Methods and systems for deep brain stimulation of the subthalamic nucleus

Abstract

A system for stimulating a patient's basal ganglia (NBM) includes an implanted electrical stimulation lead including electrodes, at least one of the electrodes configured to be implanted adjacent to or within the patient's NBM, and an implanted pulse generator configured to couple to the implanted electrical stimulation lead and deliver electrical stimulation to the NBM through at least one of the electrodes of the implanted electrical stimulation lead, the implanted pulse generator including at least one processor configured to increase, upon a user request, at least one of a duration or amplitude of the electrical stimulation over time during an initial stimulation period at least one month in duration and having a beginning and an end, from an initial value at a start of the initial stimulation period to a final value at an end of the initial stimulation period.

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application No. 63 / 153,775, filed on February 25, 2021, which is incorporated herein by reference.

[0002] (Description of Research and Development Sponsored by the Federal Government) This invention was made with government support under RF1 - AG060754 awarded by the National Institutes of Health. The government has certain rights in the invention.

[0003] (Technical Field) This disclosure relates to the area of methods and systems for deep brain stimulation. This disclosure also relates to methods and systems for deep brain stimulation of the nucleus basalis of Meynert (NBM).

Background Art

[0004] Implanted electrical stimulation systems have demonstrated therapeutic effects in various diseases and disorders. For example, deep brain stimulation systems are used as therapies for Parkinson's disease, essential tremor, and other treatments.

[0005] Stimulators have been developed to provide therapy for various treatments. A stimulator can include an implantable pulse generator (IPG), one or more leads, and an array of stimulator electrodes on each lead. The stimulator electrodes are in contact with or near a nerve, muscle, or other tissue to be stimulated. The pulse generator of the IPG generates electrical pulses that are sent to body tissue by the electrodes.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Patent Document 87

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Patent Document 111

Patent Document 112

Summary of the Invention

[0007] One aspect is a system for stimulating a patient's nucleus basalis of Meynert (NBM). The system includes an implantable electrical stimulation lead including electrodes, the implantable electrical stimulation lead configured such that at least one of the electrodes is implanted adjacent to or within the patient's NBM; and an implantable pulse generator coupled to the implantable electrical stimulation lead and configured to deliver electrical stimulation to the NBM through at least one of the electrodes of the implantable electrical stimulation lead. The implantable pulse generator includes at least one processor configured to increase over time at least one of the duration or amplitude of the electrical stimulation from an initial value at the start of an initial stimulation period having a duration of at least one month and having a start and an end to a final value at the end of the initial stimulation period in response to a user request.

[0008] In at least some embodiments, the processor is configured to deliver an electrical stimulus during an initial stimulation period while increasing the amplitude of the electrical stimulus over time. In at least some embodiments, the processor is configured to deliver an electrical stimulus during an initial stimulation period while increasing the duration of the electrical stimulus over time. In at least some embodiments, the processor is configured to deliver an electrical stimulus during an initial stimulation period while increasing the amplitude of the electrical stimulus over time.

[0009] In at least some embodiments, the increase over time of at least one of the duration or the amplitude includes increasing at least one of the duration or the amplitude from an initial value to a final value according to a linear ramp. In at least some embodiments, the increase over time of at least one of the duration or the amplitude includes increasing at least one of the duration or the amplitude from an initial value to a final value according to a non - linear ramp.

[0010] In at least some embodiments, the processor is further configured not to deliver an electrical stimulus during a period when the patient's cognitive load is expected during the initial stimulation period. In at least some embodiments, the processor is further configured to indicate to the user at least one of i) an electrical stimulus is being delivered, or ii) an electrical stimulus will be delivered soon, and the processor is further configured to provide the user with control to delay the delivery of the electrical stimulus and, when the control is actuated, is configured to delay the delivery of the electrical stimulus.

[0011] In at least some embodiments, the system further includes a sensor selected from a blood flow sensor, an electroencephalogram (EEG) sensor, an electrocorticogram (ECoG) sensor, a motion sensor, a chemical concentration sensor, an enzyme activity sensor, or any combination thereof, and the sensor is configured to monitor the patient's response to the electrical stimulus. In at least some embodiments, the processor is configured to monitor the patient's alpha - wave brain activity using an EEG or ECoG sensor.

[0012] Another aspect is a method of stimulating a patient's nucleus basalis of Meynert (NBM). The method includes the step of implanting an electrical stimulation lead into the patient's brain, wherein the electrical stimulation lead includes electrodes and at least one of the electrodes is disposed adjacent to or within the patient's NBM; and the step of delivering electrical stimulation to the NBM through at least one of the electrodes, wherein during an initial stimulation period having a duration of at least one month and having a start and an end, at least one of the duration or the amplitude of the electrical stimulation increases over time from an initial value at the start of the initial stimulation period to a final value at the end of the initial stimulation period.

[0013] A further aspect is a method of stimulating a patient's nucleus basalis of Meynert (NBM). The method includes the step of implanting an electrical stimulation lead into the patient's brain in a lateral-to-medial trajectory, wherein the electrical stimulation lead includes electrodes and at least one of the electrodes is disposed adjacent to or within the patient's NBM; and the step of delivering electrical stimulation to the NBM through at least one of the electrodes, wherein during an initial stimulation period having a duration of at least one month, no electrical stimulation is delivered during periods when the patient's cognitive load is expected.

[0014] In at least some aspects, the method further includes the step of indicating to the user that electrical stimulation is being or about to be delivered, either before or during the delivery of the electrical stimulation. In at least some aspects, the method further includes the step of delaying the delivery of the electrical stimulation in response to a user operation of a delay control. In at least some aspects, the method further includes the step of increasing over time the amount of time per day that electrical stimulation is delivered during periods when the patient's cognitive load is expected, after the initial stimulation period.

[0015] In at least some embodiments, the method further includes, during an initial stimulation period, increasing over time at least one of a duration or an amplitude of the electrical stimulation from an initial value at the start of the initial stimulation period to a final value at the end of the initial stimulation period. In at least some embodiments, increasing includes increasing at least one of the duration or the amplitude over time from the initial value to the final value according to a linear ramp. In at least some embodiments, increasing includes increasing at least one of the duration or the amplitude over time from the initial value to the final value according to a non-linear ramp.

[0016] In at least some embodiments, the method further includes monitoring the patient using a sensor selected from a blood flow sensor, an electroencephalogram (EEG) sensor, an electrocorticogram (ECoG) sensor, a motion sensor, or any combination thereof.

[0017] Yet another embodiment is a system for stimulating a patient's nucleus basalis of Meynert (NBM). The system includes an implantable electrical stimulation lead including electrodes, the implantable electrical stimulation lead configured such that at least one of the electrodes is implanted adjacent to or within the patient's NBM, and an implantable pulse generator coupled to the implantable electrical stimulation lead and configured to deliver electrical stimulation to the NBM through at least one of the electrodes of the implantable electrical stimulation lead, the implantable pulse generator including at least one processor configured, in response to a user request, not to deliver electrical stimulation during a period in which the patient's cognitive load is expected during an initial stimulation period having a duration of at least one month and having a start and an end.

[0018] Another aspect is a method for stimulating a patient's nucleus basalis of Meynert (NBM). The method includes the steps of implanting an electrical stimulation lead into the patient's brain, wherein the electrical stimulation lead includes electrodes and at least one of the electrodes is disposed adjacent to or within the patient's NBM; delivering electrical stimulation to the NBM through at least one of the electrodes; monitoring the patient using a sensor selected from a blood flow sensor, an electroencephalogram (EEG) sensor, an electrocorticogram (ECoG) sensor, a motion sensor, or any combination thereof; and changing the electrical stimulation based on the monitoring of the sensor.

[0019] In at least some aspects, the step of monitoring the patient includes monitoring the patient's alpha wave brain activity using an EEG or ECoG sensor.

[0020] A further aspect is a system for stimulating a patient's nucleus basalis of Meynert (NBM). The system includes an implantable electrical stimulation lead including a plurality of electrodes configured such that at least one of the electrodes is implanted adjacent to or within the patient's NBM; and an implantable pulse generator coupled to the implantable electrical stimulation lead and configured to deliver electrical stimulation to the NBM through at least one of the electrodes of the implantable electrical stimulation lead. The implantable pulse generator includes at least one processor configured to deliver electrical stimulation to the NBM through at least one of the electrodes, monitor the patient using a sensor selected from a blood flow sensor, an electroencephalogram (EEG) sensor, an electrocorticogram (ECoG) sensor, a motion sensor, or any combination thereof, and change the electrical stimulation based on the monitoring of the sensor.

[0021] Non-limiting and non-exhaustive embodiments of the present invention will be described with reference to the following drawings. In the drawings, like reference numerals refer to like elements throughout the various figures unless otherwise specified.

[0022] To better understand the present invention, reference is made to the following detailed description, which should be read in conjunction with the accompanying drawings.

Brief Description of the Drawings

[0023]

Figure 1

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[0024] The present disclosure relates to methods and systems for deep brain stimulation. The present disclosure also relates to methods and systems for deep brain stimulation of the nucleus basalis of Meynert (NBM).

[0025] Suitable implantable electrical stimulation systems include, but are not limited to, at least one electrical stimulation lead having one or more electrodes disposed along a distal end of the lead and one or more terminals disposed along one or more proximal ends of the lead. Examples of electrical stimulation systems having leads are found, for example, in U.S. Patent 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 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, which are hereby incorporated by reference in their entirety.

[0026] Referring to FIG. 1, one embodiment of the electrical stimulation system 10 includes one or more electrical stimulation leads 12 and an implantable pulse generator (IPG) 14. The system 10 can also include one or more of an external remote control (RC) 16, a clinician programmer (CP) 18, an external test stimulator (ETS) 20, or an external charger 22. The IPG and the ETS are examples of control modules of the electrical stimulation system.

[0027] The IPG 14 is optionally physically connected to the electrical stimulation lead 12 via one or more lead extensions 24. Each electrical stimulation lead has a plurality of electrodes 26 arranged in an array. The IPG 14 includes a pulse generation circuit that supplies electrical stimulation energy to one or more of the electrodes 26 of the array, for example in the form of a pulsed electrical waveform (i.e., a series of electrical pulses over time), according to a set of stimulation parameters. The IPG 14 can be implanted in the patient's body, for example, under the patient's clavicle, in the patient's abdominal cavity, or at any other suitable site. The implantable pulse generator 14 can have a plurality of stimulation channels that are independently programmable to control the magnitude of the current stimulation from each channel. In some embodiments, the implantable pulse generator 14 can have any suitable number of stimulation channels, including but not limited to 4, 6, 8, 12, 16, 32, or more. The implantable pulse generator 14 can have one, two, three, four, or more connector ports for receiving the terminals of the lead and / or the lead extension.

[0028] The ETS20 can also be physically connected to the stimulation lead 12, optionally via a percutaneous lead extension 28 and an external cable 30. The ETS20, which can have a pulse generation circuit similar to the IPG14, also supplies electrical stimulation energy to the electrodes 26 according to a set of stimulation parameters, for example, in the form of a pulsed electrical waveform. One difference between the ETS20 and the IPG14 is that the ETS20 is often a non-implanted device that is used experimentally to test the responsiveness of the provided stimulation after the electrical stimulation lead 12 has been implanted and before the implantation of the IPG14. The functions described herein with respect to the IPG14 can similarly be performed with respect to the ETS20.

[0029] The RC16 can be used to remotely communicate with or control the IPG14 or the ETS20 via a unidirectional or bidirectional wireless communication link 32. When the IPG14 and the electrical stimulation lead 12 are implanted, the RC16 can be used to remotely communicate with or control the IPG14 via a unidirectional or bidirectional communication link 34. Such communication or control can turn the IPG14 on or off and program it with different sets of stimulation parameters. The IPG14 can also be operated to change the programmed stimulation parameters in order to actively control the characteristics of the electrical stimulation energy output by the IPG14. The CP18 enables a user, such as a clinician, to program the stimulation parameters of the IPG14 and the ETS20 in the operating room and follow-up sessions. Alternatively, or additionally, the stimulation parameters can be programmed via wireless communication (e.g., Bluetooth) between the RC16 (or an external device such as a portable electronic device such as a mobile phone, tablet, etc.) and the IPG14.

[0030] CP18 can perform this function by communicating indirectly with IPG14 or ETS20 via RC16 through wireless communication link 36. Alternatively, CP18 may communicate directly with IPG14 or ETS20 via a wireless communication link (not shown). The stimulation parameters provided by CP18 are also used to program RC16, so the stimulation parameters can then be changed by the operation of RC16 in stand-alone mode (i.e., without the assistance of CP18).

[0031] Additional examples of RC16, CP18, ETS20, and external charger 22 can be found in the documents cited herein, as well as U.S. Patent 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 hereby incorporated by reference in their entirety.

[0032] FIG. 2 schematically shows another embodiment of the electrical stimulation system 10. The electrical stimulation system includes an IPG (e.g., a control module) 14 and at least one electrical stimulation lead 12 that can be coupled to the IPG14. The electrical stimulation lead 12 includes one or more lead bodies 106, an array of electrodes such as electrode 134, and an array of terminals (e.g., 210 in FIGS. 3 and 4) disposed along one or more lead bodies 106. In at least some embodiments, the leads are equidistant along the longitudinal direction of the lead body 106. FIG. 2 shows one lead 12 coupled to the IPG14. Other embodiments can include two, three, four, or more leads 12 coupled to the IPG14.

[0033] The electrical stimulation lead 12 can be coupled to the IPG 14 in any suitable manner. In at least some embodiments, the electrical stimulation lead 12 is coupled directly to the IPG 14. In at least some other embodiments, the electrical stimulation lead 12 is coupled to the IPG 14 via one or more intermediate devices. For example, in at least some embodiments, one or more lead extensions 224 (see, e.g., FIG. 4) can be disposed between the electrical stimulation lead 12 and the IPG 14 to extend the distance between the electrical stimulation lead 12 and the IPG 14. The lead extension can also be useful for crossing a joint or can be more easily replaced if the lead extension breaks due to fatigue since such replacement does not affect the placement of the distal end of the lead. Other intermediate devices can be used in addition to or instead of one or more lead extensions, including, for example, splitters, adapters, or any combination thereof. It will be understood that if the electrical stimulation system 10 includes a plurality of elongated devices disposed between the electrical stimulation lead 12 and the IPG 14, the intermediate devices can be configured in any suitable arrangement.

[0034] In FIG. 2, the electrical stimulation system 10 is shown to have a splitter 107 configured and arranged to facilitate coupling of the electrical stimulation lead 12 to the IPG 14. The splitter 107 includes a splitter connector 108 configured to couple to the proximal end of the electrical stimulation lead 12 and one or more splitter tails 109a and 109b configured and arranged to couple to the IPG 14 (or another splitter, lead extension, adapter, etc.).

[0035] In at least some embodiments, the IPG 14 includes a connector housing 112 and a sealed electronics housing 114. An electronics subassembly 110 and an optional power source 121 are disposed within the electronics housing 114. An IPG connector 144 is disposed within the connector housing 112. The IPG connector 144 is configured and arranged to make an electrical connection between the electrical stimulation lead 12 and the electronics subassembly 110 of the IPG 14.

[0036] The electrode 134 can be formed using any conductive biocompatible material. Examples of suitable materials include metals, alloys, conductive polymers, conductive carbon, etc., and combinations thereof. In at least some embodiments, one or more of the electrodes 134 are formed from one or more of platinum, platinum iridium, palladium, palladium rhodium, or titanium. Any number of electrodes 134 can be used for each array 26. For example, it can be 2, 4, 6, 8, 10, 12, 14, 16 or more electrodes 134. As will be appreciated, other numbers of electrodes 134 can also be used.

[0037] The electrodes of the one or more lead bodies 106 are typically disposed within or separated by a non-conductive biocompatible material such as, for example, silicone, polyurethane, polyetheretherketone (“PEEK”), epoxy, etc. or combinations thereof. The lead body 106 can be formed into a desired shape by, for example, molding (including injection molding), casting, and any process including these. The non-conductive material typically extends from the distal end of the one or more lead bodies 106 to the proximal end of each of the one or more lead bodies 106.

[0038] Terminals (e.g., 210 in FIGS. 3 and 4) are typically disposed along the proximal end of one or more lead bodies 106 (as well as any splitters, lead extensions, adapters, etc.) of the electrical stimulation system 10 for electrical connection to corresponding connector contacts (e.g., 214 in FIG. 3 and 240 in FIG. 4). The connector contacts are disposed in a connector (e.g., 144 in FIGS. 2 - 4, and 221 in FIG. 4), and this connector is disposed in, for example, the IPG 14 (or a lead extension, splitter, adapter, etc.). A conductive wire, cable or other (not shown) extends from the terminal to the electrode 134. Typically, one or more electrodes 134 are electrically coupled to each terminal. In at least some embodiments, each terminal is connected to only one electrode 134.

[0039] The conductive wire ("conductor") can be embedded in the non-conductive material of the lead body 106 or can be disposed in one or more lumens (not shown) extending along the lead body 106. In some embodiments, there is a separate lumen for each conductor. In other embodiments, two or more conductors extend through one lumen. Also, for example, there may be one or more lumens (not shown) that open at or near the proximal end of the lead body 106 for inserting a stylet to facilitate placement of the lead body 106 into the patient's body. Further, for example, there can be one or more lumens (not shown) that open at or near the distal end of the lead body 106 for injecting a drug or agent at the implantation site of one or more lead bodies 106. In at least some embodiments, one or more lumens can be sealed permanently or removably at the distal end.

[0040] FIG. 3 is a schematic side view of one embodiment of the proximal end of one or more elongated devices 200 configured and arranged to couple to one embodiment of the IPG connector 144. The one or more elongated devices can include, for example, the lead body 106, one or more intermediate devices (e.g., the splitter 107 of FIG. 2, the lead extension 224 of FIG. 4, an adapter, etc., or combinations thereof), or combinations thereof. FIG. 3 shows two elongated devices 200 coupled to the IPG 14. These two elongated devices 200 can be two tails as illustrated in FIG. 2 or any other combination of two different leads or elongated devices.

[0041] The IPG connector 144 defines at least one port into which the proximal end of the elongate device 200 can be inserted, as indicated by the direction arrows 212a and 212b. In FIG. 3 (and other figures), the connector housing 112 is shown as having two ports 204a and 204b. The connector housing 112 can define any suitable number of ports, including, for example, 1, 2, 3, 4, 5, 6, 7, 8, or more ports.

[0042] The IPG connector 144 also includes a plurality of connector contacts, such as connector contacts 214 disposed within each of the ports 204a and 204b. When the elongate device 200 is inserted into the ports 204a and 204b, the connector contacts 214 can align with a plurality of terminals 210 disposed along the proximal end of the elongate device 200 to electrically couple the IPG 14 to the electrodes (134 in FIG. 2) disposed at the distal end of the electrical stimulation lead 12. Examples of connectors in an IPG are described, for example, in U.S. Pat. Nos. 7,244,150 and 8,224,450, which are hereby incorporated by reference in their entirety.

[0043] FIG. 4 is a schematic side view of another embodiment of the electrical stimulation system 10. The electrical stimulation system 10 includes a lead extension 224 configured and arranged to couple one or two or more elongate devices 200 (e.g., lead body 106, splitter 107, adapter, another lead extension, etc. or combinations thereof) to the IPG 14. In FIG. 4, the lead extension 224 is shown coupled to a single port 204 defined by the IPG connector 144. Further, the lead extension 224 is shown configured and arranged to couple to a single elongate device 200. In an alternative embodiment, the lead extension 224 is configured and arranged to couple to a plurality of ports 204 defined within the IPG connector 144, or to receive a plurality of elongate devices 200, or both.

[0044] A lead extension connector 221 is disposed on the lead extension 224. In FIG. 4, the lead extension connector 221 is shown disposed at the distal end 226 of the lead extension 224. The lead extension connector 221 includes a connector housing 228. The connector housing 228 defines at least one port 230 into which a terminal 210 of the elongated device 200 can be inserted, as indicated by the direction arrow 238. The connector housing 228 also includes a plurality of connector contacts, such as connector contacts 240. When the elongated device 200 is inserted into the port 230, the connector contacts 240 disposed in the connector housing 228 can be aligned with the terminals 210 of the elongated device 200 to electrically couple the lead extension 224 to an electrode (134 in FIG. 2) disposed along the lead (12 in FIG. 2).

[0045] In at least some embodiments, the proximal end of the lead extension 224 is configured and arranged similar to the proximal end of the lead 12 (or other elongated device 200). The lead extension 224 can include a plurality of conductive wires (not shown) that electrically couple the connector contacts 240 to a proximal end 248 of the lead extension 224 on the side opposite the distal end 226. In at least some embodiments, the conductive wires disposed on the lead extension 224 can be electrically coupled to a plurality of terminals (not shown) disposed along the proximal end 248 of the lead extension 224. In at least some embodiments, the proximal end 248 of the lead extension 224 is configured and arranged to be inserted into a connector disposed on another lead extension (or another intermediate device). In other embodiments (and as shown in FIG. 4), the proximal end 248 of the lead extension 224 is configured and arranged to be inserted into the IPG connector 144.

[0046] Returning to FIG. 2, in at least some embodiments, at least a portion of the stimulation electrodes take the form of segment electrodes that only partially extend around (e.g., circumferentially) the lead. These segment electrodes can be provided in sets, each set having electrodes that are distributed circumferentially about the lead at a particular longitudinal position.

[0047] In FIG. 2, electrode 134 is shown as including both ring electrode 120 and segment electrodes 122. In some embodiments, electrode 134 may be all segment electrodes or all ring electrodes. The segment electrodes 122 in FIG. 2 are in three sets (one of which is not visible in FIG. 2), and the three segment electrodes of a particular set are electrically insulated from each other and circumferentially offset along lead 12. Any suitable number of segment electrodes can be formed into sets including, for example, 2, 3, 4, or more segment electrodes. Lead 12 in FIG. 2 has 30 segment electrodes 122 (10 sets of 3 electrodes each) and 2 ring electrodes 120, for a total of 32 electrodes 134.

[0048] Segment electrodes can be used to direct a stimulation current to one side, or a portion of one side, of the lead. When segment electrodes are used with an implantable pulse generator that supplies multiple current stimulations simultaneously, current steering can be achieved to more accurately deliver the stimulation to a position around the axis of the lead (i.e., radial positioning around the axis of the lead). Since the target structure in deep brain stimulation is generally not symmetric with respect to the axis of the distal electrode array, segment electrodes may provide better current steering than ring electrodes. Instead, the target can be located on one side of a plane passing through the axis of the lead. By using a segment electrode array, current can be passed not only along the length of the lead but also around the lead. This enables accurate three-dimensional targeting and delivery of current stimulation to nerve target tissue while potentially avoiding stimulation of other tissues.

[0049] FIG. 5A shows a 32 - electrode lead 12 having two ring electrodes 120 proximal to thirty segment electrodes 122, with ten sets of three segment electrodes 122 each disposed on a lead body 106. In the illustrated embodiment, the ring electrodes 120 are proximal to the segment electrodes 122. In other embodiments, one or more of the ring electrodes 120 can be proximal to one or more of the segment electrodes 122, or distal to one or more of the segment electrodes 122.

[0050] Any number of segment electrodes 122 can be disposed on a lead body including, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 20, 24, 28, 30, 32 or more segment electrodes 122. It will be understood that any number of segment electrodes 122 can be disposed along the length of the lead body. The segment electrodes 122 typically extend 75%, 67%, 60%, 50%, 40%, 33%, 25%, 20%, 17%, 15% or less of the circumference of the lead.

[0051] The segment electrodes 122 can be grouped into sets of segment electrodes, with each set disposed around the circumference of the electrical stimulation lead 12 at a particular longitudinal portion of the electrical stimulation lead 12. The electrical stimulation lead 12 can have any number of segment electrodes 122 in a given set of segment electrodes. The electrical stimulation lead 12 can have 1, 2, 3, 4, 5, 6, 7, 8 or more segment electrodes 122 in a given set. The electrical stimulation lead 12 can have any number of sets of segment electrodes including, but not limited to, 1, 2, 3, 4, 5, 6, 8, 10, 12, 15, 16, 20, or more sets. The segment electrodes 122 can be of uniform or different sizes and shapes. In some embodiments, all of the segment electrodes 122 are of the same size, shape, diameter, width or area, or a combination thereof. In some embodiments, the segment electrodes 122 of each circumferential set (or all of the segment electrodes disposed on the lead 12) can be of the same size and shape.

[0052] Each set of segment electrodes 122 can be arranged on the circumference of the lead body so as to form a substantially cylindrical shape around the lead body. The spacing between the individual electrodes of a given set of segment electrodes may be the same as or different from the spacing between the individual electrodes of another set of segment electrodes on the electrical stimulation lead 12. In at least some embodiments, an equal space, gap or notch is disposed between each of the segment electrodes 122 on the circumference of the lead body. In other embodiments, the spaces, gaps or notches between the segment electrodes 122 may differ in size or shape. In other embodiments, the spaces, gaps or cutouts between the segment electrodes 122 can be made uniform for a particular set of segment electrodes 122 or for all sets of segment electrodes 122. The sets of segment electrodes 122 can be arranged at irregular or regular intervals along the length of the lead body.

[0053] Figures 5B - 5E show other embodiments of a lead having segment electrodes 122. Figure 5B illustrates a 16 - electrode lead 12 having one ring electrode 120 proximal to each of five sets of three segment electrodes 122. Figure 5C illustrates a 16 - electrode lead 12 having eight sets of two segment electrodes 122 each. As shown in Figure 5C, an embodiment of the lead 12 does not necessarily include a ring electrode. Figure 5D illustrates a 16 - electrode lead 12 having four ring electrodes 120 proximate to each of six sets of two segment electrodes 122 each. Figure 5E shows a 32 - electrode lead 12 having 16 sets of two segment electrodes 122 each (not all electrodes are shown for clarity of illustration). It will be appreciated that any combination of ring electrodes, segment electrodes, or both types of electrodes can be used.

[0054] When lead 12 includes both ring electrode 120 and segment electrode 122, ring electrode 120 and segment electrode 122 can be arranged in any suitable configuration. For example, when lead 12 includes a set of two or more ring electrodes 120 and one or more segment electrodes 122, ring electrode 120 can be arranged laterally with respect to one or more sets of segment electrodes 122. Alternatively, two or more ring electrodes 120 can be arranged proximally to one or more sets of segment electrodes 122, or two or more ring electrodes 120 can be arranged distally to one or more sets of segment electrodes 122, or any other suitable arrangement of ring electrode 120 and segment electrode 122 can be made.

[0055] Electrodes 120, 122 can 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 electrodes 120, 122 can 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 closest ends of two adjacent electrodes. In some embodiments, the spacing is uniform between electrodes adjacent in the longitudinal direction of the lead. In other embodiments, the spacing between adjacent electrodes in the longitudinal direction can be different or non-uniform along the length of the lead.

[0056] Examples of electrical stimulation leads having segmented electrodes include U.S. Patent Application Publication 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. Patent No. 8,483,237, all of which are hereby incorporated by reference in their entirety. The electrical stimulation lead can also include a tip electrode, and examples of leads having a tip electrode include at least some of the previously cited documents, as well as U.S. Patent Application Publication Nos. 2014 / 0296953 and 2014 / 0343647, all of which are hereby incorporated by reference in their entirety. A lead having segmented electrodes can be a directional lead that can deliver stimulation in a specific direction using the segmented electrodes.

[0057] FIG. 6 is a schematic overview of one embodiment of the components of an electrical stimulation system 600 that includes an electronic sub-assembly 610 disposed within an IPG. It will be understood that the electrical stimulation system can include one or more components and can have a variety of different configurations including those disclosed in the stimulator references cited herein.

[0058] Some of the components of the electrical stimulation system (e.g., power supply 612, antenna 618, receiver 602, processor 604, and memory 605) can, if desired, be disposed on one or more circuit boards or similar carriers within the sealed housing of the implantable pulse generator. For example, any power supply 612 that includes a battery such as a primary battery or a rechargeable battery can be used. Examples of other power supplies include supercapacitors, nuclear batteries or atomic batteries, mechanical resonators, infrared collectors, thermodynamic energy sources, flexure power energy sources, bioenergy power supplies, fuel cells, bioelectric batteries, osmotic pumps, and similar ones including the power supplies described in U.S. Patent No. 7,437,193, which is hereby incorporated by reference in its entirety.

[0059] As another alternative, power can be supplied from an external power source via inductive coupling through an optional antenna 618 or a secondary antenna. The external power source can be within a device worn on the user's skin or within a unit provided permanently or periodically near the user.

[0060] If the power supply 612 is a rechargeable battery, the battery can be charged using the optional antenna 618 as needed. By inductively coupling the battery to a charging unit 616 external to the user via the antenna, power can be supplied to the battery for charging. Examples of such arrangements can be found in the literature identified above.

[0061] In one embodiment, current is emitted by electrode 134 of the lead body to stimulate nerve fibers, muscle fibers, or other body tissues near the electrical stimulation system. Processor 604 is generally included to control the timing and electrical characteristics of the electrical stimulation system. For example, processor 604 can control one or more of the pulse timing, frequency, amplitude, width, and waveform, if desired. Further, processor 604 can select which electrodes to use to provide stimulation, if desired. In some embodiments, processor 604 can select which electrodes are cathodes and which are anodes, and the amount of anode current or cathode current assigned to each. In some embodiments, processor 604 can be used to identify which electrodes provide the most useful stimulation to the desired tissue. Instructions for processor 604 can be stored on memory 605.

[0062] Any processor can be used and can be simple, such as an electronic device that generates pulses at regular intervals, or the processor can be one that can receive and interpret instructions from a CP / RC 606 (such as CP 18 or RC 16 in FIG. 1) that enables changes in pulse characteristics, for example. In the illustrated embodiment, processor 604 is coupled to receiver 602, which is coupled to optional antenna 618. Thereby, processor 604 can receive instructions from the outside to indicate, for example, pulse characteristics and electrode selection, if desired.

[0063] In one embodiment, the antenna 618 can receive a signal (e.g., an RF signal) from the CP / RC 606 (refer to CP18 or RC16 in FIG. 1) that is operated by a user in a program or other ways. The signal transmitted to the processor 604 via the antenna 618 and the receiver 602 can be used to change or otherwise instruct the operation of the electrical stimulation system. For example, the signal can be used to change the pulses of the electrical stimulation system such as one or more changes in pulse width, pulse frequency, pulse waveform, and pulse amplitude. The signal can also instruct the electrical stimulation system 600 to stop operation, start operation, start battery charging, or stop battery charging. In other embodiments, the stimulation system does not include the antenna 618 or the receiver 602, and the processor 604 operates as programmed.

[0064] Optionally, the electrical stimulation system 600 can include a transmitter (not shown) coupled to the processor 604 and the antenna 618 to send a signal back to the CP / RC 606 or other unit that can receive the signal. For example, the electrical stimulation system 600 can transmit a signal indicating whether the electrical stimulation system 600 is operating properly, or a signal indicating the time when battery charging is required or the remaining battery charge. The processor 604 can also transmit information regarding pulse characteristics so that a user or clinician can determine or verify the characteristics.

[0065] Dementia, such as Alzheimer's disease, is generally associated with a decrease in acetylcholine (Ach), an important neurotransmitter in the cerebral cortex. According to research, anticholinergic drugs (for other health problems) are associated with an increased risk of dementia, and one class of FDA-approved dementia medications is anticholinesterase drugs (i.e., drugs that slow down the metabolism of ACh to act longer / stronger).

[0066] The cells that produce and send out ACh in the cerebral cortex are located in the nucleus basalis of Meynert (NBM). Stimulation of this site is thought to induce the release of ACh in the cerebral cortex and to counteract the effects of dementia. The release of ACh may also be used in the treatment of depression and neuropsychological disorders. In non-human primates, it has been demonstrated that stimulation of the NBM significantly improves performance on memory tasks. It has also been shown that an intermittent stimulation protocol is effective, while a continuous stimulation protocol is not.

[0067] In addition to stimulating NBM neurons to supply more ACh, it is also desirable to slow or stop the neurodegeneration of these cells.

[0068] The NBM has a unique curved shape, like a bent oval pancake or a flat banana. An approximation of the shape of the NBM 760 in one hemisphere of the brain is shown in FIG. 7. This shape can make it difficult to fully engage the NBM 760 using an electrical stimulation lead because it may be difficult for a single electrode array to stimulate a relatively large portion or all of the cells to fully utilize the ACh machinery of each cell.

[0069] In at least some embodiments, to address the unique shape of the target NBM 760 and to stimulate the target NBM more, a plurality of electrical stimulation leads 12 can be placed at different portions of the target NBM 760, and as shown in FIG. 7, stimulation can be cycled between the electrodes 134 of the electrical stimulation leads 12 to generate a plurality of stimulation regions 762. In the illustrated embodiment of FIG. 7, two electrical stimulation leads 12 are implanted using an upper-to-lower trajectory, and one electrical stimulation lead is used to generate two different stimulation regions 762, while the other electrical stimulation lead provides another stimulation region.

[0070] In at least some embodiments, as shown in FIG. 8, to address the unique shape of the target NBM760, at least one stimulation lead 12 is embedded along a lead trajectory generally or approximately (e.g., within 10 degrees, 15 degrees, 25 degrees, 30 degrees, or 45 degrees) from the side toward the center rather than the typical top-down to stimulate more of the target. The electrode 134 of the lead can be aligned along or adjacent to the axis of the target NBM760. Along this lead trajectory, a plurality of stimulation regions 762 can be generated in which more electrodes 134 from a single electrical stimulation lead 12 are brought close (including across) to a portion of the target NBM760 and circulated as will be described in more detail below.

[0071] Any suitable number of electrical stimulation leads 12 can be used to stimulate the NBM, including but not limited to 1, 2, 3, 4, or more leads. When multiple electrical stimulation leads 12 are used, any suitable combination of electrical stimulation leads 12 embedded in a top-down trajectory (FIG. 7) and leads embedded in a side-to-center trajectory (FIG. 8) can exist. The electrical stimulation lead 12 can be embedded in one or both hemispheres of the brain to stimulate one or both NBM760s. The placement of the electrical stimulation lead 12 for each hemisphere can be the same or different.

[0072] The electrical stimulation lead 12 can generate any suitable number of stimulation regions 762, including but not limited to 1, 2, 3, 4, or more stimulation regions. In at least some embodiments, one or more electrical stimulation leads 12 include segment electrodes 122. The use of segment electrodes 122 can facilitate the selection of the directivity of the stimulation region 762.

[0073] To generate electrical stimulation for the stimulation region 762, one or more electrodes 134 can be used. The electrodes can be cathodes or anodes or combinations of either. In at least some embodiments, the sealed electronics housing 114 of the IPG 14 (or other portion of the case) can be used as a common return electrode, as 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., the active electrode is an anode), which is often more effective for selective stimulation of cell bodies than cathodic stimulation.

[0074] By generating combinations of the stimulation regions 762, effective stimulation of a relatively large portion or all of the NBM 760 can be facilitated. The stimulation regions 762 illustrated in FIGS. 7 and 8 correspond to the estimated effective regions of stimulation for a particular set of stimulation parameters. Examples of stimulation parameters include, but are not limited to, electrode selection, stimulation amplitude (which can be independent for each electrode), pulse frequency, pulse duration or width, etc. In at least some embodiments, the stimulation regions 762 of FIGS. 7 and 8 can be determined or estimated algorithmically or manually. The terms “stimulation field map” (SFM), “volume of activation” (VOA), or “volume of activated tissue” (VTA) are often used to designate the estimated stimulation region 762 of the tissue that is stimulated for a particular set of stimulation parameters. Any suitable method for determining the VOA / SFM / VTA is described, for example, in 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 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 No. 62 / 030,655, all of which are hereby incorporated by reference in their entirety.

[0075] In at least some embodiments, a plurality of stimulation regions 762 are selected such that combinations of these stimulation regions can cover many of the target NBM760 using electrodes of the same or different electrical stimulation leads. Any suitable number of stimulation regions 762 can be used, including, but not limited to, 1, 2, 3, 4, 5, 6, 8, 10, 12, or more stimulation regions. In at least some embodiments, the stimulation regions 762 can also be selected to limit or avoid overlap between the stimulation regions.

[0076] In at least some embodiments, the selection of the plurality of stimulation regions 762 (e.g., SFM) can be based on postoperative X-ray imaging, MRI, or other imaging techniques, or any combination thereof. In at least some embodiments, the selection of the plurality of stimulation regions 762 (e.g., SFM) can be based on the surgical plan, either alone or in combination with postoperative imaging. In at least some embodiments, the selection of the plurality of stimulation regions 762 (e.g., SFM) is performed offline.

[0077] In at least some embodiments, the selection of the plurality of stimulation regions 762 (e.g., SFM) can be performed manually using a programmer or other device user interface that enables simultaneous display of the plurality of stimulation regions. In at least some embodiments, the selection of the plurality of stimulation regions 762 (e.g., SFM) can be performed algorithmically using techniques such as, for example, binary search, gradient descent search, genetic search, or particle swarm search, or any combination thereof.

[0078] In at least some embodiments, the stimulation region 762 is selected based on a scoring or other criterion that increases based on the amount of the NBM 760 covered by the stimulation region or that penalizes portions of the target NBM 760 not covered by the stimulation region. In at least some embodiments, the stimulation region 762 has a scoring criterion that penalizes overlap between stimulation regions. In at least some embodiments, the scoring criterion can weight overlapping or non-stimulation regions. Examples of scoring and scoring criteria can be found, for example, in U.S. Patent Application Publication Nos. 2016 / 0001080; 2014 / 0277284; 2014 / 0200633; 2014 / 0067022; 2014 / 0066999; 2013 / 0116929; 2013 / 0116748; 2013 / 0060305; and 2012 / 0271376, all of which are hereby incorporated by reference in their entirety.

[0079] Delivery of electrical stimulation to the stimulation area can include additional stimulation parameters that exceed amplitude, pulse width, pulse frequency, etc. Examples of additional stimulation parameters include, but are not limited to, duty cycle ratio, duration of the stimulation cycle, total number of pulses during the stimulation period, duration of the stimulation period, number of stimulation periods per day, or combinations thereof. The supply of stimulation to the stimulation area can be described by a series of cycles that stimulate during one part of the cycle and do not stimulate during another part of the cycle. The duty cycle ratio can be made equal to the ratio of the time during which stimulation is provided to the time during which stimulation is not provided. For example, a 60-second cycle can include 20 seconds of stimulation and 40 seconds of no stimulation, and as a result, the duty cycle ratio of the stimulation is 1:2. The duration of the cycle can be any suitable number including, but not limited to, 5 seconds, 10 seconds, 15 seconds, 20 seconds, 30 seconds, or 45 seconds, or 1 minute, 2 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, or 60 minutes, or more. The duty cycle ratio can be any suitable ratio including, but not limited to, a ratio in the range of 1:5 to 5:1, or a ratio in the range of 1:3 to 3:1, or a ratio in the range of 1:5 to 1:1.

[0080] The stimulation period can be defined as the period during which multiple cycles of stimulation are performed. The duration of the stimulation period can be any appropriate 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 can be defined as the number of pulses instead of, or in addition to, the period. The number of pulses during the stimulation period can be any appropriate number, and in at least some embodiments, can be in the range of 1,000 to 100,000, or in the range of 5,000 to 50,000, or in the range of 10,000 to 30,000.

[0081] The number of stimulation periods per day can be any suitable number including, but not limited to, 1, 2, 3, 4, 5, 6, 8, 10, 12, 15, 20, or more. In at least some embodiments, the number of stimulation periods per day or the number of stimulation pulses delivered per day can be considered a "dose". As an example, stimulation to one of the stimulation regions 762 can be delivered at a pulse rate of 20 Hz for a 20 - second period (duty cycle ratio of 1:2) out of a 60 - second cycle for a 60 - minute stimulation period (i.e., 60 cycles) with one stimulation period per day (a total of 24,000 stimulation pulses per day).

[0082] In at least some embodiments, the stimulation region 762 is stimulated for the same or a similar amount of time during one cycle or stimulation period. In other embodiments, different amounts of stimulation time (e.g., different amounts of time within a cycle or stimulation period) can exist for different stimulation regions 762.

[0083] When multiple stimulation regions 762 are stimulated, in at least some embodiments, the stimulation of each of the stimulation regions 762 can be performed using a temporal offset. In at least some embodiments, the delivery of the stimulation can be interleaved. For example, one stimulation region can be followed by another stimulation region and so on. For example, during a 60 - second cycle, the first stimulation region can be stimulated for 20 seconds, then the second stimulation region can be stimulated for 20 seconds, and then the third stimulation region can be stimulated for 20 seconds. In this way, each stimulation region is stimulated at a 1:2 duty cycle ratio. In this example, the overlap between the three stimulation regions is preferably relatively small or zero.

[0084] As another example, the cycles can be interleaved such that during the first 60 - second cycle, the stimulus is delivered to the first stimulation region for 20 seconds, then during the second 60 - second cycle, the stimulus is delivered to the second stimulation region for 20 seconds, and then during the third 60 - second cycle, the stimulus is delivered to the third stimulation region for 20 seconds. In this example, since 40 seconds out of each 60 - second period have no stimulus at all, the overlap between the three stimulation regions may not be very important.

[0085] In other embodiments, the stimulation periods for at least some of the stimulation regions 762 are executed sequentially. For example, during the first stimulation period, the first stimulation region is stimulated, then during the second stimulation period, the second stimulation region is stimulated, and then during the third stimulation period, the third stimulation region is stimulated. For example, the first stimulation region can be stimulated during a single 3 - hour stimulation period, then the second stimulation region can be stimulated during a second 3 - hour stimulation period, and then the third stimulation region can be stimulated during a third 3 - hour stimulation period.

[0086] Since periodic stimulation is thought to be more beneficial, these arrangements avoid continuous stimulation of the stimulation regions 762. In at least some embodiments, one or more of the stimulation regions 762 can be stimulated during any given period, and preferably, the stimulation regions 762 that are stimulated simultaneously do not overlap, and more preferably, are spaced apart from each other by at least 0.1 - 1 millimeter.

[0087] In at least some embodiments, the delivery of the stimulus can be automated using a stimulation setting programmed by a clinician or other caregiver. In some embodiments, the delivery of the stimulus can be manually initiated by the patient, clinician, or other caregiver. In at least some embodiments, the automated delivery of the stimulus can complement or replace the manual initiation of the stimulus. In at least some embodiments, the system can limit the manual initiation of the stimulus by the patient, clinician, or other caregiver to the number of stimulation periods deliverable in a day, or a week, or other defined period.

[0088] In at least some embodiments, a patient, clinician, or other caregiver may initiate a bolus of therapeutic stimulation from an external device (such as RC16 or CP18) at a convenient time. In at least some embodiments, the electrical stimulation system 10 may be configured to allow a patient to initiate only a predetermined number of boluses per unit of time (e.g., per day or per week). In at least some embodiments, the electrical stimulation system 10 includes an external device (such as RC16 or CP18) that reflects a warning when connected to the IPG12 if the patient has not initiated a predetermined or appropriate number of treatment sessions. In at least some embodiments, this data or warning may be sent to the clinician or other caregiver so that the clinician or other caregiver can respond.

[0089] In at least some embodiments, the system or method allows a patient, clinician, or caregiver to have the ability to defer stimulation. In at least some embodiments, the system (e.g., IPG14, RC16, CP18, or another device) can use an external device (e.g., RC16, CP18, a mobile phone, etc.) to warn a patient, clinician, or caregiver that stimulation is being delivered or about to be delivered. In at least some embodiments, a patient, clinician, or caregiver can use the external device to defer stimulation. In at least some embodiments, the external device includes at least one controller that enables deferral of stimulation for a period of time (e.g., 1, 2, 5, 10, 15, 30, 45, or 90 minutes, or 1, 2, 3, 4, 6, 9, 12, or 18 hours, or 1 day or more, or any other appropriate period).

[0090] In at least some embodiments, the stimulation can have a detrimental effect on the patient's memory or cognitive ability during the period of stimulation. In at least some embodiments, the electrical stimulation system 10 can be programmed to deliver stimulation during the night (or other period) when the patient is likely to be asleep. In at least some embodiments, the electrical stimulation system 10 or the IPG 12 can be configured to track the time of day and can be programmed to deliver stimulation during the night (or other period) when the patient is likely to be asleep. In at least some embodiments, the electrical stimulation system 10 or the IPG 12 can be coupled to an external or implanted sensor 40 (e.g., a heart rate, respiration, posture, accelerometer, or biomarker sensor) or a device including the sensor 40 (e.g., a cellular phone or fitness tracker) that can provide information regarding the patient's state to determine or estimate whether the patient is awake or asleep. The IPG 12 can be configured to provide stimulation only if the IPG or the electrical stimulation system 10 determines that the patient is asleep (or receives information from the external sensor 40 or the device including the sensor 40). In at least some embodiments, the IPG 12 or the electrical stimulation system 10 can determine, estimate, or receive information from an external device regarding the patient's sleep stage (e.g., REM sleep) and provide stimulation only during one or more selected or designated sleep stages.

[0091] In some embodiments, the electrical stimulation system 10 or the IPG 12 can be configured with "daytime" or "awake" stimulation parameters and "nighttime" or "sleep" stimulation parameters, and can use either a clock or any of the other approaches described above to determine which should be used when the period of stimulation begins.

[0092] In at least some embodiments, the detrimental effects on memory or cognitive ability decrease with the cessation of the stimulation and can improve over time after the cessation of the stimulation. In at least some embodiments, the detrimental effects on the patient's memory or cognitive ability during the stimulation decrease over time. The methods and systems described herein do not depend on a particular theory, but it is thought that the brain or the NBM may become accustomed to the stimulation over time. In at least some embodiments, the cognitive ability during the stimulation improves over an acclimation period (which may be 1, 2, 5, 7, 10, 14, 15, 21, 28, 30, 45, 60, 90, 120, 180 days or 1, 2, 3, 4, 6, 8, 9, 10 months or 1 year or more or any other suitable period). The acclimation period may vary between individuals, may vary depending on the implantation site or placement, or may vary depending on the stimulation parameters or amount of stimulation, etc. or a combination thereof.

[0093] In at least some embodiments, the system or method can be configured to initially deliver the stimulation during a time period when a cognitive load is not expected. The term "cognitive load" refers to a period during which the patient is actively using mental capabilities and working memory, such as during periods when the patient is performing work (professional or domestic), recreation, or hobby tasks, during driving, reading, education, learning, performing tasks that require mental concentration, or during periods not limited to these, etc. Examples of periods when a cognitive load is not expected include, but are not limited to, sleep, rest, watching television, listening to music, etc. In at least some embodiments, the patient, user, clinician, programmer, or any other suitable individual (or individuals) can program the system to define activities that are not expected to require a cognitive load, activities that require a cognitive load, or any combination thereof.

[0094] In at least some embodiments, this operation of the system or method can be varied over time such that stimuli can be delivered during time periods of cognitive load. In at least some embodiments, this variation can be automatic, or can be manually initiated, or both options can be present. In at least some embodiments, the variation can be gradual while increasing the time during which the stimuli are delivered during the time of cognitive load.

[0095] In at least some embodiments, the method or system can initially deliver a relatively low level of stimuli (e.g., relatively low amplitude, relatively low duration, etc. or any combination thereof). In at least some embodiments, the relatively low level of stimuli can reduce or eliminate a detrimental effect on memory or cognitive ability during the stimuli. Over time, the stimulus level can be increased or ramped up. For example, the amplitude, duration, etc. or any combination thereof can be increased or ramped up over time (e.g., over a period of 1, 2, 5, 7, 10, 14, 15, 21, 28, 30, 45, 60, 90, 120, 180 days or 1, 2, 3, 4, 6, 8, 9, 10 months or 1 year or more or any other suitable period). In at least some embodiments, the final amplitude or final duration is at least 1.2 times, 1.5 times, 2 times, 3 times, 4 times, 5 times, 8 times, 10 times, 15 times or 20 times the initial amplitude or initial duration.

[0096] The methods and systems described herein are not dependent on a particular theory, but it is believed that during this period of increasing or ramping up the stimulation, the brain can become accustomed to receiving the stimulation. In at least some embodiments, the increasing or ramp parameters (e.g., start intensity or amplitude, end intensity or amplitude, start duration (e.g., start daily duration), end duration (e.g., end daily duration), duration of the period, type of increase or ramp - linear, non - linear, step - wise, exponential, etc., or any combination thereof) can be selected or programmed by a clinician or other individual. In at least some embodiments, the ramp can include an increase in intensity, an increase in duration (e.g., an increase in daily duration), or any combination thereof.

[0097] In at least some embodiments, the system or method can include or utilize one or more sensors 40 (FIG. 1) to detect when the stimulation elicits a physiological response. Examples of suitable sensors 40 include blood flow sensors (e.g., implanted or external blood flow sensors), electrocorticogram (ECoG) sensors (e.g., implanted ECoG sensors that can be implanted on the cerebral cortex, for example, when the leads are placed), electroencephalogram (EEG) sensors (e.g., external or implanted EEG sensors), motion sensors (e.g., at least one accelerometer, gyroscope, chemical substance concentration sensor, enzyme activity sensor, etc., or combinations thereof), which can be incorporated into or mounted on an internal or external device (e.g., a mobile phone, a watch, a motion monitor, etc.). ECoG or EEG sensors can be used to detect changes in brain activity such as alpha - wave brain activity (e.g., brain activity in the range of 8 - 12 Hz). Motion sensors can be used to detect changes in activity level, such as increases or decreases in activity level.

[0098] In at least some embodiments, the measurements of sensor 40 are used to determine or change stimulation parameters, to assist with surgical implantation, or to assist with system programming. In at least some embodiments, the measurements of sensor 40 are used to adjust a patient's treatment (e.g., to induce a physiological response at a certain level, to induce a physiological response a certain number of times per day or per a specified period, to measure a response rate to determine or change an appropriate treatment, or the like or any combination thereof).

[0099] In at least some embodiments, an implantable pulse generator (such as IPG14) can receive the measurements of sensor 40, determine or change stimulation parameters based on the measurements, or modulate therapy based on the measurements. In at least some embodiments, an external device (RC16, CP18, a mobile phone, a computer, etc., or any combination thereof) can receive the measurements of the sensor, determine or change stimulation parameters based on the measurements, or modulate therapy based on the measurements, and then transmit the stimulation parameters or the modulated therapy to the implantable pulse generator.

[0100] Additionally or alternatively, optical stimulation of the NBM can be performed. In at least some embodiments, delivery of light to the NBM may have the potential to alleviate neurodegeneration. Optical stimulation systems having optical or electro-optical stimulation leads, at least some of which also produce electrical stimulation (e.g., electro-optical stimulation systems) are found, for example, in U.S. Patent No. 9,415,154 and U.S. Patent Application Publication Nos. 2013 / 0317573; 2017 / 0225007; 2017 / 0259078; 2018 / 0110971; 2018 / 0369606; 2018 / 0369608; 2020 / 0155854; and 2020 / 0376262, all of which are hereby incorporated by reference in their entirety.

[0101] Figures 9 and 10 show a light stimulation lead 912 (or the electro-optical lead of FIG. 9 having optional electrodes 134) having a light delivery element 970 that generates a stimulating light 972 that stimulates the target NBM760. The electrical stimulation components described above and illustrated in FIGS. 1-6 can be used or adapted for use in a light or electro-optical stimulation system as further described in the references cited above.

[0102] Examples of the light delivery element 970 include, but are not limited to, a light emitting diode (LED), a laser diode, or an optical fiber coupled to a light source (such as an LED or a laser diode). In FIG. 9, the light delivery element 970 can be a combination of a plurality of light delivery elements.

[0103] Any suitable number of leads 912, including but not limited to 1, 2, 3, 4, or more leads, can be used to stimulate the NBM. When multiple leads 912 are used, they can be any suitable combination of leads 912 embedded in an upper to lower trajectory (FIG. 10) and leads embedded in a side to center trajectory (FIG. 9). The leads 912 can be implanted in one or both hemispheres of the brain to stimulate one or both NBM760s. The placement of the leads 912 for each hemisphere can be the same or different.

[0104] In at least some embodiments, the illumination area by one or more light delivery elements 970 can be considered to be similar to the stimulation area 762 for electrical stimulation. All of the features, additional parameters, and other options and considerations described above for electrical stimulation can be applied to light stimulation. In at least some embodiments, the light stimulation can be delivered in 1 or more stimulation periods per day for a duration of 1 minute, 2 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 60 minutes, or more per stimulation period (or any other suitable duration).

[0105] Any suitable wavelength, wavelength range, or combination of wavelengths can be emitted by the light delivery element 970. In at least some embodiments, the lead 912 can include a light delivery element 970 that can emit light of different wavelengths or deliver light of multiple wavelengths. In at least some embodiments, at least one of the light delivery elements 970 of the lead 912 can emit light having at least one wavelength in the range of 600 - 850 nm or in the range of 620 - 720 nm.

[0106] In at least some embodiments, the system is configured to provide both optical and electrical stimulation using the same or different leads. For example, any combination of leads 12 and 912 can be used, and any combination of lead trajectories can be used.

[0107] In at least some embodiments, the electro - optical stimulation lead can include both the electrode 134 and the light delivery element 970. Examples of such leads are described in the references cited above. In at least some embodiments, the electrode 12 and the light delivery element 912 are both powered by a common implantable power source (e.g., the power source 612 of FIG. 6). In other embodiments, the electrode and the light delivery element are delivered using different leads coupled to different implantable power sources. The implantable power source can be rechargeable or non - rechargeable.

[0108] In at least some embodiments, the power, optical, or combined stimulation system is powered transcutaneously via a high - frequency energy or other external energy source (e.g., ultrasound).

[0109] FIG. 11 is a flowchart of one embodiment of a method of stimulating the NBM. The purpose of stimulating the NBM can be to increase the production or delivery of Ach, slow or stop the degeneration of neurons in the NBM, or such things, or any combination of these. In step 1102, one or more electrical stimulation leads, optical stimulation leads, electro-optical stimulation leads, or any combination thereof are implanted within or near the NBM. For example, an electrical stimulation lead or an electro-optical stimulation lead can be implanted into a patient's brain such that at least one or more electrodes are disposed within or near the NBM. As another example, an optical stimulation lead or an electro-optical stimulation lead can be implanted into a patient's brain such that at least one or more of the light delivery elements are disposed within or near the NBM. After implantation, a programming process can be used to determine a set of stimulation parameters for treatment as described above. An IPG can also be implanted. In at least some embodiments, the IPG is implanted into the torso with the lead, or the lead extension coupled to the lead, extending under the skin to the IPG. In at least some embodiments, the lead can alternatively be coupled to an ETS or other external stimulator.

[0110] In step 1104, electrical / optical stimulation is supplied through the leads to stimulate the NBM using the set stimulation parameters. The methods, considerations, and examples of electrical / optical stimulation are as described above.

[0111] One aspect is a method of stimulating the substantia nigra pars compacta (NBM) comprising implanting an electrical stimulation lead in a lateral central tract in a patient's brain, the electrical stimulation lead including electrodes, at least one of the electrodes being disposed adjacent to or within the patient's NBM; and delivering electrical stimulation to the NBM through at least one of the electrodes.

[0112] In at least some embodiments, the method further comprises delivering light stimulation to the NBM using at least one light delivery element of an electrical stimulation lead. In at least some embodiments, the method further comprises implanting a light stimulation lead into the patient's brain, the light stimulation lead including at least one light delivery element disposed adjacent to or within the patient's NBM, and delivering light stimulation to the NBM through at least one of the at least one light delivery elements.

[0113] Another embodiment is a method of stimulating the substantia nigra pars compacta (NBM) that includes implanting a plurality of electrical stimulation leads into a patient's brain, each of the electrical stimulation leads including a plurality of electrodes, with at least one of the electrodes of each of the electrical stimulation leads disposed adjacent to or within the patient's NBM; and delivering electrical stimulation through at least one of the electrodes to each of a plurality of different stimulation regions of the NBM, wherein delivery of the electrical stimulation to at least some of the stimulation regions is interleaved or continuous.

[0114] In at least some embodiments, the implantation includes implanting at least one of the electrical stimulation leads in a superior to inferior trajectory. In at least some embodiments, the implantation includes implanting at least one of the electrical stimulation leads in a lateral to central trajectory.

[0115] Yet another aspect is a method of stimulating the nucleus basalis of Meynert (NBM) that includes a) implanting at least one electro - optical stimulation lead into a patient's brain or b) implanting either at least one electrical stimulation lead and at least one optical stimulation lead into a patient's brain, where each electrical stimulation lead or electro - optical stimulation lead includes at least one electrode, and at least one of the at least one electrode is disposed adjacent to or within the patient's NBM, each optical stimulation lead or electro - optical stimulation lead includes at least one light - delivery element, and at least one of the at least one light - delivery element is disposed adjacent to or within the patient's NBM, and the method further includes delivering electrical stimulation to the NBM through at least one of the electrodes and delivering optical stimulation to the NBM through at least one of the at least one light - delivery elements.

[0116] In at least some aspects, implanting includes implanting at least one of the at least one electro - optical stimulation lead or at least one optical stimulation lead in a trajectory from above downward. In at least some aspects, implanting includes implanting at least one of the at least one electro - optical stimulation lead or at least one optical stimulation lead in a lateral or central trajectory.

[0117] In at least some aspects, delivering electrical or optical stimulation includes delivering electrical or optical stimulation to the NBM to stimulate neurons of the NBM to deliver one or more acetylcholines or to support the survival of neurons of the NBM such that the neurons of the NBM can perform functions of neurons that include delivery of acetylcholine to the cerebral cortex. In at least some aspects, the electrodes of the electrical or electro - optical stimulation leads include a set of at least segment electrodes disposed on the outer periphery of the electrical or electro - optical stimulation leads.

[0118] In at least some embodiments, delivering electrical stimulation includes delivering electrical stimulation to a plurality of stimulation regions of the NBM at different times. In at least some embodiments, the method further includes selecting a plurality of stimulation regions such that each stimulation region covers a portion of the NBM. In at least some embodiments, selecting includes using a scoring criterion that promotes covering more of the NBM and penalizes overlap of the stimulation regions to select the plurality of stimulation regions. In at least some embodiments, the method further includes algorithmically determining each of the stimulation regions as an estimated volume of the effective region of stimulation for a particular set of stimulation parameters.

[0119] In at least some embodiments, delivering electrical stimulation includes delivering anodal stimulation to the NBM.

[0120] In at least some embodiments, delivering electrical or optical stimulation includes delivering electrical or optical stimulation when the patient is presumed to be asleep. In at least some embodiments, presuming that the patient is asleep when delivering electrical or optical stimulation includes presuming that the patient is asleep based on a clock in an electrical stimulation lead or optical stimulation lead or an implantable pulse generator connected to the implantable pulse generator or a clock in an external device that communicates with the electrical stimulation lead or optical stimulation lead or implantable pulse generator. In at least some embodiments, presuming that the patient is asleep when delivering electrical or optical stimulation includes presuming that the patient is asleep based on measurements or indications from an external sensor or external device that communicates with an implantable pulse generator coupled to the electrical stimulation lead or optical stimulation lead.

[0121] In at least some embodiments, delivering electrical stimulation includes delivering electrical or optical stimulation when the patient or another person has instructed delivery.

[0122] It will be understood that each block of the flowchart illustrations, and combinations of blocks in the flowchart illustrations and methods disclosed herein, can be implemented by computer program instructions. Additionally, the feature extraction engine, memory engine, visualization engine, and memory programming engine can be implemented by computer program instructions. These program instructions can be provided to a processor to generate a machine or engine such that the instructions executed on the processor create means for performing the operations specified in the flowchart block or blocks or engines disclosed herein. The computer program instructions can be executed by a processor to cause the processor to execute a series of operational steps to generate a computer implemented process. Also, the computer program instructions can cause at least some of the operational steps to be executed in parallel. Further, some of the steps may be executed across one or more processors so as to occur in a multi-processor computing device. Additionally, one or more processes can be executed concurrently with other processes or in a different order than that illustrated, without departing from the scope or spirit of the present invention.

[0123] The computer program instructions can be stored in any appropriate 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 non-locally (e.g., in the cloud).

[0124] The above specification and examples provide an explanation of the configuration and use of the present invention. Since many embodiments of the present invention can be made without departing from the spirit and scope of the present invention, the present invention also resides in the appended claims.

Explanation of Reference Numerals

[0125] 10 Electrical stimulation system 12 Stimulation lead 14 Implantable pulse generator (IPG) 16 External remote control (RC) 20 External test stimulator (ETS) 22 Charger 24 Lead extension 28 Transcutaneous lead extension 30 External cable 40 Sensor

Claims

**Claim 1** A system for stimulating a patient's nucleus basalis of Meynert (NBM), comprising: An implantable electrical stimulation lead including a plurality of electrodes, configured such that at least one of the electrodes is implanted adjacent to or within the patient's NBM; An implantable pulse generator coupled to the implantable electrical stimulation lead and configured to deliver electrical stimulation to the NBM through at least one of the electrodes of the implantable electrical stimulation lead; Comprising: The implantable pulse generator includes at least one processor configured to increase, over time, at least one of a duration of a stimulation period or an amplitude of the electrical stimulation from an initial value at the start of an initial stimulation phase having a continuous duration of at least one month and having a start and an end to a final value at the end of the initial stimulation phase, in response to a user request. **Claim 2** The system according to claim 1, wherein the processor is configured to deliver the electrical stimulation during the initial stimulation phase while increasing the amplitude of the electrical stimulation over time. **Claim 3** The system according to claim 1 or 2, wherein the processor is configured to deliver the electrical stimulation during the initial stimulation phase while increasing the duration of the electrical stimulation over time. **Claim 4** The system according to any one of claims 1 to 3, wherein the increase over time of at least one of the duration or the amplitude includes increasing at least one of the duration or the amplitude linearly in a ramp shape from the initial value to the final value. **Claim 5** The system according to any one of claims 1 to 4, wherein the increase over time of at least one of the duration or the amplitude includes increasing at least one of the duration or the amplitude non-linearly in a ramp shape from the initial value to the final value. **Claim 6** The system according to any one of claims 1 to 5, wherein the processor is further configured not to deliver the electrical stimulation during a period in which the cognitive load of the patient is expected during the initial stimulation phase. **Claim 7** The processor is further configured to indicate to the user at least one of i) the electrical stimulation is being delivered, or ii) the electrical stimulation will be delivered shortly. The system according to claim 6, wherein the processor provides control to the user for delaying delivery of the electrical stimulation, and is further configured to delay delivery of the electrical stimulation when the control is activated.

8. The system according to any one of claims 1 to 6, further comprising a sensor selected from a blood flow sensor, an electroencephalogram (EEG) sensor, an electrocorticogram (ECoG) sensor, a motion sensor, or any combination thereof, the sensor being configured to monitor the patient's response to the electrical stimulation, and the processor being optionally configured to monitor the patient's alpha wave brain activity using an EEG sensor or an ECoG sensor.

9. A system for stimulating a patient's nucleus basalis of Meynert (NBM), an implantable electrical stimulation lead including a plurality of electrodes and configured such that at least one of the electrodes is implanted adjacent to or within the patient's NBM; an implantable pulse generator coupled to the implantable electrical stimulation lead and configured to deliver electrical stimulation to the NBM through at least one of the electrodes of the implantable electrical stimulation lead; comprising the implantable pulse generator including at least one processor configured to deliver electrical stimulation to the NBM through at least one of the electrodes, and during an initial stimulation phase having a duration of at least one month, the electrical stimulation is not delivered during periods when the patient's cognitive load is expected.

10. The system according to claim 9, wherein the processor is further configured to increase over time the amount of time during which the electrical stimulation is delivered during periods when the patient's cognitive load is expected after the initial stimulation phase.

11. The system according to claim 9 or 10, wherein the processor is further configured to increase over time at least one of the duration or amplitude of the electrical stimulation from an initial value at the start of the initial stimulation phase to a final value at the end of the initial stimulation phase.

12. The system according to claim 11, wherein increasing comprises increasing at least one of the duration or the amplitude linearly ramp-like from the initial value to the final value over time.

13. The system according to claim 11, wherein the increasing comprises increasing at least one of the duration length or the amplitude non-linearly in a ramp shape from the initial value to the final value over time.

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