Patent Grant
7684866
The present disclosure is related to systems and methods for applying stimulation to a target neural population within a patient, for example, a surface site on the patient's cortex.
A wide variety of mental and physical processes are controlled or influenced by neural activity in particular regions of the brain. The neural-functions in some areas of the brain (i.e., the sensory or motor cortices) are organized according to physical or cognitive functions, and various areas of the brain appear to have distinct functions in most individuals. In the majority of people, for example, the occipital lobes relate to vision, the left interior frontal lobes relate to language, and the cerebral cortex appears to be involved with conscious awareness, memory, and intellect.
Many problems or abnormalities can be caused by damage, disease and/or disorders in the brain. Effectively treating such abnormalities may be very difficult. For example, a stroke is a common condition that damages the brain. Strokes are generally caused by emboli (e.g., obstruction of a vessel), hemorrhages (e.g., rupture of a vessel), or thrombi (e.g., clotting) in the vascular system of a specific region of the brain. Such events generally result in a loss or impairment of a neural function (e.g., neural functions related to facial muscles, limbs, speech, etc.). Stroke patients are typically treated using various forms of physical therapy to rehabilitate the loss of function of a limb or another affected body part. Stroke patients may also be treated using physical therapy plus an adjunctive therapy such as amphetamine treatment. For most patients, however, such treatments are minimally effective and little can be done to improve the function of an affected body part beyond the recovery that occurs naturally without intervention.
Neurological problems or abnormalities are often related to electrical and/or chemical activity in the brain. Neural activity is governed by electrical impulses or “action potentials” generated in neurons and propagated along synaptically connected neurons. When a neuron is in a quiescent state, it is polarized negatively and exhibits a resting membrane potential typically between −70 and −60 mV. Through chemical connections known as synapses, any given neuron receives excitatory and inhibitory input signals or stimuli from other neurons. A neuron integrates the excitatory and inhibitory input signals it receives, and generates or fires a series of action potentials when the integration exceeds a threshold potential. A neural firing threshold, for example, may be approximately−55 mV.
It follows that neural activity in the brain can be influenced by electrical energy supplied from an external source such as a waveform generator. Various neural functions can be promoted or disrupted by applying an electrical current to the cortex or other region of the brain. As a result, researchers have attempted to treat physical damage, disease and disorders in the brain using electrical or magnetic stimulation signals to control or affect brain functions.
Transcranial electrical stimulation is one such approach that involves placing an electrode on the exterior of the scalp and delivering an electrical current to the brain through the scalp and skull. Another treatment approach, transcranial magnetic stimulation, involves producing a high-powered magnetic field adjacent to the exterior of the scalp over an area of the cortex. Yet another treatment approach involves direct electrical stimulation of neural tissue using implanted electrodes.
The neural stimulation signals used by these approaches may comprise a series of electrical or magnetic pulses directed toward affecting neurons within a target neural population. Stimulation signals may be defined or described in accordance with stimulation signal parameters including pulse amplitude, pulse frequency, duty cycle, stimulation signal duration, and/or other parameters. Electrical or magnetic stimulation signals applied to a population of neurons can depolarize neurons within the population toward their threshold potentials. Depending upon stimulation signal parameters, this depolarization can cause neurons to generate or fire action potentials. Neural stimulation that elicits or induces action potentials in a functionally significant proportion of the neural population to which the stimulation is applied is referred to as supra-threshold stimulation; neural stimulation that fails to elicit action potentials in a functionally significant proportion of the neural population is defined as sub-threshold stimulation. In general, supra-threshold stimulation of a neural population triggers or activates one or more functions associated with the neural population, but sub-threshold stimulation by itself does not trigger or activate such functions. Supra-threshold neural stimulation can induce various types of measurable or monitorable responses in a patient. For example, supra-threshold stimulation applied to a patient's motor cortex can induce muscle fiber contractions in an associated part of the body.
Although electrical or magnetic stimulation of neural tissue may be directed toward producing an intended type of therapeutic, rehabilitative, or restorative neural activity, such stimulation may result in collateral neural activity. In particular, neural stimulation delivered beyond a certain intensity, period of time, level, or amplitude can give rise to seizure activity and/or other types of collateral activity. It will be appreciated that certain types of collateral neural activity may be undesirable and/or inconvenient in a neural stimulation situation.
Another concern that arises in association with stimulating a surface site on a patient's cortex is conservation or minimization of applied power while operating a stimulation device. Various types of systems have an implanted pulse generator (“IPG”) and an electrode assembly. The electrode assembly generally has a plurality of contacts that are carried by a common support member, such that the contacts are positionally fixed in close or generally close proximity relative to each other. In operation, the IPG delivers an electrical waveform to the electrode assembly, such that a first set of contacts provides a current delivery path and a second set of contacts provides a current return path. Thus, at any given time during waveform delivery, at least one contact has a positive bias and at least one contact has a negative bias, resulting in the generation of a bipolar field at the surface of the cortex within the area of the stimulation site. The bipolar field has a lower current density in the deeper layers of the cortex compared to the current density at the surface layers, and the bipolar field runs generally parallel to the cranium of the patient in the deeper layers of the cortex. Systems that generate a bipolar field at the stimulation site may require relatively high current levels to achieve an intended or desired therapeutic effect. This may result in increased power consumption, and possibly increase the likelihood of inducing collateral neural activity.
The present disclosure describes systems and methods for neural stimulation that may enhance the efficacy and/or increase the efficiency of neural stimulation procedures. The neural stimulation may comprise a set of stimulation signals applied or delivered to or through target neural structures, target neural projections, and/or one or more target neural populations associated with controlling, influencing, or affecting one or more neurological functions under consideration. The neural stimulation may be directed toward facilitating and/or effectuating at least some degree of symptomatic relief and/or restoration or development of functional abilities in patients experiencing neurologic dysfunction arising from neurological damage, neurologic disease, neurodegenerative conditions, neuropsychiatric disorders, cognitive or learning disorders, and/or other conditions. Such neurologic dysfunction may correspond to Parkinson's Disease, essential tremor, Huntington's disease, stroke, traumatic brain injury, Cerebral Palsy, Multiple Sclerosis, a central pain syndrome, a memory disorder, dementia, Alzheimer's disease, an affective disorder, depression, bipolar disorder, anxiety, obsessive/compulsive disorder, Post Traumatic Stress Disorder, an eating disorder, schizophrenia, Tourette's Syndrome, Attention Deficit Disorder, an addiction, autism, epilepsy, a sleep disorder, a hearing disorder (e.g., tinnitis or auditory hallucinations), a speech disorder (e.g., stuttering), and/or one or more other disorders, states, or conditions.
For example, relative to controlling, influencing, stabilizing, restoring, enhancing, or gaining a motor function, a target neural population may comprise one or more portions of a patient's motor cortex. A neural location at which or a neural region in which stimulation signals are applied or delivered to or through a target neural population may be defined as a stimulation site. Thus, for a target neural population corresponding to the motor cortex, an exemplary stimulation site may comprise a location or region upon the patient's dura mater.
As another example, relative to controlling, influencing, stabilizing, restoring, or enhancing an auditory function, a target neural population may correspond to one or more portions of a patient's auditory cortex. A stimulation site may comprise an epidural or subdural cortical region that may facilitate the application, delivery, and/or transfer of stimulation signals to such a target neural population, for example, an epidural site adjacent or proximate to the Sylvian fissure. The application of unipolar stimulation signals to such a stimulation site in accordance with particular embodiments of the invention may increase a likelihood of affecting the target neural population in an intended manner.
A stimulation site may be identified in accordance with a variety of techniques, including (1) identification of one or more anatomical landmarks; (2) preoperatively (e.g., using Transcranial Magnetic Stimulation) and/or intraoperatively stimulating one or more brain locations to identify or map particular neural regions that induce or evoke a given type of patient response (for example, a movement or a sensation); (3) estimating a location at which the brain may recruit neurons to carry out a given type of neural activity that was previously performed by a damaged portion of the brain; (4) an electrophysiologic signal measurement and/or analysis procedure (e.g., acquisition and/or analysis of EEG, EMG, MEG, coherence, partial coherence, and/or other signals); and/or (5) a neural imaging procedure. In general, the number and/or location of stimulation sites under consideration may depend upon the nature, number, and/or extent of a patient's neurological condition and/or functional deficits.
Several embodiments of such systems and methods apply or deliver a unipolar, monopolar, or isopolar stimulation signal that may provide enhanced efficacy or efficiency stimulation using a low current level that reduces power consumption and/or mitigates collateral effects. Various embodiments of the present invention may apply or deliver neural stimulation at a subthreshold level or intensity, that is, at a level that raises or generally raises membrane potentials associated with a target neural population while avoiding the generation of a sufficient or statistically significant number of action potentials capable of triggering a neural function corresponding to the target neural population as a result of neural stimulation alone.
Stimulation systems and methods in accordance with the present invention may be used to treat various neurological conditions and/or facilitate particular types of neurological or functional patient outcomes. Depending upon the nature of a particular condition, neural stimulation applied or delivered in accordance with several embodiments of the invention may affect neural firing likelihoods and/or influence, facilitate, and/or effectuate reorganization of interconnections or synapses between neurons to (a) provide at least some degree of functional recovery and/or functional gain; and/or (b) develop one or more compensatory mechanisms to at least partially overcome a functional deficit or shortcoming. Such reorganization of neural interconnections may be achieved, at least in part, by a change in the strength of synaptic connections through a process that corresponds to a mechanism commonly known as Long-Term Potentiation (LTP). Neural stimulation applied or delivered in accordance with certain embodiments of the invention may alternatively or additionally affect particular neural populations through a process that corresponds to a mechanism commonly known as Long-Term Depression (LTD). Neural stimulation delivered or applied to one or more target neural populations either alone or in conjunction or association with one or more behavioral activities and/or other types of adjunctive or synergistic therapies (e.g., a drug or chemical substance therapy, a neurotrophic or growth factor therapy, and/or a cell implantation therapy) may facilitate, effectuate, or enhance therapeutic efficacy, for example, through neural plasticity and the reorganization of synaptic interconnections between neurons.
A. Systems for Applying Electrical Stimulation
Depending upon embodiment details, the system may also include a sensing unit 180 (shown schematically) configured to monitor one or more types of patient responses, activities, and/or behaviors. The sensing unit 180 may be further configured to communicate with the stimulus unit 120. The sensing unit 180 may include, for example, electrodes 182 and/or other devices (e.g., an accelerometer or motion detector) configured to sense a patient's neural activity (e.g., an EEG signal), neuromuscular activity (e.g., an EMG signal), behavioral activity (e.g., patient motion), and/or other types of patient activity.
The stimulus unit 120 generates and outputs stimulation signals, and the set of electrode assemblies 160 facilitates application or delivery of the stimulation signals to the patient P. The stimulus unit 120 may perform, direct, and/or facilitate neural stimulation procedures in a manner that enhances efficacy, mitigates a likelihood of inducing collateral neural activity, and/or conserves power, as described in detail below.
The stimulus unit 120 may comprise a pulse generator that is implanted into the patient P. In the embodiment shown in
The stimulus unit 120 may comprise a controller 130 and a pulse system 140. The stimulus unit 120 may further comprise a power source, a battery, an energy storage device, and/or power conversion circuitry (not shown). The controller 130 may include a processor, a memory, and a programmable computer medium. The controller 130 may be implemented as a computer or a microcontroller, and the programmable medium may comprise software, instructions, and/or configuration information loaded into the memory and/or hardware that performs, directs, and/or facilitates neural stimulation procedures in accordance with one or more methods of the present invention.
The pulse system 140 generates and outputs stimulation signals.
In certain embodiments, the pulse system 140 may generate and/or output stimulation signals in accordance with a theta burst pattern. In general, theta burst stimulation may comprise pulse bursts and/or pulse packets separated by quiescent intervals, such that the number of pulse packets per seconds corresponds or approximately corresponds to theta wave frequencies exhibited by the brain. In general, theta wave frequencies may range from approximately 3 to 10 Hz, and more particularly in certain embodiments, 4 to 8 Hz.
In particular embodiments, the pulse system 140 may vary and/or modulate stimulation signals in one or more manners, for example, in accordance with one or more mathematical operations and/or functions upon or corresponding to particular stimulation signal parameters. Exemplary manners of varying stimulation signals are described in detail in U.S. application Ser. No. 60/588,406, filed on Jul. 15, 2004, entitled “System and Method for Enhancing or Affecting Neural Stimulation Efficiency and/or Efficacy,” incorporated herein by reference in its entirety.
The pulse system 140 may apply or output stimulation signals to, across, or between a first terminal 142a and a second terminal 142b. Since a stimulation signal may comprise a time-varying waveform, a relative polarity of the stimulation signal, and hence that of the first and second terminals 142a–b, may change or vary with time. With respect to outputting one or more stimulation signals having phases that differ in polarity, an anode may be defined as a terminal 142a–b to which a positive polarity phase within an initial pulse is first applied. For example, for a stimulation signal comprising a series of biphasic pulses where each pulse includes a positive polarity phase followed by a negative polarity phase, where positive and negative may respectively be defined relative to a zero potential level or a potential offset, an anode may be designated as the particular terminal 142a–b that first receives a positive polarity phase following the stimulus start time t0. A cathode may be defined as a terminal 142a–b that provides electrical continuity for the stimulation signal delivered through the anodal terminal 142a–b. The polarity of the cathode may thus be opposite to that of the anode, or neutral. Depending upon embodiment details, a cathode may be defined as a terminal 142a–b to which a first negative polarity or lower potential phase within an initial pulse is first applied. Those skilled in the art will recognize that the terms anode and cathode could be defined in an opposite or different manner than as defined above, yet such opposite or different definitions would be equivalent, essentially equivalent, or consistent from a mathematical or circuit analysis perspective.
Depending upon embodiment details, (a) the first terminal 142a may be configured as an anode, while the second terminal 142b may be configured as a cathode; (b) the first terminal 142a may be configured as a cathode, while the second terminal 142b may be configured as an anode; or (c) the first and second terminals 142a–b may be selectively or programmably configured as an anode and a cathode, possibly in a predetermined, aperiodic, or pseudo-random time dependent manner. Such anode/cathode selectivity may occur on a subseconds-based, a seconds-based, an hours-based, and/or another type of time domain, and/or may be facilitated by signal selection circuitry (e.g., a multiplexor or a switch matrix) and/or redundant output circuitry within the stimulus unit 120. In particular embodiments, stimulus periods provided by the stimulus unit 120 can have durations of 30 seconds or less, 10 seconds or less, 2–5 seconds, about one second, and/or less than one second. The stimulus periods can include but are not limited to alternating cathodal and anodal periods, alternating unipolar periods, alternating bipolar periods, and/or periods that alternate between unipolar and bipolar. The electrical potential of the stimulation signal can also alternate between subthreshold levels and suprathreshold levels.
The first electrode assembly 160a may be positioned or implanted at a stimulation site that is located upon, essentially upon, or proximate to a target neural population upon, within, or near the patient's cerebral cortex. The first electrode assembly 160a may comprise a support member 162a and one or more contacts 164a carried by the support member 162a. The support member 162a may be configured for implantation at a stimulation site upon or at least proximate to the surface of the patient's cortex. The support member 162a, for example, can be a flexible or rigid substrate that is implanted under the cranium S such that the contacts 164a are positioned upon or adjacent to the dura mater at the stimulation site. In other embodiments, the support member 162a can be a portion of a cranial screw or a housing that is implanted through the cranium S, in a manner identical or analogous to that described in U.S. patent application Ser. No. 10/418,796, which is incorporated herein by reference.
The first electrode assembly 160a can have one or more contacts 164a arranged or positioned in a desired configuration. For example, the first electrode assembly 160a may include a single contact 164a, or a plurality of contacts 164a arranged as an array, grid, or other pattern. In the embodiment shown in
The second electrode assembly 160b can be similar to the first electrode assembly 160a, or it can be a different type of electrode assembly. The second electrode assembly 160b may be positioned remotely from the first electrode assembly 160a. Since the second electrode assembly 160b provides electrical continuity with respect to the first electrode assembly 160a, the second electrode assembly 160b may be defined to reside at a circuit completion site. In the embodiment shown in
In the embodiment shown, the second electrode assembly 160b, and more particularly the second electrode assembly's contacts 164b, are separate or otherwise detached from the first electrode assembly 160a. Thus, the second electrode assembly's contacts 164b are not attached to the first electrode assembly 160a, and the second electrode assembly's contacts 164b may be movable with respect to the contacts 164a of the first electrode assembly 164a before being implanted in the patient. The second electrode assembly 160b may accordingly be configured to be attached to or implanted in the patient at a location spaced apart from a stimulation site on or proximate to the cortex of the patient where electrical stimulation is to be applied to facilitate and/or effectuate a given neurological or neurofunctional outcome, such as neural plasticity or another type of neural reorganization corresponding to one or more neural populations.
In the embodiment shown in
Neural stimulation in which both an anode and a cathode are positioned, located, or situated within, essentially directly across, or proximate to a stimulation site may be defined as bipolar stimulation. In contrast, neural stimulation in which one of an anode and a cathode is positioned, located, or situated within or proximate to a stimulation site, while a respective corresponding cathode or anode is positioned, located, or situated remote from the stimulation site to provide electrical continuity may be defined as unipolar, monopolar, or isopolar stimulation. Thus, neural stimulation characterized by a biasing configuration in which an anode and a cathode are positioned, located, or situated in different neurofunctional areas or functionally distinct anatomical regions may be defined as unipolar stimulation. In a unipolar configuration, the pulse system 140 applies an identical polarity signal to each non-floating contact 162a–b positioned upon or proximate to a stimulation site. Unipolar stimulation may be defined as anodal unipolar stimulation when an anode is positioned upon or proximate to a stimulation site or a target neural population; and as cathodal unipolar stimulation when a cathode is positioned upon or proximate to a stimulation site or a target neural population.
In several embodiments, the second electrode assembly 160b is positioned apart or remote from the first electrode assembly 160a to establish an electric field that passes through deep layers of the cortex and/or other neural regions in a direction that is generally perpendicular or oblique with respect to (a) the first electrode assembly's contacts 164a; (b) the surface of the cortex under the first electrode assembly 160a; and/or (c) the cranium of the patient at or proximate to the stimulation site. The electric field, for example, is substantially normal to the first electrode assembly 160a in the deep layers of the cortex and/or other neural layers beneath the stimulation site.
The stimulus unit 120 may provide an output at a first polarity to the non-floating contacts 164a of the first electrode assembly 160a, and provide an output at a second polarity to the non-floating contacts 164b of the second electrode assembly 160b. The first electrode assembly's contacts 164a accordingly provide a unipolar, monopolar, or isopolar bias at the stimulation site upon or proximate to the patient's cortex C. The first polarity may be anodal or cathodal, and the second polarity may respectively be cathodal or anodal (i.e., opposite to the first polarity or neutral). A unipolar signal applied to the first electrode assembly's contacts 164a may establish an electric field that extends through deep layers of the cortex and/or other neural regions along a vector V extending generally perpendicular to, or at least oblique with respect to, the orientation of (a) the first electrode assembly 160a; (b) the surface of the cortex C at or proximate to the stimulation site; and/or (c) the cranium of the patient adjacent to the stimulation site (
Certain systems and/or methods in accordance with the present invention may utilize or rely upon a single electrode assembly having a design that is suitable for providing unipolar stimulation rather than relying upon separate electrode assemblies.
The combined electrode assembly 260 may be implanted into a patient such that the local portion 263a resides at, upon, or proximate to a stimulation site, while the remote portion 263b resides at a circuit completion site that is distant or remote from the stimulation site. The separation portion 263c may have a length L that is sufficient to ensure that in a typical patient, an electric field generated at or in the vicinity of the local portion 263a is substantially perpendicular to the patient's cranium, cortical surface, and/or targeted neural tissues (which may include deep cortical layers or regions, as discussed below) beneath the stimulation site. In one embodiment, the value of L may be roughly an order of magnitude greater than the distance between the stimulation site and a target neural population or neural region that is deepest or farthest from the stimulation site. For subdural stimulation, an exemplary value of L may be roughly an order of magnitude or more greater than approximately 2.5 to 3.0 mm; and for epidural stimulation, an exemplary value of L may be roughly an order of magnitude greater than approximately 4.0 to 6.0 mm.
The location, depth, and/or spatial boundaries of target neural structures and/or a target neural population may depend upon the nature of a neurological condition or disorder under consideration. The extent to which an electric field reaches, penetrates, and/or travels into or through target neural structures and/or a target neural population may affect neural stimulation efficiency and/or efficacy. An electric field generated by unipolar stimulation may reach or penetrate deeper neural regions at a lower current level than an electric field generated by bipolar stimulation, as further described hereafter.
In general, an electrical potential gradient or difference between an anode and a cathode configured to provide unipolar stimulation exists over a longer or greater distance than an electrical potential gradient between an anode and a cathode configured to provide bipolar stimulation. Thus, an anode to cathode electrical current pathway associated with unipolar stimulation will typically be longer than an electrical current pathway associated with bipolar stimulation. Unipolar stimulation may therefore provide a greater degree of therapeutic efficacy than bipolar stimulation when stimulation of neural regions, structures, and/or projections that are deeper or more distant than those just beneath and/or in the near vicinity of the stimulation site may be of importance. Moreover, unipolar stimulation may deliver more current to such deeper or more distant neural regions at a lower power level than bipolar stimulation, which may result in greater stimulation efficiency and/or a reduced likelihood of inducing collateral neural activity. Enhanced stimulation efficiency may be important when treating chronic, near-chronic, and/or longer-term conditions, for example, movement disorders or central pain syndrome.
In addition to or association with the foregoing, an electric field polarity, orientation and/or distribution relative to particular types of neurons, neural projections, neural structures, and/or neurofunctional regions may influence or affect neural stimulation efficiency and/or efficacy. The cortex C may be organized as a set of 6 layers, where layer 1 maintains a boundary corresponding to the cortical surface. Successive cortical layers exist or reside at increasing depths relative to the cortical surface. Thus, layer 6 corresponds to a deepest cortical layer. The thickness or extent of any given cortical layer, and the type, number, and/or size of neurons, neural projections, and/or neural structures therein depends upon the cortical neurofunctional region under consideration.
Neurons convey input signals along their dendrites toward their cell bodies. Neurons in the cortex C include pyramidal cells 302 and interneurons 304. In the motor cortex, the largest pyramidal cells 320 have soma or cell bodies that reside in deep cortical layer 5. Pyramidal cells 302 have dendrites that project away from their cell bodies into overlying or superficial cortical layers, toward the cortical surface in a manner that is approximately perpendicular or normal to the layer structure of the cortex C. Interneurons 304 have cell bodies that commonly reside in cortical layers 2, 3, and 4, and include dendrites that tend to project away from their cell bodies within the same layer or into an adjacent layer in a manner that is generally lateral or parallel with respect to the layer structure of the cortex C.
An optimal, near optimal, or desirable electric field orientation for therapeutic neural stimulation may be based upon or determined by the orientation of one or more types of neurons, neural structures, and/or neural projections within or associated with a target neural population N. For example, an electric field that is oriented generally parallel to a main or overall direction in which pyramidal cell dendrites project, that is, generally perpendicular or normal to the cortical layer structure (or equivalently, generally perpendicular or normal to the surface of the cortex C or the cranium), may preferentially influence or exert a more significant effect upon pyramidal cells 302 than interneurons 304, which include dendrites that generally project lateral to the cortical layer structure. In an analogous manner, an electric field that is oriented generally parallel to a typical or overall direction in which interneuron dendrites project, that is, generally parallel or lateral to the cortical layer structure, may preferentially influence or exert a more significant effect upon interneurons 304 than pyramidal cells 302.
In view of the foregoing, systems and/or methods in accordance with particular embodiments of the invention may apply or deliver stimulation signals having one or more polarities that may enhance a likelihood of facilitating or effectuating a desired neurological and/or functional outcome based upon the types of neurons, neural structures, and/or neural projections involved in subserving such an outcome. For example, specific embodiments of the invention may apply unipolar stimulation at one or more times to patients experiencing certain types of central pain syndrome. As another example, various embodiments of the invention may apply unipolar stimulation, possibly in conjunction with a behavioral therapy, to patients having functional deficits associated with stroke, traumatic brain injury, cerebral palsy, and/or other disorders (e.g., tinnitus). In certain situations, unipolar stimulation may more effectively facilitate or effectuate neural disinhibition and/or neuroplastic change associated with a target neural population than bipolar stimulation, thereby enhancing the extent to which such patients can recover lost functional abilities and/or develop new abilities.
Unipolar stimulation may facilitate or effectuate enhanced recovery or development of functional abilities in patients experiencing particular types of neurologic dysfunction when compared to bipolar stimulation. For example, cathodal unipolar stimulation in conjunction or association with a behavioral therapy such as an Activity of Daily Living (ADL) may facilitate or effectuate a greater degree of functional development and/or recovery in a patient experiencing functional deficits associated with stroke, traumatic brain injury, and/or neurological damage than bipolar stimulation either alone or in association or conjunction with such a behavioral therapy. Moreover, such enhanced recovery may occur using lower current or average power levels than would be required for bipolar stimulation, thereby conserving power and/or reducing a likelihood of inducing collateral neural activity.
Certain systems and/or methods in accordance with the invention may deliver unipolar stimulation during a unipolar stimulation period and bipolar stimulation during a bipolar stimulation period. For example, relative to facilitating or effectuating neuroplasticity, both pyramidal cells 302 and interneurons 304 may play a role in neural reorganization. Thus, a system and/or method may deliver unipolar stimulation to more selectively influence or affect pyramidal cells 302 during a unipolar stimulation period, and deliver bipolar stimulation to more selectively influence or affect interneurons 304 during a bipolar stimulation period. One or more unipolar and/or bipolar stimulation periods may be identical or different in duration, and may occur in a successive or generally successive manner, with or without one or more types of intervening delays, interruptions, or cessations. Any given unipolar stimulation period, bipolar stimulation period, and/or interruption period between unipolar and/or bipolar stimulation periods may correspond to a subseconds-based, a seconds-based, an hours-based, and/or another type of time domain. Depending upon embodiment details, alternation between unipolar and/or bipolar stimulation periods and/or intervals between such periods may temporally occur in a predetermined, aperiodic, or pseudo-random manner. Neural stimulation may be delivered during one or more unipolar and/or bipolar stimulation periods in conjunction or association with one or more adjunctive or synergistic therapies, for example, a behavioral therapy and/or a drug therapy. An adjunctive therapy corresponding to a unipolar stimulation period may be identical to or different from an adjunctive therapy corresponding to a bipolar stimulation period.
In cortical regions associated with motor control, pyramidal cell axons that project into the spinal cord, brain stem, basal ganglia, and/or other areas may serve as cortical outputs involved in facilitating or controlling movement. In view of manners in which pyramidal cell dendrites and axons project as described above, a given type of unipolar neural stimulation may elicit or generate a patient response or movement at a different (e.g., lower) current level or intensity than bipolar stimulation. Thus, unipolar stimulation may provide or induce an intended or desired effect at a lower current level than bipolar stimulation, thereby conserving power and/or reducing a likelihood of inducing collateral activity. Similarly, unipolar stimulation may facilitate determination of a therapeutic current level using lower amplitude test stimulation signals than required by bipolar stimulation. In some embodiments, a therapeutic current level corresponding to a given type of unipolar stimulation may be mapped to a therapeutic current level that corresponds to a different type of unipolar stimulation and/or bipolar stimulation in accordance with a mapping function and/or empirical data.
In addition to the foregoing, certain types of neural cells may exhibit different types of signal conductance properties based upon whether the motion of electrical charges or electrically charged particles (i.e., ions) is toward or away from the axon hillock, the initial axonal region proximate to the cell body through which dendritic inputs are integrated. For instance, in pyramidal cells 302, intracellular ions diffusing toward the axon hillock experience a lower impedance than intracellular ions diffusing toward the dendritic tree, thereby giving rise to an intracellular differential impedance (Neurophysiological Techniques: Applications to Neural Systems, Neuromethods 15, Eds. A. A. Boulton, G. B. Baker, and C. H. Vanderwolf). As a result, anodal unipolar stimulation may affect or influence a neural population, neural structures, and/or neural projections differently than cathodal unipolar stimulation.
Stimulation signal polarity characteristics may influence or affect an extent to which and/or a manner in which particular neural structures experience a potential difference and/or depolarization or polarization relative to each other, which may affect neural stimulation efficacy and/or efficiency. For example, due to the existence of a potential gradient between a cathode and an anode, a relative dendrite to axon hillock or axon depolarization or hyperpolarization state may give rise to neural stimulation efficacy differences between cathodal unipolar stimulation and anodal unipolar stimulation.
During cathodal unipolar stimulation, a negative first pulse phase applied at a stimulation site may give rise to an intracellular concentration of positive ions, thereby shifting the electrical state of proximate dendrites toward a more depolarized state than, for example, axon hillocks corresponding to such dendrites.
In an analogous manner, during anodal unipolar stimulation, a positive first pulse phase applied at a stimulation site may give rise to an enhanced intracellular concentration of negative ions, thereby shifting the electrical state of such dendrites toward a more hyperpolarized state than axon hillocks corresponding to such dendrites.
A dendritic potential shift toward a more depolarized state and/or a more hyperpolarized state may affect dendritic signal processing and/or signal generation and/or signal transfer mechanisms. Such a potential shift may affect neural stimulation efficacy, for example, by influencing an extent to and/or manner in which postsynaptic dendrites react or respond to and/or process presynaptic input.
In certain neural stimulation situations directed toward facilitating and/or effectuating neural plasticity, cathodal unipolar stimulation may increase a likelihood that dendrites within a target neural population respond to and/or process neurofunctionally relevant synaptic input in a manner that enhances a likelihood of generating action potentials that may subserve the development and/or recovery of one or more functional abilities. Neurofunctionally relevant synaptic input may arise from or correspond to an adjunctive or synergistic therapy, for example, a behavioral therapy. The aforementioned neural stimulation situations may include, for example, neural stimulation directed toward rehabilitation of patients experiencing symptoms associated with neurological damage (e.g., arising from stroke or traumatic brain injury), neurodegenerative disorders (e.g., Parkinson's disease, Alzheimer's disease), neuropsychiatric disorders (e.g., depression, OCD), and/or other types of neurologic dysfunction.
In general, anodal or cathodal unipolar stimulation may be more efficacious and/or efficient than cathodal or anodal unipolar stimulation, respectively, or bipolar stimulation in the context of particular neural stimulation situations, which may include, for example, neural stimulation directed toward traumatic brain injury, cerebral palsy, movement disorders, central pain syndrome, tinnitus, neuropsychiatric disorders, auditory hallucinations, and/or other conditions.
In particular neural stimulation situations, a likelihood of realizing a given type of neurofunctional outcome may be enhanced through multiple anodal unipolar, cathodal unipolar, and/or bipolar stimulation procedures, which may be applied in a simultaneous, alternating, and/or varying manner. Such stimulation procedures may correspond to identical, generally identical, or different stimulation sites and/or stimulation parameters (e.g., pulse repetition frequency, first phase pulse width, a peak current and/or voltage amplitude or magnitude, theta burst characteristics, a waveform variation and/or modulation function, and/or other parameters) depending upon the nature of a patient's neurologic dysfunction, patient condition, and/or embodiment details. Moreover, any given stimulation procedure and/or an interval between stimulation procedures may correspond to a subseconds-based, a seconds-based, an hours-based, and/or another type of time period or domain. In one embodiment, before, during, and/or after one or more portions of a cathodal stimulation procedure directed toward a first target neural population, an anodal unipolar stimulation procedure may be directed toward a second target neural population. The first and second target neural populations may reside in the same or different brain hemispheres.
The first electrode assembly 560a can be similar to the first electrode assembly 160a described above with reference to
The second electrode assembly 560b can be a separate item or element attached to the stimulus unit 520, or the second electrode assembly 560b can be an integral component of the stimulus unit 520. The second electrode assembly 560b, for example, can be a conductive portion of the housing 580 of the stimulus unit 520. In other embodiments, the entire housing 580 of the stimulus unit 520 can be a conductive material that defines the second electrode assembly 560b, or a portion of the housing 580 can be covered with an appropriate type of dielectric or insulating material or be composed of such a material to limit the conductive surface area of the second electrode assembly 560b to a desired shape or area. In still other embodiments, the second electrode assembly 560b is a separate set of contacts attached to the housing 580. The second electrode assembly 560b is coupled to a second terminal 542b of the pulse system 540.
The system shown in
Another aspect of the invention may involve configuring a neural stimulation system to induce a desired electrical field and/or current density at or proximate to a stimulation site as well as a remote circuit completion site. In one embodiment, the aggregate surface area of conductive surfaces that provide circuit completion or electrical continuity remote or generally remote from the stimulation site (e.g., contacts 164b carried by a second electrode assembly 160b or 560b, or an exposed conductive surface of a housing 580) is approximately 200%–1500% of the aggregate surface area of conductive surfaces that apply or deliver stimulation signals to one or more stimulation sites (e.g., contacts 164a or 564a carried by a first electrode assembly 160a or 560a), and more specifically 250%–450%. The larger conductive surface area corresponding to the circuit completion site reduces the current density at the current completion site compared to the stimulation site; this is expected to reduce collateral neural activity, muscle activity, and/or patient sensation in the region of the circuit completion site.
The embodiment of the system illustrated in
The first electrode assembly 860a may comprise a biasing element 862 that carries a first set of electrical contacts 864a. The biasing element 862 may be formed using a soft, conformable, and/or compressible biocompatible material. In one embodiment, the first electrode assembly 860a is coupled to a first terminal 842a of the pulse system 840. The second electrode assembly 860b may comprise one or more exposed conductive portions of the housing 802 and/or the attachment element 804, and/or a second set of electrical contacts 864b that are carried by the housing 802 and/or the attachment element 804. The second electrode assembly 860b may be coupled to a second terminal 842b of the pulse system 840. Depending upon embodiment details, the pulse system's first and second terminals 842a–b may be configured as an anode and a cathode, possibly in a selectable or programmable manner. Additionally, configuration or establishment of an anodal and a cathodal relationship between the pulse system's first and second terminals 842a–b may occur in a predetermined, aperiodic, or pseudo-random time-varying manner.
The support member 800 may be implanted into or through a craniotomy that is above a stimulation site, such that one or more portions of the biasing element 862 and/or the first set of contacts 864a reside upon, essentially upon, or proximate to the stimulation site. Following implantation, the attachment element 804 may be covered by the patient's scalp 892. The first electrode assembly 860a may be biased in accordance with a first polarity to apply or deliver unipolar stimulation to a target neural population, neural projections, and/or neural structures associated with the stimulation site. The second electrode assembly 860b may be biased in accordance with a second polarity to provide electrical continuity for stimulation signals delivered by the first electrode assembly 860a. In such a configuration, an electrical current pathway between the first and second electrode assemblies 842a–b may include one or more portions of the patient's cortex, one or more neural regions below the cortex, vasculature, and/or portions of the patient's scalp. In order to eliminate, essentially eliminate, or minimize electrical current flow from the first electrode assembly 860a to the second electrode assembly 860b along a current path that includes an interface between the skull 890 and the edge of the housing 802 and/or the attachment element 804, one or more portions of the housing 802 and/or the attachment element 804 may comprise or include an insulating material that forms a nonconductive seal or barrier between the skull 890 and the housing 802 and/or the attachment element 804.
The local electrode assembly 860 may comprise a biasing element 862 that carries a first set of contacts 864. In one embodiment, the local electrode assembly 860 is coupled to the pulse system's first terminal 842a. The remote electrode assembly 960 may comprise a support member 962 that carries a second set of contacts 964, and may have a structure analogous to one or more types of electrodes described in U.S. patent application Ser. No. 10/877,830, which is incorporated herein by reference. Alternatively, the remote electrode assembly 960 may comprise a cranial screw or peg type electrode as described in U.S. patent application Ser. No. 10/418,796 (previously incorporated herein by reference); or a depth, deep brain, or other type of electrode. In certain embodiments, the remote electrode assembly 960 may provide an active or aggregate conductive surface area that is greater than an active or aggregate conductive surface area associated with the local electrode assembly 860 in a manner analogous to that described above. The remote electrode assembly 960 may be coupled to the pulse system's second terminal 842b by a link 970. Depending upon embodiment details, the pulse system's first and second terminals 842a–b may be configured as an anode and a cathode, possibly in a selective, programmable, deterministic, and/or pseudo-random manner.
The support member 800 may be implanted into or through a craniotomy that is above a stimulation site in a manner analogous to that described above. The remote electrode assembly 960 may be implanted or positioned distant or remote from the support member 800. The remote electrode assembly 960, for example, may be positioned upon or beneath the patient's skin at an anatomical location that is above or below the patient's neck; or within the patient's cranium at a cortical, subcortical, or deep brain location that is distant, distinct, or remote from the local electrode assembly 860. The local electrode assembly 860 may be biased in accordance with a first signal polarity, and the remote electrode assembly 960 may be biased in accordance with a second signal polarity to provide unipolar stimulation.
The embodiment shown in
In various embodiments, the support member 800 may be implanted at a stimulation site in a manner analogous to that described above. The first and second remote electrode assemblies 960a–b may be respectively positioned or implanted at a first and a second anatomical location that is distant, remote, or distinct from the stimulation site. The local electrode assembly 860 may be biased in accordance with a first signal polarity, while one or both of the remote electrode assemblies 960a–b may be biased in accordance with a second signal polarity at any given time to provide unipolar stimulation.
The use of multiple remote electrode assemblies 960a–b positioned at different anatomical locations may provide multiple current pathways through which neural stimulation may affect or influence particular target cortical and/or subcortical neural populations, neural structures, and/or neural projections, possibly in an alternating or time-dependent manner. For example, unipolar stimulation delivered or applied along or with respect to a first current pathway may be directed toward affecting neural activity in a first hemisphere of the brain, while unipolar stimulation applied with respect to a second current pathway may be directed toward affecting neural activity in a second hemisphere of the brain. Neural activity in each hemisphere may influence the development, recovery, and/or retention of functional abilities, possibly through neuroplastic mechanisms. In certain embodiments, one or more stimulation parameters such as stimulation signal frequency, amplitude, and/or polarity may differ or vary in accordance with a current pathway that is active or under consideration at any given time.
One or more embodiments described above may be modified to include or exclude elements or features described in association with other embodiments, for example a signal selection module 880, 980. Additionally or alternatively, particular embodiments may include multiple local electrode assemblies positioned at multiple stimulation sites, in conjunction with one or more remote electrode assemblies positioned distant from such stimulation sites to provide electrical continuity for unipolar stimulation.
B. Methods for Applying Electrical Stimulation
The unipolar stimulation procedure 1004 can be performed using any of the systems set forth above with respect to
An optional or alternative embodiment of the method 1000 can further include at least one bipolar stimulation procedure 1006 in which a first set of contacts at a stimulation site are biased at a first signal polarity, while a second set of contacts at a stimulation site are biased at a second signal polarity. The bipolar stimulation procedure 1006 may be performed in a manner identical or analogous to that described above, and may involve the delivery of stimulation signals at a subthreshold and/or a suprathreshold level. The bipolar stimulation procedure 1006 may also involve the application of theta burst stimulation signals during one or more time periods.
The decision procedure 1008 may decide whether the stimulation has been of sufficient or adequate duration and/or effect. In particular embodiments, the decision procedure 1008 may involve monitoring or measuring patient progress and/or functional capabilities through one or more standardized measures, tests, or tasks. Such standardized measures may include or be based upon, for example, a Fugl-Meyer Assessment of Sensorimotor Impairment; a National Institute of Health (NIH) Stroke Scale; a Stroke Impact Scale (SIS); an ADL scale; a Quality of Life (QoL) scale; physical measures such as grip strength or finger tapping speed; a neuropsychological testing battery; a walking, movement, and/or dexterity test; a behavioral test; a language test; a comprehension test; and/or other measures of patient functional ability. In certain embodiments, the decision procedure 1008 may alternatively or additionally involve an electrophysiological signal acquisition and/or analysis procedure, and/or a neural imaging procedure (e.g., MRI, fMRI, or PET). The decision procedure 1008 may direct the method 1000 to apply either a unipolar stimulation procedure 1004 and/or a bipolar stimulation procedure 1006 depending upon the particular characteristics of the therapy and/or the nature or extent of the patient's neurofunctional condition. One or more stimulation sites and/or stimulation parameters (e.g., pulse repetition frequency, first phase pulse width, peak current and/or voltage amplitude, theta burst characteristics, a waveform variation and/or modulation function, and/or other parameters) corresponding to particular unipolar and/or bipolar stimulation procedures 1004, 1006 may be identical, generally identical, or different depending upon the nature of a patient's neurologic dysfunction, patient condition, and/or embodiment details. The method 1000 may further include a termination procedure 1010 that is performed based upon the outcome of the decision procedure 1008.
The unipolar stimulation procedure 1104 and the first adjunctive therapy procedure 1106 can be performed concurrently or serially depending upon the nature and/or extent of a patient's neurologic dysfunction, patient condition, and/or embodiment details. The first adjunctive therapy procedure 1106 may comprise a behavioral therapy procedure that can include a physical therapy, an activity of daily living, an intentional use of an affected body part, a speech therapy, a vision therapy, an auditory task or therapy (e.g., an auditory discrimination task), a reading task, a memory task, a visualization, imagination, or thought task, and/or another type of task or therapy. A subthreshold unipolar stimulation procedure 1104 may be performed concurrent with a first behavioral therapy procedure 1106 to enhance or maximize a likelihood generating action potentials that may subserve the development and/or recovery of one or more functional abilities.
The method 1100 may additionally include a first decision procedure 1108 that may decide whether the unipolar stimulation procedure 1104 and/or the first adjunctive therapy procedure 1106 have been of sufficient or adequate duration and/or effect. The first decision procedure 1108 may involve measurement or assessment of patient status, progress, and/or functional capabilities using one or more standardized measures, tests, or tasks; an electrophysiological signal acquisition and/or analysis procedure; and/or a neural imaging procedure. If additional unipolar stimulation and/or adjunctive therapy is warranted, the method 1100 may continue, resume, or restart a unipolar stimulation procedure 1104 and/or a first adjunctive therapy procedure 1106.
In certain embodiments, the method 1100 may further include a bipolar stimulation procedure 1110, and/or a second adjunctive or synergistic therapy procedure 1112. The bipolar stimulation procedure 1110 may involve the application or delivery of stimulation signals at a subthreshold and/or suprathreshold level, and may possibly involve theta burst stimulation at one or more times. The bipolar stimulation procedure 1110 may be directed toward the same, essentially the same, or different target neural structures, target neural projections, and/or target neural populations than the unipolar stimulation procedure 1104. Thus, the bipolar stimulation procedure 1110 may deliver or apply stimulation signals to the same or a different stimulation site than the unipolar stimulation procedure 1104, either in the same and/or a different brain hemisphere. For example, both the unipolar and bipolar stimulation procedures 1104, 1110 may deliver stimulation signals to identical or essentially identical portions of a patient's motor cortex; or the unipolar stimulation procedure 1104 may apply stimulation signals to portions of the patient's motor cortex, while the bipolar stimulation procedure 1110 may apply stimulation signals to portions of the patient's premotor cortex or another region of the brain.
The second adjunctive therapy procedure 1112 may involve, for example, a drug therapy and/or a behavioral therapy that is identical or essentially identical to or different from a therapy associated with the first adjunctive therapy procedure 1106. The second adjunctive therapy procedure 1112 may involve, for example, a visualization procedure such as thinking about performing one or more types of motions and/or tasks, while the first adjunctive therapy procedure 1106 may involve attempting to actually perform such motions and/or tasks.
Depending upon the nature and/or extent of a patient's neurologic dysfunction, patient condition, and/or embodiment details, the bipolar stimulation procedure 1110 and the second adjunctive therapy procedure 1112 may be performed concurrently or serially, in a manner analogous to that described above for the unipolar stimulation procedure 1104 and the first adjunctive therapy procedure 1106. Moreover, the bipolar stimulation procedure 1110 and/or the second adjunctive therapy procedure 1112 may precede or follow the unipolar stimulation procedure 1104 and/or the first adjunctive therapy procedure 1106 in either a generally continuous or an interrupted manner.
The method 1100 may further include a second decision procedure 1114 that may decide whether the bipolar stimulation procedure 1110 and/or the second adjunctive therapy procedure 1112 have been of sufficient or adequate duration and/or effect. The second decision procedure 1114 may involve measurement or assessment of patient status, progress, and/or functional capabilities using one or more standardized measures, tests, or tasks; an electrophysiological signal acquisition and/or analysis procedure; and/or a neural imaging procedure. If additional bipolar stimulation and/or adjunctive therapy is warranted, the method 1100 may continue, resume, or restart a bipolar stimulation procedure 1110 and/or a second adjunctive therapy procedure 1112. Finally, the method 1100 may include a termination procedure 1116 that may be performed based upon an outcome of the first and/or second decision procedure 1108, 1116.
Depending upon embodiment details, a method 1100 may comprise a number of anodal unipolar, cathodal unipolar, and/or bipolar stimulation procedures 1104, 1110, where the number, duration of, and/or time between such procedures and/or the particular stimulation sites to which such procedures are directed may be identical, essentially identical, or different. Moreover, one or more stimulation signal parameters (e.g., pulse repetition frequency, first phase pulse width, peak current and/or voltage amplitude, theta burst characteristics, a waveform variation and/or modulation function, and/or other parameters) corresponding to particular unipolar and/or bipolar stimulation procedures 1104, 1110 may be identical, generally identical, or different depending upon the nature of a patient's neurologic dysfunction, patient condition, and/or embodiment details.
In certain embodiments, one or more procedures described herein may form portions of a limited duration treatment program, in a manner analogous to that described in U.S. application Ser. No. 10/606,202, incorporated herein by reference. In accordance with various embodiments of the present invention, a limited duration treatment program may apply or deliver unipolar stimulation, and possibly bipolar stimulation, to a patient for a limited period of time to facilitate or effectuate complete, essentially complete, significant, or partial rehabilitation, restoration, or functional healing of or recovery from a neurological condition such as a neurological malfunction and/or a neurologically based deficit or disorder. Depending upon the extent or nature of the patient's neurological condition and/or functional deficits, a limited duration treatment program may last, for example, a number of weeks, months, or possibly one or more years.
From the foregoing, it will be appreciated that specific embodiments of the invention have been described herein for purposes of illustration, but that various modifications may be made without deviating from the spirit and scope of the invention. For example, aspects of the invention described in the context of particular embodiments can be combined or eliminated in other embodiments. Accordingly, the invention is not limited except as by the appended claims.
This application claims priority to pending U.S. Provisional Application No. 60/492,273, filed on Aug. 1, 2003, and incorporated herein in its entirety by reference. This application is related to U.S. patent application Ser. No. 09/802,808 entitled “Methods and Apparatus for Effectuating a Lasting Change in a Neural-Function of a Patient,” which claims the benefit of U.S. Provisional Application 60/217,981, filed Jul. 31, 2000, both of which are herein incorporated by reference. Additional applications are incorporated by reference in other portions of this application.
| Number | Name | Date | Kind |
|---|---|---|---|
| 2716226 | Jonas | Aug 1955 | A |
| 2721316 | Shaw | Oct 1955 | A |
| 3628193 | Collins | Dec 1971 | A |
| 3650276 | Burghele et al. | Mar 1972 | A |
| 3850161 | Liss | Nov 1974 | A |
| 4019518 | Maurer et al. | Apr 1977 | A |
| 4030509 | Heilman et al. | Jun 1977 | A |
| 4125116 | Fischell | Nov 1978 | A |
| 4140133 | Kastrubin et al. | Feb 1979 | A |
| 4214804 | Little | Jul 1980 | A |
| 4245645 | Picard et al. | Jan 1981 | A |
| 4308868 | Jhabvala | Jan 1982 | A |
| 4328813 | Ray | May 1982 | A |
| 4340038 | McKean | Jul 1982 | A |
| 4390023 | Rise | Jun 1983 | A |
| 4431000 | Butler et al. | Feb 1984 | A |
| 4474186 | Ledley et al. | Oct 1984 | A |
| 4532931 | Mills | Aug 1985 | A |
| 4541432 | Molina-Negro et al. | Sep 1985 | A |
| 4542752 | DeHaan | Sep 1985 | A |
| 4590946 | Loeb | May 1986 | A |
| 4607639 | Tanagho | Aug 1986 | A |
| 4646744 | Capel | Mar 1987 | A |
| 4817634 | Holleman et al. | Apr 1989 | A |
| 4844075 | Liss | Jul 1989 | A |
| 4865048 | Eckerson | Sep 1989 | A |
| 4869255 | Putz | Sep 1989 | A |
| 4903702 | Putz | Feb 1990 | A |
| 4969468 | Byers et al. | Nov 1990 | A |
| 5002053 | Garcia-Rill | Mar 1991 | A |
| 5024226 | Tan | Jun 1991 | A |
| 5031618 | Mullett | Jul 1991 | A |
| 5044368 | Putz | Sep 1991 | A |
| 5054906 | Lyons | Oct 1991 | A |
| 5063932 | Dahl et al. | Nov 1991 | A |
| 5092835 | Schurig | Mar 1992 | A |
| 5119832 | Xavier | Jun 1992 | A |
| 5121754 | Mullett | Jun 1992 | A |
| 5143089 | Alt | Sep 1992 | A |
| 5169384 | Bosniak | Dec 1992 | A |
| 5184620 | Cudahy et al. | Feb 1993 | A |
| 5193540 | Schulman et al. | Mar 1993 | A |
| 5215086 | Terry | Jun 1993 | A |
| 5215088 | Normann et al. | Jun 1993 | A |
| 5224491 | Mehra | Jul 1993 | A |
| 5255678 | Deslauriers | Oct 1993 | A |
| 5263967 | Lyons | Nov 1993 | A |
| 5269303 | Wernicke et al. | Dec 1993 | A |
| 5271417 | Swanson et al. | Dec 1993 | A |
| 5282468 | Klepinski | Feb 1994 | A |
| 5299569 | Wernicke et al. | Apr 1994 | A |
| 5303705 | Nenov | Apr 1994 | A |
| 5304206 | Baker | Apr 1994 | A |
| 5314458 | Najafi et al. | May 1994 | A |
| 5342410 | Braverman | Aug 1994 | A |
| 5358513 | Powell | Oct 1994 | A |
| 5358514 | Schulman et al. | Oct 1994 | A |
| 5370672 | Fowler | Dec 1994 | A |
| 5405375 | Ayers et al. | Apr 1995 | A |
| 5406957 | Tansey | Apr 1995 | A |
| 5411540 | Edell | May 1995 | A |
| 5417719 | Hull | May 1995 | A |
| 5423864 | Ljungstroem | Jun 1995 | A |
| 5423877 | Mackey | Jun 1995 | A |
| 5441528 | Chang et al. | Aug 1995 | A |
| 5458631 | Xavier | Oct 1995 | A |
| 5464446 | Dreessen et al. | Nov 1995 | A |
| 5470846 | Sandyk | Nov 1995 | A |
| 5520190 | Benedict et al. | May 1996 | A |
| 5522864 | Wallace et al. | Jun 1996 | A |
| 5537512 | Hsia | Jul 1996 | A |
| 5540734 | Zabara | Jul 1996 | A |
| 5540736 | Haimovich | Jul 1996 | A |
| 5549655 | Erickson | Aug 1996 | A |
| 5562708 | Combs et al. | Oct 1996 | A |
| 5575813 | Edell | Nov 1996 | A |
| 5591216 | Testerman | Jan 1997 | A |
| 5593432 | Crowther, deceased et al. | Jan 1997 | A |
| 5601611 | Fayram et al. | Feb 1997 | A |
| 5618531 | Cherksey | Apr 1997 | A |
| 5628317 | Starkebaum | May 1997 | A |
| 5674251 | Combs et al. | Oct 1997 | A |
| 5674264 | Carter et al. | Oct 1997 | A |
| 5676655 | McCulloch et al. | Oct 1997 | A |
| 5683422 | Rise | Nov 1997 | A |
| 5702429 | King | Dec 1997 | A |
| 5707334 | Young | Jan 1998 | A |
| 5711316 | Elsberry | Jan 1998 | A |
| 5713922 | King | Feb 1998 | A |
| 5713923 | Ward | Feb 1998 | A |
| 5716377 | Rise | Feb 1998 | A |
| 5722401 | Pietroski | Mar 1998 | A |
| 5735814 | Elsberry | Apr 1998 | A |
| 5750376 | Weiss et al. | May 1998 | A |
| 5752979 | Benabid | May 1998 | A |
| 5753505 | Luskin | May 1998 | A |
| 5769778 | Abrams et al. | Jun 1998 | A |
| 5772591 | Cram | Jun 1998 | A |
| 5782798 | Rise | Jul 1998 | A |
| 5782873 | Collins | Jul 1998 | A |
| 5792186 | Rise | Aug 1998 | A |
| 5797970 | Pouvreau | Aug 1998 | A |
| 5814014 | Elsberry | Sep 1998 | A |
| 5814092 | King | Sep 1998 | A |
| 5824021 | Rise | Oct 1998 | A |
| 5824030 | Yang et al. | Oct 1998 | A |
| 5832932 | Elsberry | Nov 1998 | A |
| 5833603 | Kovacs et al. | Nov 1998 | A |
| 5833709 | Rise | Nov 1998 | A |
| 5843148 | Gijsbers | Dec 1998 | A |
| 5843150 | Dressen | Dec 1998 | A |
| 5846196 | Siekmeyer et al. | Dec 1998 | A |
| 5865842 | Knuth et al. | Feb 1999 | A |
| 5871517 | Abrams et al. | Feb 1999 | A |
| 5873849 | Bernard | Feb 1999 | A |
| 5885976 | Sandyk | Mar 1999 | A |
| 5886769 | Zolten | Mar 1999 | A |
| 5893883 | Torgerson | Apr 1999 | A |
| 5904916 | Hirsch | May 1999 | A |
| 5913882 | King | Jun 1999 | A |
| 5916171 | Mayevsky | Jun 1999 | A |
| 5925070 | King | Jul 1999 | A |
| 5928144 | Real | Jul 1999 | A |
| 5938688 | Schiff | Aug 1999 | A |
| 5938689 | Fischell | Aug 1999 | A |
| 5941906 | Barreras | Aug 1999 | A |
| 5964794 | Bolz | Oct 1999 | A |
| 5975085 | Rise | Nov 1999 | A |
| 5978702 | Ward | Nov 1999 | A |
| 5983140 | Smith | Nov 1999 | A |
| 6006124 | Fischell | Dec 1999 | A |
| 6011996 | Gielen | Jan 2000 | A |
| 6016449 | Fischell | Jan 2000 | A |
| 6018682 | Rise | Jan 2000 | A |
| 6021352 | Christopherson | Feb 2000 | A |
| 6024702 | Iversen | Feb 2000 | A |
| 6026326 | Bardy | Feb 2000 | A |
| 6035236 | Jarding et al. | Mar 2000 | A |
| 6038480 | Hrdlicka et al. | Mar 2000 | A |
| 6042579 | Elsberry | Mar 2000 | A |
| 6051017 | Loeb et al. | Apr 2000 | A |
| 6052624 | Mann | Apr 2000 | A |
| 6055456 | Gerber | Apr 2000 | A |
| 6057846 | Sever, Jr. | May 2000 | A |
| 6057847 | Jenkins | May 2000 | A |
| 6058331 | King | May 2000 | A |
| 6060048 | Cherksey | May 2000 | A |
| 6061593 | Fischell | May 2000 | A |
| 6066163 | John | May 2000 | A |
| 6078838 | Rubinstein | Jun 2000 | A |
| 6094598 | Elsberry et al. | Jul 2000 | A |
| 6095148 | Shastri et al. | Aug 2000 | A |
| 6104956 | Naritoku | Aug 2000 | A |
| 6104960 | Duysens | Aug 2000 | A |
| 6111911 | Sanderford, Jr. et al. | Aug 2000 | A |
| 6122548 | Starkebaum | Sep 2000 | A |
| 6126657 | Edwards | Oct 2000 | A |
| 6128527 | Howard, III et al. | Oct 2000 | A |
| 6128537 | Rise | Oct 2000 | A |
| 6128538 | Fischell | Oct 2000 | A |
| 6134474 | Fischell | Oct 2000 | A |
| 6152143 | Edwards | Nov 2000 | A |
| 6161044 | Silverstone | Dec 2000 | A |
| 6161045 | Fischell | Dec 2000 | A |
| 6161047 | King et al. | Dec 2000 | A |
| 6176242 | Rise | Jan 2001 | B1 |
| 6190893 | Shastri et al. | Feb 2001 | B1 |
| 6198958 | Ives et al. | Mar 2001 | B1 |
| 6205360 | Carter et al. | Mar 2001 | B1 |
| 6205361 | Kuzma et al. | Mar 2001 | B1 |
| 6210417 | Baudino et al. | Apr 2001 | B1 |
| 6221908 | Kilgard et al. | Apr 2001 | B1 |
| 6230049 | Fischell et al. | May 2001 | B1 |
| 6236892 | Feler | May 2001 | B1 |
| 6246912 | Sluijter et al. | Jun 2001 | B1 |
| 6251115 | Williams et al. | Jun 2001 | B1 |
| 6263225 | Howard, III | Jul 2001 | B1 |
| 6263237 | Rise | Jul 2001 | B1 |
| 6280462 | Hauser et al. | Aug 2001 | B1 |
| 6301493 | Marro et al. | Oct 2001 | B1 |
| 6304787 | Kuzma et al. | Oct 2001 | B1 |
| 6319241 | King et al. | Nov 2001 | B1 |
| 6339725 | Naritoku et al. | Jan 2002 | B1 |
| 6353754 | Fischell | Mar 2002 | B1 |
| 6353762 | Baudino et al. | Mar 2002 | B1 |
| 6354299 | Frischell | Mar 2002 | B1 |
| 6356786 | Rezai et al. | Mar 2002 | B1 |
| 6356792 | Errico et al. | Mar 2002 | B1 |
| 6360122 | Fischell | Mar 2002 | B1 |
| 6366813 | DiLorenzo | Apr 2002 | B1 |
| 6375666 | Mische | Apr 2002 | B1 |
| 6381496 | Meadows et al. | Apr 2002 | B1 |
| 6393319 | Bock et al. | May 2002 | B1 |
| 6405079 | Ansarinia | Jun 2002 | B1 |
| 6418344 | Rezai | Jul 2002 | B1 |
| 6421566 | Holsheimer et al. | Jul 2002 | B1 |
| 6425852 | Epstein et al. | Jul 2002 | B1 |
| 6427086 | Fischell | Jul 2002 | B1 |
| 6456886 | Howard, III et al. | Sep 2002 | B1 |
| 6459936 | Fischell | Oct 2002 | B2 |
| 6463328 | John | Oct 2002 | B1 |
| 6464356 | Sabel | Oct 2002 | B1 |
| 6466822 | Pless | Oct 2002 | B1 |
| 6473568 | Kashiyama | Oct 2002 | B2 |
| 6473639 | Fischell | Oct 2002 | B1 |
| 6480743 | Kirkpatrick | Nov 2002 | B1 |
| 6484059 | Gielen | Nov 2002 | B2 |
| 6487450 | Chen | Nov 2002 | B1 |
| 6497699 | Ludvig et al. | Dec 2002 | B1 |
| 6499488 | Hunter et al. | Dec 2002 | B1 |
| 6505075 | Weiner | Jan 2003 | B1 |
| 6507755 | Gozani et al. | Jan 2003 | B1 |
| 6529774 | Greene | Mar 2003 | B1 |
| 6539263 | Schiff et al. | Mar 2003 | B1 |
| 6549814 | Strutz et al. | Apr 2003 | B1 |
| 6556868 | Naritoku et al. | Apr 2003 | B2 |
| 6569654 | Shastri et al. | May 2003 | B2 |
| 6591138 | Fischell et al. | Jul 2003 | B1 |
| 6597954 | Pless et al. | Jul 2003 | B1 |
| 6609030 | Rezai et al. | Aug 2003 | B1 |
| 6609031 | Law et al. | Aug 2003 | B1 |
| 6615065 | Barrett et al. | Sep 2003 | B1 |
| 6622048 | Mann | Sep 2003 | B1 |
| 6631295 | Rubinstein et al. | Oct 2003 | B2 |
| 6633780 | Berger | Oct 2003 | B1 |
| 6647296 | Fischell et al. | Nov 2003 | B2 |
| 6665562 | Gluckman et al. | Dec 2003 | B2 |
| 6684105 | Cohen et al. | Jan 2004 | B2 |
| 6687525 | Llinas | Feb 2004 | B2 |
| 6690974 | Archer | Feb 2004 | B2 |
| 6708064 | Rezai | Mar 2004 | B2 |
| 6725094 | Saberski | Apr 2004 | B2 |
| 6735475 | Whitehurst et al. | May 2004 | B1 |
| 6764498 | Mische | Jul 2004 | B2 |
| 6782292 | Whitehurst | Aug 2004 | B2 |
| 6788975 | Whitehurst et al. | Sep 2004 | B1 |
| 6795737 | Gielen et al. | Sep 2004 | B2 |
| 6810286 | Donovan et al. | Oct 2004 | B2 |
| 6819956 | DiLorenzo | Nov 2004 | B2 |
| 6839594 | Cohen et al. | Jan 2005 | B2 |
| 6850802 | Holsheimer | Feb 2005 | B2 |
| 6871098 | Nuttin et al. | Mar 2005 | B2 |
| 6873872 | Gluckman et al. | Mar 2005 | B2 |
| 6892097 | Holsheimer | May 2005 | B2 |
| 6895280 | Meadows et al. | May 2005 | B2 |
| 6907296 | Doan et al. | Jun 2005 | B1 |
| 6922590 | Whitehurst | Jul 2005 | B1 |
| 6934580 | Osorio et al. | Aug 2005 | B1 |
| 6944497 | Stypulkowski | Sep 2005 | B2 |
| 6944501 | Pless | Sep 2005 | B1 |
| 6959215 | Gliner et al. | Oct 2005 | B2 |
| 6990377 | Gliner et al. | Jan 2006 | B2 |
| 7006859 | Osorio et al. | Feb 2006 | B1 |
| 7010351 | Firlik et al. | Mar 2006 | B2 |
| 7024247 | Gliner et al. | Apr 2006 | B2 |
| 7050856 | Stypulkowski | May 2006 | B2 |
| 7107097 | Stern et al. | Sep 2006 | B2 |
| 7110820 | Tcheng et al. | Sep 2006 | B2 |
| 7112319 | Broderick et al. | Sep 2006 | B2 |
| 7146222 | Boling | Dec 2006 | B2 |
| 7187968 | Wolf et al. | Mar 2007 | B2 |
| 7187977 | Paul, Jr. | Mar 2007 | B2 |
| 7346395 | Lozano et al. | Mar 2008 | B2 |
| 20010037134 | Munshi | Nov 2001 | A1 |
| 20010051819 | Fischell et al. | Dec 2001 | A1 |
| 20010053885 | Gielen et al. | Dec 2001 | A1 |
| 20020028072 | Kashiyama | Mar 2002 | A1 |
| 20020062143 | Baudino et al. | May 2002 | A1 |
| 20020077670 | Archer et al. | Jun 2002 | A1 |
| 20020087201 | Firlik et al. | Jul 2002 | A1 |
| 20020091419 | Firlik et al. | Jul 2002 | A1 |
| 20020099295 | Gil et al. | Jul 2002 | A1 |
| 20020099412 | Fischell | Jul 2002 | A1 |
| 20020169485 | Pless | Nov 2002 | A1 |
| 20030028072 | Fischell et al. | Feb 2003 | A1 |
| 20030074032 | Gliner | Apr 2003 | A1 |
| 20030078633 | Firlik et al. | Apr 2003 | A1 |
| 20030088274 | Gliner et al. | May 2003 | A1 |
| 20030097159 | Schiff et al. | May 2003 | A1 |
| 20030097161 | Firlik et al. | May 2003 | A1 |
| 20030114886 | Gluckman et al. | Jun 2003 | A1 |
| 20030125772 | Olson et al. | Jul 2003 | A1 |
| 20030125786 | Gliner et al. | Jul 2003 | A1 |
| 20030130706 | Sheffield et al. | Jul 2003 | A1 |
| 20030149457 | Tcheng et al. | Aug 2003 | A1 |
| 20030176901 | May | Sep 2003 | A1 |
| 20030181954 | Rezai | Sep 2003 | A1 |
| 20030187490 | Gliner | Oct 2003 | A1 |
| 20030187491 | Greenberg et al. | Oct 2003 | A1 |
| 20030195602 | Boling | Oct 2003 | A1 |
| 20030233137 | Paul | Dec 2003 | A1 |
| 20040073270 | Firlik et al. | Apr 2004 | A1 |
| 20040082847 | McDermott | Apr 2004 | A1 |
| 20040088024 | Firlik et al. | May 2004 | A1 |
| 20040092809 | DeCharms | May 2004 | A1 |
| 20040102828 | Lowry et al. | May 2004 | A1 |
| 20040111127 | Gliner et al. | Jun 2004 | A1 |
| 20040138550 | Hartlep et al. | Jul 2004 | A1 |
| 20040158298 | Gliner et al. | Aug 2004 | A1 |
| 20040176831 | Gliner et al. | Sep 2004 | A1 |
| 20040181263 | Balzer et al. | Sep 2004 | A1 |
| 20040215287 | Swoyer et al. | Oct 2004 | A1 |
| 20040215288 | Lee et al. | Oct 2004 | A1 |
| 20040236388 | Gielen et al. | Nov 2004 | A1 |
| 20040243205 | Keravel et al. | Dec 2004 | A1 |
| 20040249422 | Gliner et al. | Dec 2004 | A1 |
| 20050004620 | Singhal et al. | Jan 2005 | A1 |
| 20050015129 | Mische | Jan 2005 | A1 |
| 20050021104 | DiLorenzo | Jan 2005 | A1 |
| 20050021105 | Firlik et al. | Jan 2005 | A1 |
| 20050021106 | Firlik et al. | Jan 2005 | A1 |
| 20050021107 | Firlik et al. | Jan 2005 | A1 |
| 20050021118 | Genau et al. | Jan 2005 | A1 |
| 20050033378 | Sheffield et al. | Feb 2005 | A1 |
| 20050033379 | Lozano et al. | Feb 2005 | A1 |
| 20050070971 | Fowler et al. | Mar 2005 | A1 |
| 20050075679 | Gliner et al. | Apr 2005 | A1 |
| 20050075680 | Lowry et al. | Apr 2005 | A1 |
| 20050090756 | Wolf et al. | Apr 2005 | A1 |
| 20050096701 | Donovan et al. | May 2005 | A1 |
| 20050113882 | Cameron et al. | May 2005 | A1 |
| 20050119712 | Shafer | Jun 2005 | A1 |
| 20050154425 | Boveja et al. | Jul 2005 | A1 |
| 20050154426 | Boveja et al. | Jul 2005 | A1 |
| 20050182453 | Whitehurst | Aug 2005 | A1 |
| 20050228451 | Jaax et al. | Oct 2005 | A1 |
| 20060004422 | De Ridder | Jan 2006 | A1 |
| 20060004423 | Boveja et al. | Jan 2006 | A1 |
| 20060015153 | Gliner et al. | Jan 2006 | A1 |
| 20060020297 | Gerber et al. | Jan 2006 | A1 |
| 20060064138 | Velasco et al. | Mar 2006 | A1 |
| 20060095088 | De Ridder | May 2006 | A1 |
| 20060106430 | Fowler et al. | May 2006 | A1 |
| 20060106431 | Wyler et al. | May 2006 | A1 |
| 20060129205 | Boveja et al. | Jun 2006 | A1 |
| 20060173522 | Osorio | Aug 2006 | A1 |
| 20060217782 | Boveja et al. | Sep 2006 | A1 |
| 20060241717 | Whitehurst et al. | Oct 2006 | A1 |
| 20060259094 | Naisberg et al. | Nov 2006 | A1 |
| 20070032834 | Gliner et al. | Feb 2007 | A1 |
| 20070032839 | Parramon et al. | Feb 2007 | A1 |
| 20070060974 | Lozano | Mar 2007 | A1 |
| 20070078495 | Caillat et al. | Apr 2007 | A1 |
| Number | Date | Country |
|---|---|---|
| 19750043 | May 1999 | DE |
| 0214527 | Mar 1987 | EP |
| 0319844 | Jun 1989 | EP |
| 1180056 | Sep 2000 | EP |
| 0 998 958 | Oct 2000 | EP |
| 1 145 736 | Oct 2001 | EP |
| WO8707511 | Dec 1987 | WO |
| WO9407564 | Apr 1994 | WO |
| WO9521591 | Aug 1995 | WO |
| WO 97-45160 | Dec 1997 | WO |
| WO9806342 | Feb 1998 | WO |
| WO-0007494 | Feb 2000 | WO |
| WO-0040295 | Jul 2000 | WO |
| WO 0197906 | Dec 2001 | WO |
| WO-0193953 | Dec 2001 | WO |
| WO 0209811 | Feb 2002 | WO |
| WO 0236003 | May 2002 | WO |
| WO 0238031 | May 2002 | WO |
| WO 0238217 | May 2002 | WO |
| WO-02073526 | Sep 2002 | WO |
| WO 03082402 | Mar 2003 | WO |
| WO 03043690 | May 2003 | WO |
| WO 03-101532 | Dec 2003 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 20050070971 A1 | Mar 2005 | US |
| Number | Date | Country | |
|---|---|---|---|
| 60492273 | Aug 2003 | US |
