TRANSCUTANEOUS ELECTRICAL NERVE STIMULATION USING NOVEL UNBALANCED BIPHASIC WAVEFORM AND NOVEL ELECTRODE ARRANGEMENT Applicant

Neurometrix, Inc. Inventors

Glenn Herb

Andres Aguirre

Xuan Kong

Shai N. Gozani Reference To Pending Prior Patent Application

This patent application is a continuation-in-part of pending prior U.S. Patent Application Serial No.14/610,757, filed 01/30/2015 by NeuroMetrix, Inc. and Shai N. Gozani et al. for APPARATUS AND METHOD FOR RELIEVING PAIN USING TRANSCUTANEOUS ELECTRICAL NERVE STIMULATION (Attorney’s Docket No. NEURO-5960 CON), which patent application is a continuation of prior U.S. Patent Application Serial No.13/678,221, filed 11/15/2012 by NeuroMetrix, Inc. and Shai N. Gozani et al. for APPARATUS AND METHOD FOR RELIEVING PAIN USING TRANSCUTANEOUS ELECTRICAL NERVE STIMULATION (Attorney’s Docket No. NEURO-5960), which in turn claims benefit of (i) NEURO-81 prior U.S. Provisional Patent Application Serial No. 61/560,029, filed 11/15/2011 by Shai N. Gozani for SENSUS OPERATING MODEL (Attorney's Docket No. NEURO-59 PROV); and (ii) prior U.S. Provisional Patent Application Serial No. 61/657,382, filed 06/08/2012 by Shai N. Gozani et al. for APPARATUS AND METHOD FOR RELIEVING PAIN USING

TRANSCUTANEOUS ELECTRICAL NERVE STIMULATION (Attorney's Docket No.

NEURO-60

PROV).

The four (4) above-identified patent applications are hereby incorporated herein by reference.

Field Of The Invention

This invention relates generally to Transcutaneous Electrical Nerve Stimulation (TENS) devices that deliver electrical current across the intact skin of a user via electrodes so as to provide symptomatic relief of chronic pain and other therapeutic benefits. More particularly, this invention discloses the construction of novel TENS stimulation waveforms and novel arrangements of TENS electrodes which improve the efficiency of power consumption while enhancing therapeutic effects.

Background Of The Invention

Transcutaneous electrical nerve stimulation (TENS) is the delivery of electricity across the intact surface of the skin to activate underlying nerves; generally with the objective of pain relief. An electrical circuit generates stimulation pulses with specified characteristics. One or more pairs of electrodes, placed on the user's skin, transduce the electrical pulses and thereby stimulate underlying nerves in order to trigger an analgesic response.

Pain relief from TENS stimulation often begins within 15 minutes of the stimulation onset and may last up to an hour following the completion of the stimulation period (also known as a "therapy session"). For optimal pain relief, each therapy session should run for at least 30 minutes and preferably 60 minutes. To maintain pain relief (i.e., analgesia), TENS therapy sessions typically need to be initiated at regular intervals, such as every other hour. Newly developed wearable TENS devices such as the QUELL ^® device by Neurometrix, Inc. of Waltham, Massachusetts, USA provide users with an option to automatically restart therapy sessions at pre-determined time intervals.

Battery life is an engineering challenge in portable devices. The waveform of the stimulation pulse has a significant impact on the battery life of a TENS device. Symmetric biphasic rectangular pulses are often used in TENS devices but such pulse waveforms may not be optimal for maximizing battery life.

The present invention is directed to TENS devices which utilize novel stimulation waveforms and novel arrangements of TENS electrodes to improve the efficiency of power consumption while enhancing therapeutic effects.

Summary Of The Invention The present invention is directed to transcutaneous electrical nerve stimulation (TENS) devices which utilize novel stimulation waveforms and novel arrangements of electrodes to improve the efficiency of power consumption while enhancing therapeutic effects.

In one preferred form of the present invention, there is provided apparatus for providing transcutaneous electrical nerve stimulation to a user, said apparatus comprising:

a housing;

a stimulation unit for electrically stimulating nerves using asymmetric biphasic electrical pulses, wherein during each phase of an asymmetric biphasic electrical pulse, said stimulation unit generates a voltage at an anode that is higher than a voltage at a cathode so as to allow current to flow from the anode to the cathode, and wherein said stimulation unit delivers a larger amount of electrical charge in the second phase of the asymmetric biphasic electrical pulse than the amount of electrical charge delivered in the first phase of the asymmetric biphasic electrical pulse using the same anode voltage setting in both phases of the asymmetric biphasic electrical pulse by taking advantage of the electrical charge accumulated during the first phase of the asymmetric biphasic electrical pulse;

a control unit for controlling the electrical stimulation delivered by said stimulation unit; and

an electrode array connectable to said stimulation unit, said electrode array comprising a substrate and at least first and second electrodes, the at least first and second electrodes being mounted to said substrate with a predetermined arrangement, such that when said substrate is placed on the user, said first electrode overlays a first nerve but not a second nerve and said second electrode overlays the second nerve but not the first nerve.

In another preferred form of the present invention, there is provided apparatus for providing transcutaneous electrical nerve stimulation to a user, said apparatus comprising:

a housing;

a stimulation unit for electrically stimulating nerves using asymmetric biphasic electrical pulses, wherein said stimulation unit delivers a larger amount of electrical charge in the second phase of the asymmetric biphasic electrical pulse than the amount of electrical charge delivered in the first phase of the asymmetric biphasic electrical pulse using the same voltage output level by taking advantage of the electrical charge accumulated during the first phase of the asymmetric biphasic electrical pulse;

a control unit for controlling the stimulation delivered by said stimulation unit; and an electrode array connectable to said stimulation unit, said electrode array comprising a substrate and at least first and second electrodes, the at least first and second electrodes being mounted to said substrate with a predetermined arrangement, such that when said substrate is placed on the user, said first electrode overlays a first nerve but not a second nerve and said second electrode overlays the second nerve but not the first nerve.

In another preferred form of the present invention, there is provided a method for providing transcutaneous electrical nerve stimulation therapy to a user, said method comprising: providing a stimulation unit for generating asymmetric biphasic electrical pulses, wherein the asymmetric biphasic electrical pulses are generated by creating a voltage difference between an anode voltage and a cathode voltage, and the amount of electrical charge delivered in the second phase of an asymmetric biphasic electrical pulse is larger than the amount of electrical charge delivered in the first phase of the asymmetric biphasic electrical pulse using the same anode voltage during the first and second phases of the asymmetric biphasic electrical pulse by taking advantage of the electrical charge accumulated during the first phase of the asymmetric biphasic electrical pulse;

providing an electrode array connectable to said stimulation unit, said electrode array comprising a substrate and at least first and second electrodes, the at least first and second electrodes being mounted to said substrate with a predetermined arrangement, such that when said substrate is placed on the user, said first electrode overlays a first nerve but not a second nerve and said second electrode overlays the second nerve but not the first nerve; and

using said stimulation unit and said electrode array to apply asymmetric biphasic electrical pulses to the skin of a user.

In another preferred form of the present invention, there is provided a method for providing transcutaneous electrical nerve stimulation to a user, the method comprising:

providing a stimulation unit for generating asymmetric biphasic electrical pulses, wherein said stimulation unit delivers a larger amount of electrical charge in the second phase of the asymmetric biphasic electrical pulse than the amount of electrical charge delivered in the first phase of the asymmetric biphasic electrical pulse without increasing the voltage output of said stimulator unit by taking advantage of the electrical charge accumulated during the first phase of the asymmetric biphasic electrical pulse, and providing an electrode array connectable to said stimulation unit, said electrode array comprising at least first and second electrodes;

placing the electrode array on the user so that the first electrode overlays a first nerve but not a second nerve and the second electrode overlays the second nerve but not the first nerve; and

using said stimulation unit to apply asymmetric biphasic electrical pulses to the skin of the user.

In another preferred form of the present invention, there is provided apparatus for providing transcutaneous electrical muscle stimulation to a user, said apparatus comprising: a housing;

a stimulation unit for electrically stimulating muscles using an asymmetric biphasic electrical pulse, wherein during each phase of an asymmetric biphasic electrical pulse, said stimulation unit generates a voltage at an anode that is higher than a voltage at a cathode so as to allow current to flow from the anode to the cathode, and said stimulation unit delivers a larger amount of electrical charge in the second phase of the asymmetric biphasic electrical pulse than the amount of electrical charge delivered in the first phase of the asymmetric biphasic electrical pulse using the same anode voltage setting in both phases of the asymmetric biphasic electrical pulse by taking advantage of the electrical charge accumulated during the first phase of the asymmetric biphasic electrical pulse;

a control unit for controlling the stimulation delivered by said stimulation unit; and an electrode array connectable to said stimulation unit, said electrode array comprising a substrate and at least first and second electrodes, the at least first and second electrodes being mounted to said substrate with a predetermined arrangement, such that when said substrate is placed on the user, said first electrode overlays a first muscle but not a second muscle and said second electrode overlays the second muscle but not the first muscle.

In another preferred form of the present invention, there is provided a method for providing transcutaneous electrical muscle stimulation therapy to a user, said method comprising of the steps of:

placing an electrode array on the skin of a user so that a first electrode of said electrode array overlays a first muscle but not a second muscle and so that a second electrode of said electrode array overlays the second muscle but not the first muscle;

controlling a stimulator unit to generate asymmetric biphasic electrical pulses; and delivering said asymmetric biphasic electrical pulses to the electrode array, wherein the second phase of the asymmetric biphasic electrical pulses delivers a larger amount of electrical charge than the first phase of the asymmetric biphasic electrical pulses without the need to increase the output voltage of the stimulator unit during the second phase of the asymmetric biphasic electrical pulses by taking advantage of the electrical charge accumulated during the first phase of the asymmetric biphasic electrical pulse.

Brief Description Of The Drawings

These and other objects and features of the present invention will be more fully disclosed or rendered obvious by the following detailed description of the preferred embodiments of the invention, which is to be considered together with the accompanying drawings wherein like numbers refer to like parts, and further wherein:

Fig. 1 is a schematic view of a traditional TENS stimulator using monophasic stimulation pulses to stimulate a nerve via a conventional electrode arrangement;

Fig. 2 is a schematic view of a traditional TENS stimulator using biphasic stimulation pulses to stimulate a nerve via the conventional electrode arrangement shown in Fig. 1;

Fig. 3 is a schematic view of a novel TENS stimulator formed in accordance with the present invention;

Fig. 4 is a schematic view of novel arrangements of TENS electrodes placed on the lower leg of a user for delivering asymmetric biphasic stimulation pulses regulated by the novel TENS stimulator shown in Fig. 3;

Fig. 5 is a schematic view of an asymmetric biphasic stimulation current pulse and associated voltage profile on the current source of the novel TENS stimulator shown in Fig. 3 when the biphasic stimulation current pulse is applied to a human body as modeled by a resistor- capacitor network;

Fig. 6 is a schematic view of targeted and actual biphasic stimulation current pulse and associated voltage profile of the novel TENS stimulator shown in Fig 3 when the voltage falls below the target value to cause actual stimulation current pulse profile to be different from the target profile; and

Fig. 7 is a schematic flowchart showing exemplary operation of the novel TENS stimulator shown in Fig. 3 to regulate the high voltage circuit output for increasing battery efficiency.

Detailed Description Of The Preferred Embodiments

TENS In General

Transcutaneous electrical nerve stimulation, typically abbreviated as TENS, is the delivery of electricity across the intact surface of the skin so as to activate underlying nerves, generally with the objective of pain relief. A conceptual model for how peripheral nerve stimulation leads to pain relief was proposed by Melzack and Wall in 1965 (Melzack R, Wall PD. Pain mechanisms: a new theory. Science. Nov 19 1965;150(699):971-979). Their theory suggests that the activation of sensory nerves (Αβ fibers) closes a "pain gate" in the spinal cord which inhibits the transmission of pain signals carried by nociceptive afferents (C and Αδ fibers) to the brain. In the past 20 years, the anatomic pathways and molecular mechanisms that may underlie the pain gate have been elucidated. Sensory nerve stimulation activates the descending pain inhibition system, primarily the periaqueductal gray (PAG) and rostroventral medial medulla (RVM) located in the midbrain and medulla sections of the brainstem, respectively (DeSantana JM, Walsh DM, Vance C, Rakel BA, Sluka KA. Effectiveness of transcutaneous electrical nerve stimulation for treatment of hyperalgesia and pain. Curr Rheumatol Rep. Dec 2008;10(6):492-499). The PAG has neural projections to the RVM, which in turn has diffuse bilateral projections into the spinal cord dorsal horn (Ossipov MH, Dussor GO, Porreca F. Central modulation of pain. J Clin Invest. Nov 2010;120(l l):3779-3787). Peripheral nerve stimulation activates the PAG, which triggers the RVM to broadly inhibit pain signal

transmission in the spinal cord dorsal horn. Although it is activated by localized peripheral nerve stimulation, the descending pain inhibition system has analgesic effects that may extend beyond the stimulation site to provide broad pain relief (Dailey DL, Rakel BA, Vance CG, et al.

Transcutaneous electrical nerve stimulation reduces pain, fatigue and hyperalgesia while restoring central inhibition in primary fibromyalgia. Pain. Nov 2013;154(l l):2554-2562).

As described above, TENS induces analgesia by stimulating peripheral nerves. A peripheral nerve is defined as a nerve, which is a collection of nerve fibers (i.e., axons), that is outside of the brain and spinal cord. Peripheral nerves may comprise nerve fibers that provide sensory, motor or autonomic functions. TENS is primarily intended to stimulate somatic peripheral nerves, meaning nerve fibers that either bring sensory information into the nervous system or carry motor control information to the muscles. As peripheral nerves descend from the spinal cord they may break off into various branches. Some of these branches may be large enough that they are named peripheral nerves. For example, the sciatic nerve, which is formed from spinal nerves in the lumbosacral region, travels all the way from the lower back to the knee as one major nerve. In the popliteal fossa (i.e., behind the knee) it branches into the tibial nerve and the common peroneal nerve. These two nerves then branch into additional nerves further down the leg and into the foot. Most peripheral nerve branches are smaller and provide limited function such as innervating a muscle or providing sensation to a particular area of skin. In the latter case, the branch may be described as a cutaneous branch. In some cases, small branches of peripheral nerves are called collaterals.

TENS is characterized by a number of stimulation parameters including the stimulation pulse shape, amplitude, duration, pattern, and frequency. Increasing pulse amplitude or duration, or both, increases the pulse intensity (intensity = amplitude * duration) of the TENS therapy. For the same intensity, the relative effectiveness of the stimulation pulse decreases with longer duration due to the strength-duration relation of a nerve. Stimulation at an intensity below the level of sensory perception does not provide pain relief, and the degree of analgesia is correlated to the stimulation intensity. Scientific studies and clinical experience suggest that therapeutically effective TENS occurs at an intensity that feels "strong but comfortable" to the user.

Looking now at Fig. 1, the dose of the TENS therapy is approximately defined as C _E * f * Δ. Quantity C _E 223 is the effective charge per pulse, or the portion of total pulse charge that is actually effective in stimulating nerve fibers with the resulting nerve pulses traveling proximally to the central nervous system. Quantity / is the pulse frequency, and its inverse is the pulse period T 224. Quantity Δ 242 is the therapy session duration. Pulse frequency / is limited by the frequency response of the nerve, which is determined by the temporal excitability profile of the nerve including its refractory period, and the frequency response of the central neural circuits associated with analgesia. In general, analgesic efficacy drops off over about 100 Hz. Therapy session duration Δ 242 is limited by patient preferences and by the physiology of the endogenous opioid system, where opioid concentration starts to drop after about 1 hour of stimulation. To stimulate a peripheral nerve 205, a TENS stimulator 201 needs at least two separate contact areas with the skin (e.g., cathode electrode 210 and anode electrode 215) so that a closed circuit can be formed. Hydrogel-based electrodes (e.g., cathode electrode 210 and anode electrode 215) are preferably used to create the electrical interface between the TENS stimulator and the skin in the contact areas. Important parameters for electrical pulses are amplitude Ic 221 and duration Dc 222. For each monophasic pulse 235, its intensity or total pulse charge INc is defined as the product of Ic and Dc: IN _C = I _c * D _c . The nerve segment under cathode electrode 210 is activated by an electrical pulse when the intensity INc exceeds a threshold. The exact threshold value depends upon many factors, including the user' s age, height and weight, biophysical characteristics of the nerve being stimulated, and electrode geometry. In general, the stimulation current amplitude Ic 221 must also be above a minimum value called the rheobase to activate the nerve segment under the electrode. For a sequence of monophasic pulses 220, each pulse with the total pulse charge INc contributes effectively to the activation of the nerve impulse 216 that travels proximally along the nerve. Therefore, the effective charge C _E 223 equals the total pulse charge: C _E = IN _C = I _c * D _c in the case of monophasic pulse TENS.

Although monopolar stimulation pulses 220 are efficient in that the effective charge is equal to the pulse charge, monopolar stimulation pulses are not generally used in TENS stimulation due to known adverse skin reactions under anode 215 and cathode 210 following a prolonged period of stimulation. More particularly, during stimulation, negatively charged ions in the skin will be attracted towards the anode electrode and their excessive accumulation will cause an acid reaction in the skin area under the anode 215. Similarly, positively charged ions in the skin will move to the cathode electrode and their excessive concentration will cause an alkaline reaction in the skin area under the cathode 210. To overcome these adverse skin reactions, biphasic stimulation pulses are typically used in modern TENS devices.

Looking now at Fig. 2, the biphasic pulses 230 typically used in modern TENS devices (e.g., TENS stimulator 201) have a second phase 236 following the first phase 235 for each stimulation pulse. The second phase 236 of the biphasic pulse serves a primary purpose of balancing the charge delivered during the first phase 235 of the biphasic pulse, thereby preventing adverse skin reactions due to the build-up of charged ions under the electrodes.

Electrically, the second phase 236 of the biphasic pulse reverses the roles of the anode and cathode, but no effective nerve stimulation should be expected under the "new" cathode (i.e., electrode 215) with the electrode arrangement shown in 245. There are two reasons for this. First, the nerve segment under electrode 215 is hyperpolarized during the first phase 235 of the biphasic pulse, making it more difficult to be activated by the stimulation current IA 237 in the second phase 236 of the biphasic pulse. Second, even if the nerve segment under electrode 215 could be activated by the second phase 236 of the biphasic stimulation pulse, any resulting nerve pulses 217 could not travel proximally (i.e., towards the central nervous system) past electrode 210 because of the refractory period of the nerve segment located under electrode 210. More particularly, the refractory period refers to the inability of a nerve fiber to transmit a second pulse within a certain time period of the first pulse passing through the nerve segment. The refractory period for a human peripheral nerve is generally on the order of several milliseconds, while the delay between the two phases of a TENS biphasic pulse is usually less than one-tenth of a millisecond. Hence, the second phase 236 of the biphasic pulse is delivered to electrode 215 and activates a nerve pulse 217 originating from the nerve segment under electrode 215. Because the nerve segment under electrode 210 is still in its refractory period due to nerve pulse activation earlier from the first phase 235 of the biphasic pulse, the nerve pulse 217 is prevented from traveling through the nerve segment under the electrode 210 in the proximal direction. As a result, the second phase 236 of the biphasic pulse does not provide the beneficial effect of activating any nerve pulse that can travel proximally to contribute to pain relief. In this case, the effective charge is still even though the biphasic pulses have a total pulse charge

of , i.e., the pulse charge I of the first phase of the biphasic pulse plus

the pulse charge of the second phase of the biphasic pulse. In other words, the effective

charge 233 of the biphasic pulse is essentially just the pulse charge of the first phase of the biphasic pulse, and the second phase of the biphasic pulse does not produce effective nerve stimulation. However, as noted above, the use of biphasic pulses is nonetheless beneficial to overcome adverse skin reactions under the electrodes, and hence has often been adopted with TENS devices.

Fig. 3 provides a functional block diagram for a novel TENS stimulator 300 when connected to a patient load 350. Novel TENS stimulator 300 is configured to provide biphasic pulses in accordance with the present invention, however, for clarity of illustration, Fig. 3 shows only the first phase of a biphasic pulse generated by novel TENS stimulator 300 (and omits the second phase of the biphasic pulse). Switch 308 can be open when the TENS stimulator is not delivering current to the patient load. The load to the TENS stimulator output terminals (i.e., anode terminal 302 and cathode terminal 303) consists of the electrodes, body tissue, and the interface between the electrodes and skin (note that, even though TENS stimulator 300 is configured to deliver biphasic pulses, terminal 302 is referred to as the "anode" terminal, and terminal 303 is referred to as the "cathode" terminal, since they typically serve this function during the first phase of the biphasic pulse). A common and effective circuit model of the skin- electrode contact and tissue volumetric impedance (i.e., the load to the stimulator) is a resistor in series with a parallel resistor-capacitor (RC) circuit as shown inside 350. When switch 308 is closed, anode terminal voltage VA at the anode terminal 302 is the same as the high voltage circuit voltage V _P at the high voltage circuit output 309. In order to deliver an electrical stimulation pulse 320 with a target current amplitude I 321 for a duration D 322, a minimum voltage bias must be maintained at the current source 306. The voltage

between anode terminal 302 (i.e., the anode electrode connector) and cathode terminal 303 (i.e., the cathode electrode connector), as a result of a stimulation current pulse with amplitude / 321, is given by

where the time constant a product of capacitor value C _P of a capacitive

component 351 and resistor value of a resistive component 353. Resistor value R _S is for a

resistive component 352 of the patient load. The above equation has the solution

Using R (an equivalent circuit model of a healthy subject

electrode-skin interface) gives τ = 13 milliseconds. Stimulation current pulse duration D 322 has a typical range of 100-200 microseconds, so we have D « τ. Given that can

be approximated by

To maintain proper operation of the TENS stimulator for delivering a current pulse of amplitude I and duration D, the high voltage V _P must be set high enough to ensure is at least The required anode voltage VA reaches its maximum value at time D, and the maximum value

is approximately

where R _j 355 is a sensing resistor with a known value internal to the TENS stimulator for measuring the actual current delivered to the stimulator load 350. In a preferred embodiment of the present invention, the voltage V ₁ across the sensing resistor R ₁ is measured via an analog-to- digital converter ADC 311 and the microprocessor μPC 312 then calculates the actual current delivered to the load 350 by dividing the voltage value V by the resistance value of In a preferred embodiment of the present invention, the value of R _j is set to 10Ω. Therefore, the target output voltage V _P must be set minimally at the value in order for the TENS

stimulator to deliver current pulses with the required amplitude and duration. In a preferred embodiment, V _AC (D) is not directly measured. Rather, the voltage V _c is measured by the measurement circuit MMC 314 at time t = D or at a slightly earlier time. High voltage circuit output V _P is adjusted through microprocessor μPC 312 so that voltage V _c is as close as possible to zero at the end of the stimulation pulse duration D while maintaining the current amplitude during the pulse duration D.

The setting of the high voltage V _P directly affects battery life. Nominal voltage of a battery V _B 305 is about 4.2 volts. A high- voltage generating circuit 310 is used to step-up the battery nominal voltage to the required high voltage V _P . Power conservation principles dictate the following relationship between battery current draw I _B 301 and high voltage V _P at 309:

where β (<100%) is the high-voltage circuit efficiency. For a battery of a given capacity Q _B , the time T _B for the battery capacity to deplete is given by

The actual battery life is shorter than, but proportional to, this theoretical upper bound. It will, therefore, be appreciated that battery life can be improved if the high voltage V _P can be maintained at the minimum value that is required to deliver a desired stimulation pulse of amplitude / and duration D.

Maximizing Battery Life Through The Use Of Novel Biphasic Waveform With Asymmetric

Phase Morphology And Novel Arrangement Of TENS Electrodes The novel TENS stimulator of the present invention is designed to maximize battery life (i.e., maximize T _B ) while maintaining the TENS therapeutic effectiveness. More particularly, the novel TENS stimulator of the present invention utilizes biphasic stimulation pulses (instead of monophasic pulses). The addition of a second phase with reversed polarity minimizes skin irritation due to acid or alkaline reactions. In accordance with the present invention, a novel asymmetric biphasic stimulation pulse morphology is used which leverages the "voltage multiplier effect" (see below) to maximize the stimulation intensity effect of both phases of the pulse without increasing high voltage settings. Significantly, a novel electrode placement scheme allows both positive and negative phases of each biphasic stimulation pulse to effectively activate peripheral nerves for pain relief. In this application, the word "asymmetric" is used to describe differences in the electrical current profiles of the two phases of a biphasic stimulation pulse. In addition, the word

"asymmetric" is used to describe differences in the geometric areas of the two phases of a biphasic stimulation pulse. The area of an electrical stimulation pulse corresponds to the total charge delivered. Therefore, an asymmetric biphasic stimulation pulse may deliver unequal charges in each of the two phases of the biphasic stimulation pulse, causing the total charge delivered in the asymmetric biphasic stimulation pulse to be unbalanced (i.e., causing the accumulation of a "net" positive charge or a "net" negative charge under an electrode at the end of the second phase of the biphasic stimulation pulse).

In a preferred embodiment of the present invention, two electrode pads are placed on the user's body in such a way that each electrode pad overlays a distinct set of nerve fibers. Fig. 4 provides an illustrative example. More particularly, an electrode array 405 with two electrodes (e.g., electrode A 402 and electrode B 404) is placed on the lower leg 410 of a user, with the two electrodes aligned approximately on the same cross- sectional plane 411. Preferably, electrode array 405 comprises a substrate having electrode A 402 and electrode B 404 mounted thereto with a predetermined configuration, wherein the substrate is configured to be held against the skin of the patient in a band-like matter. By way of example but not limitation, the TENS device may be configured as an adjustable band for mounting circumferentially around the limb of the user, with electrode array 405 being secured to the skin-facing side of the TENS device and captured against the skin of the patient. See, for example, U.S. Patent No. 8,948,876, issued 02/03/2015 to NeuroMetrix, Inc. and Shai N. Gozani et al. for APPARATUS AND METHOD FOR RELIEVING PAIN USING TRANSCUTANEOUS ELECTRICAL NERVE

STIMULATION (Attorney's Docket No. NEURO-5960), which patent is hereby incorporated herein by reference. Because peripheral nerves in the lower leg region primarily traverse in the proximal-to-distal direction, each electrode 402, 404 will overlay a different nerve (e.g., electrode A 402 will overlay nerve X 412 and electrode B 404 will overlay nerve Y 414). In this context, the term "nerve" is used, without limitation, to refer to a collection of nerve fibers such as from a major peripheral nerve or a branch of a peripheral nerve. By forming electrode array 405 as a substrate with electrodes 402, 404 mounted thereto with a predetermined configuration, and by appropriately sizing electrode array 405 for the target anatomy, electrodes 402, 404 may be quickly and easily positioned to overlay the appropriate nerves (e.g., nerve X 412 and nerve Y 414) when electrode array 405 is secured to the remainder of the TENS device and the TENS device is mounted to the limb of the patient in a band-like manner. The two electrodes 402, 404 are electrically connected to the cathode and anode terminals 303, 302 of the TENS stimulator unit (Fig. 3).

During the stimulation pulse segment P1A (i.e., the first phase of the first biphasic pulse), nerve X 412 under electrode A 402 is activated by electrical stimulation with intensity INIA = Ic * Dc and the resulting nerve pulses 416 travel proximally to contribute to the effective dose for pain relief. During the stimulation pulse segment P1B (i.e., the second phase of the first biphasic pulse), nerve Y 414 under electrode B 404 is activated by electrical stimulation with intensity INI _B = IA * DA and the resulting nerve pulses 418 travel proximally to contribute to the effective dose for pain relief. Significantly, even though the temporal separation between stimulation pulse segment PI A and stimulation pulse segment PIB is typically 0.1 milliseconds or shorter (i.e., less than the refractory period of a peripheral nerve), nerves X and Y are activated only once (by either stimulation pulse segment PI A or stimulation pulse segment PIB) due to the non-overlapping nature of the nerves, and therefore nerve fibers, under the electrodes and the disposition of the electrodes relative to the nerves. Therefore, both nerves X 412 and Y 414 can be activated during the first biphasic pulse (i.e., nerve X can be activated during the first phase of the biphasic pulse and nerve Y can be activated during the second phase of the biphasic pulse) and contribute to the overall effective dose for pain relief. Because each phase of the biphasic pulse activates a separate nerve with resulting nerve pulses contributing to the effective dose for pain relief, the effective charge C _E is the same as the total pulse charge of of

this biphasic pulse. Stated another way, by applying the biphasic stimulation pulse across two electrodes, wherein each electrode overlies a different nerve, one electrode can activate one nerve during the first phase of the biphasic pulse and the other electrode can activate a second nerve during the second phase of the biphasic pulse. Therefore, each phase of the biphasic pulse operates to provide therapeutic nerve stimulation to the user, and the effective charge C _E is provided by both phases of the biphasic pulse. As a result, with the electrode arrangement shown in Fig. 4, the effective charge C _E delivered to the user with a biphasic pulse is (

by contrast, with the electrode arrangement shown in Fig. 2, the effective charge delivered to the user with a biphasic pulse is

The next biphasic stimulation pulse (i.e., stimulation pulse segment P2B and stimulation pulse segment P2A) occurs at approximately 125 milliseconds (80 Hertz) after the first biphasic stimulation pulse, allowing both nerves time to recover from their respective refractory period and to be activated again. During the stimulation pulse segment P2B, the nerve Y 414 under electrode B 404 is activated by electrical stimulation with intensity IN ₂ B = Ic * Dc- Similarly, the nerve X 412 under electrode A 402 is activated during the stimulation pulse segment P2A with intensity Again the effective charge C _E delivered by the biphasic stimulation pulse using the electrode configuration of Fig. 4 is the same as the total pulse charge of of this biphasic pulse. Therefore, the effective charge for each biphasic

pulse increases to with the novel electrode arrangement of Fig. 4, which is

significantly greater than the effective charge using the electrode arrangement 245 of Fig.

2.

Other electrode placements have also been considered. More than one electrode can be connected to the anode and cathode connectors of the TENS stimulator unit. Electrodes may also be placed on the body in such a manner that the nerves underneath the electrodes connected to the cathode terminal are also partially under the electrodes connected to the anode terminal. Additionally, not all electrodes need to be connected to either cathode or anode terminals during stimulation. Electrode array 421 in Fig. 4 provides an example. Electrodes Al 422 and B l 424 are first connected to the cathode and anode terminals respectively to transmit one or more biphasic pulses. Then electrodes A2 423 and B2 425 are connected to the cathode and anode terminals for the next one or several biphasic pulses. Then electrode Al 422 and B2 425 are connected to the cathode and anode terminals again. Then electrodes A2 423 and B 1 424 are connected to the cathode and anode terminals again. One advantage of alternating the electrode connections may be a reduction of nerve habituation as the relative timing of the nerve pulses 426 and 427 (traveling along the two nerve fiber bundles X 412 and Y 414) becomes variable.

In a preferred embodiment, the target nerve which is to be stimulated is a peripheral sensory nerve. In another preferred embodiment, the target nerve is a cutaneous branch of a mixed motor and sensory nerve.

Fig. 5 shows an illustrative example of the voltage profile across the current

source 306 corresponding to the biphasic stimulation pulse 510. Voltage starts out at when because voltages on all other components to the right of high voltage circuit 310 are

zero as a result of zero current amplitude. At time t there is an immediate voltage drop

531 across the resistive components 352 and 355 (Fig. 3) due to stimulation current.

Between the time interval the capacitive component (Fig. 3) is being

charged and the voltage across the load 350 causes a further gradual drop 532 of the voltage As long as minimum voltage 541 of stays above or the

current source will function properly during the first phase 514 of the biphasic pulse and deliver stimulation at the required current amplitude I _c 512. At time instance t = t ₂ , the current source 306 is turned off and any voltage across the resistive components R _s and R _j will become zero, causing a sudden increase 533 of . During the time period , the current source

306 remains off and the capacitive component C _P 351 (Fig. 3) in the load 350 discharges slightly through the resistive component , causing a slight increase 534 of In a

preferred embodiment, the delay < is set to 100 microseconds. At time

instance t = t ₃ , the load is reversed so that the original voltage drop in the direction from point T to point W in the load 350 becomes a voltage increase from point W to point T since voltage across the capacitor C _P 351 (Fig. 3) cannot be changed instantaneously. As a result, the voltage across the current source 306 experiences a sudden increase 535 to a level usually above

Between the time interval the capacitive component is being charged and

the voltage across the load 350 causes another gradual drop 536 of the voltage V Again, as

long as the minimum voltage 542 of V stays above , or V the current

source will function properly during the second phase 516 of the biphasic pulse and deliver stimulation at the required current amplitude

If the voltage V _P at output terminal 309 of the high voltage circuit 310 is set too low, the voltage V 530 across the current source 306 may not stay above its minimum voltage requirement V during the first phase of the pulse, or the second phase of the pulse, or both phases of the pulse. When the voltage falls below the current source may not be

able to deliver the stimulation current at the required amplitude. Figure 6 provides an illustrative example of the actual current pulse delivered 550 compared with the targeted stimulation current pulse 510. In this case, the first phase of the stimulation current pulse 552 fails to maintain the targeted stimulation current amplitude I _c during the entire first phase of the biphasic stimulation pulse while the second phase of the stimulation current pulse 556 matches the targeted stimulation current amplitude I _A throughout the entire second phase of the biphasic stimulation pulse. At time instance t _c 553, the voltage falls below the threshold V because of the

voltage increase across the capacitor C _P (351 in Fig. 3) as a result of the capacitor being charged by the stimulation current I _c . Actual stimulation current amplitude can be monitored via voltage readings from the resistor R _j as described above. If the actual stimulation current amplitude is not maintained at the same level throughout the entire phase duration, its stimulation intensity is no longer The actual stimulation intensity is the size of the shaded area 552 and can be

approximated by a summation of a series of stimulation current amplitude measurements multiplied by the time interval between the consecutive current measurements. The shaded area 522 sometimes is referred to as the actual charge delivered by the stimulator during the first phase. In one embodiment, if the actual charge delivered is 10% (error percentage) smaller than the target charge the voltage V _P is adjusted higher by an amount proportional to the error

percentage value.

The voltage V _P at output terminal 309 of the high voltage circuit 310 is regulated so that it stays as low as possible while maintaining the integrity of the stimulation pulse. In one embodiment, the integrity of the stimulation pulse is defined as the amplitude of the stimulation current /(t) of the biphasic stimulation pulse 510 being within a predetermined percentage of the target value I _c for all and the target value for all . An example of this

predetermined percentage value is 95%. In another embodiment, the integrity of the stimulation pulse is defined as the intensity IN^ 552 being within a predetermined percentage of the target intensity value . An example of this predetermined percentage value is 90%. The

actual amplitude of the stimulation current delivered can be measured via the voltage drop V ₁ (t) across the resistor 355 over time.

Fig. 7 shows a flowchart of a high voltage control algorithm to regulate the high voltage V _P . The actual amplitude of the stimulation current delivered /(t) can be measured via voltage across the resistor 355. Step 610 determines the actual stimulation current amplitude.

Depending upon the exact definition of the pulse integrity, the most recent current amplitude or the integration of current amplitude measurements are obtained in step 620. The pulse integrity value is compared against appropriate threshold values to determine whether the pulse integrity is acceptable in step 630. If the integrity is not OK, the target value of the high voltage circuit output is increased through step 640 and the stimulation current amplitude is measured again at a pre-determined time interval. If the integrity is found to be OK in step 630, then the voltage is obtained in step 650. If the voltage exceeded the minimum threshold

then the target value of the high voltage circuit output is decreased through step 660. In

a preferred embodiment,

As seen in Fig. 5, the voltage decreases during the first phase 514 of the biphasic

stimulation pulse and during the second stimulation phase 516 of the biphasic stimulation pulse. The sizes of the decreases 532 and 536 are proportional to the stimulation intensity _c and

respectively. For the first phase 514 of the biphasic pulse, the stimulation intensity is

limited by ^or the maximum voltage drop possible on the capacitor 351 within the load 350. However, the stimulation intensity upper limit for the second phase 516 of the biphasic pulse is twice as large as that for the first phase 514 of the biphasic pulse: This is because the voltage on the capacitor is added to at

time instance t = t ₃ so as to provide the starting voltage at the cathode terminal 303. Thus, the upper limit of the stimulation intensity for the second phase 516 of the biphasic pulse is twice as large as the upper limit of the stimulation intensity for the first phase 514 of the biphasic pulse. This phenomenon is sometimes referred to as the "voltage multiplier effect". In practice, the value of the voltage multiplier effect is smaller than 2 due to discharge of the capacitor C _P during the time period t ₂ < t < t ₃ and leakage currents in the stimulator circuit.

The amplitude and duration parameters of each phase 514, 516 of the biphasic pulse can be independently specified. In one embodiment, I _c (the stimulation current amplitude of the first phase) and I _A (the stimulation current amplitude of the second phase) are set to one common value, and D _c (the duration of the first phase) and D _A (the duration of the second phase) are set to another common value. This configuration is the traditional biphasic symmetrical waveform. In another embodiment, I _c and I _A are set to the same value, but D _A is set to be longer than D _c in order to take advantage of the aforementioned voltage multiplier effect of the stimulator circuit (which is due to the electric charge accumulated in the capacitor C _P during the first phase of the biphasic pulse). This configuration is a biphasic asymmetrical waveform.

In yet another embodiment, the amplitude of the second phase I _A is set to a value higher than I _c so that is the same as Setting I _A higher than

I _c may not require a higher target value for high voltage circuit output V _P because of the aforementioned voltage multiplier effect. Being able to set I _A higher, without requiring a higher output voltage V _P , has several advantages. One of these advantages is to allow more effective stimulation of the nerve due to the well-known strength-duration relationship governing nerve stimulation efficacy. The charge required to stimulate a nerve fiber, increases linearly with

the stimulation duration D as follows where b and c are constants called the rheobase and chronaxie, respectively. These constants are influenced by many factors that include the biophysical properties of the nerve fiber being stimulated, the characteristics of the intervening tissue between the electrode and nerve fiber, and the characteristics of the stimulation waveform. However, in all cases b > 1 and c > 0.

Therefore, the same nerve fiber will have a lower if it is subject to a stimulation pulse with a

higher amplitude / and shorter duration D. In other words, stimulation pulses with the same intensity, but a shorter duration, are more effective than those with a longer duration.

In yet another embodiment, both amplitude I _A and duration D _A of the second phase of the biphasic pulse can be set higher than their corresponding values of the first phase without the need to increase the high voltage circuit output V _P due to the aforementioned voltage multiplier effect.

In yet another embodiment, the amplitude of the second phase I _A is set to a different value, for example in a random fashion, for consecutive biphasic pulses such that all amplitude values are within a range. The lower limit of the range can be the amplitude of the first phase I _c and the upper limit of the range can be the highest value without increasing the high voltage circuit output V _P requirement that is needed to support the first phase of the biphasic pulse stimulation. The duration of the second phase of the biphasic stimulation pulse can similarly be set to a range of values. An advantage of varying the intensity of the second phase of the biphasic pulse is to reduce nerve habituation and to increase TENS analgesia effectiveness. With the same high voltage circuit output V _P , the second phase of the biphasic stimulation pulse is capable of stimulating a nerve whose Q ^TU may exceed what the first phase of the biphasic stimulation pulse may be able to do, even when , where is the

maximum output voltage that can be delivered by the high voltage circuit 310. In another embodiment, the high voltage circuit output is adjusted to a level only high enough to

guarantee the integrity of the second phase of the biphasic stimulation pulse. At least two advantages are obtained with such an approach. Firstly, by leveraging the voltage multiplier effect at the second phase of the biphasic pulse, some pain relief can be provided to users of the TENS device whose cannot be supported with the existing TENS hardware design

specifications if only monophasic pulses are used. Secondly, battery life can be extended inasmuch as the high voltage circuit output is lower than what would otherwise be required.

If the amplitude of the stimulation current remains the same for both phases of the biphasic stimulation pulse one can optimize the duration ratio between the two

phases of the biphasic pulse to maximize the total intensity of the biphasic pulse for a given high voltage V _P . For simplicity, we assume D where D _s is the

summation of the first and second phases of the biphasic pulse. Thus a represents the ratio of the duration of the first phase of the biphasic pulse to the sum of the durations of the first phase of the biphasic pulse plus the second phase of the biphasic pulse. Consequently, the total intensity delivered would be / Recall earlier that we have shown that the voltage over the current source 306 is is the voltage across the capacitor C _P as a result

of a current pulse with amplitude / and duration The minimum required high voltage output is Ignoring the voltage change 534 due to

capacitor C _P discharge during the inter-phase interval the voltage over the current source 306 at the beginning of second phase is

The maximum voltage change over the capacitor 351 during the second phase of the

biphasic pulse must satisfy

Utilizing the aforementioned Eq. (1), we have

In a preferred embodiment, the value a is set to 0.36. Using the approximation of I

where y « 1.0 is a constant, we have the minimum required high voltage for a

given a as

For a fixed effective charge (total stimulation intensity) I the minimum high voltage setting

at of what would be required for a symmetric biphasic pulse (i.e., a

biphasic pulse having equal duration for both phases, or a = 0.5). As a result, battery life is expected to be 39% longer under the asymmetric pulse duration case (a = 0.36) than under the symmetric pulse duration case (a = 0.5) when both cases deliver the same effective charge

Achieving Net Zero Charge Accumulation By Reversing The Polarity Of The Biphasic Pulses In one form of the present invention, each biphasic pulse has unbalanced total charge for its two phases. See, for example, the biphasic waveform shown in Fig. 5. The total charge of the first phase of the biphasic pulse is not balanced by the total charge of the second phase of the biphasic pulse: Accordingly, in one preferred embodiment of the present

invention, the polarity of the leading phase of consecutive biphasic pulses alternates so as to allow balanced charge to be delivered to each electrode skin contact area. More particularly, and looking at Fig. 4, the total (negative) charge flowing into the skin area under electrode A 402 is during the first phase PI A of the biphasic pulse and the total (negative) charge flowing

out of the same skin area is during the second phase P1B of the biphasic pulse. The

second biphasic pulse has the polarity of its leading phase P2B reversed when compared with the polarity of the leading phase P1A of the first biphasic pulse. Consequently, the total (negative) charge flowing out of the skin area is I _c * D _c during the first phase P2B of the biphasic pulse and the total (negative) charge flowing into the skin area is I _A * D _A during the second phase P2A of the biphasic pulse. So the net charge is effectively balanced over a span of two biphasic pulses. Similarly, there is no net charge accumulation in the skin areas under electrode B 404.

Instead of alternating the polarity of the leading phase for every biphasic pulse (i.e., as shown in Fig. 4), the frequency of alternating the polarity of the leading phase of the biphasic pulses can be set to a lower value as long as the zero net charge accumulation is maintained across a reasonable period of time. In other words, the polarity of the leading phase of the biphasic pulses may be changed every two pulses, or every three pulses, or every four pulses, etc., so long as there is no net charge accumulation over a selected period of time (which is not so long as to result in adverse skin reactions under the electrodes). In one preferred embodiment, polarity alternating occurs every two biphasic pulses.

Experimental Data Demonstrating Benefits of Asymmetric Biphasic Pulse Stimulation

To demonstrate the benefits of the asymmetric pulse duration approach disclosed herein, ten healthy subjects were recruited and consented to participate in a study to compare the effectiveness of two different biphasic pulse stimulation patterns. Pattern A was the symmetric biphasic pulse pattern wherein both phases of the biphasic pulse had the same amplitude and duration, e.g., such as the biphasic pulse pattern shown in Fig. 2. The duration was fixed at 100 microseconds and amplitude was allowed to be adjusted by each subject to evoke the first sensation of electrical stimulation. Pattern B was the asymmetric biphasic pulse pattern wherein the second phase of the biphasic pulse had a longer duration (180 microseconds) than the first phase of the biphasic pulse (100 microseconds), e.g., such as the biphasic pulse pattern shown in Fig. 5. The amplitude of both phases of the Pattern B asymmetric biphasic pulse pattern was kept the same and allowed to be adjusted by each subject so as to evoke the same first sensation of electrical stimulation as for Pattern A. Subjects were blinded to the stimulation pattern used and carried out the sensation threshold discovery process three times for each stimulation pattern. During each trial, the subject indicated the minimum stimulation pulse amplitude that evoked the first sensation of electrical stimulation. Table 1 summarizes the study results. For each subject, the three identified stimulation pulse amplitudes (in milliamps) were averaged for Pattern A and Pattern B, respectively. Among the ten test subjects, the minimum stimulation current amplitude to evoke a first sensation of electrical stimulation was 14% - 35% lower for asymmetric pulse pattern B than that for symmetric pulse pattern A. Since both pulse patterns had the same duration in the first phase of the biphasic pulse, the reduction in stimulation current amplitude required to evoke the first sensation can only be attributed to longer duration of the second phase of the asymmetric pulse Pattern B. Earlier analyses indicate that the minimum high voltage V _P required will be lower if the first phase current amplitude is lower. Because of the voltage multiplier effect, the high voltage requirement for any pulse with a second phase duration less than 2-times the first phase duration will be approximately the same as that for the first phase.

Direct Muscle Stimulation Using Asymmetric Biphasic Electrical Pulses With An Alternating Polarity Of The Leading Phase Of The Pulses Electrical pulses can also be used to stimulate muscles directly so as to cause muscle contractions. Electrical pulses are delivered through electrodes on the skin. Instead of placing the electrodes so as to overlay peripheral nerves, the electrodes are placed on the skin in direct proximity to the muscles which are to be stimulated. Electrical muscle stimulation (EMS) can be used to improve muscle strength in athletes, to prevent muscle atrophy in patients with musculo skeletal injuries, and to provide external muscle control when the nerve supply to the muscle is compromised.

Portable EMS devices face similar challenges to TENS devices in terms of battery life and stimulation intensity. Applying asymmetric biphasic stimulation pulses in EMS can overcome these challenges by leveraging charge build-up during the first phase of the biphasic stimulation pulse in order to deliver more powerful stimulation during the second phase of the biphasic stimulation pulse. Delivering stronger stimulation pulses with a higher amplitude or a longer duration in the second phase of the biphasic stimulation pulse, without requiring an increase in the output of the high- voltage circuit, will lead to savings in battery life. Alternating the polarity of the leading phase of the biphasic electrical pulses allows the muscles under each electrode to receive the same total stimulation intensity. Alternating the polarity of the leading phases of the biphasic electrical pulses also ensures zero net charge flowing into each electrode even when asymmetric biphasic pulses are used.

Modifications Of The Preferred Embodiments

It should be understood that many additional changes in the details, materials, steps and arrangements of parts, which have been herein described and illustrated in order to explain the nature of the present invention, may be made by those skilled in the art while still remaining within the principles and scope of the invention.