Patent ID: 12220583

DETAILED DESCRIPTION

The present disclosure is directed to the area of methods and systems for deep brain electrical stimulation. The present disclosure is also directed to methods and systems for deep brain stimulation of the nucleus basalis of Meynert (NBM).

Suitable implantable electrical stimulation systems include, but are not limited to, a least one electrical stimulation lead with one or more electrodes disposed along a distal end of the lead and one or more terminals disposed along the one or more proximal ends of the lead. Examples of electrical stimulation systems with leads are found in, for example, U.S. Pat. Nos. 6,181,969; 6,295,944; 6,391,985; 6,516,227; 6,609,029; 6,609,032; 6,741,892; 7,244,150; 7,450,997; 7,672,734; 7,761,165;

7,783,359; 7,792,590; 7,809,446; 7,949,395; 7,974,706; 8,831,742; 8,688,235; 8,175,710; 8,224,450; 8,271,094; 8,295,944; 8,364,278; and 8,391,985; U.S. Patent Application Publications Nos. 2007/0150036; 2009/0187222; 2009/0276021; 2010/0076535; 2010/0268298; 2011/0004267; 2011/0078900; 2011/0130817; 2011/0130818; 2011/0238129; 2011/0313500; 2012/0016378; 2012/0046710;

2012/0071949; 2012/0165911; 2012/0197375; 2012/0203316; 2012/0203320; 2012/0203321; 2012/0316615; 2013/0105071; 2011/0005069; 2010/0268298; 2011/0130817; 2011/0130818; 2011/0078900; 2011/0238129; 2011/0313500; 2012/0016378; 2012/0046710; 2012/0165911; 2012/0197375; 2012/0203316; 2012/0203320; and 2012/0203321, all of which are incorporated by reference in their entireties.

Turning toFIG.1, one embodiment of an electrical stimulation system10includes one or more electrical stimulation leads12and an implantable pulse generator (IPG)14. The system10can also include one or more of an external remote control (RC)16, a clinician's programmer (CP)18, an external trial stimulator (ETS)20, or an external charger22. The IPG and ETS are examples of control modules for the electrical stimulation system.

The IPG14is physically connected, optionally via one or more lead extensions24, to the electrical stimulation lead(s)12. Each electrical stimulation lead carries multiple electrodes26arranged in an array. The IPG14includes pulse generation circuitry that delivers electrical stimulation energy in the form of, for example, a pulsed electrical waveform (i.e., a temporal series of electrical pulses) to one or more electrodes26of the array in accordance with a set of stimulation parameters. The IPG14can be implanted into a patient's body, for example, below the patient's clavicle area or within the patient's abdominal cavity or at any other suitable site. The implantable pulse generator14can have multiple stimulation channels which may be independently programmable to control the magnitude of the current stimulus from each channel. In some embodiments, the implantable pulse generator14can have any suitable number of stimulation channels including, but not limited to,4,6,8,12,16,32, or more stimulation channels. The implantable pulse generator14can have one, two, three, four, or more connector ports, for receiving the terminals of the leads and/or lead extensions.

The ETS20may also be physically connected, optionally via the percutaneous lead extensions28and external cable30, to the stimulation leads12. The ETS20, which may have similar pulse generation circuitry as the IPG14, also delivers electrical stimulation energy in the form of, for example, a pulsed electrical waveform to the electrodes26in accordance with a set of stimulation parameters. One difference between the ETS20and the IPG14is that the ETS20is often a non-implantable device that is used on a trial basis after the electrical stimulation leads12have been implanted and prior to implantation of the IPG14, to test the responsiveness of the stimulation that is to be provided. Any functions described herein with respect to the IPG14can likewise be performed with respect to the ETS20.

The RC16may be used to telemetrically communicate with or control the IPG14or ETS20via a uni- or bi-directional wireless communications link32. Once the IPG14and electrical stimulation leads12are implanted, the RC16may be used to telemetrically communicate with or control the IPG14via a uni- or bi-directional communications link34. Such communication or control allows the IPG14to be turned on or off and to be programmed with different stimulation parameter sets. The IPG14may also be operated to modify the programmed stimulation parameters to actively control the characteristics of the electrical stimulation energy output by the IPG14. The CP18allows a user, such as a clinician, the ability to program stimulation parameters for the IPG14and ETS20in the operating room and in follow-up sessions. Alternately, or additionally, stimulation parameters can be programed via wireless communications (e.g., Bluetooth) between the RC16(or external device such as a hand-held electronic device like a mobile phone, tablet, or the like) and the IPG14.

The CP18may perform this function by indirectly communicating with the IPG14or ETS20, through the RC16, via a wireless communications link36. Alternatively, the CP18may directly communicate with the IPG14or ETS20via a wireless communications link (not shown). The stimulation parameters provided by the CP18are also used to program the RC16, so that the stimulation parameters can be subsequently modified by operation of the RC16in a stand-alone mode (i.e., without the assistance of the CP18).

Additional examples of the RC16, CP18, ETS20, and external charger22can be found in the references cited herein as well as U.S. Pat. Nos. 6,895,280; 6,181,969; 6,516,227; 6,609,029; 6,609,032; 6,741,892; 7,949,395; 7,244,150; 7,672,734; and 7,761,165; 7,974,706; 8,175,710; 8,224,450; and 8,364,278; and U.S. Patent Application Publication No. 2007/0150036, all of which are incorporated herein by reference in their entireties.

FIG.2illustrates schematically another embodiment of an electrical stimulation system10. The electrical stimulation system includes an IPG (e.g., a control module)14and at least one electrical stimulation lead12coupleable to the IPG14. The electrical stimulation lead12includes one or more lead bodies106, an array of electrodes, such as electrode134, and an array of terminals (e.g.,210inFIGS.3and4) disposed along the one or more lead bodies106. In at least some embodiments, the lead is isodiametric along a longitudinal length of the lead body106.FIG.2illustrates one lead12coupled to an IPG14. Other embodiments may include two, three, four, or more leads12coupled to the IPG14.

The electrical stimulation lead12can be coupled to the IPG14in any suitable manner. In at least some embodiments, the electrical stimulation lead12couples directly to the IPG14. In at least some other embodiments, the electrical stimulation lead12couples to the IPG14via one or more intermediate devices. For example, in at least some embodiments one or more lead extensions224(see e.g.,FIG.4) can be disposed between the electrical stimulation lead12and the IPG14to extend the distance between the electrical stimulation lead12and the IPG14. Lead extensions may also be useful to cross a joint or can be more easily replaced if the lead extension breaks due to fatigue as such replacement will not affect the placement of the distal end of the lead. Other intermediate devices may be used in addition to, or in lieu of, one or more lead extensions including, for example, a splitter, an adaptor, or the like or any combination thereof. It will be understood that, in the case where the electrical stimulation system10includes multiple elongated devices disposed between the electrical stimulation lead12and the IPG14, the intermediate devices may be configured into any suitable arrangement.

InFIG.2, the electrical stimulation system10is shown having a splitter107configured and arranged for facilitating coupling of the electrical stimulation lead12to the IPG14. The splitter107includes a splitter connector108configured to couple to a proximal end of the electrical stimulation lead12, and one or more splitter tails109aand109bconfigured and arranged to couple to the IPG14(or another splitter, a lead extension, an adaptor, or the like).

In at least some embodiments, the IPG14includes a connector housing112and a sealed electronics housing114. An electronic subassembly110and an optional power source121are disposed in the electronics housing114. An IPG connector144is disposed in the connector housing112. The IPG connector144is configured and arranged to make an electrical connection between the electrical stimulation lead12and the electronic subassembly110of the IPG14.

The electrodes134can be formed using any conductive, biocompatible material. Examples of suitable materials include metals, alloys, conductive polymers, conductive carbon, and the like, as well as combinations thereof. In at least some embodiments, one or more of the electrodes134are formed from one or more of: platinum, platinum iridium, palladium, palladium rhodium, or titanium. Any number of electrodes134can be used for each array26. For example, there can be two, four, six, eight, ten, twelve, fourteen, sixteen, or more electrodes134. As will be recognized, other numbers of electrodes134may also be used.

The electrodes of the one or more lead bodies106are typically disposed in, or separated by, a non-conductive, biocompatible material such as, for example, silicone, polyurethane, polyetheretherketone (“PEEK”), epoxy, and the like or combinations thereof. The lead bodies106may be formed in the desired shape by any process including, for example, molding (including injection molding), casting, and the like. The non-conductive material typically extends from the distal end of the one or more lead bodies106to the proximal end of each of the one or more lead bodies106.

Terminals (e.g.,210inFIGS.3and4) are typically disposed along the proximal end of the one or more lead bodies106of the electrical stimulation system10(as well as any splitters, lead extensions, adaptors, or the like) for electrical connection to corresponding connector contacts (e.g.,214inFIGS.3and240inFIG.4). The connector contacts are disposed in connectors (e.g.,144inFIGS.2to4; and221inFIG.4) which, in turn, are disposed on, for example, the IPG14(or a lead extension, a splitter, an adaptor, or the like). Electrically conductive wires, cables, or the like (not shown) extend from the terminals to the electrodes134. Typically, one or more electrodes134are electrically coupled to each terminal. In at least some embodiments, each terminal is only connected to one electrode134.

The electrically conductive wires (“conductors”) may be embedded in the non-conductive material of the lead body106or can be disposed in one or more lumens (not shown) extending along the lead body106. In some embodiments, there is an individual lumen for each conductor. In other embodiments, two or more conductors extend through a lumen. There may also be one or more lumens (not shown) that open at, or near, the proximal end of the lead body106, for example, for inserting a stylet to facilitate placement of the lead body106within a body of a patient. Additionally, there may be one or more lumens (not shown) that open at, or near, the distal end of the lead body106, for example, for infusion of drugs or medication into the site of implantation of the one or more lead bodies106. In at least some embodiments, the one or more lumens are permanently or removably sealable at the distal end.

FIG.3is a schematic side view of one embodiment of a proximal end of one or more elongated devices200configured and arranged for coupling to one embodiment of the IPG connector144. The one or more elongated devices may include, for example, the lead body106, one or more intermediate devices (e.g., the splitter107ofFIG.2, the lead extension224ofFIG.4, an adaptor, or the like or combinations thereof), or a combination thereof.FIG.3illustrates two elongated devices200coupled to the IPG14. These two elongated devices200can be two tails as illustrated inFIG.2or two different leads or any other combination of elongated devices.

The IPG connector144defines at least one port into which a proximal end of the elongated device200can be inserted, as shown by directional arrows212aand212b. InFIG.3(and in other figures), the connector housing112is shown having two ports204aand204b. The connector housing112can define any suitable number of ports including, for example, one, two, three, four, five, six, seven, eight, or more ports.

The IPG connector144also includes a plurality of connector contacts, such as connector contact214, disposed within each port204aand204b. When the elongated device200is inserted into the ports204aand204b, the connector contacts214can be aligned with a plurality of terminals210disposed along the proximal end(s) of the elongated device(s)200to electrically couple the IPG14to the electrodes (134ofFIG.2) disposed at a distal end of the electrical stimulation lead12. Examples of connectors in IPGs are found in, for example, U.S. Pat. Nos. 7,244,150 and 8,224,450, which are incorporated by reference in their entireties.

FIG.4is a schematic side view of another embodiment of the electrical stimulation system10. The electrical stimulation system10includes a lead extension224that is configured and arranged to couple one or more elongated devices200(e.g., the lead body106, the splitter107, an adaptor, another lead extension, or the like or combinations thereof) to the IPG14. InFIG.4, the lead extension224is shown coupled to a single port204defined in the IPG connector144. Additionally, the lead extension224is shown configured and arranged to couple to a single elongated device200. In alternate embodiments, the lead extension224is configured and arranged to couple to multiple ports204defined in the IPG connector144, or to receive multiple elongated devices200, or both.

A lead extension connector221is disposed on the lead extension224. InFIG.4, the lead extension connector221is shown disposed at a distal end226of the lead extension224. The lead extension connector221includes a connector housing228. The connector housing228defines at least one port230into which terminals210of the elongated device200can be inserted, as shown by directional arrow238. The connector housing228also includes a plurality of connector contacts, such as connector contact240. When the elongated device200is inserted into the port230, the connector contacts240disposed in the connector housing228can be aligned with the terminals210of the elongated device200to electrically couple the lead extension224to the electrodes (134ofFIG.2) disposed along the lead (12inFIG.2).

In at least some embodiments, the proximal end of the lead extension224is similarly configured and arranged as a proximal end of the lead12(or other elongated device200). The lead extension224may include a plurality of electrically conductive wires (not shown) that electrically couple the connector contacts240to a proximal end248of the lead extension224that is opposite to the distal end226. In at least some embodiments, the conductive wires disposed in the lead extension224can be electrically coupled to a plurality of terminals (not shown) disposed along the proximal end248of the lead extension224. In at least some embodiments, the proximal end248of the lead extension224is configured and arranged for insertion into a connector disposed in another lead extension (or another intermediate device). In other embodiments (and as shown inFIG.4), the proximal end248of the lead extension224is configured and arranged for insertion into the IPG connector144.

Returning toFIG.2, in at least some embodiments at least some of the stimulation electrodes take the form of segmented electrodes that extend only partially around the perimeter (for example, the circumference) of the lead. These segmented electrodes can be provided in sets of electrodes, with each set having electrodes circumferentially distributed about the lead at a particular longitudinal position.

InFIG.2, the electrodes134are shown as including both ring electrodes120and segmented electrodes122. In some embodiments, the electrodes134are all segmented electrode or all ring electrodes. The segmented electrodes122ofFIG.2are in sets of three (one of which is not visible inFIG.2), where the three segmented electrodes of a particular set are electrically isolated from one another and are circumferentially offset along the lead12. Any suitable number of segmented electrodes can be formed into a set including, for example, two, three, four, or more segmented electrodes. The lead12ofFIG.2has thirty segmented electrodes122(ten sets of three electrodes each) and two ring electrodes120for a total of 32 electrodes134.

Segmented electrodes can be used to direct stimulus current to one side, or even a portion of one side, of the lead. When segmented electrodes are used in conjunction with an implantable pulse generator that delivers multiple current stimuli simultaneously, current steering can be achieved to deliver the stimulus more precisely to a position around an axis of the lead (i.e., radial positioning around the axis of the lead). Segmented electrodes may provide for superior current steering than ring electrodes because target structures in deep brain stimulation are not typically symmetric about the axis of the distal electrode array. Instead, a target may be located on one side of a plane running through the axis of the lead. Through the use of a segmented electrode array, current steering can be performed not only along a length of the lead but also around a perimeter of the lead. This provides precise three-dimensional targeting and delivery of the current stimulus to neural target tissue, while potentially avoiding stimulation of other tissue.

FIG.5Aillustrates a 32-electrode lead12with a lead body106and two ring electrodes120proximal to thirty segmented electrodes122arranged in ten sets of three segmented electrodes each. In the illustrated embodiments, the ring electrodes120are proximal to the segmented electrodes122. In other embodiments, one or more of the ring electrodes120can be proximal to, or distal to, one or more of the segmented electrodes122.

Any number of segmented electrodes122may be disposed on the lead body including, for example, one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, twenty, twenty-four, twenty-eight, thirty, thirty-two, or more segmented electrodes122. It will be understood that any number of segmented electrodes122may be disposed along the length of the lead body. A segmented electrode122typically extends only 75%, 67%, 60%, 50%, 40%, 33%, 25%, 20%, 17%, 15%, or less around the circumference of the lead.

The segmented electrodes122may be grouped into sets of segmented electrodes, where each set is disposed around a circumference of the electrical stimulation lead12at a particular longitudinal portion of the electrical stimulation lead12. The electrical stimulation lead12may have any number of segmented electrodes122in a given set of segmented electrodes. The electrical stimulation lead12may have one, two, three, four, five, six, seven, eight, or more segmented electrodes122in a given set. The electrical stimulation lead12may have any number of sets of segmented electrodes including, but not limited to, one, two, three, four, five, six, eight, ten, twelve, fifteen, sixteen, twenty, or more sets. The segmented electrodes122may be uniform, or vary, in size and shape. In some embodiments, the segmented electrodes122are all of the same size, shape, diameter, width or area or any combination thereof. In some embodiments, the segmented electrodes122of each circumferential set (or even all segmented electrodes disposed on the lead12) may be identical in size and shape.

Each set of segmented electrodes122may be disposed around the circumference of the lead body to form a substantially cylindrical shape around the lead body. The spacing between individual electrodes of a given set of the segmented electrodes may be the same, or different from, the spacing between individual electrodes of another set of segmented electrodes on the electrical stimulation lead12. In at least some embodiments, equal spaces, gaps, or cutouts are disposed between each segmented electrode122around the circumference of the lead body. In other embodiments, the spaces, gaps, or cutouts between the segmented electrodes122may differ in size or shape. In other embodiments, the spaces, gaps, or cutouts between segmented electrodes122may be uniform for a particular set of the segmented electrodes122, or for all sets of the segmented electrodes122. The sets of segmented electrodes122may be positioned in irregular or regular intervals along a length of the lead body.

FIG.5B to5Eillustrate other embodiments of leads with segmented electrodes122.FIG.5Billustrates a sixteen electrode lead12having one ring electrode120that is proximal to five sets of three segmented electrodes122each.FIG.5Cillustrates a sixteen electrode lead12having eight sets of two segmented electrodes122each. As illustrated inFIG.5C, an embodiment of a lead12does not necessarily include a ring electrode.FIG.5Dillustrates a sixteen electrode lead12having four ring electrodes120that are proximal to six sets of two segmented electrodes122each.FIG.5Eillustrates a thirty-two electrode lead12having sixteen sets of two segmented electrodes122each (for clarity of illustration, not all of the electrodes are shown). It will be recognized that any other electrode combination of ring electrodes, segmented electrodes, or both types of electrodes can be used.

When the lead12includes both ring electrodes120and segmented electrodes122, the ring electrodes120and the segmented electrodes122may be arranged in any suitable configuration. For example, when the lead12includes two or more ring electrodes120and one or more sets of segmented electrodes122, the ring electrodes120can flank the one or more sets of segmented electrodes122. Alternately, the two or more ring electrodes120can be disposed proximal to the one or more sets of segmented electrodes122or the two or more ring electrodes120can be disposed distal to the one or more sets of segmented electrodes122or any other suitable arrangement of the ring electrodes120and segmented electrodes122.

The electrodes120,122may have any suitable longitudinal length including, but not limited to, 1, 1.5, 2, 3, 4, 4.5, 5, or 6 mm. The longitudinal spacing between adjacent electrodes120,122may be any suitable amount including, but not limited to, 0.25, 0.5, 0.75, 1, 2, or 3 mm, where the spacing is defined as the distance between the nearest edges of two adjacent electrodes. In some embodiments, the spacing is uniform between longitudinally adjacent of electrodes along the length of the lead. In other embodiments, the spacing between longitudinally adjacent electrodes may be different or non-uniform along the length of the lead.

Examples of electrical stimulation leads with segmented electrodes include U.S. Patent Application Publications Nos. 2010/0268298; 2011/0005069; 2011/0078900; 2011/0130803; 2011/0130816; 2011/0130817; 2011/0130818; 2011/0078900; 2011/0238129; 2011/0313500; 2012/0016378; 2012/0046710; 2012/0071949; 2012/0165911; 2012/0197375; 2012/0203316; 2012/0203320; 2012/0203321;

2013/0197602; 2013/0261684; 2013/0325091; 2013/0317587; 2014/0039587; 2014/0353001; 2014/0358209; 2014/0358210; 2015/0018915; 2015/0021817; 2015/0045864; 2015/0021817; 2015/0066120; 2013/0197424; 2015/0151113; 2014/0358207; and U.S. Pat. No. 8,483,237, all of which are incorporated herein by reference in their entireties. An electrical stimulation lead may also include a tip electrode and examples of leads with tip electrodes include at least some of the previously cited references, as well as U.S. Patent Application Publications Nos. 2014/0296953 and 2014/0343647, all of which are incorporated herein by reference in their entireties. A lead with segmented electrodes may be a directional lead that can provide stimulation in a particular direction using the segmented electrodes.

FIG.6is a schematic overview of one embodiment of components of an electrical stimulation system600including an electronic subassembly610disposed within an IPG. It will be understood that the electrical stimulation system can include more, fewer, or different components and can have a variety of different configurations including those configurations disclosed in the stimulator references cited herein.

Some of the components (for example, power source612, antenna618, receiver602, processor604, and memory605) of the electrical stimulation system can be positioned on one or more circuit boards or similar carriers within a sealed housing of an implantable pulse generator, if desired. Any power source612can be used including, for example, a battery such as a primary battery or a rechargeable battery. Examples of other power sources include super capacitors, nuclear or atomic batteries, mechanical resonators, infrared collectors, thermally-powered energy sources, flexural powered energy sources, bioenergy power sources, fuel cells, bioelectric cells, osmotic pressure pumps, and the like including the power sources described in U.S. Pat. No. 7,437,193, incorporated herein by reference in its entirety.

As another alternative, power can be supplied by an external power source through inductive coupling via the optional antenna618or a secondary antenna. The external power source can be in a device that is mounted on the skin of the user or in a unit that is provided near the user on a permanent or periodic basis.

If the power source612is a rechargeable battery, the battery may be recharged using the optional antenna618, if desired. Power can be provided to the battery for recharging by inductively coupling the battery through the antenna to a recharging unit616external to the user. Examples of such arrangements can be found in the references identified above.

In one embodiment, electrical current is emitted by the electrodes134on the lead body to stimulate nerve fibers, muscle fibers, or other body tissues near the electrical stimulation system. A processor604is generally included to control the timing and electrical characteristics of the electrical stimulation system. For example, the processor604can, if desired, control one or more of the timing, frequency, amplitude, width, and waveform of the pulses. In addition, the processor604can select which electrodes can be used to provide stimulation, if desired. In some embodiments, the processor604may select which electrode(s) are cathodes and which electrode(s) are anodes and the amount of anodic or cathodic current assigned to each. In some embodiments, the processor604may be used to identify which electrodes provide the most useful stimulation of the desired tissue. Instructions for the processor604can be stored on the memory605.

Any processor can be used and can be as simple as an electronic device that, for example, produces pulses at a regular interval or the processor can be capable of receiving and interpreting instructions from the CP/RC606(such as CP18or RC16ofFIG.1) that, for example, allows modification of pulse characteristics. In the illustrated embodiment, the processor604is coupled to a receiver602which, in turn, is coupled to the optional antenna618. This allows the processor604to receive instructions from an external source to, for example, direct the pulse characteristics and the selection of electrodes, if desired.

In one embodiment, the antenna618is capable of receiving signals (e.g., RF signals) from a CP/RC606(see, CP18or RC16ofFIG.1) which is programmed or otherwise operated by a user. The signals sent to the processor604via the antenna618and receiver602can be used to modify or otherwise direct the operation of the electrical stimulation system. For example, the signals may be used to modify the pulses of the electrical stimulation system such as modifying one or more of pulse width, pulse frequency, pulse waveform, and pulse amplitude. The signals may also direct the electrical stimulation system600to cease operation, to start operation, to start charging the battery, or to stop charging the battery. In other embodiments, the stimulation system does not include an antenna618or receiver602and the processor604operates as programmed.

Optionally, the electrical stimulation system600may include a transmitter (not shown) coupled to the processor604and the antenna618for transmitting signals back to the CP/RC606or another unit capable of receiving the signals. For example, the electrical stimulation system600may transmit signals indicating whether the electrical stimulation system600is operating properly or not or indicating when the battery needs to be charged or the level of charge remaining in the battery. The processor604may also be capable of transmitting information about the pulse characteristics so that a user or clinician can determine or verify the characteristics.

Dementias like Alzheimer's disease are generally associated with the reduction of a key neurotransmitter, Acetylcholine (Ach), in the cortex. Studies suggest that anticholinergic medications (for other health issues) are associated with an increased likelihood of dementia, and one of the FDA approved classes of drugs for dementia is an anticholinesterase (i.e., a drug to slow metabolism of ACh so that it can have a longer/stronger effect).

The cells that produce ACh and send and release it in the cortex are located in the nucleus basalis of Meynert (NBM). It is thought that stimulation of this region can evoke a release of ACh in the cortex and counteract effects of dementia. The release of ACh may also be used to treat depression and neuropsychological disorders. It has been demonstrated that in non-human primates stimulation of the NBM notably improves performance in a memory task. It has also been shown that an intermittent stimulation protocol is effective, but that a continuous stimulation protocol is not effective, perhaps because synaptic machinery is overworked.

In addition to stimulating the NBM neurons to deliver more ACh, it is desirable to also slow or halt the neurodegeneration of those cells.

The NBM has a unique, curved shape that may be characterized as a bent oval pancake or a flat banana. An approximation of the shape of the NBM760of one hemisphere of the brain is illustrated inFIG.7. The shape can make the NBM760difficult to fully engage using an electrical stimulation lead as it may be difficult for one electrode array to stimulate a relatively large portion, or even all, of the cells to take full advantage of the ACh machinery of each cell.

In at least some embodiments, to address the unique shape of the target NBM760and to stimulate more of the target NBM, multiple electrical stimulation leads12can be placed at different parts of the target NBM760, and stimulation can be cycled between the electrodes134of the electrical stimulation leads12to produce multiple stimulation regions762, as illustrated inFIG.7. In the illustrated embodiment ofFIG.7, two electrical stimulation leads12are implanted using a superior-to-inferior trajectory and one electrical stimulation lead is used to produce two different stimulation regions762and the other electrical stimulation lead provides another stimulation region.

In at least some embodiments, as illustrated inFIG.8, to address the unique shape of the target NBM760, to stimulate more of the target, at least one stimulation lead12can be implanted along a lead trajectory that is generally or approximately (for example, within 10, 15, 25, 30, or 45 degrees) oriented lateral-to-medial, rather than the typical superior-to-inferior, to align electrodes134of the lead along or adjacent the axis of the target NBM760. Along this lead trajectory, more electrodes134from a single electrical stimulation lead12can be near (including traversing) portions of the target NBM760to produce multiple stimulation regions762which can be cycled through as described in more detail below.

Any suitable number of electrical stimulation leads12can be used to stimulate the NBM including, but not limited to, one, two, three, four, or more leads. When multiple electrical stimulation leads12are used, there can be any suitable combination of electrical stimulation lead(s)12implanted in the superior-to-inferior trajectory (FIG.7) and lead(s) implanted in the lateral-to-medial trajectory (FIG.8). Electrical stimulation lead(s)12can be implanted in one or both hemispheres of the brain to stimulate one or both NBMs760. The arrangement of electrical stimulation lead(s)12for each hemisphere can be the same or different.

An electrical stimulation lead12can produce any suitable number of stimulation regions762including, but not limited to, one, two, three, four, or more stimulation regions. In at least some embodiments, one or more electrical stimulation leads12include segmented electrodes122. The use of segmented electrodes122may facilitate the selection of directionality of the stimulation regions762.

One or more electrodes134can be used to generate the electrical stimulation for a stimulation region762. The electrode(s) can be cathodes or anodes or any combination thereof. In at least some embodiments, the sealed electronics housing114(or other portion of the case) of the IPG14can be used as a return electrode, which is often the case for monopolar electrical stimulation. Multipolar electrical stimulation can also be used. In at least some embodiments, the electrical stimulation is anodic stimulation (e.g., where the active electrode(s) are anodes), which is often more effective for selective stimulation of cell bodies than cathodic stimulation.

Producing a combination of stimulation regions762may facilitate effective stimulation of a relatively large part, or even all, of the NBM760. The stimulation regions762illustrated inFIGS.7and8correspond to the estimated effective regions of stimulation for a particular set of stimulation parameters. Examples of stimulation parameters include, but are not limited to, selection of electrode(s), stimulation amplitude (which can be independent for each electrode), pulse frequency, pulse duration or width, or the like. In at least some embodiments, the stimulation regions762ofFIGS.7and8can be determined or estimated algorithmically or manually. The terms “stimulation field map” (SFM), “volume of activation” (VOA), or “volume of tissue activated (VTA)” are often used to designate the estimated stimulation region762of tissue that will be stimulated for a particular set of stimulation parameters. Any suitable method for determining the VOA/SFM/VTA can be used including those described in, for example, U.S. Pat. Nos. 8,326,433; 8,675,945; 8,831,731; 8,849,632; and 8.958,615; U.S. Patent Application Publications Nos. 2009/0287272; 2009/0287273; 2012/0314924; 2013/0116744; 2014/0122379; 2015/0066111; 2016/0346557; 2016/0375248; 2016/0375258; 2017/0304633; 2018/0064930; 2018/0078776; 2018/0185650; 2018/0193655; 2019/0282820; 2019/0329049; 2019/0358458; 2019/0358461; and 2020/0289834 and U.S. Provisional Patent Application Ser. No. 62/030,655, all of which are incorporated herein by reference in their entireties.

In at least some embodiments, using electrodes of the same or different electrical stimulation leads, multiple stimulation regions762are chosen so that the combination of these stimulation regions can cover much of the target NBM760. Any suitable number of stimulation regions762can be used including, but not limited to, one, two, three, four, five, six, eight, ten, twelve, or more stimulation regions. In at least some embodiments, the stimulation regions762may also be chosen to limit or avoid overlap between stimulation regions.

In at least some embodiments, the selection of multiple stimulation regions762(for example, SFMs) can be based on post-op radiography, an MRI, or any other imaging technique or any combination thereof. In at least some embodiments, the selection of multiple stimulation regions762(for example, SFMs) can be based on a surgical plan, alone or in combination with post-op imaging. In at least some embodiments, the selection of multiple stimulation regions762(for example, SFMs) is performed offline.

In at least some embodiments, the selection of multiple stimulation regions762(for example, SFMs) can be performed manually using a user interface of a programmer or other device that enables display of multiple stimulation regions simultaneously. In at least some embodiments, the selection of multiple stimulation regions762(for example, SFMs) can be performed algorithmically by using techniques, such as, for example, binary search, gradient descent searches, genetic or particle swarm searches, or the like or any combination thereof.

In at least some embodiments, the stimulation regions762are chosen based on scoring or other criteria that increases based on the amount of the NBM760is covered by the stimulation regions or penalizes for portions of the target NBM760that are not covered by the stimulation regions. In at least some embodiments, the stimulation regions762the scoring criteria penalizes for overlap between stimulation regions. In at least some embodiments, the scoring criteria may be weighted for the overlap or non stimulation regions. Examples of scoring and scoring criteria can be found at, for example, U.S. Patent Application Publications Nos. 2016/0001080; 2014/0277284;

2014/0200633; 2014/0067022; 2014/0066999; 2013/0116929; 2013/0116748; 2013/0060305; and 2012/0271376, all of which are incorporated herein by reference in their entireties.

The delivery of electrical stimulation to the stimulation regions can include additional stimulation parameters beyond amplitude, pulse width, pulse frequency, and the like. Examples of additional stimulation parameters include, but are not limited to, duty cycle ratio, duration of a stimulation cycle, total number of pulses in a stimulation period, duration of a stimulation period, number of stimulation periods a day, or the like or any combination thereof. The delivery of stimulation to the stimulation region can be described in a series of cycles with stimulation during a portion of the cycle and no stimulation during another portion of the cycle. The duty cycle ratio can be equal to the ratio of the time during which stimulation is provided to the time during which no stimulation is provided. For example, a 60 second cycle may include 20 seconds of stimulation and 40 seconds of no stimulation resulting in a stimulation duty cycle ratio of 1:2. The duration of the cycle can be any suitable number including, but not limited to, 5, 10, 15, 20, 30, or 45 seconds or 1, 2, 5, 10, 15, 30, or 60 minutes or more, or the like. The duty cycle ratio can be any suitable ratio including, but not limited to, a ratio in a range from 1:5 to 5:1 or from 1:3 to 3:1 or from 1:5 to 1:1.

The stimulation period can be defined as the period of time when multiple cycles of stimulation are performed. The duration of the stimulation period can be any suitable number including, but not limited to, 1, 2, 5, 10, 15, 30, or 45 minutes or 1, 1.25, 1.5, 1.75, 2, 2.5, or 3 hours or more. In at least some embodiments, the duration of the stimulation period may be defined as a number of pulses instead or, or in addition to, a period of time. The number of pulses in a stimulation period can be any suitable number and, at least in some embodiments, can be in a range of 1,000 to 100,000 or in a range of 5,000 to 50,000 or in a range of 10,000 to 30,000.

The number of stimulation periods per day can be any suitable number including, but not limited to, one, two, three, four, five, six, eight, ten, twelve, 15, 20, or more. In at least some embodiments, the number of stimulation periods per day or the number or stimulation pulses delivered per day may be considered a “dose”. As an example, stimulation to one of the stimulation regions762can be delivered at a pulse rate of 20 Hz during 20 seconds of a 60 second cycle (for a duty cycle ratio of 1:2) for a stimulation period of 60 minutes (i.e., 60 cycles) with one stimulation period per day (for a total of 24,000 stimulation pulses per day).

In at least some embodiments, the stimulation regions762are stimulated for the same or similar amounts of time during a cycle or a stimulation period. In other embodiments, there may be a different amount of stimulation time (e.g., different amount of time for a cycle or a stimulation period) for different stimulation regions762.

When multiple stimulation regions762are to be stimulated, in at least some embodiments, the stimulation of each of the stimulation regions762can be performed using temporal offsets. In at least some embodiments, the delivery of stimulation may be interleaved. For example, one stimulation region can be stimulated followed by another and so on. For example, during a 60 second cycle stimulation is delivered to first stimulation region for 20 seconds, then to a second stimulation region for 20 seconds, and then to third stimulation region for 20 seconds. Thus, each stimulation region is stimulated at a duty cycle ratio of 1:2. In this example, overlap between the three stimulation regions is preferably relatively small or zero.

As another example, the cycles can be interleaved so that during the first 60 second cycle stimulation is delivered to first stimulation region for 20 seconds, then for a second 60 second cycle stimulation is delivered to a second stimulation region for 20 seconds, and then for a third 60 second cycle stimulation is delivered to third stimulation region for 20 seconds. In this example, overlap between the three stimulation regions may be less important because 40 seconds of each 60 second period has no stimulation at all.

In other embodiments, the stimulation periods for at least some stimulation regions762are performed sequentially. For example, during a first stimulation period the first stimulation region is stimulated, then for a second stimulation period the second stimulation region is stimulated, and then for a third stimulation period the third stimulation region is stimulated. For example, the first stimulation region can be stimulated for one three hour stimulation period, followed by the second stimulation region being stimulated for a second three hour stimulation period, and then followed by the third stimulation region being stimulated for a third stimulation period.

These arrangements avoid continual stimulation of the stimulation regions762as it is believed that periodic stimulation is more beneficial. In at least some embodiments, more than one stimulation region762can be stimulated at any given period of time and, preferably, stimulation regions762that are simultaneously stimulated do not overlap and are more preferably separated from each other by at least 0.1 to 1 millimeter.

In at least some embodiments, the delivery of stimulation may be performed automatically using stimulation settings programmed by a clinician or other caregiver.

In at last some embodiments, the delivery of stimulation may be initiated manually by a patient, clinician, or other caregiver. In at least some embodiments, the automated delivery of stimulation may be supplemented or replaced by manual initiation of stimulation. In at least some embodiments, a system may limit the manual initiation of stimulation by a patient, clinician, or other caregiver to number of stimulation periods that can be delivered in a day, or a week, or other defined period of time.

In at least some embodiments, a patient, clinician, or other caregiver can initiate a bolus of therapeutic stimulation from an external device (such as RC16or CP18) at a time that is convenient. In at least some embodiments, the electrical stimulation system10can be configured to only allow the patient to initiate a prescribed number of boluses per unit time (e.g., day or week). In at least some embodiments, the electrical stimulation system10includes an external device (such as RC16or CP18) that when connected to the IPG12will reflect a warning if the patient has not initiated a predetermined or suitable number of therapy sessions. In at least some embodiments, this data or warning may be sent to a clinician or other caregiver, so that they can respond.

In at least some embodiments, stimulation may have a detrimental effect on the memory or cognitive ability of the patient during the period of stimulation. In at least some embodiments, the electrical stimulation system10can be programmed to deliver stimulation at night (or other periods of time) when the patient is likely asleep. In at least some embodiments, the electrical stimulation system10or IPG12is configured to track the time of day and can be programmed to deliver stimulation at night (or other periods of time) when the patient is likely asleep. In at least some embodiments, the electrical stimulation system10or IPG12can be coupleable to an external sensor40(for example, a heart rate, respiration, posture, accelerometer, or biomarker sensor) or device that contains a sensor40(for example, a mobile phone or fitness tracker) that can provide information about the state of the patient to determine or estimate whether the patient is awake or asleep. The IPG12may be configured to provide stimulation only when the IPG or electrical stimulation system10determines (or receives information from an external sensor40or device that contains a sensor40) that the patient is asleep. In at least some embodiments, the IPG12or electrical stimulation system10may determine, estimate, or receiving information from an external device regarding a sleep stage (for example, REM sleep) of the patient and provide stimulation only during one or more selected or specified sleep stages.

In some embodiments, the electrical stimulation system10or IPG12can be configured with “daytime” or “awake” stimulation parameters and with “nighttime” or “asleep” stimulation parameters, and can use a clock or any of the other approaches described above to determine which should be used when a period of stimulation is initiated.

Additionally or alternatively, optical stimulation of the NBM may be performed. In at least some embodiments, the delivery of light to the NBM may mitigate neurodegeneration. Examples of optical stimulation systems (at least some of which also produce electrical stimulation, e.g., electro-optical stimulation systems) with optical or electro-optical stimulation leads are found in, for example, U.S. Pat. No. 9,415,154 and U.S. Patent Application Publications Nos. 2013/0317573; 2017/0225007; 2017/0259078; 2018/0110971; 2018/0369606; 2018/0369608; 2020/0155854; and 2020/0376262, all of which are incorporated by reference in its entirety.

FIGS.9and10illustrate optical stimulation leads912(or electro-optical lead inFIG.9with optional electrodes134) with light delivery elements970that produce stimulation light972to stimulate the target NBM760. The electrical stimulation components described above, and illustrated inFIGS.1to6, can be used or adapted for use in optical or electro-optical stimulation systems, as further described in the references cited above.

Examples of light delivery elements970include, but are not limited to, light emitting diodes (LEDs), laser diodes, or a fiber optic coupled to a light source (such as an LED or laser diode). InFIG.9, the light delivery element970can be a combination of multiple light delivery elements.

Any suitable number of leads912can be used to stimulate the NBM including, but not limited to, one, two, three, four, or more leads. When multiple leads912are used, there can be any suitable combination of lead(s)912implanted in the superior-to-inferior trajectory (FIG.10) and lead(s) implanted in the lateral-to-medial trajectory (FIG.9). Lead(s)912can be implanted in one or both hemispheres of the brain to stimulate one or both NBMs760. The arrangement of lead(s)912for each hemisphere can be the same or different.

In at least some embodiments, the area of illumination by one or more light delivery elements970can be considered analogous to a stimulation region762for electrical stimulation. All of the features, additional parameters, and other options and considerations described above for electrical stimulation can be applied to optical stimulation. In at least some embodiments, the optical stimulation can be delivered in one or more stimulation periods per day for a duration of 1, 2, 5, 10, 15, 30, 60, or more minutes (or any other suitable duration) per stimulation period.

Any suitable wavelength, wavelength range, or combination of wavelengths can be emitted by the light delivery elements970. In at least some embodiments, a lead912can include light delivery elements970that emit different wavelengths of light or are capable of delivering multiple wavelengths of light. In at least some embodiments, at least one of the light delivery elements970of a lead912is capable of emitting light having at least one wavelength in a range of 600 to 850 nm or in a range of 620 to 720 nm.

In at least some embodiments, a system is configured to deliver both optical and electrical stimulation using the same or different leads. For example, any combination of leads12and lead912can be used and any combination of lead trajectories.

In at least some embodiments, an electro-optical stimulation lead can include both electrode(s)134and light delivery element(s)970. Examples of such leads are described in the references cited above. In at least some embodiments, the electrode(s)12and light deliver element(s)912are both powered by a common implantable power source (for example, power source612ofFIG.6). In other embodiments, the electrode(s) and light deliver element(s) are delivered using different leads coupled to different implantable power sources. The implantable power source(s) can be rechargeable or non-rechargeable.

In at least some embodiments, the electrical, optical, or combined stimulation system is powered transcutaneously via radiofrequency energy or some other external energy source (e.g., ultrasound).

FIG.11is a flowchart of one embodiment of a method of stimulating the NBM. The objective of stimulation of the NBM can be to increase production or delivery of Ach, to reduce slow or halt degeneration of the neurons of the NBM, or the like or any combination thereof. In step1102, one or more electrical stimulation lead, optical stimulation leads, electro-optical stimulation leads, or any combination thereof is implanted in or near the NBM. For example, an electrical stimulation lead or electro-optical stimulation lead may be implanted into the brain of the patient so that at least one or more of the electrodes are disposed in or near the NBM. As another example, an optical stimulation lead or electro-optical stimulation lead may be implanted into the brain of the patient so that at least one or more of the light delivery elements are disposed in or near the NBM. Following implantation, a programming process may be used to determine a set of stimulation parameters for the treatment as discussed above. The IPG may also be implanted. In at least some embodiments, the IPG is implanted in the torso with the lead, or a lead extension coupled to the lead, extending under the skin to the IPG. In at least some embodiments, the lead can be coupled instead to an ETS or other external stimulator.

In step1104, electrical/optical stimulation is delivered through the lead to stimulate the NBM using the set of stimulation parameters. Methods, considerations, and examples of electrical/optical stimulation are described above.

It will be understood that each block of the flowchart illustration, and combinations of blocks in the flowchart illustration and methods disclosed herein, can be implemented by computer program instructions. In addition, the feature extraction engine, storage engine, visualization engine, and storage programming engine may be implemented by computer program instructions. These program instructions may be provided to a processor to produce a machine or engine, such that the instructions, which execute on the processor, create means for implementing the actions specified in the flowchart block or blocks or engine disclosed herein. The computer program instructions may be executed by a processor to cause a series of operational steps to be performed by the processor to produce a computer implemented process. The computer program instructions may also cause at least some of the operational steps to be performed in parallel. Moreover, some of the steps may also be performed across more than one processor, such as might arise in a multi-processor computing device. In addition, one or more processes may also be performed concurrently with other processes, or even in a different sequence than illustrated without departing from the scope or spirit of the invention.

The computer program instructions can be stored on any suitable computer-readable medium including, but not limited to, RAM, ROM, EEPROM, flash memory or other memory technology, CD-ROM, digital versatile disks (“DVD”) or other optical storage, magnetic cassettes, magnetic tape, magnetic disk storage or other magnetic storage devices, or any other medium which can be used to store the desired information and which can be accessed by a computing device. The computer program instructions can be stored locally or nonlocally (for example, in the Cloud).

The above specification and examples provide a description of the arrangement and use of the invention. Since many embodiments of the invention can be made without departing from the spirit and scope of the invention, the invention also resides in the claims hereinafter appended.