Systems and methods for inducing electric field pulses in a body organ

Systems and methods for providing controllable pulse parameter magnetic stimulation are described. One aspect is directed to a magnetic stimulation system for inducing approximately rectangular electric field pulses in a body organ, comprising an electrical energy storage device, a stimulating coil, and a switching means for electrically coupling said electrical energy storage device to said stimulating coil to produce current pulses in said stimulating coil which generates, in response to the current pulses, magnetic field pulses that can induce approximately rectangular electric field pulses in the body organ.

FIELD

The disclosed subject matter relates to systems and methods for providing controllable pulse parameter magnetic stimulation that induces electric field pulses in a body organ.

BACKGROUND

Magnetic stimulation is a noninvasive tool for the study of the human brain and peripheral nerves that is being investigated as a potential therapeutic agent in psychiatry and neurology. When applied to the brain, this technique is commonly referred to as Transcranial Magnetic Stimulation (TMS). However, the term “TMS” is often used to refer to magnetic stimulation of other body organs as well. Therefore, the term TMS will be used hereinafter to refer to magnetic stimulation of the brain or other body organs.

In TMS, a pulsed current sent through a coil produces a magnetic field that induces an electric field in the brain, which can affect neuronal activity. A single TMS pulse can activate a targeted brain circuit. For example, a TMS pulse delivered to the motor cortex can result in a twitch of the associated muscles in the body. Further, a single TMS pulse can also disrupt neural activity. For example, a TMS pulse delivered to the occipital cortex can mask the perception of a visual stimulus. This allows researchers to probe brain circuits on a millisecond time scale.

A train of TMS pulses, referred to as repetitive TMS (rTMS), can produce excitatory or inhibitory effects which last beyond the stimulation interval. Repetitive TMS provides a means to study higher cognitive functions, and it could potentially be used as a therapeutic intervention in psychiatry and neurology.

The neural response to TMS is sensitive to the parameters of the stimulating TMS pulse. The pulse width (PW), shape (e.g., sinusoidal vs. rectangular), and the relative amplitude of the positive and negative phases (degree of bidirectionality) of the induced electric field affect the physiological response to TMS, the power efficiency of the stimulator, and the heating of the stimulating coil. Existing TMS systems are capable of inducing only damped cosine electric field pulse shapes, with a limited set of discrete choices of pulse width and degree of bidirectionality. Further, in existing TMS systems, monophasic magnetic field pulse shapes are associated with very low power efficiency of the stimulator in rTMS applications.

DESCRIPTION

Systems and methods are disclosed for providing controllable pulse parameter magnetic stimulation that induces electric field pulses in a body organ. One aspect is directed to a magnetic stimulation system for inducing approximately rectangular electric field pulses in a body organ, comprising an electrical energy storage device, a stimulating coil, and a switching means for electrically coupling said electrical energy storage device to said stimulating coil to produce current pulses in said stimulating coil which generates, in response to the current pulses, magnetic field pulses that can induce approximately rectangular electric field pulses in the body organ.

Another aspect is directed to a magnetic stimulation system for inducing approximately rectangular electric field pulses in a body organ, comprising a first and a second electrical energy storage device, a stimulating coil, a first switching means to electrically couple said first electrical energy storage device to the stimulating coil to produce current pulses with a positive rate of change in the stimulating coil, and a second switching means to electrically couple said second electrical energy storage device to said stimulating coil to produce current pulses with a negative rate of change in the stimulating coil, wherein the stimulating coil produces, in response to a combination of the current pulses with the positive and negative rates of change, magnetic field pulses that can induce approximately rectangular electric field pulses in the body organ.

Another aspect is directed to a method of inducing approximately rectangular electric field pulses in a body organ with a magnetic stimulation system. The method comprises providing a first and a second energy storage device, providing a stimulating coil, providing a first switching means electrically coupled to the first energy storage device and the stimulating coil, providing a second switching means electrically coupled to the second energy storage device and the stimulating coil, actuating the first switching means to electrically couple the first energy storage device to the stimulating coil for a first period of time to produce current pulses with a positive rate of change in the stimulating coil, actuating the second switching means to electrically couple the second energy storage device to the stimulating coil for a second period of time to produce current pulses with a negative rate of change in the stimulating coil, and thereby causing the stimulating coil to produce, in response to a combination of the current pulses with the positive and negative rates of change, magnetic field pulses that can induce approximately rectangular electric field pulses in the body organ, and positioning the stimulating coil proximate to the body organ and exposing the body organ to the magnetic field pulses thereby inducing the approximately rectangular electric field pulses in the body organ.

Another aspect is directed to a magnetic stimulation system for inducing adjustable pulse width electric field pulses in a body organ, comprising an electrical energy storage device, a stimulating coil; and a switching means for electrically coupling said electrical energy storage device to said stimulating coil to produce selectively-adjustable-width current pulses in said stimulating coil which generates, in response to the current pulses, magnetic field pulses that can induce selectively-adjustable-width electric field pulses in the body organ.

Another aspect is directed to a method of inducing adjustable pulse width electric field pulses in a body organ. The method comprises providing an electrical energy storage device, providing a switching means, providing a stimulating coil, and electrically coupling said electrical energy storage device to said stimulating coil with said switching means to produce selectively-adjustable-width current pulses in said stimulating coil which generates, in response to the current pulses, magnetic field pulses that can induce selectively-adjustable-width electric field pulses in the body organ.

Another aspect is directed to a magnetic stimulation system for inducing electric field pulses with an adjustable degree of bidirectionality in a body organ, comprising a first and a second electrical energy storage device, a charging means electrically coupled to the first and second electrical energy storage devices for charging the first electrical energy storage device to a selectable first voltage and charging the second electrical energy storage device to a selectable second voltage, a stimulating coil, a first switching means to electrically couple the first electrical energy storage device to the stimulating coil to produce current pulses with a positive rate of change in the stimulating coil, and a second switching means to electrically couple the second electrical energy storage device to said stimulating coil to produce current pulses with a negative rate of change in the stimulating coil, wherein the stimulating coil produces, in response to a combination of the current pulses with the positive and negative rates of change, magnetic field pulses that can induce electric field pulses in the body organ, the degree of bidirectionality being determined by the ratio of the selectable first voltage and the selectable second voltage.

Another aspect is directed to a method of inducing electric field pulses with an adjustable degree of bidirectionality in a body organ. The method comprises providing a first and a second electrical energy storage device, providing a charging means electrically coupled to the first and second electrical energy storage devices for charging the first electrical energy storage device to a selectable first voltage and charging the second electrical energy storage device to a selectable second voltage, providing a stimulating coil, providing a first switching means electrically coupled to the first electrical energy storage device and the stimulating coil, providing a second switching means electrically coupled to the second electrical energy storage device and the stimulating coil, setting a desired degree of bidirectionality by selecting respective amplitudes for the first and second voltages, the degree of bidirectionality being determined by the ratio of the selected first voltage and the selected second voltage, actuating said first switching means to electrically couple the first electrical energy storage device to the stimulating coil for a first period of time to produce current pulses with a positive rate of change in the stimulating coil, actuating said second switching means to electrically couple the second electrical energy storage device to the stimulating coil for a second period of time to produce current pulses with a negative rate of change in the stimulating coil, and thereby causing the stimulating coil to produce magnetic field pulses in response to a combination of the current pulses with the positive and negative rates of change; and positioning the stimulating coil proximate to the body organ and exposing the body organ to the magnetic field pulses thereby inducing electric field pulses in the body organ with the desired degree of bidirectionality.

Another aspect is directed to a magnetic stimulation system for inducing electric field pulses in a body organ, comprising an electrical energy storage device, a stimulating coil, a switching means for electrically coupling said electrical energy storage device to said stimulating coil to produce current pulses in said stimulating coil which generates, in response to the current pulses, magnetic field pulses that can induce electric field pulses in the body organ, the electric field pulses having a plurality of selectively adjustable parameters from a group consisting of amplitude, pulse width, degree of bidirectionality and pulse repetition frequency; and an operator-controlled apparatus including means for independently controlling at least two of said parameters.

Another aspect is directed to a method for inducing electric field pulses in a body organ with a magnetic stimulation system. The method comprises providing an electrical energy storage device, providing a stimulating coil, electrically coupling said electrical energy storage device to said stimulating coil with a switching means to produce current pulses in said stimulating coil which generates, in response to the current pulses, magnetic field pulses that can induce electric field pulses in the body organ, the electric field pulses having a plurality of selectively adjustable parameters from a group consisting of amplitude, pulse width, degree of bidirectionality and pulse repetition frequency, detecting physiological effects induced in the body organ by the electric field pulses, and controlling at least two of said parameters based on the detected physiological effects.

Another aspect is directed to a magnetic stimulation system for inducing approximately rectangular electric field pulses in a body organ, comprising an electrical energy storage device, a stimulating coil, and a switching circuit configured for electrically coupling said electrical energy storage device to said stimulating coil to produce current pulses in said stimulating coil which generates, in response to the current pulses, magnetic field pulses that can induce approximately rectangular electric field pulses in the body organ.

Another aspect is directed to a method for inducing approximately rectangular electric field pulses in a body organ, comprising storing electrical energy M in an electrical energy storage device, generating with a stimulating coil magnetic field pulses that can induce electric field pulses in the body organ, and switchably electrically coupling the electrical energy storage device to the stimulating coil to produce current pulses in the stimulating coil which generates, in response to the current pulses, magnetic field pulses that can induce approximately rectangular electric field pulses in the body organ.

In a first embodiment, two energy storage capacitors are connected to a common ground. A positive pulse is created in a transcranial magnetic stimulation (TMS) coil by connecting it between a first of two capacitors and ground for a first interval of time and then disconnecting the first capacitor and permitting a current to continue to flow through the TMS coil through a first diode connected between the coil and ground and a second diode connected between the coil and a second capacitor, thereby charging the second capacitor using the magnetic field energy stored in the TMS coil.

In a second embodiment, two energy storage capacitors are connected to a common ground. A positive pulse is created in a transcranial magnetic stimulation (TMS) coil by connecting it between a first of two capacitors and a second of the two capacitors for a first interval of time and then disconnecting the first capacitor and permitting a current to continue to flow through the TMS coil through a first diode connected between the coil and ground and a second diode connected between the coil and the second capacitor, thereby charging the second capacitor using the magnetic field energy stored in the TMS coil. In this embodiment, the first capacitor voltage may be higher than the second.

In either of the above two embodiments, the coil can be short-circuited by closing respective switches on either side of the TMS coil to connect either side of the TMS coil together. In a variation this causes both sides of the TMS coil to be connected to ground.

In either of the embodiments, a negative voltage is applied across the TMS coil by closing third and fourth switches.

Another aspect is directed to a magnetic stimulation system for inducing approximately rectangular electric field pulses in a body organ, comprising a first and second electrical energy storage device, a stimulating coil, a first and second switching means to electrically couple said first electrical energy storage device to the stimulating coil to produce current pulses with a positive rate of change in the stimulating coil, and a third and fourth switching means to electrically couple said second electrical storage device to said stimulating coil to produce current pulses with a positive rate of change in the stimulating coil, wherein the stimulating coil produces, in response to a combination of the current pulses with the positive rates of change, magnetic field pulses that can induce approximately rectangular electric field pulses in the body organ.

Another aspect is directed to a method of inducing approximately rectangular electric field pulses in a body organ with a magnetic stimulation system. The method comprises providing a first and second energy storage device, providing a stimulation coil, providing a first and second switching means coupled to the first energy storage device and the stimulating coil, providing a third and fourth switching means electrically coupled to the second energy storage device and the stimulating coil, actuating the first and second switching means to electrically couple the first energy storage device to the stimulating coil for a first period of time to produce current pulses with a positive rate of change in the stimulating coil, actuating the third and fourth switching means to electrically couple the second energy storage device to the stimulating coil for a second period of time to produce current pulses with a negative rate of change in the stimulating coil, and thereby causing the stimulating coil to produce, in response to a combination of the current pulses with the positive rates of change, magnetic field pulses that can induce approximately rectangular electric field pulses in the body organ, and positioning the stimulating coil proximate to the body organ and exposing the body organ to the magnetic field pulses thereby inducing the approximately rectangular electric field pulses in the body organ.

In a variation of the above, the two energy storage devices include two capacitors, each charged to a different voltage level relative to a common ground. The circuit common ground can be directly connected to earth ground. For a positive phase of a pulse sequence, a first capacitor with a voltage V1is applied to the coil with a polarity relative to ground to generate a forward current. Then the first capacitor is disconnected allowing current in the coil to decline over an interval. Then a voltage from the second capacitor is applied to the coil to generate a negative current opposite to the direction of the forward current for another interval after which the voltage from the second capacitor is disconnected causing the current to decline for another interval.

DETAILED DESCRIPTION

The disclosed subject matter provides, among other things, a controllable pulse parameter transcranial magnetic stimulation (cTMS) system that induces approximately rectangular electric field pulses in an organ of a body, such as a human brain for example. The amplitude, pulse width, and degree of bidirectionality of the induced electric field pulses are adjustable over a continuous range of values. The degree of bidirectionality is defined as the ratio of the positive phase amplitude to the negative phase amplitude of the induced electric field pulse. By adjusting the degree of bidirectionality, the induced electric field pulse can be varied from bipolar (i.e., equal amplitudes of the positive and negative phases) to predominantly unipolar (i.e., a large amplitude of one phase for one polarity and a small amplitude of the other phase for the opposite polarity).

In some embodiments, the cTMS system disclosed herein switches a stimulating coil between positive-voltage and negative-voltage energy storage capacitors or capacitor banks using high-power semiconductor devices. Controlling the pulse parameters facilitates enhancement of TMS as a probe of brain function and as a potential therapeutic intervention. Independent control over the pulse parameters (e.g., pulse width, pulse amplitude, degree of bidirectionality, pulse repetition frequency) facilitates defining dose-response relationships for neuronal populations and producing clinical and physiological effects. For example, dose-response relationships for specific neuronal populations can be defined, and selected clinical and physiological effects can be enhanced. Moreover, the cTMS system disclosed herein also enables high-frequency (>1 Hz) repetitive TMS (rTMS) with predominantly unipolar induced electric fields.

Referring toFIG. 1, in one embodiment, an illustrative component diagram of a controllable pulse parameter transcranial magnetic stimulation system100is shown. The cTMS system100includes a power electronics housing120, a positioning arm130, a stimulating coil L, and a digital data processing device, such as control computer electronics110. The control computer electronics110includes a control computer electronics housing102with analog-digital interface devices, a digital data processing device, and a storage device (e.g., a hard disk), a keyboard104, a monitor106, and a mouse105(or trackball), and/or other data entry devices. The power electronics circuitry in housing120includes cTMS system power electronics that supply current to the stimulating coil L, which can be positioned and held proximate to a patient's head by the positioning arm130. The power electronics circuitry in the power electronics housing120is controlled by the control computer electronics110. An operator, operating the control computer electronics110, controls the power electronics in power electronics housing120to produce one or more adjustable current pulses that are passed through the stimulating coil L held by positioning arm130. During a medical treatment, the stimulating coil L is positioned proximate to a patient's head. The adjustable current pulses that are passed through the stimulating coil L result in the stimulating coil L generating adjustable magnetic field pulses, which induce adjustable electric field pulses which, in turn, induce adjustable current pulses in the patient's brain.

Referring toFIGS. 2A and 2B, illustrative block diagrams of embodiments of the power electronics circuitry in housing120and the control computer electronics in housing102are respectively shown. The power electronics housing120houses electronics used to drive the stimulating coil L. The electronics in the housing120include a charger210, a first capacitor C1, a second capacitor C2, a first capacitor discharger215, a second capacitor discharger216, a first semiconductor switch Q1, a second semiconductor switch Q2, a first snubber circuit222, a second snubber circuit223, a third snubber circuit224, a fourth snubber circuit225, a fifth snubber circuit226, a first gate drive220, and a second gate drive221.

The control computer housing102houses a typical central processing unit (CPU) (not shown), and various standard printed circuit board slots (not shown). Inserted into one of the slots is a controller board205that provides control signals used to control the cTMS system100, and is discussed in further detail below.

In one embodiment, capacitor C1and capacitor C2are single capacitors. In another embodiment, capacitor C1and capacitor C2each represent a separate bank of capacitors. The capacitors in each separate bank are connected in parallel and/or in series with each other.

Referring toFIG. 3A, an illustrative schematic diagram of the controllable pulse parameter transcranial magnetic stimulation circuit for driving the stimulation coil L is shown. As previously described in connection with the block diagram ofFIGS. 2A and 2B, the controllable pulse parameter transcranial magnetic stimulation circuit for driving the stimulation coil L includes energy storage capacitor (or bank of capacitors) C1, energy storage capacitor (or bank of capacitors) C2, controllable semiconductor switch Q1, controllable semiconductor switch Q2, the first and second gate drives220,221, and charger210. The circuit ofFIG. 3Aadditionally includes a diode D1connected in anti-parallel with the controllable semiconductor switch Q1, and a diode D2connected in anti-parallel with the controllable semiconductor switch Q2.

Referring again toFIGS. 2A, 2B, and 3A, in one embodiment, an operator controls the cTMS system using the control computer electronics110. The operator selects cTMS system operation with monophasic or biphasic magnetic pulses and a desired set of induced electric field pulse parameters such as pulse amplitude (A), width of positive pulse phase (PW+), width of initial negative pulse phase (PW−can be chosen for the biphasic magnetic pulse only), ratio of negative to positive capacitor voltage (M), which determines the degree of bidirectionality, and the frequency of pulse repetition (ftrain) via a graphical user interface (discussed below) executing on the control computer102. The selected values are stored in the control computer102.

The controller board205is in communication with and controls the charger210, the first gate drive220, the second gate drive221, and capacitor discharger215(which includes resistor340and normally closed relay342) and capacitor discharger216(which includes resistor344and normally closed relay346) via connections273,275,276,277, and278, respectively. The controller board205is also in communication with, and receives data from, the energy storage capacitors C1and C2, and the stimulating coil L via connections272,271,274, respectively.

The charger210charges the energy storage capacitor C1to a positive voltage VC1(set by the operator), and the energy storage capacitor C2is charged to a negative voltage −VC2(set by the operator). The charger transfers energy from a power line to the capacitors, and transfers energy between the two capacitors. The positive and negative capacitor voltages are independently selectable. Voltage VC1is set based on the pulse amplitude (A) selected by the operator, and voltage VC2is set equal to M*VC1, where M is the ratio of negative to positive capacitor voltage selected by the operator. The stimulating coil L is connected to capacitors C1and C2via the semiconductor switches Q1and Q2, and diodes D1and D2, respectively.

The controller board205also supplies separate sets of timing pulses with adjustable widths (set by the operator) to the first and second gate drives220,221. The first and second gate drives220,221each use the timing pulses to produce separate sets of voltage pulses with adjustable widths.

InFIG. 3A, each semiconductor switch Q1and Q2includes a gate terminal305and310, respectively. The gate terminals305and310are driven (i.e., clocked) by the voltage pulses supplied by the gate drives220and221. The voltage pulses from controller board205are used to switch the semiconductor switches Q1and Q2to an on state or an off state. Anti-parallel connected diodes D1and D2transfer energy from the stimulating coil L back to capacitors C1and C2, respectively.

The semiconductor switch Q1connects coil L to energy storage capacitor C1for an interval of time equal to the pulse width of the voltage pulses received at the gate terminal305from the first gate drive220, which causes the coil current ILto increase during this interval of time. When semiconductor switch Q1is turned off, the coil current commutates to capacitor C2through diode D2, and the coil current starts to decrease until it reaches zero. Thus, turning switch Q1on and off results in an approximately triangular positive coil current pulse, which induces an approximately triangular positive monophasic magnetic field pulse. This is discussed in further detail with respect toFIG. 4A. Likewise, the semiconductor switch Q2connects coil L to energy storage capacitor C2for an interval of time equal to the pulse width of the voltage pulses received at the gate terminal310from the second gate drive221, which causes the coil current ILto decrease (i.e., become more negative) during this interval of time. When semiconductor switch Q2is turned off, the coil current commutates to capacitor C1through diode D1, and the coil current starts to increase (i.e., become more positive) until it reaches zero. Thus, turning switch Q2on and off results in an approximately triangular negative coil current pulse, which produces an approximately triangular negative monophasic magnetic field pulse. This is discussed in further detail with respect toFIG. 4B. If an adjustable negative monophasic magnetic field pulse and an adjustable positive monophasic magnetic field pulse are both generated subsequently, an adjustable biphasic magnetic pulse is produced. The approximately triangular magnetic field pulses with adjustable widths induce approximately rectangular electric field pulses in an organ of a body. The approximately rectangular electric field pulses, in turn, induce approximately rectangular, adjustable-pulse-parameter current pulses in an organ of a body, such as a human brain, for example.

The controller board205provides timing signals with microsecond resolution to control the semiconductor switches. The cTMS system uses timing of the turn-on and turn-off transitions of the control signals for both semiconductor switches Q1and Q2to provide accurate pulse waveform control.

In one embodiment, the controller board205is a PCI card from National Instruments (Austin, Tex.) with additional interface electronics that provides sub-microsecond timing signals. Additional interface electronics includes signal conditioning and isolation circuits such as optocouplers, fiber optic links, isolation transformers, attenuators, amplifiers, and filters, as required to connect the controller board205to the power electronics in the power electronics housing120. The PCI card (controller board205) resides in the control computer housing102that provides a GUI for interfacing and configuring the controller board205. The control computer housing102also houses a mass storage device, such as a hard disk (not shown) for storing data. The GUI is implemented in LabVIEW software (available from National Instruments Corp.). The operator inputs various pulse parameters, which are discussed in detail below. The controller board software computes the corresponding capacitor voltages (VC1, VC2) and switch timing. The controller board205then sends the capacitor voltage commands to the charger210, capacitor dischargers215,216, and the switch timing signals to the gate drives220,221. The controller board205also samples VC1, VC2, and IL(via connections271,272,274) to monitor circuit operation, and inhibits or prevents coil currents from exceeding specifications.

Typically, the controllable semiconductor switches Q1and Q2should be able to withstand the peak coil current and the peak voltages appearing across their terminals at the peak pulse repetition frequency. The switches Q1and Q2should also have turn-on and turn-off times of no more than a few microseconds. The maximum voltage of the semiconductor switches Q1and Q2is ideally VC1+VC2. However, during current commutation between the two energy storage capacitors C1and C2, the switch voltage can overshoot this value due to stray inductance and the finite turn-off and turn-on times of the semiconductor switches Q1and Q2, and diodes D1and D2. To address this issue, semiconductor devices with fast switching times should be used.

In one embodiment, insulated gate bipolar transistors (IGBTs—shown inFIG. 3Band available from Powerex of Youngwood, Pa.) are used for the switches Q1and Q2. In another embodiment, gate-turn-off thyristors (GT0s), such as integrated gate-commutated thyristors (IGCTs) (shown inFIG. 3C) are used for switches Q1and Q2. Both of these devices can sustain pulse currents of thousands of amperes at voltages of a few kilovolts while turning on and off in a few microseconds. Since these devices can turn off while the coil current is not zero, they are used with the snubber circuits222,223,224,225,226(discussed in detail below) which absorb the energy of the commutation transients, thus inhibiting and/or preventing voltage overshoots that exceed the voltage ratings of the semiconductor switches, and energy dissipation in the semiconductor switches, which occurs during switching.

Unlike the silicon-controlled rectifiers (SCRs) used in conventional stimulators, IGBTs can be both turned on and off from the gate terminal. There are existing IGBT modules with peak voltage/surge current ratings of 3300 Volts/12000 Amperes, 4500 Volts/6000 Amperes, 4500 Volts/9000 Amperes, and 6500 Volts/6000 Amperes, and switching times of about one microsecond, which can be used to implement a cTMS system. These IGBT modules have an integrated ultra-fast reverse diode between the emitter and the collector (e.g., D1and D2inFIG. 3), which clamps the IGBT reverse voltage, and provides a free-wheeling path for the coil current IL.

IGCTs behave like efficient SCRs when turning on and during conduction, and behave like IGBTs when turning off. The turn-on time for an IGCT is approximately 1 μs, but the turn-off time can be as long as 10 μs. IGCTs with integrated reverse diodes (e.g., D1and D2) and gate drives (e.g., gate drive220,221) are available with ratings of 4500 Volts and 17000 Amperes surge current, providing for robustness of the design.

In the cTMS system, the stimulating coil L is forced to commutate between the two energy storage capacitors C1and C2when the coil current is at its peak. Managing the forced commutation transient is a challenging aspect of implementing the cTMS system. The finite turn-off and turn-on times of the semiconductor switches Q1and Q2, and the stray inductance in the capacitor banks C1and C2, the switches Q1and Q2, the diodes D1and D2, and the wiring between them, can result in voltage overshoots that exceed the voltage ratings of the semiconductor switches, and switching power loss and heating in the semiconductor switches. The stray inductances are reduced and/or minimized by installing the semiconductor switches Q1and Q2, the diodes D1and D2, and the capacitor banks C1and C2as close together as allowed by the physical dimensions of the components, and interconnecting them with wires or bus bars arranged to minimize the area of the current loop. Still, stray inductance cannot be completely eliminated. For example, a typical capacitor bank series inductance of 150 nH with 7 kA current stores magnetic energy sufficient to produce a 27 kV spike on an IGBT switch with 10 nF collector capacitance, which would exceed the voltage rating of a 4500 V IGBT by 22500 V, resulting in potential damage to the IGBT. Therefore, the snubber circuits222,223,224,225,226are used to slow down the transients, ameliorate power dissipation in the semiconductor switches Q1and Q2, and provide paths for stray inductances to discharge in order to suppress the voltage overshoots.

In one embodiment, as shown inFIG. 3A, the snubber circuits222,223each include a capacitor312,318in series with a diode314,320and resistor316,322, which are in parallel with each other. Snubber circuits222,223each also include capacitors326,330. This configuration allows the stimulating coil current to flow through the snubber capacitor312,318when the corresponding semiconductor switch Q1, Q2is turning off, thus inhibiting and/or preventing voltage overshoots. The snubber capacitor312,318should be large enough to hold the peak switch voltage below its rated limit. If the snubber capacitor312,318is too large, switching losses are increased. Snubber circuit224includes capacitor324, snubber circuit225includes capacitor328, and snubber circuit226includes capacitor332and resistor334.

Approaches for sizing of snubber components will be readily understood by those of ordinary skill in the art, and include, but are not limited to, approaches discussed in manufacturer application notes and books on the subject of power electronics.

The gate drives220,221serve to drive (clock) the semiconductor switches Q1and Q2to an on state or an off state. As previously discussed, the gate drives220,221receive timing signals from the controller board205, and apply gate voltages to the gates305,310. Some high-power switches, such as IGCTs, are manufactured with an integrated gate drive unit. IGBTs typically require a separate external gate drive. For high-power IGBTs, 10-20 μC is delivered to the gate to raise the gate-emitter voltage to 15-20 Volts to turn on the device. To switch the gate in about 1 μs, IGBT gate drives need an output impedance of a few ohms, and provide peak currents of a few Amperes. IGBT gate drives are available commercially. In some implementations, the gate drives220,221incorporate short-circuit protection which prevents the switch from turning on if a short circuit is detected between the collector and emitter terminals (in IGBTs) or the anode and cathode terminals (in GTOs and IGCTs), which improves the fault tolerance and safety of the cTMS system.

The pulse width control parameters, PW+ and PW″ are limited by the discharge of C1and C2, respectively. To enable pulse width control over a significant range (e.g., up to hundreds of microseconds) and to produce approximately rectangular induced electric field pulses, the energy storage capacitors C1and C2, in most embodiments disclosed herein, have capacitances in the range of 300 to 800 μF, and 1000 to 3000 μF, respectively. These capacitance values can be accomplished with single pulse capacitors or with banks of parallel and/or series connected pulse capacitors. Suitable capacitor technologies for implementation of C1and C2use oil, polypropylene, and/or polyester dielectrics. For example, in one embodiment, C1is implemented using two parallel 185 μF, 3 kV oil-filled pulse capacitors (e.g., General Atomics model 39504), and C2is implemented using two parallel 750 μF, 1 kV oil-filled pulse capacitors (e.g., General Atomics model 310DM475). The maximum C1voltage VC1is 2,800 V, and the minimum (maximum negative) C2voltage−VC2is 900 V.

Whereas in conventional TMS systems the voltage on the energy storage capacitor is reversed during the pulse, in the disclosed cTMS system the voltages on the capacitors C1and C2are never reversed, i.e., always VC1>0 and −VC2<0. Capacitor voltage reversal decreases the capacitor life expectancy by as much as ten times. Therefore, the energy-storage capacitors C1and C2of the disclosed cTMS system have a longer life expectancy since no capacitor voltage reversal occurs.

The capacitor charger210for the cTMS system supplies energy to both the capacitors C1and C2at two independently controlled DC voltages, VC1and VC2, respectively. The capacitor charger210also transfers energy from capacitor C2to capacitor C1to recover energy accumulated on capacitor C2after a monophasic positive current pulse in coil L, corresponding to a positive monophasic magnetic field pulse. The capacitor charger210also transfers energy from capacitor C1to capacitor C2to recover energy accumulated on capacitor C1after a monophasic negative current pulse in coil L, corresponding to a negative monophasic magnetic field pulse. In one embodiment, a charging unit such as the Magstim Super Charger (available from The Magstim Corp., Whitland, UK) is used to charge the positive capacitor C1. A bidirectional inverting DC/DC power supply is used to transfer energy between capacitor C1and capacitor C2so that VC2is maintained at a set level. Capacitor dischargers215,216, which constitute a resistor and a normally closed relay connected in series, are included and activated when the energy stored in capacitors C1and C2has to be reduced, such as when the pulse amplitude setting A is decreased by the operator, or when the energy stored in capacitors C1and C2has to be completely dissipated, such as when the cTMS system is shutdown, power is lost, or a system fault is detected by the controller.

A stimulating coil L known in the art is used with the cTMS system. Both air core and ferromagnetic core coils can be used with the cTMS system. In one embodiment, a coil connector compatible with Magstim 200 coils is used to connect the stimulating coil L to the cTMS circuitry. In one embodiment, a Magstim 16.4 μH 70 mm double stimulating coil (commonly referred to in the art as a figure-of-8) is used.

Due to the rate of change and peak strength of the magnetic field required to achieve transcranial cortical stimulation, TMS systems operate at very high capacitor voltages (up to 3 kV) and peak coil currents (up to 10 kA). In one embodiment, the cTMS system employs maximum positive and negative capacitor voltages of 2800 Volts and −900 Volts, respectively, and a peak coil current of 7 kA.

The currents, voltages, and pulse widths applied to the energy storage capacitors C1and C2, stimulating coil L, coil cable and connector, and internal wiring in the cTMS system typically do not exceed the currents, voltages, and pulse widths in conventional TMS systems. The cTMS system power consumption in rTMS operation typically does not exceed that of existing TMS systems, since commensurate pulse energies and pulse train frequencies are used. Further, given the higher electrical efficiency of triangular magnetic pulses, the peak values of the pulse parameters could be reduced in comparison with available stimulators. Thus, existing solutions for these system components can be used in the cTMS system.

An analysis of the cTMS circuit shown inFIG. 3Awill now be presented in connection withFIGS. 4A, 4B. For this analysis, it is assumed that storage capacitors C1and C2are large. Specifically, it is assumed that the following conditions are met:
trise<<π/2*(inductance of coilL*capacitance of capacitorC1)½ and
tfall<<π/2*(inductance of coilL*capacitance of capacitorC2)½,
where triseand tfallare the rise and fall times of the magnetic field generated by the stimulating coil L. Further, in this analysis, the component parasitics and losses in the circuit are ignored.

Under these conditions, the cTMS system induces approximately rectangular current pulses in the targeted body organ.

Referring toFIGS. 4A and 4B, in one embodiment, under the conditions specified above, graphs of positive and negative monophasic magnetic field pulses generated using the controllable pulse parameter transcranial magnetic stimulation circuit are shown. For this illustration, the ratio of the voltage across the capacitor C1to the voltage across the capacitor C2(VC1:VC2) is assumed to be 5:1.FIG. 4Adepicts the generation of a positive magnetic field pulse405, which is proportional to the current in the coil L.

When switch Q1is switched to an on state410, the resulting current (IL) in the stimulating coil L increases at a rate of dIL/dt=VC1/(inductance of coil L), as shown by waveform416in plot415. Since capacitor C1is very large, VC1stays approximately constant. After rise time trise, which is set by the operator by choosing when to turn Q1on and off, switch Q1is switched to an off state forcing the current ILin the stimulating coil L to commutate to capacitor C2via the diode D2. While diode D2is on, switch Q2can be either on or off (referred to as a “don't care state” of the switch, and indicated with “x” symbols in the switch state waveforms). Since a negative voltage −VC2is now applied across the stimulating coil L, the stimulating coil current ILstarts to decrease at a rate of −VC2/(inductance of coil L) as shown by waveform417in plot415. The coil current ILdecays to zero in fall time tfall, where tfall:trise=VC1:VC2. Under ideal conditions, all the energy transferred from capacitor C1to the stimulating coil L, which is equal to (inductance of coil L)*ILpk2/2, is returned to capacitor C2, where ILpk is the peak current in the coil L. Of course, as will be understood by those of ordinary skill in the art, losses will arise under ordinary (i.e., non-ideal) conditions, resulting in somewhat less than this amount of energy being transferred. This energy can be transferred back to capacitor C1and reused in a subsequent pulse, which makes this strategy effective for repetitive TMS (rTMS).

FIG. 4Bdepicts the generation of a negative magnetic field pulse, which is proportional to the current in the coil L as previously described. When switch Q2is switched to an on state425, the resulting current (IL) in the stimulating coil L decreases at a rate of dIL/dt=−VC2/(inductance of coil L), as shown by waveform429in plot430. After rise time trise, which is chosen by the operator, switch Q2is switched to an off state forcing the current ILin the stimulating coil L to commutate to capacitor C1via the diode D1. While diode D1is on, switch Q1can be either on or off (referred to as a “don't care state” of the switch, and indicated with “x” symbols in the switch state waveforms). Since a positive voltage VC1is now applied across the stimulating coil L, the stimulating coil current ILstarts to increase at a rate of VC1/(inductance of coil L) as shown by waveform428in plot430.

When the cTMS system is operated in monophasic magnetic pulse mode, as shown inFIG. 5A, the energy exchange between the storage capacitors C1and C2is implemented using charger circuit210to transfer energy from capacitor C2to C1, or from capacitor C1to C2between pulses. When the cTMS system is operated in biphasic magnetic pulse mode, as shown inFIG. 5B, the energy exchange between the storage capacitors C1and C2is implemented by having a negative magnetic pulse precede a positive magnetic pulse. The energy from the storage capacitor C1at the beginning of the pulse is returned to the storage capacitor C1by the end of the pulse. The capability to operate in both monophasic and biphasic magnetic pulse modes enables optimization of the pulse type for specific research and clinical applications of the cTMS system.

Referring toFIG. 5A, in one embodiment, illustrative monophasic waveforms of a magnetic field pulse (B)505, an electric field (E)510, and a neuronal membrane voltage (Vm)515, induced in the brain by the controllable pulse parameter transcranial magnetic stimulation system are shown.

As previously described, during a medical treatment, the stimulating coil L is positioned proximate to a patient's head. Adjustable current pulses are passed through the stimulating coil L and cause the stimulating coil L to generate adjustable magnetic field pulses. The adjustable magnetic field pulses induce adjustable electric field pulses which, in turn, induce adjustable current pulses in the patient's brain. The induced adjustable current pulses in the patient's brain result in voltage change on the neuronal membrane that can be measured.

The waveforms shown inFIG. 5Aare produced by the current IL(plot405) in the stimulating coil L shown inFIG. 4A. As previously described, the magnetic field B (plot505) is proportional to the current ILin the stimulating coil L, and thus also has a triangular shape. The induced electric field E (plot510) is proportional to the magnetic field rate of change (dB/dt), and correspondingly has a rectangular shape, rather than the cosine shape of existing TMS systems. Different rising and falling slopes of the magnetic field B (plot505) result in different magnitudes of the positive and negative phases of the induced electric field E (plot510), respectively. As previously described, the rate of change of the coil current (dIddt) and, therefore, the rate of change of the magnetic field (dB/dt) is proportional to the voltage across the coil L. The voltage across the coil L is equal to the voltage of the capacitor to which the coil is connected. Therefore, the ratio of peak positive to negative electric field E is VC1:VC2. This is true in general, even when the circuit non-idealities are considered. Since the induced electric field pulse has a rectangular shape, and due to the neuronal membrane capacitance, the neuronal membrane voltage (Vm) follows a decaying exponential curve characterized by the membrane time constant, as shown by plot515. If the neuronal membrane is depolarized (i.e., made more positive) by more than approximately 15 mV relative to its resting potential (−60 to −70 mV), the neuron is likely to produce an action potential (i.e., to fire).

Referring toFIG. 5B, in one embodiment, illustrative waveforms of a biphasic magnetic field (B)520, and the associated electric field (E)525and neuronal membrane voltage (Vm)530induced in the brain by the controllable pulse parameter transcranial magnetic stimulation system are shown. Although the magnetic field B of plot520is biphasic with symmetric positive and negative phases, the induced electric field (plot525) has a large positive amplitude and a comparatively small negative amplitude, since the rate of change of the rising magnetic field is much larger than the rate of change of the falling magnetic field. As a result (plot530), the depolarization amplitude (as the neuronal membrane is made more positive) is larger than the hyperpolarization amplitude (as the neuronal membrane is made more negative). This example demonstrates how the cTMS system can produce predominantly unipolar electric field pulses and neuronal membrane voltage changes with biphasic magnetic pulses. In contrast, conventional sinusoidal biphasic magnetic pulses induce electric fields and neuronal membrane voltage changes that are bipolar (i.e., have approximately equal amplitudes of the positive and negative phases of the electric pulse). Biphasic magnetic pulses are more electrically efficient and produce less coil heating than monophasic magnetic pulses. Further, TMS biphasic magnetic pulses can be used inside a magnetic resonance imaging (MRI) scanner, since the torque on the wire loops of the stimulating coil L in the strong magnetic field of the scanner averages to approximately zero. In contrast, monophasic pulses cannot be used in an MRI scanner, since the average toque on the coil loops is non-zero, resulting in high mechanical stress in the coil that can damage the coil.

Referring toFIG. 6, in one embodiment, an illustrative waveform depicting user-adjustable pulse parameters is shown. The user-adjustable parameters include: induced positive electric field amplitude (A)602(which corresponds to the intensity setting on conventional TMS systems), the pulse width of the positive phase (PW+)608, the induced negative electric field amplitude (M*A=(VC2/VC1)*A)604, which is specified through M, the ratio of negative to positive capacitor voltage, and the frequency of the pulse repetition (ftrain). For biphasic operation, the duration of an initial negative electric field phase (PW−)606can also be specified (PW−=PW+/2M for symmetric negative side lobes of the pulse).

Referring toFIG. 7, in one embodiment, illustrative waveforms of approximately rectangular, predominantly unipolar current pulses with adjustable pulse width are shown. Control over the pulse width (PW+) of the induced electric field pulse is accomplished by controlling the on and off timing of the semiconductor switches Q1and Q2.

Referring toFIG. 8, in one embodiment, illustrative waveforms depicting user-adjustable degree of bidirectionality of approximately rectangular electric field pulses are shown. Control over the degree of bidirectionality is accomplished by adjustment of the voltages of energy storage capacitors C1and C2relative to each other.

FIG. 9shows an illustrative waveform of rTMS with a predominantly unipolar induced electric field. Computer simulations of a representative implementation of the cTMS system (FIG. 10) indicate that the cTMS pulses can induce membrane depolarization and hyperpolarization equal to that of commercial monophasic stimulators at only 16-18% of the power dissipation. This results in a reduction of power supply demands, heating, noise, and component size, and enables the cTMS system to produce high-frequency rTMS with predominately unipolar induced electric fields.

The cTMS system described in the disclosed subject matter was simulated and compared to existing TMS systems. A schematic of the cTMS simulation circuit is shown inFIG. 10. Further, a set of pulse performance metrics, i.e. performance figures, used to evaluate the efficiency of cTMS pulses compared to conventional pulse configurations of commercial TMS systems is shown inFIG. 11. The values were derived from computer simulations using PSIM circuit simulation software (available from Powersim Inc.) and the simulation circuit shown inFIG. 10.

Realistic component values are used. As previously described, snubber circuits1001and1002are added across the semiconductor devices Q1and Q2, snubber capacitors C1aand C1bare added across the capacitor bank C1, and snubber capacitors C2aand C2bare added across capacitor bank C2to handle transient energy. Waveforms showing the coil current IL, peak induced electric field (E), and estimated neuronal membrane voltage change (dVm) corresponding to the cTMS configuration shown inFIG. 10are shown inFIGS. 12A, 12B, and 12C, respectively.

To allow a valid comparison of the pulse shape efficiency, all configurations use a model of Magstim “figure-of-8”, air-core coil (L=16.4 μH), parasitic series resistance and inductance of 25 mΩ and 0.6 μH and neuronal membrane time constant τm=150 μs. The actual Neuronetics 2100 and Medtronic MagPro X100 systems use different coils than the Magstim figure-of-8 used in the comparison. Therefore, for the calculations for these systems, the capacitance was adjusted to match their typical pulse periods of approximately 200 and 270 μs, respectively, for the given 16.4 μH coil, because the objective is to compare the waveform efficiency rather than the actual commercial systems and coils.

To account for the higher efficiency of ferromagnetic (iron) core coils, standard with the Neuronetics 2100 machine, the total energy loss per pulse and the load integral (proportional to coil heating) are recalculated for an iron core coil, as indicated inFIG. 11. The iron core proportionally increases the efficiency of all pulse configurations, and can be used with the cTMS system to improve efficiency. Four representative cTMS pulse configurations are simulated (see columns cTMS1-cTMS4ofFIG. 11). For biphasic cTMS pulses (cTMS2-cTMS4), the duration of the initial negative phase was set to PW−=PW+/2M. The amplitude of the commercial device (Magstim, MagPro, Neuronetics) pulses is adjusted to produce equal neuronal membrane depolarization of ΔVm=18 mV, which is 20% above the assumed neuronal firing threshold of 15 mV depolarization. The amplitude and pulse width of the cTMS pulse configuration are also adjusted to produce identical neuronal membrane depolarization of ΔVm=18 mV.

FIG. 11shows that the cTMS system can produce predominantly unipolar neuronal membrane potential change with both monophasic (cTMS1) and biphasic (cTMS2-TMS4) magnetic field pulses. For example, the cTMS2pulse configuration yields a membrane hyperpolarization/depolarization ratio of 0.27, which is comparable to that of the Magstim 200 and MagPro X100 (monophasic mode), while dissipating only 16% and 18% of the energy, respectively. The energy dissipation per pulse was calculated using the following equation:

Δ⁢⁢WC=(12⁢∑sum⁢⁢of⁢⁢allcapacitorsbefore⁢⁢pulse⁢⁢Ci⁡(VCi)2)-(12⁢∑sum⁢⁢of⁢⁢allcapacitorsafter⁢⁢pulse⁢⁢Ci⁡(VCi)2),
where Ci refers to each capacitor in the stimulator power electronics, and where capacitor Ci has voltage VCi.

Further, coil heating (proportional to the load integral IL2dt) with the cTMS2pulse is only 32% and 36% that of the Magstim 200 and MagPro X100, respectively. cTMS is able to achieve a total energy dissipation AWCcomparable to efficient biphasic systems, such as the Neuronetics 2100, with 8-59% less coil heating (load integral) while adding the previously unavailable functionalities of control over the induced electric field pulse width, degree of bidirectionality, approximately rectangular shape, and predominantly unipolar electric field pulses. It should be noted that for very brief, high-intensity rectangular pulses (cTMS4), the coil heating decreases dramatically, while the total energy dissipation increases slightly. This is due to energy loss in the cTMS snubber circuits, which is proportional to the square of the capacitor voltage. However, since it is easier to cool the snubber circuits, which are inside the power electronics enclosure, than the coil, the reduced coil heating of brief, rectangular, high-voltage pulses can be advantageous in high-power applications such as magnetic seizure therapy (MST) where coil heating is currently the bottleneck for pulse train duration. Finally, in this model we have not accounted for ferromagnetic core losses, which could be higher for briefer pulses.

When monophasic magnetic field pulses are generated, energy is transferred from capacitor C1to C2, and has to be transferred back to C1by the power supply before the subsequent pulse in repetitive TMS (rTMS) operation. However, if a biphasic magnetic pulse is used to produce a predominantly unipolar electric field pulse, as shown inFIG. 5BandFIG. 12A-C, energy is transferred from C2to C1and then back from C1to C2during the pulse. Thus, there is no need for rebalancing a large amount of energy between the capacitors before the subsequent pulse, except for “topping off” the capacitors to compensate for the energy dissipated in losses during the pulse, as is the case in conventional biphasic TMS systems. With both monophasic and biphasic cTMS magnetic field pulses, the energy returning from the coil after each pulse is recycled, unlike that in conventional monophasic converters, which is dissipated in a resistor. However, compared to cTMS biphasic magnetic field pulses, monophasic magnetic field pulses require higher power capability of the cTMS power supply circuit that moves charge between the two capacitors.

Thus, the cTMS system is particularly well suited to generate high-frequency trains of predominantly unipolar electric field pulses. Using the results inFIG. 11, the unipolar rTMS power dissipation and coil heating of cTMS can be compared to that of conventional monophasic stimulators. The cTMS2configuration is 5-6 times more efficient and has about three times less coil heating than the Magstim 200 and MagPro X100 while producing the same neuronal depolarization and comparable hyperpolarization/depolarization ratio. For a pulse train frequency of 10 Hz, the Magstim 200, MagPro X100, and cTMS2pulse configurations described inFIG. 11dissipate 1600, 1420, and 260 W, respectively, while the coil dissipation, assuming coil resistance of 10 mfl, is 248, 222, and 80 W, respectively. If an iron-core coil is used, cTMS energy dissipation and coil heating can be further reduced to about 65 and 20 W, respectively. Therefore, with its substantially lower power dissipation and coil heating, the cTMS system can enable rTMS with predominantly unipolar electric field pulses. Recent research has indicated that rTMS with predominantly unipolar electric field pulses may have a stronger modulating effect on brain function, and, therefore, could be a more effective therapeutic intervention.

Referring toFIGS. 13A and 13B, in an alternative embodiment, illustrative block diagrams of power electronics and a control computer system102afor a controllable pulse parameter transcranial magnetic stimulation (cTMS) system are shown. The cTMS system includes a cTMS circuit1320for driving a stimulating coil L. The cTMS circuit1320includes energy storage capacitor (or bank of capacitors) C1, controllable semiconductor switch Q1, a gate drive1302, charger1310, capacitor discharger1322, diode D1, and resistor R1. The cTMS system further includes a digital data processing device, such as control computer system102a, which includes a controller board1305.

This particular embodiment enables adjustment of the amplitude and the pulse width of the induced electric field over a continuous range of values, and the induced electric field pulses have an approximately rectangular shape. The semiconductor switch Q1is implemented with an IGBT, which unlike an SCR, can be turned off from a gate terminal1304. Further, the diode D1and the energy dissipation resistor R1are connected across the TMS coil L, to provide a discharge path for the coil current when Q1is turned off. The energy storage capacitor C1is larger than those used in conventional TMS stimulators to provide a wider range of pulse width control and approximately rectangular induced electric field pulses.

Similar to the cTMS circuit described in connection withFIGS. 2A, 2B, and 3A, the cTMS circuit1320shown inFIG. 13Ais controlled by the controller board1305shown inFIG. 13B, which resides in the control computer102a. Through the controller board1305, the operator specifies the voltage of capacitor C1, which determines the amplitude of the induced electric field. The operator also specifies the on time and the off time of switch Q1, which determine the pulse timing and the pulse width (PW+).

Referring toFIG. 14, in another embodiment, a schematic diagram of the cTMS circuit is shown. Stray inductance in the critical high-current paths of the circuit can cause power loss and voltage spikes during turn-off of switch Q1, which can cause component damage, as previously discussed. Therefore, the wiring and component locations in the cTMS circuit are arranged to reduce and/or minimize the stray inductance. However, stray inductances cannot be completely eliminated. Therefore, the cTMS circuit includes a number of snubber components. The snubber components assist the coil current commutation between the switch Q1and the diode D1and inhibits and/or prevents voltage overshoots and energy dissipation in the semiconductor switch Q1. A snubber capacitor or combination of capacitors C5is mounted between the collector terminal of switch Q1and the anode terminal of diode D1to prevent the collector voltage from spiking during switch Q1turn-off as a result of parasitic inductance of the capacitor bank C1and the connecting wires. A capacitor C3is mounted between the collector and emitter terminals of the switch Q1to suppress high-voltage spikes across the terminals of switch Q1. A snubber circuit1402, which includes diode D2, capacitor C4, and resistor R2, transiently absorbs the current flowing through the coil L when Q1is turned off. This supports the current commutation to diode D1and resistor R1, as previously discussed.

The energy storage bank of capacitors C1comprises six 118 μF (average measured value) oil-filled pulse capacitors. The bank of capacitors C1is charged by a Magstim Booster Module Plus (The Magstim Co., Whitland, UK) and a Magstim capacitor voltage control circuit. The semiconductor switch Q1is a 4500 Volt/600 Amp (direct current rating) IGBT module from Powerex, Inc. (Youngwood, Pa.). The IGBT (switch Q1) is controlled with a high-voltage optically-isolated gate drive1302by Applied Power Systems, Inc. (Hicksville, N.Y.). The controller board1305sends triggering pulses to the gate drive1302. As previously described, the pulse width is set by the operator. The diode D1is implemented with two series-connected, fast 1800 Volt/102 Amp (direct current rating) diodes by Semikron GmbH (Nuremberg, Germany). The snubber capacitors C3-05are high-voltage, high-current polypropylene film and paper film/foil capacitors. The snubber diode D2includes three series-connected fast-recovery 1200 Volt/60 Amp (direct current rating) diodes from International Rectifier (El Segundo, Calif.). The stimulating coil L is a custom-made Magstim 5.5 cm mean diameter round coil with an inductance of 16 μH.

The cTMS circuit ofFIG. 14was tested with capacitor voltages of up to 1650 Volts, and peak coil currents of up to 7 kA. The peak intensity (i.e. amplitude of the electric field) of the cTMS system is equal to that of commercial Magstim Rapid stimulators. Unlike conventional stimulators, however, the cTMS system of the disclosed subject matter allows pulse width control with a range between 5 μs and 160 μs.

The electric field induced by the cTMS system was estimated with a single-turn 5 cm diameter search coil placed two centimeters from the face of the cTMS coil L. The search coil was connected to a digitizing oscilloscope as well as to a first-order low-pass filter with 150 μs time constant, which outputs a scaled estimate of the neuronal membrane voltage waveform.

Referring toFIGS. 15A-C, illustrative waveforms of measured capacitor C5voltage (FIG. 15A), search coil voltage VS(proportional to the induced electric field,FIG. 15B), and the estimated shape of the neuronal membrane voltage (VF) (FIG. 15C), which is determined by filtering the search coil voltage VSthrough a low-pass filter with 150 μs time constant, are shown. The waveforms show six different pulse widths (i.e., 20, 40, 60, 80, 100, and 120 μs). It can be seen inFIG. 15Bthat the induced pulses, which are proportional to the electric field, have approximately rectangular shape, especially for brief pulses (e.g., 20 μs pulse).

As expected, overshoot and high-frequency ringing are present on the capacitor C5voltage (FIG. 15A) and search coil voltage (proportional to the electric field,FIG. 15B) during switch Q1turn-off, due to stray inductance. However, these transients are suppressed to a safe level by the snubber circuits. In particular, the capacitor voltage overshoot does not exceed 7% of the initial capacitor voltage, and the voltage across the switch Q1never exceeds approximately twice the initial capacitor voltage, and is thus well below the 4,500 V rating of the IGBT (Q1). These results indicate the feasibility of high coil current commutation through appropriate choice of semiconductor switches, switch gating, snubber design, and minimization of stray inductance.

The above described cTMS implementation can be used to compare the intrinsic efficiency of rectangular unipolar electric field pulses versus conventional unipolar cosine pulses. In order to emulate conventional monophasic magnetic field pulses, the cTMS implementation was reconfigured to use a smaller capacitor and switch Q1was kept on until the coil current decayed to zero. The comparison of rectangular pulses used the same initial capacitor voltage, and the cTMS pulse width was adjusted to achieve the same estimated neuronal depolarization. The energy dissipation per pulse was calculated using the formula:

Δ⁢⁢WC=(12⁢∑sum⁢⁢of⁢⁢allcapacitorsbefore⁢⁢pulse⁢⁢Ci⁡(VCi)2)-(12⁢∑sum⁢⁢of⁢⁢allcapacitorsafter⁢⁢pulse⁢⁢Ci⁡(VCi)2),
where Ci refers to each capacitor in the stimulator power electronics, and where capacitor Ci has voltage VCi.

Compared to conventional monophasic magnetic field pulses with rise times of 72 and 101 μs, the corresponding rectangular pulses dissipated 20 and 28% less energy, respectively. The cTMS circuit ofFIG. 14does not recycle pulse energy (pulse energy is dissipated in resistor R1inFIG. 14), so this gain in efficiency comes solely from the rectangular pulse shape. With energy recycling, which is implemented in the circuit inFIG. 2andFIG. 3, efficiency will be even higher, as discussed above.

InFIG. 16is shown an active snubber circuit connected in parallel with a magnetic stimulation coil L. The active snubber circuit can be used in any of the disclosed embodiments and others as illustrated inFIG. 16. For example, it can be used as the snubber circuit226in the embodiment ofFIG. 2A.

The active snubber circuit ofFIG. 16may include a non-inductive resistor Rsnub and at least two current-unidirectional switches (switch) as shown inFIG. 17. The value of the non-inductive resistor Rsnub may be chosen to provide critically damped, or overdamped, response of the resonance between the coil L inductance and the capacitance of the pulse generator switching node, i.e., the capacitance that appears in parallel with the coil L when the coil is disconnected from the energy storage capacitors C1and C2. This switching node capacitance typically results from the capacitance of snubbers222and223and from the capacitance of switches Q1and Q2inFIG. 2A.

In embodiments, when CTRL1is activated, current in a first direction is permitted to be established in Rsnub and when CTRL2is activated, current in a second, reverse, direction is permitted to be established in Rsnub. Referring toFIG. 16, when an undesired resonance generates a positive voltage across coil L, for example after a pulse is generated by the pulse generator circuit (not shown), the activation of CTRL1will cause dissipation of the energy in Rsnub. For example, the CTRL1can be activated at any time during a negative phase for the electric field pulse when the coil current is ramping down toward zero and as soon as the coil voltage becomes positive due to resonance, the active snubber will permit current to flow through Rsnub and dissipate the energy.

In a similar manner, when CTRL2is activated, current in the second direction is permitted to be established in Rsnub. When an undesired resonance generates a negative voltage across coil L, for example after a pulse is generated by the pulse generator circuit (not shown), the activation of CTRL2will cause dissipation of the energy in Rsnub. For example, the CTRL2can be activated at any time during a positive phase of the electric field pulse when the coil current is ramping up toward zero and as soon as the coil voltage becomes negative due to resonance, the active snubber will permit current to flow through Rsnub and dissipate the energy.

Different circuit embodiments for the switches included in the active snubber circuit ofFIG. 17are shown inFIGS. 18A-18E. The switches can be implemented, for example, with IGTB (QS1, QS2) and diode (DS1, DS2) combinations, as shown inFIGS. 18A-18B, and/or SCRs (QS1, QS2), as shown inFIG. 18C, and/or MOSFET (QS1, QS2) and diode (DS1, DS2) combinations, as shown inFIGS. 18D-18-E. In each of these cases, CTRL1and CTRL2signals are generated by a controller similar to that described with regard to the embodiment ofFIG. 2B, modified by providing appropriate control signals for CTRL1and CTRL2. Also illustrated inFIGS. 18A-18Eare gate drivers, as indicated at GDS, if and as appropriate for the type of switch employed.

The Q1, Q2switch functions (responsive to CTRL1and CTRL2) can also be implemented with components with lower voltage rating than the peak value of the voltage across the coil L by connecting a plurality n of switches (SW1-SWn) in series, as shown inFIG. 19. A resistor-capacitor voltage divider ladder (Rdiv-Cdiv) including n resistors Rdivand n capacitors Cdivcan be installed to force equal voltage drops on all n switch stages (SW1-SWn). Rdiv can also be implemented with non-linear resistance elements, such as transient voltage suppressor (TVS) diodes. The control signals CTRL1and CTRL2are applied to the same effect as described above. In embodiments, each of SW1can assume any of the configurations ofFIGS. 18A-18Eor others.

FIGS. 20 and 21illustrate activating a positive and a negative current conducting active snubber switch, respectively. In operation, if a TMS pulse ends with a negative voltage phase (voltage VLapplied to the coil L ofFIG. 16or similarly in other embodiments), then the positive-current conducting snubber switch is activated by the controller (CTRL1—ON) anytime during the voltage negative phase (FIG. 20). When the voltage VLgoes positive at the end of the negative phase, due to resonance of the coil L with the capacitance of the pulse generator switching node, current will start to flow in the active snubber. Thus, the energy in the coil L and in the capacitance of the pulse generator switching node will be dissipated in Rsnub. If, on the other hand, the TMS pulse ends with a positive voltage VLphase, then the negative-current conducting snubber switch is activated by the controller (CTRL2—ON) anytime during the VLpositive phase (FIG. 21). When VLgoes negative after the end of the positive phase, due to resonance of the coil L with the capacitance of the pulse generator switching node, current will start to flow in the active snubber. Thus, the energy in the coil L and in the capacitance of the pulse generator switching node will be dissipated in Rsnub. Although the discussion ofFIGS. 20 and 21assumed a biphasic pulse sequence, it should be clear that the snubber can be used for the control of transients in mono-phasic pulses or any other pulse sequences with appropriate configurations. For example, to control transients of a single polarity, a single control signal and switch may be used. Also, although Rsnub is described above as critically, or over damped, it is possible for it to be under damped. In the case of underdamping, oscillating may be tolerated or additional switching cycles may be provided to pass current through Rsnub in both directions during a parasitic oscillation event.

Referring toFIG. 22, an illustrative schematic diagram of an alternative controllable pulse parameter transcranial magnetic stimulation circuit for driving the stimulation coil L is shown. The controllable pulse parameter transcranial stimulation circuit for driving the stimulation coil L includes energy storage capacitor (or bank of capacitors connected in series and/or parallel) C1, energy storage capacitor (or bank of capacitors connected in series and/or parallel) C2, four (4) controllable current-unidirectional semiconductor switches Q1-Q4, (Q1and Q2connected to C1and Q3and Q4connected to C2), four (4) gate drives GD1-GD4, controlled by the system controller, for turning switches Q1-Q4, on and off, respectively, and a capacitor charger/discharger (shown connected to a power source such as voltage mains). The circuit additionally includes four (4) diodes D1-D4connected in anti-parallel with respective controllable semiconductor switches Q1-Q4, as well as snubber circuits SN1-SN8. Note that any and all of the snubber circuits SN1-SN8is optional and provided as required for controlling transients and reducing switching losses as desired.

Referring toFIG. 22, an operator may control the cTMS system using control computer electronics110, shown inFIG. 1. For example, the operator may select cTMS system operation with monophasic magnetic pulses and a desired set of induced electric field pulse parameters, such as the pulse amplitude (A), width of positive pulse phase (PW+), and the frequency of pulse repetition via a graphical user interface.

The controller board is in communication with and controls the charger/discharger, and also receives data from the energy storage capacitors C1and C2, and the stimulating coil L.

The charger/discharger may charge the energy storage capacitor C1to a positive voltage VC1(set by the operator), and the energy storage capacitor C2also to a positive voltage VC2(set by the operator). This is in contrast to the embodiments described above with reference toFIGS. 2A and 3A. The charger/discharger may charge the capacitors from the mains we well as transfer energy between the two capacitors C1and C2. The charger/discharger can also dissipate energy from C1to C2, for example in the form of heat. The positive capacitor voltages VC1and VC2are independently selectable via the controller and implemented through the charger/discharger.

The stimulating coil L is connected to capacitor C1via semiconductor switches Q1and Q2and diodes D1and D2, and is connected to capacitor C2via semiconductor switches Q3and Q4and diodes D3and D4. The controller supplies separate sets of timing pulses with adjustable widths (set by the operator) to the first, second, third and fourth gate drives (GD1-GD4), which use the timing pulses to produce separate sets of voltage pulses with adjustable widths.

The voltage pulses from the controller board are used to switch the semiconductor switches Q1-Q4to an on or an off state, and the anti-parallel connected diodes D1-D4conduct current depending on the state of switches Q1-Q4and the coil current L.

The semiconductor switches Q1-Q4and diodes D1-D4are connected to the stimulation coil L in such a way as to be able to apply to a first terminal Vx1of the coil L a voltage VC1or 0, and the second terminal Vx2to a voltage VC2or 0. Thus, the coil voltage VLcould have any of the following values applied across it (reference polarity as indicated inFIG. 22being positive on the left and negative on the right): 0, VC1, −VC2, or VC1-VC2. The switches Q1-Q4are turned on and off by the controller so that VLcan assume the desired value.

For example, to provide a voltage of VC1to L, Q1and Q4may be turned on and Q2and Q3turned off. The coil L may be connected thusly for an interval of time equal to the pulse widths of voltage pulses received from gate drives GD1and GD2, which causes the coil current to increase during a first time interval. When the switches are turned off, the coil current commutates to diodes D2and D3to capacitor C2charging C2and thereby recovering energy in C2. During this phase, the coil current decreases until it is zero at a rate determined by VC2. A negative pulse can be generated in a similar fashion by turning on (then off) switches Q2and Q3to create a negative current in L (applying a voltage −VC2across coil L) and then switching off to obtain energy recovery in capacitor C1via diodes D1and D4. The magnetic field pulses induce approximately rectangular electric field pulses in an organ of a body, which in turn, induce approximately rectangular, adjustable pulse current pulses in an organ body. The exact shape of the magnetic field and electric field pulses is piecewise sinusoidal, resulting from the resonant ringing behavior between the coil L and capacitors C1and C2. The values of L, C1, and C2can be chosen so that the piecewise sinusoidal electric field pulse waveform is approximately rectangular in shape.

For other examples, turning on switch Q1alone may cause a voltage of VC1−VC2to be applied across coil L (assuming VC1is higher—If VC2is higher Q3may be closed). In these cases, one of D1or D2, respectively, turns on and connects the other terminal of the coil L to C2or C1, respectively.

Since the switches Q1-Q4can turn off while the coil current is not zero, snubber circuits SN1-SN8can be implemented in the circuit to facilitate the turn off of the switches and to reduce the switching losses by taking over part of the switch current during the turn off of the corresponding switch, as well as to suppress ringing in the circuit during switching resulting from parasitic inductances and capacitances in the circuit. Snubber circuits SN1-SN8can take the form of any of the previously described snubber circuits, as appropriate.

In the circuit embodiment ofFIG. 22, the maximum voltage difference between any two parts of the circuit is the higher of VC1and VC2. The circuit design may provide the advantage that the maximum voltage required to be withstood by the semiconductor switches Q1and Q2as well as D1and D2is only VC1, and thus, their voltage rating need be no higher than VC1plus a margin for derating and to accommodate transient voltage spikes. Similarly the maximum voltage required to be withstood by the semiconductor switches Q3and Q4as well as D3and D4is only VC2, and thus, their voltage rating need be no higher than VC2plus a margin for derating and to accommodate transient voltage spikes. Switches with lower voltage ratings are generally less costly, smaller, and have lower conduction and switching losses.

Additionally, at the end of the magnetic field pulse, both terminals Vx1and Vx2can be connected together by turning Q2and Q4on, which then prevents ringing of current in the coil L that would otherwise occur due to the snubber capacitance.

In an embodiment, a 16 μH stimulating coil L, a Powerex CM800HB-66H or CM1200HC-66HH single IGBT module for switch (Q1/D1), a Powerex CM800HB-66H or CM1200HC-66HH single IGBT module for switch (Q2/D2), a Powerex CM800HA-28H or CM1000HA-28H single IGBT module or (½) CM800DZ-34H or (½) CM1000DU-34NF dual IGBT module for switch (Q3/D3), and a Powerex CM800HA-28H or CM1000HA-28H single IGBT module or (½) CM800DZ-34H or (½) CM1000DU-34NF dual IGBT module for switch (Q4/D4) is used to induce approximately rectangular current pulses in the targeted body organ. The energy storage capacitors C1and C2have capacitances in the range of 370-740 μF and 1,500-3,000 μF, respectively. These capacitance values can be accomplished with single pulse capacitors or with banks of parallel and/or series connected pulse capacitors with polypropylene dielectrics or paper/oil dielectrics. The maximum setting of voltage VC1is 2,800V and the maximum setting of voltage VC2is 1,000 V. Snubber circuit SN1-SN4can each include a 0.25 μF capacitor in parallel with series combination of 0.5 μF capacitor and a 1Ω resistor. Snubber circuits SN5-SN8can be omitted in this embodiment.

The cTMS system disclosed herein enables an operator to adjust various pulse shape parameters (previously described in detail) of an electric field pulse induced in the brain of a patient. The values of these pulse shape parameters can be chosen based on which medical application is being implemented and/or a patient's physiological characteristics. Further, the capability to control pulse parameters enables a medical professional to study the contribution of pulse characteristics to observed physiological effects of an induced electric field pulse.

Additionally, the cTMS systems disclosed herein (seeFIGS. 2 and 3) produce approximately rectangular induced electric field pulses, which are more energy efficient for neuronal stimulation than sinusoidal pulses produced by existing TMS systems, as previously described. Moreover, the cTMS systems depicted inFIGS. 2 and 3also enable an operator to vary the degree of bidirectionality of the induced pulse over a continuous range from a predominantly unipolar to a bipolar electric field pulse.

In view of the effects of the TMS pulse characteristics on physiological responses and the capability of cTMS systems disclosed herein to control the pulse parameters, the cTMS systems disclosed herein have the potential for enabling diverse clinical and research applications. For example, the cTMS systems can be used to determine strength-duration curves (i.e., the induced electric field pulse amplitude vs. the pulse width that produces threshold neuronal stimulation). Strength-duration curves can be used to estimate a neuronal membrane time constant, and can therefore be a useful tool for diagnosing and studying neurological disease. Strength-duration curves can also be used to optimize stimulation paradigms for different cortical regions, and activate selectively different neuronal types possessing different membrane time constants and responsivity to pulse shape characteristics. Thus, the capability to adjust the pulse shape in the cTMS system could enable optimization of the stimulus parameters for various applications.

TMS with briefer, high-amplitude pulses requires less energy delivered to the stimulating coil, thereby increasing efficiency and decreasing heating. Thus, TMS and rTMS with brief (e.g., 20-50 μs) rectangular pulses are more energy efficient.

Recent studies indicate that rTMS with predominately unipolar induced electric fields can yield more potent modulation of neuronal excitability compared to standard bidirectional rTMS.

The cTMS system circuit (seeFIGS. 2 and 3) is intrinsically energy efficient since the coil transfers charge between two energy-storage capacitors, rather than dissipating it in a resistor, like the conventional monophasic TMS topology does. Further, the cTMS system (seeFIGS. 2 and 3) can induce predominately unipolar electric fields with biphasic magnetic pulses having fast rise time and slow fall times, which require substantially less energy delivered to the coil. Thus, such cTMS enables high-frequency unidirectional rTMS, yielding potentially stronger neuromodulation effects that can be used for therapeutic purposes in neurological and psychiatric illness.

Variations, modifications, and other implementations of what is described herein may occur to those of ordinary skill in the art without departing from the spirit and scope of the disclosed subject matter. Further, the various features of the embodiments described herein also can be combined, rearranged, or separated without departing from the spirit and scope of the disclosed subject matter as defined by the following claims.