 μsec based upon projections of Power SNR analysis which showed that optimal Power SNR would be achieved as burst duration approached 500 μsec. The results are shown in FIG. 7 wherein burst width 701 in μsec is plotted on the x-axis and Myosin Phosphorylation 702 as treated/sham is plotted on the y-axis. It can be seen that the PMF effect on Ca²⁺ binding to CaM approaches its maximum at approximately 500 μsec, just as illustrated by the Power SNR model.
These results confirm that a PMF signal, configured according to an embodiment of the present invention, would maximally increase myosin phosphorylation for burst durations sufficient to achieve optimal Power SNR for a given magnetic field amplitude.

Example 2

According to an embodiment of the present invention use of a Power SNR model was further verified in an in vivo wound repair model. A rat wound model has been well characterized both biomechanically and biochemically, and was used in this study. Healthy, young adult male Sprague Dawley rats weighing more than 300 grams were utilized.
The animals were anesthetized with an intraperitoneal dose of Ketamine 75 mg/kg and Medetomidine 0.5 mg/kg. After adequate anesthesia had been achieved, the dorsum was shaved, prepped with a dilute betadine/alcohol solution, and draped using sterile technique. Using a #10 scalpel, an 8-cm linear incision was performed through the skin down to the fascia on the dorsum of each rat. The wound edges were bluntly dissected to break any remaining dermal fibers, leaving an open wound approximately 4 cm in diameter. Hemostasis was obtained with applied pressure to avoid any damage to the skin edges. The skin edges were then closed with a 4-0 Ethilon running suture. Post-operatively, the animals received Buprenorphine 0.1-0.5 mg/kg, intraperitoneal. They were placed in individual cages and received food and water ad libitum.
PMF exposure comprised two pulsed radio frequency waveforms. The first was a standard clinical PRF signal comprising a 65 μsec burst of 27.12 MHz sinusoidal waves at 1 Gauss amplitude and repeating at 600 bursts/sec. The second was a PRF signal reconfigured according to an embodiment of the present invention. For this signal burst duration was increased to 2000 μsec and the amplitude and repetition rate were reduced to 0.2 G and 5 bursts/sec respectively. PRF was applied for 30 minutes twice daily.
Tensile strength was performed immediately after wound excision. Two 1 cm width strips of skin were transected perpendicular to the scar from each sample and used to measure the tensile strength in kg/mm². The strips were excised from the same area in each rat to assure consistency of measurement. The strips were then mounted on a tensiometer. The strips were loaded at 10 mm/min and the maximum force generated before the wound pulled apart was recorded. The final tensile strength for comparison was determined by taking the average of the maximum load in kilograms per mm²of the two strips from the same wound.
The results showed average tensile strength for the 65 μsec 1 Gauss PRF signal was 19.3±4.3 kg/mm²for the exposed group versus 13.0±3.5 kg/mm²for the control group (p<0.01), which is a 48% increase. In contrast, the average tensile strength for the 2000 μsec 0.2 Gauss PRF signal, configured according to an embodiment of the present invention using a Power SNR model was 21.2±5.6 kg/mm²for the treated group versus 13.7±4.1 kg/mm²(p<0.01) for the control group, which is a 54% increase. The results for the two signals were not significantly different from each other.
These results demonstrate that an embodiment of the present invention allowed a new PRF signal to be configured that could be produced with significantly lower power. The PRF signal configured according to an embodiment of the present invention, accelerated wound repair in the rat model in a low power manner versus that for a clinical PRF signal which accelerated wound repair but required more than two orders of magnitude more power to produce.

Example 3

In this example Jurkat cells react to PMF stimulation of a T-cell receptor with cell cycle arrest and thus behave like normal T-lymphocytes stimulated by antigens at the T-cell receptor such as anti-CD3. For example in bone healing, results have shown both 60 Hz and PEMF fields decrease DNA synthesis of Jurkat cells, as is expected since PMF interacts with the T-cell receptor in the absence of a costimulatory signal. This is consistent with an anti-inflammatory response, as has been observed in clinical applications of PMF stimuli. The PEMF signal is more effective. A dosimetry analysis performed according to an embodiment of the present invention demonstrates why both signals are effective and why PEMF signals have a greater effect than 60 Hz signals on Jurkat cells in the most EMF-sensitive growth stage.
Comparison of dosimetry from the two signals employed involves evaluation of the ratio of the Power spectrum of the thermal noise voltage that is Power SNR, to that of the induced voltage at the EMF-sensitive target pathway structure. The target pathway structure used is ion binding at receptor sites on Jurkat cells suspended in 2 mm of culture medium. The average peak electric field at the binding site from a PEMF signal comprising 5 msec burst of 200 μsec pulses repeating at 15/sec, was 1 mV/cm, while for a 60 Hz signal it was 50 μV/cm.
FIG. 8 is a graph of results wherein Induced Field Frequency 801 in Hz is plotted on the x-axis and Power SNR 802 is plotted on the y-axis. FIG. 8 illustrates that both signals have sufficient Power spectrum that is Power SNR≈1, to be detected within a frequency range of binding kinetics. However, maximum Power SNR for the PEMF signal is significantly higher than that for the 60 Hz signal. This is because a PEMF signal has many frequency components falling within the bandpass of the binding pathway. The single frequency component of a 60 Hz signal lies at the mid-point of the bandpass of the target pathway. The Power SNR calculation that was used in this example is dependant upon τ_ionwhich is obtained from the rate constant for ion binding. Had this calculation been performed a priori it would have concluded that both signals satisfied basic detectability requirements and could modulate an EMF-sensitive ion binding pathway at the start of a regulatory cascade for DNA synthesis in these cells. The previous examples illustrated that utilizing the rate constant for Ca/CaM binding could lead to successful projections for bioeffective EMF signals in a variety of systems.
Having described embodiments for an apparatus and a method for delivering electromagnetic treatment to human, animal and plant molecules, cells, tissue and organs, it is noted that modifications and variations can be made by persons skilled in the art in light of the above teachings. It is therefore to be understood that changes may be made in the particular embodiments of the invention disclosed which are within the scope and spirit of the invention as defined by the appended claims.

Claims

1. An electromagnetic treatment device for treating plant, animal or human tissue by modulating the kinetics of a target pathway for therapeutic and prophylactic purposes, the device configured to maximize the frequency distribution within the bandpass of the target pathway, the device comprising:

an applicator; and

a control circuit configured to provide an electromagnetic signal to the applicator to induce an electric field of peak amplitude between about 1 μV/cm and about 100 mV/cm in the target tissue and a peak induced magnetic field between about 1 μT and about 0.1 T, wherein the signal generated by the control circuit comprises a burst of waveforms having a burst duration of greater than 65 μsec and a burst repetition rate of about 0.01 to about 1000 bursts per second;

wherein the signal is detectable in a target pathway structure in the target tissue above background electrical activity in the target pathway structure.

2. The device of claim 1, wherein the electromagnetic signal has been configured according to a mathematical model.

3. The device of claim 1, wherein the electromagnetic signal has been configured according to a mathematical model which incorporates a SNR or PSNR analysis with respect to the target pathway.

4. The device of claim 1, wherein the electromagnetic treatment device is lightweight.

5. The device of claim 1, wherein the electromagnetic treatment device is disposable.

6. The device of claim 1, wherein the lightweight electromagnetic treatment device is configured to be worn.

7. The device of claim 1, wherein the applicator comprises a coil applicator.

8. The device of claim 1, wherein the applicator comprises a lightweight coil applicator.

9. The device of claim 1, wherein the applicator comprises a disposable coil applicator

10. The device of claim 1, wherein the applicator comprises a wire loop configured to conform to the anatomical site of the target tissue.

11. The device of claim 1, wherein the coil applicator comprises at least one inductive coil applicator.

12. The device of claim 1, wherein the applicator comprises at least one capacitively coupled electrode.

13. The device of claim 1, wherein the applicator comprises at least one electrochemically coupled electrode.

14. The device of claim 1, wherein the applicator is implantable.

15. The device of claim 1, wherein the entire device is implantable.

16. The device of claim 1, wherein the control circuit is a miniaturized circuit.

17. The device of claim 1, wherein the signal generated by the control circuit comprises a burst of arbitrary waveforms.

18. The device of claim 1, wherein the burst duration of the waveforms generated by the control circuit have a burst duration greater than about 0.5 msec.

19. The device of claim 1, wherein the control circuit is configured to provide an electromagnetic signal to the applicator to induce an electric field of peak amplitude between about 1 μV/cm and about 100 mV/cm in the target tissue and a peak induced magnetic field between about 1 μT and about 20 μT.

20. The device of claim 1, wherein the burst of waveforms generated by the control circuit repeat at a frequency of less than 100 MHz and have a duty cycle less than 1.

21. The device of claim 1, wherein the waveforms generated by the control circuit are selected from the group of wave shapes consisting of: sinusoidal, square, chaotic, random, symmetrical, asymmetrical, half- or full-wave rectified.

22. The device of claim 1, wherein the waveforms generated by the control circuit have a frequency of approximately 27.12 MHz.

23. The device of claim 1, further comprising an anatomical support configured to hold the treatment device adjacent to the target tissue.

24. The device of claim 1, further wherein the control circuit is configured so that the signal generated by the control circuit comprises at least one frequency component that falls within the bandpass of the kinetics of ion binding at a molecular target, the frequency component having sufficient amplitude so that the induced electric field is detectable above background electrical activity in the ion binding pathway in the target tissue.

25. The device of claim 1, further wherein the control circuit is configured so that the signal generated by the control circuit comprises at least one frequency component that falls within the bandpass of the kinetics of ion transport at a living cell boundary, the frequency component having sufficient amplitude so that the induced electric field is detectable above background electrical activity in the ion transport pathway in the target tissue.

26. The device of claim 1, further wherein the control circuit is configured so that the signal generated by the control circuit comprises at least one frequency component that falls within the bandpass of the kinetics of Ca binding to CaM having sufficient amplitude so that the induced electric field is detectable above background electrical activity in the Ca/CaM pathway in the target tissue.

27. A method for electromagnetic treatment of plants, animals, and humans for modulating a target pathway structure for therapeutic and prophylactic purposes, the method comprising:

activating an electromagnetic treatment device to treat a target tissue of the plant, animal or human; and

inducing an electric field waveform at the target tissue having frequency components of the induced electric field that fall within the bandpass of the kinetics of the target pathway structure, further wherein the electric field has sufficient amplitude so that the induced electric field is above background electrical activity in the target pathway in the target tissue.

28. The method of claim 27 further comprising configuring the induced electric field using a mathematical model which incorporates a SNR or PSNR analysis so that at least one frequency component of the induced electric field falls within the bandpass of the kinetics of the target pathway.

29. The method of claim 27, wherein the target pathway comprises the Ca/CaM pathway in the target tissue.

30. The method of claim 27, wherein the induced electric field has an amplitude of between about 1 μV/cm to about 100 mV/cm in the target pathway structure, and further wherein the induced electric field comprises a burst of waveforms having a burst duration of greater than 0.065 msec and a burst repetition rate.

31. The method of claim 27, wherein the induced electric field has an amplitude of between about 1 μV/cm to about 100 mV/cm in the target pathway structure, and further wherein the induced electric field comprises a burst of waveforms having a burst duration of greater than about 0.5 msec.

32. The method of claim 27, wherein the induced electric field has an amplitude of between about 1 μV/cm to about 100 mV/cm in the target pathway structure, and further wherein the induced electric field comprises a burst of waveforms having a burst duration of about 2 msec.

33. The method of claim 27, wherein the step of activating comprises applying a burst of waveforms repeating at a frequency of less than 100 MHz and having a duty cycle less than 1.

34. The method of claim 27, wherein the waveforms are selected from the group of wave shapes consisting of: sinusoidal, square, chaotic, random, symmetrical, asymmetrical, half- or full-wave rectified.

35. The method of claim 27, wherein the waveforms have a frequency of approximately 27.12 MHz.

36. The method of claim 27, wherein the electromagnetic treatment device is a lightweight, wearable treatment device.

37. The method of claim 27, wherein the electromagnetic treatment device comprises:

an applicator; and

a control circuit configured to provide a signal to the applicator to induce an electric field of amplitude less than 100 mV/cm in a specified target pathway in the target tissue, wherein the control circuit generates a burst of waveforms having a burst duration of greater than 0.5 msec and a burst repetition rate.

38. The method of claim 37, wherein the control circuit is a miniaturized circuit.

39. The method of claim 37, wherein the applicator comprises at least one coil.

40. The method of claim 27, wherein the applicator comprises at least one electrode.

41. The method of claim 27, wherein the applicator is implantable

42. The method of claim 27, wherein the step of activating an electromagnetic treatment device comprises applying pulsating electrical current to a lightweight coil.

43. An electromagnetic treatment device for modulating the binding of calcium to calmodulin in a target tissue by inducing an electric field having at least one frequency that falls within the bandpass of the kinetics of the binding of calcium to calmodulin to maximize signal frequency distribution within the bandpass of the Ca/CaM pathway, the device comprising:

an applicator; and

a control circuit configured to provide an electromagnetic signal to the applicator to induce a peak electric field of amplitude of less than about 100 mV/cm at the target tissue and a peak induced magnetic field between about 1 μT and about 0.1 T, wherein the signal generated by the control circuit comprises a burst of waveforms having a burst duration of greater than 65 μsec and a burst repetition rate of about 0.01 to about 1000 bursts per second;

whereby the signal is detectable above background electrical activity in the Ca/CaM pathway in the target tissue.

44. The device of claim 37, wherein the electromagnetic signal provided by the control circuit has been configured according to a mathematical model.

45. The device of claim 37, wherein the electromagnetic signal provided by the control circuit has been configured according to a mathematical model which incorporates a SNR or PSNR analysis with respect to the target pathway.

46. The device of claim 37, wherein the applicator comprises a coil applicator.

47. The device of claim 37, wherein the applicator comprises a disposable coil applicator

48. The device of claim 37, wherein the applicator comprises a lightweight coil applicator.

49. The device of claim 37, wherein the applicator comprises a wire loop configured to conform to the anatomical site of the target tissue.

50. The device of claim 37, wherein the device is configured for treatment of an animal, and the coil applicator is configured for use with the animal.

51. The device of claim 37, wherein the applicator comprises at least one inductive coil applicator.

52. The device of claim 37, wherein the applicator comprises at least one capacitively coupled electrode.

53. The device of claim 37, wherein the control circuit is a miniaturized circuit.

54. The device of claim 37, wherein the electromagnetic treatment device is a lightweight treatment device configured to be worn.

55. The device of claim 37, wherein the burst of waveforms generated by the control circuit have a frequency of less than 100 MHz and a duty cycle less than 1.

56. The device of claim 37, wherein the burst of waveforms generated by the control circuit are selected from the group of wave shapes consisting of: sinusoidal, square, chaotic, random, symmetrical, asymmetrical, half- or full-wave rectified.

57. The device of claim 37, wherein the waveforms generated by the control circuit have a frequency of approximately 27.12 MHz. Attorney No.: 11415-700.300

58. The device of claim 37, wherein the burst duration of the waveforms generated by the control circuit have a burst duration greater than about 0.5 msec.

59. The device of claim 37, wherein the control circuit is configured provide an electromagnetic signal to the applicator to induce a peak magnetic field between about 1 μT and about 20 μT.

60. The device of claim 37, further comprising an anatomical support configured to hold the treatment device adjacent to the target tissue.

61. A method of modulating calcium binding to calmodulin in a target tissue by inducing an electric field having a frequency that falls within the bandpass of the kinetics of the binding of calcium to calmodulin to maximize signal frequency distribution within the bandpass of the Ca/CaM pathway, the method comprising:

placing an applicator of an electromagnetic treatment device adjacent to a tissue target in a plant, animal or human;

activating the electromagnetic treatment device so that the applicator delivers a burst of waveforms having a burst duration and a burst repetition rate which induces an electric field having an amplitude of less than 100 mV/cm at the target tissue, such that at least one frequency component of the induced electric field falls within the bandpass of the kinetics of the Ca/CaM pathway with sufficient amplitude so that the induced electric field is detectable above background electrical activity in the target tissue.

62. The method of claim 61, further comprising configuring the induced electric field using a mathematical model.

63. The method of claim 61, further comprising configuring the induced electric field using a mathematical model which incorporates a SNR or PSNR analysis to confirm that at least one frequency component of the induced electric field falls within the bandpass of the Ca/CaM pathway.

64. The method of claim 61, wherein the induced electric field has a plurality of frequency components that fall within the bandpass of the kinetics of the Ca/CaM pathway with sufficient amplitude so that the induced electric field is detectable above background electrical activity in the target tissue.

65. The method of claim 61, wherein the induced electric field has an amplitude of between about 1 μV/cm to about 100 mV/cm at the target tissue, and further wherein the induced electric field comprises a burst of waveforms having a burst duration of greater than 0.065 msec and a burst repetition rate.

66. The method of claim 61, wherein the induced electric field has an amplitude of between about 1 μV/cm to about 100 mV/cm at the target tissue, and further wherein the induced electric field comprises a burst of waveforms having a burst duration greater than about 0.5 msec.

67. The method of claim 61, wherein the step of activating comprises applying a burst of waveforms repeating at a frequency of less than 100 MHz and having a duty cycle less than 1.

68. The method of claim 61, wherein the waveforms are selected from the group of wave shapes consisting of: sinusoidal, square, chaotic, random, symmetrical, asymmetrical, half- or full-wave rectified.

69. The method of claim 61, wherein the waveforms have a frequency of approximately 27.12 MHz.

70. The method of claim 61, wherein the electromagnetic treatment device is a lightweight, wearable treatment device.

71. The method of claim 61, wherein the electromagnetic treatment device comprises:

an applicator; and

a control circuit configured to provide a signal to the applicator to induce an electric field of peak amplitude less than 100 mV/cm in the target tissue, wherein the control circuit generates a burst of waveforms having a burst duration of greater than 0.065 msec and a burst repetition rate.

72. The method of claim 71, wherein the control circuit is a miniaturized circuit.

73. The method of claim 71, wherein the applicator comprises at least one coil.

74. The method of claim 61, wherein the step of activating an electromagnetic treatment device comprises applying pulsating current to a lightweight coil.

75. A low-power, wearable electromagnetic treatment device for modulating the binding of calcium to calmodulin in a target tissue by inducing an electric field having a frequency that falls within the bandpass of the kinetics of the binding of calcium to calmodulin to maximize signal frequency distribution within the bandpass of the Ca/CaM pathway, the device comprising:

a lightweight applicator; and

a control circuit configured to provide an electromagnetic signal to the applicator to induce an electric field of peak amplitude of less than about 100 mV/cm at the target tissue and to induce a peak magnetic field of between about 1 μT and about 20 μT, wherein the signal generated by the control circuit comprises a burst of high-frequency waveforms having a burst duration greater than 0.065 msec and a burst period of between about 0.1 to about 10 seconds;

76. The device of claim 75, wherein the burst control circuit is configured to provide a burst of high-frequency waveforms having a frequency of approximately 27.12 MHz.

77. The device of claim 75, wherein the control circuit is configured to generate a burst duration greater than about 0.5 msec.

78. The device of claim 75, wherein the burst control circuit is configured to provide a burst of high-frequency waveforms selected from the group of wave shapes consisting of: sinusoidal, square, chaotic, random, symmetrical, asymmetrical, half- or full-wave rectified.

79. A method of applying a low-power, wearable electromagnetic treatment device to modulate the binding of calcium to calmodulin in a target tissue by inducing an electric field having a frequency that falls within the bandpass of the kinetics of the binding of calcium to calmodulin to achieve maximum signal power within the bandpass of the Ca/CaM pathway, the method comprising:

positioning a target tissue adjacent to the low-power, wearable applicator; and

providing an electromagnetic signal to the applicator to induce an electric field of amplitude of less than about 100 mV/cm at the target tissue and to induce a peak magnetic field of between about 1 μT and about 20 μT, wherein the signal comprises a burst of high-frequency waveforms having a burst duration greater than about 65 μsec and a burst period of between about 0.1 to about 10 seconds;

80. The method of claim 79, wherein the burst of high-frequency waveforms have a frequency of approximately 27.12 MHz.

81. The method of claim 79, wherein the burst of high-frequency waveforms have a wave shape selected from the group of wave shapes consisting of: sinusoidal, square, chaotic, random, symmetrical, asymmetrical, half- or full-wave rectified.

82. The method of claim 79, wherein the induced electric field has a plurality of frequency components that fall within the bandpass of the kinetics of the Ca/CaM pathway with sufficient amplitude so that the induced electric field is detectable above background electrical activity in the target tissue.

83. An electromagnetic treatment device for treating a target tissue, the device comprising:

a coil applicator; and

a control circuit configured to provide a signal to the applicator to induce an electric field of amplitude less than about 100 mV/cm in a specified target pathway in the target tissue, wherein the control circuit generates a burst of waveforms having a burst duration and a burst repetition rate;

wherein the induced electric field waveform has been configured according to a mathematical model which incorporates a SNR or PSNR analysis so at least one frequency component of the induced electric field falls within the bandpass of the kinetics of Ca binding to CaM having sufficient amplitude so that the induced electric field is detectable above background electrical activity in the Ca/CaM pathway in the target tissue.