US010342980B2

(12) United States Patent (10) Patent No.: US 10 , 342,980 B2

Troosters et al. (45 ) Date of Patent: Jul. 9, 2019
(54 ) NEUROSTIMULATOR AND METHOD FOR (56 ) References Cited
REGULATING THE SAME
U . S . PATENT DOCUMENTS
( 71 ) Applicant: SORIN CRM SAS, Clamart (FR ) 4 ,602,624 A 7/ 1986 Naples et al.
5 ,782 ,876 A * 7 / 1998 Flammang ........... A61N 1/3622
( 72 ) Inventors: Michel Troosters , Dion -Valmont (BE ); 607 /4
Jean Delbeke, Kraainem (BE ); Pascal (Continued )
Doguet, Tangissart (BE); Hervé Mével, FOREIGN PATENT DOCUMENTS
Chastre (BE )
EP 0 753 284 3 / 1999
( 73 ) Assignee : Sorin CRM SAS, Clamart (FR ) WO WO -01/ 28622 4 / 2001
(Continued )
( * ) Notice : Subject to any disclaimer, the term of this
patent is extended or adjusted under 35 OTHER PUBLICATIONS
U .S .C . 154 (b ) by 237 days.
Demichele et al., “ Stimulus-Resistant Neural Recording Amplifier" ;
(21 ) Appl. No.: 15 /012 ,094 Engineering in Medicine and Biology Society , 2003 . Proceedings of
the 25th Annual International Conference of the IEEE vol. 4 , Issue ,
Sep . 17- 21, 2003 pp . 3329 -3332 vol. 4 , 4 pages.
(22) Filed : Feb . 1, 2016 (Continued )
(65 ) Prior Publication Data Primary Examiner — Michael J D Abreu
US 2016 /0151630 A1 Jun . 2 , 2016 (74 ) Attorney, Agent, or Firm — Foley & Lardner LLP
(57) ABSTRACT
Related U .S . Application Data The present invention relates to an electrode ( 30 ,30 ') for
implantation in contact with a neural tissue, said electrode
(62) Division of application No . 12/681,869, filed as extending along an axis, said neural tissue being capable of
application No. PCT/EP2007/060792 on Oct. 10 , generating one or more action potentials, and said one or
2007, now Pat. No. 9,248 ,274 . more action potentials propagating with a given speed in
said neural tissue . The electrode comprises a carrier ( 31, 31')
(51) Int. Ci. of biocompatible electrically insulatingmaterial; stimulation
A61N 136 ( 2006 .01) electrode contacts ( 32a ; 32 ' a ; 32b ; 32b) deposited on a
A61N 1/05 ( 2006 .01) surface of said carrier ( 31 , 31') for applying an electrical
stimulation to said neural tissue so as to generate , after a
(52) CPC
U .S . CI........ A61N 1 /36139 (2013 .01) ; A61N 1 /0529
given latency time, a compound action potential when
stimulated by said electrical stimulation ; one or more sens
( 2013.01); A61N 1/0556 ( 2013 .01); A6IN ing electrode contacts (33a ; 33b ; 33c; 33 'a ; 33' b ; 33 ' c )
1/ 3605 ( 2013 .01) deposited on said surface of said carrier and provided at a
(58 ) Field of Classification Search distance from said stimulation electrode contacts , said sens
ing electrode contacts being adapted to be connected to
CPC ........ A61N 1/ 05 ; A61N 1 /056 ; A61N 1 /0551;
A61N 1/0529; A61N 1/36139; A61M measuring means (23 ) having a given inactive period . The
5 / 14276 invention includes means to reduce the stimulation artifact .
See application file for complete search history . (Continued )
32 a

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332

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32 ' d
32 a

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326

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 US 10 , 342 , 980 B2
Page 2

The invention also relates to an apparatus (20 ) and method 2005/0137645 A1 6 /2005 Voipio et al.
for using various signals obtained from the stimulation 2005 /0182456 A1 * 8 /2005 Ziobro ................. A61B 5 /0488
probe itself and used to control the parameters of the current 607/ 48
2006 / 0030919 A1 2 / 2006 Mrva et al.
pulses applied to the electrodes . 2006 /0167497 A1 7 / 2006 Armstrong et al.
2008 /0046016 Al 2/2008 Ben -David et al.
20 Claims, 7 Drawing Sheets 2009 /0221897 A1 * 9 /2009 Nieuwkoop . ... . A61B 5 /04085
600 / 393
2010 /0222844 A1* 9/2010 Troosters . ........... A61N 1/0529
607/59
References Cited 2011/0082521 A1 * 4 /2011 Botros ............. A61B 5 /04001
(56 ) 607 / 57
U .S . PATENT DOCUMENTS FOREIGN PATENT DOCUMENTS
5 ,824, 027 A 10 / 1998 Hoffer et al.
5 , 857 ,980 A 1 / 1999 Wilson WO WO -01/60445 8 /2001
5 ,913 , 882 A 6 / 1999 King WO WO -2004 /034880 4 /2004
6 ,157 , 861 A * 12 /2000 Faltys ................ A61N 1/ 36036 WO WO -2004 /087256 10 / 2004
607 / 57 WO WO -2006 /017277 2 /2006
6 ,529 ,774 B1 3/ 2003 Greene wo WO -2006 /041870 4 /2006
7 , 167,751 B1 1/2007 Whitehurst et al. WO WO - 2007 /064739 6 / 2007
7 ,310 ,557 B2 12 / 2007 Maschino et al. WO WO -2009/ 046764 4 /2009
7 ,561, 918 B2 7 /2009 Armstrong et al.
2001/ 0023367 A1 * 9/ 2001 King ................. A61M 5 / 14276 OTHER PUBLICATIONS
607/ 117
2002 /0183817 Al 12/ 2002 Van Venrooij et al. Office Action on European Application No. 07821159.6 - 1657 , dated
2003/0040785 AL 2 / 2003 Maschino et al.
2004/ 0010303 A11 / 2004 Bolea et al. Jan . 3, 2014 , 7 pages.
2004/0133120 A1 * 7 / 2004 Frei .. . . . . . . . . . . . . . . . . AOIB
A61B 5 /040
048
600 /544 * cited by examiner
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 US 10 ,342 , 980 B2
NEUROSTIMULATOR AND METHOD FOR An individual neuron typically consists of a soma (i.e. cell
REGULATING THE SAME body ), which contains the nucleus of the cell ; dendrites,
which receive input from pre -synaptic neurons; and an axon ,
CROSS -REFERENCE TO RELATED which send signals via axon terminals (i.e . the distal portion
APPLICATIONS 5 of the axon ) to post-synaptic neurons (or to effector cells,
such as muscle fibers). An action potential is initiated at the
This present application is a divisional of U . S . application initial segment of the axon (i. e. the proximal portion of the
Ser. No. 12 /681, 869, entitled “ NEUROSTIMULATOR axon ) when triggered by input from the dendrites .
AND METHOD FOR REGULATING THE SAME,” filed An action potential is an electrochemical signal that
Apr. 6 , 2010 , which is a 371 U .S . national application of 10 propagates from the initial segment down the axon to the
International Application No. PCT/ EP2007 /060792 , entitled axon terminals . Such propagation is referred to as orthodro
“ NEUROSTIMULATOR AND METHOD FOR REGU mic , which is defined as " of, relating to , or inducing nerve
LATING THE SAME ,” filed Oct . 10 , 2007 , both of which impulses along an axon in the normal direction ” . Action
are hereby incorporated by reference herein in their entire 15 potential propagation in the opposite direction is referred to
ties. as antidromic, which is defined as “ proceeding or conduct
TECHNICAL FIELD ing in a direction opposite to the usual one used especially
of a nerve impulse or fiber” .
The present invention relates to the field of neurological When a neuron is at rest (i.e ., there is no propagation of
implants . More particularly, it relates to the field of stimu - 20 an action potential), the inside of the axon is negatively
lators for neural tissue and nerves, including cranial and charged with respect to the outside of the neuron, i.e., the
peripheral nerves. More specifically , the present invention membrane of the axon is at a negative resting potential. Said
relates to a neurostimulator and a method for integrated negative resting potential is typically between - 80 and -60
regulation of the intensity , regimen , shape, pulse duration , mV. Through chemical connections known as synapses, any
frequency , train rate and train length of electrical stimula - 25 given neuron receives from other neurons excitatory and
tions generated by this neurostimulator. inhibitory input signals or stimuli. A neuron integrates the
excitatory and inhibitory input signals it receives, and gen
DESCRIPTION OF RELATED ART erates or fires a series of action potentials when the integra
tion exceeds a threshold potential of about - 20 mV. A neural
Nowadays, the nerve stimulation is largely utilized in 30
several applications for treating or monitoring a variety of firing threshold may lead the inside of the axon to a charge
of about + 30 mV. Action potentials propagate to the neu
medical, psychiatric , or neurological disorders . In particular, ron 's synapses, where they are conveyed to other neurons to
vagus nerve stimulation techniques as well as deep brain
stimulation techniques have been considerably studied . which the neuron is synaptically connected .
Vagus nerve (also referred as pneumogastric nerve or 35 The deep -brain stimulation (DBS ) was first developed in
cranial nerve X ) is the tenth of twelve paired cranial nerves . France in 1987 and developed from the so -called ablative , or
It is characterized in that it is the only nerve that starts in the lesioning , surgeries in which surgeons use heat probes to
brainstem , i.e . within the medulla oblongata , and extends, burn and permanently damage small regions of the brain .
through the jugular foramen , down below the head , to the These same brain regions are now targeted with DBS, but
abdomen . In particular, it is responsible for controlling 40 instead of destroying tissue, implanted electrodes apply
and/ or receiving feedback from various glands , the heart, pulses of electricity . DBS electrodes typically have a diam
pharynx , larynx , aortic and carotid pressure sensors , lungs, eter ofabout 1.30 millimeter and are connected to wires that
stomach , ureters , and so on . Because of its broad number of snake from the skull, behind the ear and down to a small
functions with respect to a range of body systems, vagus battery -run power pack which is typically installed in the
nerve is preferred in many applications for purposes of 45 chest . When the generator is switched on , it delivers con
modulating the functions of designated organs or portions of tinuous low - voltage electrical pulses to the brain .
the central nervous system .
It is well known that neurons typically propagate signals PRIOR ART DISCUSSION
along their axon . Peripheral nerve fibers that propagate
signals away from the central nervous system (i. e ., the brain 50 A neurostimulator is an electronic device capable of
and the spinal cord ) and towards the periphery and viscera applying a neural stimulation signal to a nerve or brain tissue
are referred to as efferent nerve fibers . Peripheral nerve through one or more electrodes . A neural stimulation signal
fibers that propagate signals away from the periphery and typically comprises a series or train of electrical or magnetic
viscera and towards the central nervous system are referred pulses that can induce action potentials in some neurons (or
to as afferent nerve fibers . 55 axons) within a target neural population . These pulses may
Efferent impulses may produce a variety of actions , from be defined or described in accordance with stimulation
movement of a muscle to initiation of changes in the heart signal parameters including pulse amplitude, pulse fre
rate or force of contraction or in the level of constriction of quency , duty cycle , stimulation signal duration , and/or other
the vascular smooth muscle in arterioles. Through increas- parameters . Although electrical or magnetic stimulation of
ing or decreasing the activity of efferent fibers , the central 60 neural tissue is intended to produce a type of therapeutic ,
nervous system can , for example , alter the blood pressure by rehabilitative , or restorative neural activity , howevermost of
changing the characteristics of the cardiovascular system . such stimulations represents a waste of battery current and
Afferent impulses from specialized nerve endings or may result in collateral neural activity. In particular, neural
receptors inform the controlling neurons in the central stimulation delivered beyond a certain value of intensity,
nervous system about characteristics of the system , e.g., if a 65 level, or amplitude can produce seizure activity and/or other
limb is feeling pain . Most peripheral nerves contain both types of collateral activity , which may be undesirable and/ or
afferent and efferent nerve fibers . inconvenient in a neural stimulation situation . It is evident
 US 10 ,342 ,980 B2
that the control and the regulation of the intensity, level, or least two electrodes small enough to have the electrodes
amplitude of such electrical stimulations represent a very located adjacent to the vagus nerve. The small stimulator
important aspect . provides means for stimulating the vagus nerve when
The traditional method for obtaining a stimulation of desired . However, the regulation of the intensity and / or
sufficient magnitude ( strength ) consists in increasing pro - 5 duration of electrical stimulation required to produce the
gressively the current pulse intensity , or the pulse duration , desired effect is based on the state of the patient which is
or the frequency, or the pulse train length of the electrical additionally or alternatively sensed .
stimulation and monitoring physiological parameters, dis Document US20050137645 discloses a method for
ease state parameters and / or reactions of the patient. For adjusting the vagus nerve stimulation (VNS) signal induced
example , the amplitude or strength of the stimulation will be 10 by a stimulus generator implanted in a patient. However, the
reduced according to collateral sensations reported by the regulation of the intensity of the stimulation is based on the
patient who has noticed , perceived or experienced a physical
sensation due to that stimulation . Such a regulation , which response
eters of
of respiratory or physiological acid -base param
the patient .
is typically defined as neural stimulation threshold test
procedure, is evidently very uncomfortable for the patient 15 Document W001/60445 relates to methods and appara
and does not guarantee optimal therapeutic stimulation tuses for the detection of neural or muscular activity , analy
intensity . Furthermore , this regulation may create distur- sis of the signals and the subsequent stimulating of neural or
bance and , even pain , before the desired intensity is muscular tissue based thereon. This document discloses a
obtained . Also , the finally selected stimulation is more a combined sensing and stimulation electrode device mainly
reflection of the patient's sensitivity than a function of the 20 addressed to the hemiplegic drop foot. The device mainly
effective nerve stimulation and, as a consequence , a stronger comprises:
stimulation than required might be selected and used for at least one neurosense electrode means capable of sens
long periods of time. ing a nerve signal from a peripheral nerve and at least
Another important limitation of current neurostimulators one stimulation electrode means capable of stimulating
is represented by the so -called stimulation artifact. In order 25 a peripheral motor nerve fibre ;
to study in vitro and in vivo neural activity, neuroscience means for receiving and processing the sensed neurosig
researches are increasingly using both electrical stimulation nals to identify a signal indicative of a specific action ,
and neural recording. Typically , the neural signals that are especially a component of the gait performed by the
recorded are less than 10 uV and in order to be usable they patient and for producing a control signal in response
have to be treated by special equipment , such as low -noise 30 thereto ;
broadband amplifiers. However, when an electrical stimu means for operating the at least one stimulation electrode
lation is applied to a tissue, the electrical field generated in means in response to the control signal to produce a
the tissues by the stimulation artifact introduced into this stimulation of a peripheral motor nerve fibre .
tissue may be three or four orders of magnitude larger than Neurosense electrode means and stimulation electrode
normal activity of a neural population or compound action 35 means may be combined together in order to have a single
potential. As a consequence , this stimulation artifact electrode which , in combination with switching means, may
instantly saturates the recording equipment which remains perform stimulation or sensing of the neural activity of a
for a certain time inactive until the system regains its nerve . However, this device does not provide a single cuff
electrical equilibrium . This inactive period may be several electrode that may simultaneously stimulate and record the
hundred milliseconds long and can cause failures of the 40 effect of stimulations on said nerve. Predetermined stimu
recording equipment. For more details concerning neural - lations are applied to a neural tissue or a muscular tissue at
recording amplifier systems one can refer , for example , to a selected time based on the signals detected by neurosense
the document “ Stimulus -Resistant neural Recording Ampli - electrodes and based on the analysis of said signals. This
fier” ; DeMichele , G . A ., Troyk , P . R .; Engineering in Medi- device is capable ofmonitoring the neural activity without
cine and Biology Society, 2003. Proceedings of the 25th 45 stimulations and provides, according to the prior art, an
Annual International Conference of the IEEE Volume 4 , indirect measurement of the stimulation based on a quanti
Issue, 17 - 21 Sep . 2003 Page(s ): 3329 - 3332 Vol. 4 . tative representation of the level or " state” of the disease to
It is known from document EP0753284 a single nerve be treated . This device does not provide a direct and quali
compound action potential measuring apparatus. This appa - tative measurement of the effect of the stimulation applied to
ratus comprises in particular means for separating and 50 a nerve . Furthermore , this device does not providemeans for
extracting the nerve compound action potential generated by overcoming the stimulation artifact.
a single neuron from other neurons. However, this apparatus It is known from document WO2006 /017277 a neurologi
does not provide means for monitoring the compound action cal control system for modulating activity of a nervous
potential of the entire nerve . Moreover, it does not comprise system component in the treatment of diseases in order to
means for electrically stimulating the nerve . 55 control a therapy . This neurological control system com
It is known from document U . S . Pat. No. 4 ,602 ,624 an prises several sensing electrodes contacts for evaluating a
implantable cuff which fits around a nerve trunk . The cuff disease state and processes this information in order to
mainly comprises a self - curling sheet of non - conductive control a treatment by applying neuromodulation stimula
material which is self -biased to curl into a spiral or roll. It tion . Similarly to the above discussed documents of the prior
also comprises two electrodes (40, 50 ) for applying electri- 60 art , this device also performs indirect measurements of the
cal impulses that are disposed on said self -curling sheet such applied stimulation by evaluating the disease state or the
that one extends peripherally around each of the larger and global therapeutic efficiency . In fact said sensing electrodes
smaller diameter regions of the passage therethrough . How contacts explore effects of the stimulation at a certain
ever, this implantable cuff does not comprise means for distance from where the stimulation occurs , there where
monitoring the neural activity during the stimulations . 65 symptoms of the disease can be recorded . No verification of
It is also known from document U .S . Pat. No. 7 , 167,751 the immediate physiological effectofthe applied stimulation
a method of using a small implantable stimulator( s ) with at is performed .
 US 10 ,342 , 980 B2
The present invention aims at providing a neurostimulator In both embodiments of the invention , the sensing elec
that overcomes the above - discussed drawbacks of the prior trode contacts may form a tripole . In a tripole , one electrode
art. In particular, it is an object of the present invention to is surrounded by two other electrodes connected electrically
provide a neurostimulator wherein the regulation of the together.
magnitude or strength of the electrical stimulation is no 5 The sensing electrode contacts may comprise a single
longer based on testing subjective perceptions of the patient electrode contact, a voltage reference being provided by an
or indirect measurements. More particularly , it is an object electrode contact located in a position remote from the
of the present invention to provide a more efficient and more electrode
a
. The remote electrode contactmay be the casing of
neurostimulation apparatus .
reliable neurostimulator, in contrast with prior art, wherein 10 In a second aspect
the regulation of the stimulation strength is operated con stimulation apparatus for, the invention relates to a nerve
inducing electrical stimulations to
tinuously and automatically without disturbing the patient.
Moreover, it is an object of the present invention to provide a neural tissue , the apparatus comprising a generator for
generating electrical stimulations having specified ampli
a neurostimulator which avoids the drawback of stimulation tude and shape; electrical connectors for connecting the
artifact. 15 apparatus to the electrode of the invention . According to the
SUMMARY OF THE INVENTION invention , the apparatus comprises means for controlling the
amplitude and shape of said electrical stimulations in such a
way that the amplitude of the compound action potential
In a first aspect, the invention relates to an electrode for measured by sensing electrode contacts reaches an expected
implantation in contact with a neural tissue , said electrode 20 value within desired time constraints . By “ shape” of the
extending along an axis , said neural tissue being capable of electrical stimulation , one understands in the present context
generating one or more action potentials , said one or more the shape of a single pulse , as well as the duration of a pulse ,
action potentials propagating with a given speed in said the repetition rate , the pulse train duration or duty cycle for
neural tissue . The electrode comprises a carrier of biocom - discontinuous stimulation and the modification of these in
patible electrically insulatingmaterial; stimulation electrode 25 time.
contacts deposited on a surface of said carrier for applying The regulation means of the nerve stimulation apparatus
an electrical stimulation to said neural tissue so as to may comprises a microcontroller for controlling the ampli
generate, after a given latency time, a compound action tude and shape of the electrical stimulations ; an amplifier for
potential when stimulated by said electrical stimulation ; one amplifying and conditioning analog signals recorded by
ormore sensing electrode contacts deposited on said surface 30 sensing electrode contacts and an analog/digital signal con
of said carrier and provided at a distance from said stimu verter for converting amplified analog signals into digital
lation electrode contacts , said sensing electrode contacts signals.
being adapted to be connected to measuring means having a In one embodiment of the nerve stimulation apparatus, the
given inactive period . According to the invention , the sens 35 microcontroller comprises a programmed algorithm for
automatically computing said specified amplitude and
ing electrode contacts are located at a predetermined dis shape.
tance Ae from the stimulation electrode contacts so that said
compound action potential, generated by said stimulation In another embodiment of the nerve stimulation appara
tus , the microcontroller comprises means for exchanging
electrode contacts reaches said sensing electrode contacts information with an external output device for displaying the
when said inactive period of said measuring means is 40 compound action potential and an external input device.
already elapsed . whereby an operator adapts said specified amplitude and
In a first embodiment of the invention , the electrode shape depending on the displayed compound action poten
comprises a cuff capable of fitting closely around a selected tial. The means for exchanging information may use wire
portion of an elongated nerve, said stimulation electrode less data exchange through an antenna system , as is well
contacts and sensing electrode contacts being deposited on 45 known in the art.
a surface of said cuff in contact with said portion of the The amplifier may advantageously be a variable - gain
nerve. amplifier, wherein the gain is controlled by the microcon
Preferably , the distance Ae in this first embodiment is troller through an input gain control line. Thereby , the input
comprised between 2 mm and 20 mm . gain may be reduced to zero during the stimulation phase ,
In a second embodiment of the invention , the carrier 50 and set to an appropriate value during the measurement
comprises a lead capable of being inserted into a portion of phase .
a brain tissue, said stimulation electrode contacts and sens The amplifier may also be provided with a short circuit
next to its input ports, the short circuit being controlled the
ing electrode contacts being deposited on a surface of said microcontroller
lead in contact with said portion of the brain tissue. through the input short circuit control line
Preferably, the distance Ae in this second embodiment is 55» withThethepower
same purpose
supply voltage of the amplifier may advanta
comprised between 1 mm and 15 mm .
In the second embodiment, the stimulation electrode maximum voltage ofatstimulation
geously be selected a value which is higher than the
pulses produced by said
contacts and sensing electrode contacts may be arranged generator. Thereby, the risk of a saturation of the amplifier
alternately along said lead . 60 by the stimulation pulses is reduced .
The lead may comprise a single stimulation electrode The nerve stimulation apparatus may further comprise a
contact and a single sensing electrode contacts. high - pass filter between the sensing electrode contacts and
The lead may also comprise a single stimulation electrode the amplifier and /or a low -pass filter between the amplifier
contact and a pair of sensing electrode contacts arranged on and the A / D converter.
opposite sides of said stimulation electrode contact. 65 In a last aspect, the invention relates to a method for
The lead may also comprise a plurality of sensing elec - regulating the intensity of electrical stimulations generated
trode contacts arranged on a circumference of said lead . by a nerve stimulation apparatus characterized in that it
 US 10 ,342 ,980 B2
comprises the steps of: implanting an electrode of the ment of the present invention , is illustrated in FIG . 1. The
invention in such a way as to be in contact with a portion of neurostimulator 10 mainly comprises:
a neural tissue; applying electrical stimulations on said a circuit enclosure 20 ;
portion by means of stimulation electrode contacts ; measur a cuff electrode 30 capable of fitting closely around a
ing the compound actionion potential generated by
potential generated said stimu
by said stimu -- 55 selected portion of said nerve;
lation electrode contacts through sensing electrode contacts electrical connection wires 40 for connecting said cuff 30
and adjusting the amplitude and shape of said electrical to said circuit enclosure 20 ;
stimulations in order to obtain a desired compound action FIG . 2 and FIG . 3 show , respectively, a perspective view
potential. in a uncurled configuration and a perspective view in a
Preferably , the step of applying electrical stimulations on 10 curled configuration of the cuff electrode 30 of FIG . 1. Said
said portion comprises applying a long -duration (t1), low cuff electrode 30 comprises:
amplitude (A1) anodic phase and a subsequent relatively a carrier 31 of biocompatible electrically insulating mate
short -duration (t2 ), high - amplitude ( A2 ) cathodic phase in rial, such as silicone rubber for example ;
order to activate the neural tissue at the very end of the stimulation electrode contacts 32a , 32b deposited on said
charge balanced stimulation . 15 carrier 31, for applying an electrical stimulation to a
The anodic phase may be applied with a progressive selected portion of a nerve so as to generate a com
amplitude in order to further avoid early tissue activation . pound action potential;
One may adjust the cathodic to anodic phase ratio in order sensing electrode contacts 33a , 33b , 33c deposited on said
to minimize the stimulus artifact, the anodic charge recu carrier 31 provided along the direction of propagation
peration phase duration being equal or slightly smaller than 20 of said compound action potential signals. Sensing
the cathodic stimulating phase duration . electrode contacts 33a , 33b , 33c are positioned at a
The method may further comprise the step of reducing the predetermined axial distance Ae from the stimulation
amplitude and shape of said electrical stimulations when the electrode contacts 32a , 32b or at specified positions
measured characteristics of the compound action potential or with respect to the stimulation electrode contacts 32a ,
other measurements from the probe indicate that a prede - 25 32b or with respect to said selected portion of the nerve,
termined safety limit is reached . as described in the following description .
More preferably , the method may further comprise the As shown in FIG . 4 , the circuit enclosure 20 of FIG . 1
step ofmeasuring at least one of the following parameters : mainly comprises :
of said electrical stimulation : local DC potential values ; a generator 21 of electrical stimulations capable of vary
stimulation voltage values ; tissue impedance values , in order 30 ing certain parameters of said electrical stimulations ,
to determine said safety limit for guaranteeing the safety of such as, for example , intensity , shape, pulse duration ,
said portion of neural tissue. frequency, train rate , duty cycle and train length , etc ;
More preferably, the method further comprises the step of a micro controller 22 for automatically adjusting the
measuring the voltage applied by said generator to said parameters of said electrical stimulations, such as , for
stimulation electrode contacts in order to determine said 35 example , intensity, shape, pulse duration , frequency,
safety limit for preventing the corrosion of said stimulation train rate , duty cycle and train length , etc ;
electrode contacts. an amplifier 23 for amplifying and conditioning analog
signals recorded by sensing electrode contacts 33;
BRIEF DESCRIPTION OF THE DRAWINGS an analog/digital signal converter 24 for converting
40 amplified analogic signals into digital signals;
FIG . 1 illustrates a neurostimulator device according to a Analogic signals are recorded by sensing electrode con
preferred embodiment of the present the invention . tacts 33a , 33b , 33c, then amplified by amplifier 23 and
FIG . 2 and FIG . 3 show , respectively , a perspective view finally converted into digital signals . The latter are the input
of a cuff electrode in an uncurled configuration and a for micro controller 22 which is capable of varying certain
perspective view of the same cuff electrode in a curled 45 parameters of the electrical stimulations in such a way that
configuration , according to a first preferred embodiment of the amplitude of the resulting compound action potential (or
the present invention . any other parameter including the local DC shift or the
FIG . 4 shows a block diagram of the circuitry of the stimulus potential field , as measured by sensing electrode
circuit enclosure of FIG . 1 . contacts 33 , and the stimulation electrode potential ) reaches
FIG . 4a shows a block diagram of the circuitry according 50 an expected value within desired time constraints .
to a variant of the circuit enclosure of FIG . 1 . Sensing electrode contacts 33a , 33b , 33c are located at a
FIG . 5 is a schematic diagram of stimulation current predetermined axial distance Ae from the stimulation elec
waveforms and amplified compound action potential wave - trode contacts 32a , 32b , as shown in FIG . 2 . Sensing
forms for the neurostimulator of FIG . 1 . electrode contacts 33a , 33b , 33c form a tripole electrode
FIG . 6 shows a perspective view of a deep brain stimu - 55 contact with two dependant contacts 33a, 33c and an inde
lation electrode according to a second preferred embodiment pendent contact 33b located between said two dependent
of the invention and different electrode contacts arrange contacts 33a , 33c , as shown in FIG . 2 or FIG . 3 . In
ments . particular, the distance Ae between the central part of
stimulation electrode contact 32b and the central part of
DETAILED DESCRIPTION OF THE 60 sensing electrode contact 33b has been computed in such a
INVENTION way that compound action potential signals ( generated by
the stimulation electrode contacts 32a , 32b ) reach the sens
First Embodiment of the Invention ing electrode contacts 33b when the artifact period of the
amplifier 23 is already elapsed , in order to insure correct
A neurostimulator for inducing electrical stimulations to a 65 measurements of the amplitude of the compound action
portion of a peripheral or cranial nerve , for example to a potential. Typically, the artifact period lasts about 0 . 5 ms, the
portion of the vagus nerve , according to a preferred embodi compound action potential speed is roughly 50 m /s and the
 US 10,342 , 980 B2
latency time for a cell to generate said compound action in contrast with prior art. In such a way with this particular
potential is about 1 ms. According to a preferred embodi- choice , when the latency time required by the cells of the
ment of the invention , the predetermined distance Ae is 10 nerve for generating the compound action potential is
mm , so that the compound action potential reaches the elapsed and consequently the action potential is generated ,
sensing electrode 33b after 1 .2 ms, that is when the artifact 5 the charge equilibrium between the two phases has been
period is already elapsed ( 0 . 7 ms later ). As the compound already re - established . Individual phases of the stimulation
action potential speed as well as the latency time of a cell pulse are however not necessarily rectangular. For example,
may be different from nerve to nerve , the value of the a progressive triangular anodic phase can be applied to
distance Ae may be different. It is however clear that further minimize the risk of neural activation during that
different values of distance Ae may be chosen without 10 phase . Also , various shapes of the cathodic phase can be
departing from the condition that action potential signals used to optimize the selective activation of a subpopulation
(generated by the stimulation electrode contacts 32a , 32b ) of axons or neurons.
reach the sensing electrode contacts 33b when the artifact According to a variant of this preferred embodiment, the
period of the amplifier 23 is already elapsed . amplifier 23 is a variable - gain amplifier, as shown in FIG . 4 .
An important aspect of the present invention should be 15 The controller 22 is capable of varying the input gain of
highlighted . Contrary to prior art disclosures, sensing elec accelerator 23 through the input gain control line 25 during
trodes contacts , according to the invention , perform direct the stimulation artifact period . In such a way, during the
measurements of the stimulation effect, and such measure stimulation artifact the amplifier 23 cannot be saturated .
ments are done in close proximity to the stimulation whose According to a second variant of this preferred embodi
direct effect can be monitored . More particularly , direct 20 ment, in order not to saturate the amplifier 23, the power
effects of the stimulation over electrode potentials, gener supply voltage of this amplifier 23 is selected at a value
ated field potential and neural tissue excitation are used to which is superior to the maximum voltage of stimulation
control the electrical stimulus . Therefore, accordingly , such pulses produced by generator 21 .
a monitoring is not performed by evaluating the disease According to another variant of this embodiment, in order
state ; by contrast, the sensing electrodes contacts control 25 not to saturate the amplifier 23 , as shown in FIG . 4 , the
directly the technical efficiency of the stimulation rather than controller 22 is capable of controlling , through the input
the global therapeutic efficiency of the stimulation . short circuit control line 26 , a short circuit located between
In one embodiment of the apparatus, the controller com said amplifier 23 and sensing electrode contacts 33a , 33b ,
prises an algorithm adapted for automatically determining 33c. The controller 22 is capable of closing this short circuit
the amplitude and shape of the stimulation pulses. In this 30 during the artifact period, in order not to saturate the
embodiment the apparatus may be used permanently by a amplifier 23 and opening this short circuit at the end of the
patient. In another embodiment of the apparatus , as shown artifact period . With this arrangement, the invention permits
in FIG . 4a , a display device 29b displays the shape of the to overcome the stimulation artifact drawback .
compound action potential measured by the sensing elec
trodes . An operator, or the patient himself, may then provide 35 Second Embodiment of the Invention
adapted instructions to the controller through an input device
29a. The input device 29a may be a small keyboard or a According to a second preferred embodiment, the neuro
control panel with buttons and controls . When the apparatus stimulator comprises , instead of the cuff electrode previ
20 is implanted into the body of a patient, the communica - ously described , a deep brain stimulation electrode capable
tion between the apparatus 20 , and the keyboard 29a and 40 of being inserted stereotactically in close contact to a
display 29b may occur through a wireless connection , using selected region of the brain .
antennas . FIG . 6 shows a perspective view of such a deep brain
In a variant of this preferred embodiment of the present stimulation electrode comprising a needle 30 ' and, similarly
invention , the neurostimulator 10 comprises a high -pass to the first preferred embodiment:
filter ( 27 ) between said amplifier ( 23 ) and said sensing 45 a carrier 31 ' of biocompatible electrically insulatingmate
electrode contacts ( 33a ; 33b ; 33c; 33'a ; 33'b; 33 'c ) and /or a rial, such as silicone rubber for example ;
low -pass filter ( 28 ) between said amplifier ( 23 ) and said A /D ring -shaped stimulation electrode contacts 32'a , 32'b ,
converter ( 24 ). In this case the amplifier 23 amplifies signals 32 'c, 32'd deposited on said carrier 31', for applying an
in a preferred frequency range . electrical stimulation to said selected portion of the
FIG . 5 is a schematic diagram of stimulation current 50 brain so as to generate a compound action potential
waveforms and amplified compound action potential wave which propagates in a tri-dimensional way;
forms for the neurostimulator 10 according to a preferred a plurality of small sensing electrode contacts 33'a , 33'b ,
embodiment. The upper part of FIG . 5 shows two cycles of 33 'c, 33'd , 33'e deposited on said carrier 31' and posi
stimulation current waveforms which repeat with a period T tioned at a predetermined distance Ae from the stimu
and the corresponding lower part shows the artifact period 55 lation electrode contacts 32'a , 32'6 , 32 'c, 32 'd , similarly
AP and the compound action potential waveforms APW . to the previous preferred embodiment.
Each cycle of stimulation (upper part ) is characterized by a According to different variants of this second preferred
long -duration ( t1 ), low -amplitude (A1) anodic phase and a embodiment, the deep brain stimulation electrode may com
subsequent relatively short-duration (t2 ), high -amplitude prises a single ring -shaped stimulation electrode contact
(A2) cathodic phase . The charge delivered by the anodic 60 32'a coupled to a single sensing electrode contact 33'a ; or a
phase is equal in magnitude but opposite in polarity with single ring -shaped stimulation electrode contact 32 'a
respect to the charge delivered by the cathodic phase . In such coupled to two sensing electrode contacts 33 'a , 33'b located
a way it is possible to apply a charge- balanced stimulation up and down with respect to said stimulation electrode
which does not lead to tissue damage or electrodes corro - contact 32'a ; or a single ring - shaped stimulation electrode
sion . An important feature , according to this preferred 65 contact 32'a coupled to three sensing electrode contacts 33'b
embodiment of the present invention , is represented by the located on said carrier 31' on one side of and at intervals of
fact that the anodic phase is applied before the cathodic one , 120 degrees with respect to said stimulation electrode con
 US 10 ,342 ,980 B2
12
tact 32 'a and with three other sensing electrode contacts 33 'a The invention claimed is :
located on said carrier 31 ' on the other side of and also at 1 . A method of regulating the intensity of electrical
intervals of 120 degrees with respect to said stimulation stimulations generated by a nerve stimulation apparatus, the
electrode contact 32'a . method comprising :
According to this second preferred embodiment, the neu - 5 implanting an electrode comprising a plurality of sensing
rostimulator may be used for example for the treatment of: electrode contacts and a plurality of stimulation elec
Parkinson 's disease, dyskinesia , essential tremor, epilepsy , trode contacts such that the sensing electrode contacts
pain , obsessive compulsive disorder (OCT), dystonia , torti and the stimulation electrode contacts are in contact
collis, hemiparesis, speech impairement, cluster headaches , with a portion of a neural tissue, wherein the sensing
me, 10
orthostatic hypotension , hypertension , tourette 's syndrome electrode contacts form a tripole comprising one central
persistent vegetative state , and depression . independent sensing electrode contact located between
Depending on the particular disease , the deep brain stimu two dependent sensing electrode contacts;
lation electrode can be implanted (uni- or bilaterally ) for applying electrical stimulation to the portion of the neural
example in subthalamic nucleus , globus pallidus , periven - 15 . tissue via the stimulation electrode contacts so as to
generate , after a given latency time, a compound neural
tricular/periaqueducal gray matter (midbrain ), thalamus, action potential, wherein the electrical stimulation
ventral intermediate nucleus of the thalamus, anterior thala comprises an amplitude and a shape;
mus, sensory thalamus (ventro - postero -lateral nucleus, cen measuring the compound neural action potential gener
tromedian thalamus, centromedian - parafascicular complex ated by the stimulation electrode contacts via the sens
of thalamus, internal capsule ,hypothalamus, mesencephalic 20 ing electrode contacts , wherein the sensing electrode
reticular formation , cerebellum , caudate nucleus,hippocam contacts are capable ofbeing saturated by the electrical
pus , amygdalo -hyppocampal region, neocortex , mamillary stimulation during an artifact period , wherein the sens
body, subgenual cingulated region (frontal cortex ), nucleus ing electrode contacts are located at a predetermined
accumbens. distance from the stimulation electrode contacts such
Sensing electrode contacts, according to the invention , 25 that the compound neural action potential generated by
can be arranged in a number of montages in order to the stimulation electrode contacts reaches the sensing
precisely localize the source of the signal being recorded . electrode contacts when the artifact period is already
This includes monopolar montages whereby each derivation elapsed , and wherein the predetermined distance is
channel receives the signal from a single sensing contact of measured between a central part of the central inde
the electrode and is referred to a large distant contact higher 30 pendent sensing electrode contact and a central part of
up on the electrode shaft or on the stimulation enclosure . the stimulation electrode contact that is closest to the
Alternatively , a large number of bipolar montages can be central independent sensing electrode contact ; and
setup whereby each sensing contact is referred to another adjusting the amplitude and the shape of the electrical
contact, each contact being connected to the active lead of stimulation using the measured compound neural
one derivation and the reference lead of another one . 35 action potential to obtain a desired compound neural
One advantage of the present invention is that it is capable action potential.
of recording the synchronized compound action potentials 2 . The method of claim 1 , wherein applying electrical
generated by the stimulation for measuring the amplitude , stimulation further comprises applying a long duration ,
shape and latency of the response. low - amplitude anodic phase and a subsequent relatively
Another advantage of the present invention is that it may 40 short-duration , high -amplitude cathodic phase in order to
be utilized for potentiometric sensing, e .g . chemical sensing , activate the neural tissue at an end of a charge balanced
or for recording neural spontaneous electrical activity in stimulation .
order to evaluate the state of the system to be stimulated and 3 . The method of claim 2, wherein a charge delivered by
so doing, avoid for example a level of damaging or unsafe the anodic phase is equal in magnitude but opposite in
stimulation . 45 polarity with respect to a charge deviled by the cathodic
The present invention may also be advantageously uti - phase .
lized for detecting or recording interference activity from 4 . The method of claim 2 , further comprising applying the
physiological sources such as the ECG , plethysmographic anodic phase with a progressive amplitude in order to avoid
activities , muscle potentials , etc or from external electrical early tissue activation .
sources including electrical transmission and fault detection . 50 5 . The method of claim 2 , further comprising adjusting a
The present invention may finally advantageously utilized cathodic to anodic phase ratio in order to reduce the artifact
for providing impedance measurements as well as for the period , wherein an anodic charge recuperation phase dura
determination of contact impedances and tissue impedance tion is equal or slightly less than a cathodic stimulating
for evaluating the state of the electrode and /or of the tissue phase duration .
surrounding the electrode . 55 6 . Themethod ofclaim 1, further comprising reducing the
The terms and descriptions used herein are set forth by amplitude and the shape of the electrical stimulation when
way of illustration only and are not meant as limitations. the compound neural action potential generated by the
Those skilled in the art will recognize that many variations electrical stimulation reaches a safety limit .
are possible within the spirit and scope of the invention as 7 . The method of claim 6 , further comprising measuring
defined in the following claims, and their equivalents , in 60 at least one of localDC potential values , stimulation voltage
which all terms are to be understood in their broadest values , or tissue impedance values of the electrical stimu
possible sense unless otherwise indicated . As a consequence , lation in order to determine the safety limit of the portion of
all modifications and alterations will occur to others upon the neural tissue.
reading and understanding the previous description of the 8 . The method of claim 6 , further comprising measuring
invention . In particular, dimensions, materials , and other 65 a voltage applied by a generator to the stimulation electrode
parameters, given in the above description may vary contacts in order to determine the safety limit to prevent
depending on the needs of the application . corrosion of the stimulation electrode contacts .
 US 10 ,342, 980 B2
13 14
9 . The method of claim 1, further comprising detecting charge recuperation phase duration is equal or slightly less
interference activity from physiological sources from at least than a cathodic stimulating phase duration .
one of an ECG , plethysmographic activities, or muscle 15 . The system of claim 10 , wherein the processor is
potentials . further configured to reduce the amplitude and the shape of
al 55 the electrical stimulation when the compound neural action
10 . A system for regulating the intensity of electrical
stimulations generated by a nerve stimulation apparatus, the potential
safety
generated by the electrical stimulation reaches a
limit .
system comprising: 16 . The system of claim 15 , wherein the processor is
an electrode comprising : further configured to measure at least one of local DC
a plurality of sensing electrode contacts forming a potential values , stimulation voltage values , or tissue imped
tripole comprising: ance values of the electrical stimulation in order to deter
two dependent sensing electrode contacts ; and mine the safety limit of the portion of the neural tissue .
a central independent sensing electrode contact 17 . The system of claim 15 , wherein the processor is
located between the two dependent sensing elec further configured to measure a voltage applied by a gen
trode contacts ; and erator to the stimulation electrode contacts in order to
a plurality of stimulation electrode contacts, wherein
15
determine the safety limit to prevent corrosion of the stimu
doto

the sensing electrode contacts and the stimulation lation electrode contacts.
electrode contacts are structured to be in contact with 18 . The system of claim 10, wherein the processor is
a portion of a neural tissue , wherein the electrode further configured to detect interference activity from physi
includes a predetermined distance between the sens- 30 ological sources from at least one of an ECG , plethysmo
ing electrode contacts and the stimulation electrode 20 graphic activities , or muscle potentials.
19 . One ormore computer -readable storage media having
contacts such that a compound neural action poten
tial generated by the stimulation electrode contacts sor instructions stored thereon that, when executed by a proces
reaches the sensing electrode contacts when an arti , cause the processor to implement operations including:
fact period is already elapsed , and wherein the pre - 2525 applying electrical stimulation to a portion of a neural
determined distance is measured between a central tissue via a plurality of stimulation electrode contacts
part of the central independent sensing electrode so as to generate, after a given latency time, a com
contact and a central part of the stimulation electrode pound neural action potential, wherein the electrical
contact that is closest to the central independent stimulation comprises an amplitude and a shape;
sensing electrode contact ; and 30
measuring the compound neural action potential gener
a processor coupled to the electrode , wherein the proces ated by the stimulation electrode contacts via a plurality
sor is configured to : of sensing electrode contacts, wherein the sensing
apply electrical stimulation to the portion of the neural electrode contacts are capable of being saturated by the
tissue via the stimulation electrode contacts so as to electrical stimulation during an artifact period, wherein
generate , after a given latency time, the compound 35 the sensing electrode contacts and the stimulation elec
neural action potential, wherein the electrical stimu trode contacts are structured to be in contact with the
lation comprises an amplitude and a shape ; portion of the neural tissue, and wherein the sensing
measure the compound neural action potential gener electrode contacts form a tripole comprising one central
ated by the stimulation electrode contacts via the independent sensing electrode contact located between
sensing electrode contacts , wherein the sensing elec - 40 two dependent sensing electrode contacts , wherein the
trode contacts are capable of being saturated by the sensing electrode contacts are located at a predeter
electrical stimulation during the artifact period ; and mined distance from the stimulation electrode contacts
adjust the amplitude and the shape of the electrical such that the compound neural action potential gener
stimulation using the measured compound neural ated by the stimulation electrode contacts reaches the
action potential to obtain a desired compound neural 45 sensing electrode contacts when the artifact period is
action potential. already elapsed and wherein the predetermined dis
11 . The system of claim 10 , wherein the processor is tance is measured between a central part of the central
further configured to apply a long duration , low - amplitude independent sensing electrode contact and a central part
anodic phase and a subsequent relatively short -duration , of the stimulation electrode contact that is closest to the
high -amplitude cathodic phase in order to activate the neural 50 central independent sensing electrode contact ; and
tissue at an end of a charge balanced stimulation when adjusting the amplitude and the shape of the electrical
applying the electrical stimulation . stimulation using the measured compound neural
12 . The system of claim 11 , wherein a charge delivered by action potential to obtain a desired compound neural
the anodic phase is equal in magnitude but opposite in action potential.
polarity with respect to a charge deviled by the cathodic 5555 claim20 . The
19 ,
one or more computer -readable storage media of
wherein the processor further implements apply
phase .
13 . The system of claim 11, wherein the processor is ing a long duration , low -amplitude anodic phase and a
subsequent relatively short-duration , high -amplitude
further configured to apply the anodic phase with a progres cathodic
sive amplitude in order to avoid early tissue activation . phase in order to activate the neural tissue at an end
14 . The system of claim 11, wherein the processor is 660 ofcalastimulation
charge balanced stimulation when applying the electri
.
further configured to adjust a cathodic to anodic phase ratio
in order to reduce the artifact period , wherein an anodic