Methods and apparatus for effectuating a lasting change in a neural-function of a patient

Methods and apparatus for treating an impaired neural function in a brain of a patient. In one embodiment, a method for treating a neural function in a brain of a patient includes determining a therapy period during which a plurality of therapy sessions are to be performed to recover functional ability corresponding to the neural function. The method continues by identifying a stimulation site in or on the brain of the patient associated with the neural function, and positioning an electrode at least proximate to the identified stimulation site. The patient is then treated by providing electrical stimulation treatments to the stimulation site. The treatment can comprise delivering electrical stimulation signals to the electrode during the therapy sessions. After expiration of the therapy period, the method includes preventing electrical stimulation signals from being delivered to the stimulation site.

TECHNICAL FIELD

Several embodiments of methods and apparatus in accordance with the invention are related to electrically stimulating a region in the cortex or other area of the brain for a limited treatment period to bring about a lasting change in a physiological function and/or a mental process of a patient.

BACKGROUND

A wide variety of mental and physical processes are controlled or influenced by neural activity in particular regions of the brain. For example, the neural-functions in some areas of the brain (i.e., the sensory or motor cortices) are organized according to physical or cognitive functions. There are also several other areas of the brain that appear to have distinct functions in most individuals. In the majority of people, for example, the areas of the occipital lobes relate to vision, the regions of the left interior frontal lobes relate to language, and the regions of the cerebral cortex appear to be consistently 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. As a result, many types of physical and/or cognitive deficits that remain after treating neurological damage or disorders are typically considered permanent conditions that patients must manage for the remainder of their lives.

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 synoptically 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 (TES) 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 (TMS), involves producing a 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 that can affect 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 collateral neural activity may be undesirable and/or inconvenient in a neural stimulation situation.

Conventional neural stimulation systems and techniques are generally directed toward treating or managing chronic patient symptoms on a perpetual or essentially perpetual basis, i.e., throughout a patient's lifespan. Therefore, conventional neural stimulation systems and methods may not be ideally suited for applications directed toward restoring rather than perpetually treating impaired functions.

DETAILED DESCRIPTION

The following disclosure describes several methods and apparatus for intracranial electrical stimulation to treat or otherwise effectuate a change in neural-functions of a patient. Several embodiments of methods described herein are directed toward enhancing or otherwise inducing neuroplasticity to effectuate a particular neural-function. Neuroplasticity refers to the ability of the brain to change or adapt over time. It was once thought adult brains became relatively “hard wired” such that functionally significant neural networks could not change significantly over time or in response to injury. It has become increasingly more apparent that these neural networks can change and adapt over time so that meaningful function can be restored in response to brain injury. An aspect of several embodiments of methods in accordance with the invention is to provide the appropriate triggers for adaptive neuroplasticity. These appropriate triggers appear to cause or enable increased synchrony of functionally significant populations of neurons in a network.

Neural stimulation applied or delivered in various manners described herein may excite a portion of a neural network involved in or associated with a functionally significant task such that a selected population of neurons can become more strongly associated with that network. Because such a network will subserve a functionally meaningful task, such as motor relearning, the changes are more likely to be lasting because they are continually being reinforced by natural use mechanisms. The nature of stimulation in accordance with several embodiments of the invention ensures that the stimulated population of neurons links to other neurons in the functional network. It is expected that this occurs because action potentials are not actually caused by the stimulation, but rather the action potentials are caused by interactions with other neurons in the network. Several aspects of the electrical stimulation in accordance with selected embodiments of the invention increase the probability of restoring neural functionality when the network is activated by a combination of electrical stimulation and favorable activities, such as rehabilitation or limb use.

Various methods in accordance with the invention can be used to treat brain damage (e.g., stroke, trauma, etc.), brain disease (e.g., Alzheimer's, Pick's, Parkinson's, etc.), brain disorders (e.g., epilepsy, depression, etc.), neurological malfunction (e.g., dyslexia, autism, etc. . . . ), and/or other neurological conditions. Various methods in accordance with the invention can also be used to enhance functions of normal, healthy brains (e.g., learning, memory, etc.), or to control sensory functions (e.g., pain).

Certain embodiments of methods in accordance with the invention electrically stimulate the brain at a stimulation site where neuroplasticity is occurring. The stimulation site may be different than the region in the brain where neural activity is typically present to perform the particular function according to the functional organization of the brain. In one embodiment in which neuroplasticity related to the neural-function occurs in the brain, the method can include identifying the location where such neuroplasticity is present. This particular procedure may accordingly enhance a change in the neural activity to assist the brain in performing the particular neural function. In an alternative embodiment in which neuroplasticity is not occurring in the brain, an aspect is to induce neuroplasticity at a stimulation site where it is expected to occur. This particular procedure may thus induce a change in the neural activity to instigate performance of the neural function. Several embodiments of these methods are expected to produce a lasting effect on the intended neural activity at the stimulation site.

The specific details of certain embodiments of the invention are set forth in the following description and inFIGS. 1A-41Bto provide a thorough understanding of these embodiments to a person of ordinary skill in the art. More specifically, several embodiments of methods in accordance with the invention are initially described with reference toFIGS. 1-5E, and then several embodiments of devices for stimulating the cortical and/or deep-brain regions of the brain are described with reference toFIGS. 6-41B. A person skilled in the art will understand that the present invention may have additional embodiments, or that the invention can be practiced without several of the details described below.

A. Methods for Electrically Stimulating Regions of the Brain

1. Embodiments of Electrically Enhancing Neural Activity

FIG. 1Ais a schematic representation of several neurons N1-N3andFIG. 1Bis a graph illustrating an “action potential” related to neural activity in a normal neuron. Neural activity is governed by electrical impulses generated in neurons. For example, neuron N1can send excitatory inputs to neuron N2(e.g., times t1, t3and t4inFIG. 1B), and neuron N3can send inhibitory inputs to neuron N2(e.g., time t2inFIG. 1B). The neurons receive/send excitatory and inhibitory inputs from/to a population of other neurons. The excitatory and inhibitory inputs can produce “action potentials” in the neurons, which are electrical pulses that travel through neurons by changing the flux of sodium (Na) and potassium (K) ions across the cell membrane. An action potential occurs when the resting membrane potential of the neuron surpasses a threshold level. When this threshold level is reached, an “all-or-nothing” action potential is generated. For example, as shown inFIG. 1B, the excitatory input at time t5causes neuron N2to “fire” an action potential because the input exceeds the threshold level for generating the action potential. The action potentials propagate down the length of the axon (the long process of the neuron that makes up nerves or neuronal tracts) to cause the release of neurotransmitters from that neuron that will further influence adjacent neurons.

FIG. 1Cis a flowchart illustrating a method100for facilitating and/or effectuating a neural-function in a patient in accordance With an embodiment of the invention. The neural-function, for example, can control a specific mental process or physiological function, such as a particular motor function (e.g., movement of a limb) or sensory function that is normally associated with neural activity at a “normal” location in the brain according to the functional organization of the brain. In several embodiments of the method100, at least some neural activity related to the neural-function can be occurring at a site in the brain. The site of the neural activity may involve one or more portions of a normal location where neural activity typically occurs or is expected to occur to carry out the neural-function according to the functional organization of the brain, and/or the site of the neural activity may be at a different location where the brain has recruited material to perform the neural activity. In either situation, one aspect of several embodiments of the method100is to determine or otherwise identify the location in the brain where this neural activity is present.

The method100includes a diagnostic procedure102involving identifying a stimulation site at a location of the brain. In one approach, the stimulation site may be a location of the brain where an intended neural activity related to a given type of neural-function is present or is expected to be present. For example, the stimulation site may be particular neurological regions and/or cortical structures that are expected to direct, effectuate, and/or facilitate specific neural functions in most individuals. In another approach, the stimulation site may be a location of the brain that supports or is expected to support the intended neural-function.

The diagnostic procedure102may include identifying one or more exterior anatomical landmarks on the patient that correspond to such neurological regions and/or structures within the brain. The external anatomical landmarks serve as reference points for locating a structure of the brain where an intended neural activity may occur. Thus, one aspect of the diagnostic procedure102may include referencing the stimulation site on the brain relative to external anatomical landmarks.

More specifically, identifying an anatomical landmark may include visually determining the location of one or more reference structures (e.g., visible cranial landmarks), and locating underlying brain regions or structures (e.g., the motor strip and/or the Sylvian fissure) relative to the external location of the reference structures. Such reference structures may include, for example, the bregma, the midsagittal suture, and/or other well-known cranial landmarks in a manner understood by those skilled in the art. The methods for locating the underlying brain structure typically involve measuring distances and angles relative to the cerebral topography as known in the art of neurosurgery.

In another embodiment, the diagnostic procedure102includes generating an intended neural activity in the brain from a “peripheral” location that is remote from the normal location, and then determining where the intended neural activity is actually present in the brain. In an alternative embodiment, the diagnostic procedure102can be performed by identifying a stimulation site where neural activity has changed in response to a change in the neural-function.

The method100continues with an implanting procedure104involving positioning at least a first electrode relative to the identified stimulation site; and a stimulating procedure106involving applying an electrical current to the first electrode. Many embodiments of the implanting procedure104position two or more electrodes at the stimulation site, but other embodiments of the implanting procedure involve positioning only one electrode at the stimulation site and another electrode remotely from the stimulation site. As such, the implanting procedure104of the method100can include implanting at least one electrode at the stimulation site. Additional embodiments of the diagnostic procedure102and the procedures104and106are described in greater detail below.

FIGS. 2-4illustrate a specific embodiment of the diagnostic procedure102. The diagnostic procedure102can be used to determine the region of the brain where stimulation will likely effectuate the desired function, such as rehabilitating a loss of a neural-function caused by a stroke, trauma, disease or other circumstance.FIG. 2, more specifically, is an image of a normal, healthy brain200having a first region210where the intended neural activity occurs to effectuate a specific neural-function in accordance with the functional organization of the brain. For example, the neural activity in the first region210shown inFIG. 2is generally associated with the movement of a patient's fingers. The first region210can have a high-intensity area212and a low-intensity area214in which different levels of neural activity occur. It is not necessary to obtain an image of the neural activity in the first region210shown inFIG. 2to carry out the diagnostic procedure102, but rather it is provided to show an example of neural activity that typically occurs at a “normal location” according to the functional organization of the brain200for a large percentage of people with normal brain function. It will be appreciated that the actual location of the first region210will generally vary between individual patients, but those skilled in the art will recognize that the first region210will bear a reasonably predictable spatial relationship with respect to cranial landmarks on the patient.

The neural activity in the first region210, however, can be impaired. In a typical application, the diagnostic procedure102begins by taking an image of the brain200that is capable of detecting neural activity to determine whether the intended neural activity associated with the particular neural function of interest is occurring at the region of the brain200where it normally occurs according to the functional organization of the brain.FIG. 3is an image of the brain200after the first region210has been affected (e.g., from a stroke, trauma or other cause). As shown inFIG. 3, the neural activity that controlled the neural-function for moving the fingers no longer occurs in the first region210. The first region210is thus “inactive,” which is expected to result in a corresponding loss of the movement and/or sensation in the fingers. In some instances, the damage to the brain200may result in only a partial loss of the neural activity in the damaged region. In either case, the image shown inFIG. 3establishes that the loss of the neural-function is related to the diminished neural activity in the first region210. The brain200may accordingly recruit other neurons to perform neural activity for the affected neural-function (i.e., neuroplasticity), or the neural activity may not be present at any location in the brain.

FIG. 4is an image of the brain200illustrating a plurality of potential stimulation sites220and230for effectuating the neural-function that was originally performed in the first region210shown inFIG. 2.FIGS. 3 and 4show an example of neuroplasticity in which the brain compensates for a loss of neural-function in one region of the brain by recruiting other regions of the brain to perform neural activity for carrying out the affected neural-function. The diagnostic procedure102utilizes the neuroplasticity that occurs in the brain to identify the location of a stimulation site that is expected to be more responsive to the results of an electrical, magnetic, sonic, genetic, biologic, and/or pharmaceutical procedure to effectuate the desired neural-function.

One embodiment of the diagnostic procedure102involves generating the intended neural activity remotely from the first region210of the brain, and then detecting or sensing the location in the brain where the intended neural activity has been generated. The intended neural activity can be generated by applying an input that causes a signal to be sent to the brain. For example, in the case of a patient that has lost the use of limb, the affected limb is moved and/or stimulated while the brain is scanned using a known imaging technique that can detect neural activity (e.g., functional MRI, positron emission tomography, etc.). In one specific embodiment, the affected limb can be moved by a practitioner or the patient, stimulated by sensory tests (e.g., pricking), or subject to peripheral electrical stimulation. The movement/stimulation of the affected limb produces a peripheral neural signal from the limb that is expected to generate a response neural activity in the brain. The location in the brain where this response neural activity is present can be identified using the imaging technique.FIG. 4, for example, can be created by moving the affected fingers and then noting where neural activity occurs in response to the peripheral stimulus. By peripherally generating the intended neural activity, this embodiment may accurately identify where the brain has recruited matter (i.e., sites220and230) to perform the intended neural activity associated with the neural-function.

An alternative embodiment of the diagnostic procedure102involves identifying a stimulation site at a second location of the brain where the neural activity has changed in response to a change in the neural-function of the patient. This embodiment of the method does not necessarily require that the intended neural activity be generated by peripherally actuating or stimulating a body part. For example, the brain can be scanned for neural activity associated with the impaired neural-function as a patient regains use of an affected limb or learns a task over a period of time. This embodiment, however, can also include peripherally generating the intended neural activity remotely from the brain explained above.

In still another embodiment, the diagnostic procedure102involves identifying a stimulation site at a location of the brain where the intended neural activity is developing to perform the neural-function. This embodiment is similar to the other embodiments of the diagnostic procedure102, but it can be used to identify a stimulation site at (a) the normal region of the brain where the intended neural activity is expected to occur according to the functional organization of the brain and/or (b) a different region where the neural activity occurs because the brain is recruiting additional matter to perform the neural-function. This particular embodiment of the method involves monitoring neural activity at one or more locations where the neural activity occurs in response to the particular neural-function of interest. For example, to enhance the ability to learn a particular task (e.g., playing a musical instrument, memorizing, etc.), the neural activity can be monitored while a person performs the task or thinks about performing the task. The stimulation sites can be defined by the areas of the brain where the neural activity has the highest intensity, the greatest increases, and/or other parameters that indicate areas of the brain that are being used to perform the particular task.

FIGS. 5A and 5Bare schematic illustrations of the implanting procedure104described above with reference toFIG. 1Cfor positioning the first and second electrodes relative to a portion of the brain of a patient500. Referring toFIG. 5A, a stimulation site502is identified in accordance with an embodiment of the diagnostic procedure102. In one embodiment, a skull section504is removed from the patient500adjacent to the stimulation site502. The skull section504can be removed by boring a hole in the skull in a manner known in the art, or a much smaller hole can be formed in the skull using drilling techniques that are also known in the art. In general, the hole can be 0.2-4.0 cm in diameter. Referring toFIG. 5B, an implantable stimulation apparatus510having first and second electrodes520can be implanted in the patient500. Suitable techniques associated with the implantation procedure are known to practitioners skilled in the art. After the stimulation apparatus510has been implanted in the patient500, a pulse system generates electrical pulses that are transmitted to the stimulation site502by the first and second electrodes520. Stimulation apparatus suitable for carrying out the foregoing embodiments of methods in accordance with the invention are described in more detail below with reference to theFIGS. 6-40.

Several embodiments of methods for enhancing neural activity in accordance with the invention are expected to provide lasting results that promote a desired neural-function. Before the present invention, electrical and magnetic stimulation techniques typically stimulated the normal locations of the brain where neural activity related to the neural-functions occurred according to the functional organization of the brain. Such conventional techniques, however, may not by themselves be effective because one or more subpopulations of neurons in the “normal locations” of the brain may not be capable of carrying out the neural activity because of brain damage, disease, disorder, and/or because of variations of the location specific to individual patients. Several embodiments of methods for enhancing neural activity in accordance with the invention overcome this drawback by identifying a stimulation site based on neuroplastic activity that appears to be related to the neural-function. By first identifying a location in the brain that is being recruited to perform the neural activity, it is expected that therapies (e.g., electrical, magnetic, genetic, biologic, and/or pharmaceutical) applied to this location will be more effective than conventional techniques. This is because the location that the brain is recruiting for the neural activity may not be the “normal location” where the neural activity would normally occur according to the functional organization of the brain. Therefore, several embodiments of methods for enhancing neural activity in accordance with the invention are expected to provide lasting results because the therapies are applied to the portion of the brain where neural activity for carrying out the neural-function actually occurs in the particular patient.

Various embodiments of methods for enhancing neural activity in accordance with the invention may also provide lasting results because electrical stimulation therapies described herein may be applied or delivered to a patient in conjunction or simultaneous with one or more synergistic or adjunctive therapies. Such synertistic or adjunctive therapies may include or involve the patient's performance of one or more behavioral therapies, activities, and/or tasks.

2. Electrically Inducing Desired Neural activity

The method100for effectuating a neural-function can also be used to induce neural activity in a region of the brain where such neural activity is not present. As opposed to the embodiments of the method100described above for enhancing existing neural activity, the embodiments of the method100for inducing neural activity initiate the neural activity at a stimulation site where it is estimated that neuroplasticity will occur. In this particular situation, an image of the brain seeking to locate where neuroplasticity is occurring may be similar toFIG. 3. An aspect of inducing neural activity, therefore, is to develop a procedure to determine where neuroplasticity is likely to occur.

A stimulation site may be identified by estimating where the brain will likely recruit neurons for performing the neural-function. In one embodiment, the location of the stimulation site is estimated by defining a region of the brain that is proximate to the normal location where neural activity related to the neural-function is generally present according to the functional organization of the brain. An alternative embodiment for locating the stimulation site includes determining where neuroplasticity has typically occurred in patients with similar symptoms. For example, if the brain typically recruits a second region of the cortex to compensate for a loss of neural activity in the normal region of the cortex, then the second region of the cortex can be selected as the stimulation site either with or without imaging the neural activity in the brain.

Several embodiments of methods for inducing neural activity in accordance with the invention are also expected to provide lasting results that initiate and promote a desired neural-function. By first estimating the location of a stimulation site where desired neuroplasticity is expected to occur, therapies applied to this location may be more effective than conventional therapies for reasons that are similar to those explained above regarding enhancing neural activity. Additionally, methods for inducing neural activity may be easier and less expensive to implement because they do not require generating neural activity and/or imaging the brain to determine where the intended neural activity is occurring before applying the therapy.

3. Applications of Methods for Electrically Stimulating Regions of the Brain

The foregoing methods for enhancing existing neural activity or inducing new neural activity are expected to be useful for many applications. As explained above, several embodiments of the method100involve determining an efficacious location of the brain to enhance or induce an intended neural activity that causes the desired neural-functions to occur. Additional therapies can also be implemented in combination with the electrical stimulation methods described above. Several specific applications using embodiments of electrical stimulation methods in accordance with the invention either alone or with synergistic or adjunctive therapies will now be described, but it will be appreciated that the methods in accordance with the invention can be used in many additional applications.

a. General Applications

The embodiments of the electrical stimulation methods described above are expected to be particularly useful for rehabilitating or restoring a loss of mental functions, motor functions and/or sensory functions caused by damage to the brain. In a typical application, the brain has been damaged by a stroke or trauma (e.g., automobile accident). The extent of the particular brain damage can be assessed using functional MRI or another appropriate imaging technique as explained above with respect toFIG. 3. A stimulation site can be identified in accordance with a variety of techniques, including: (a) identification of one or more anatomical landmarks; (b) peripherally stimulating a body part that was affected by the brain damage to induce the intended neural activity and determining the location where a response neural activity occurs; (c) determining where the neural activity has changed as a patient gains more use of the affected body part; (d) estimating a location that the brain may recruit neurons to carry out a type of neural activity that was previously performed by the damaged portion of the brain; and/or (e) preoperatively (for example, using TMS) 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). One or more of the aforementioned techniques may be performed in conjunction or association with a neural imaging procedure. An electrical stimulation therapy can be applied to the selected stimulation site by placing or positioning the first and second electrodes relative to the stimulation site to apply an electrical current in or through that portion of the brain. As explained in more detail below, it is expected that applying an electrical current to the portion of the brain that has been recruited to perform the neural activity related to the affected body part will produce a lasting neurological effect for rehabilitating the affected body part. The extent to which electrical stimulation therapy produces a lasting neurological effect may also be related to the performance of behavioral therapy or tasks in conjunction or simultaneous with the electrical stimulation therapy.

Several specific applications are expected to have a stimulation site in the cortex because neural activity in this part of the brain effectuates motor functions and/or sensory functions that are typically affected by a stroke or trauma. In these applications, the electrical stimulation can be applied directly to the pial surface of the brain or at least proximate to the pial surface (e.g., the dura mater, the fluid surrounding the cortex, or neurons within the cortex). Suitable devices for applying the electrical stimulation to the cortex are described in detail with reference toFIGS. 6-41B.

FIG. 5Cis a flowchart of an embodiment of a stimulating procedure106described above with reference toFIG. 1Cfor applying electrical stimulation to a region of a patient's brain identified in accordance with an associated diagnostic procedure102. In one embodiment, the stimulating procedure106includes a limited duration treatment program110involving the application of electrical stimulation to the patient in a manner that facilitates or effectuates 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. One or more portions of the treatment program110may involve electrical stimulation by itself, and/or electrical stimulation in conjunction with one or more synergistic or adjunctive therapies, such as behavioral therapies, activities, and/or tasks. Such behavioral therapies, activities, and/or tasks may include physical therapy; physical and/or cognitive skills training or practice, such as training in Activities of Daily Living (ADL); intentional use of an affected body part; speech therapy; vision training or visual tasks; a reading task; a memory task or memory training, comprehension tasks; attention tasks; and/or other therapies or activities. Other synergistic or adjunctive therapies may include, for example, drug therapies, such as treatment with amphetamines. The electrical stimulation and synergistic or adjunctive therapies can be performed simultaneously or serially.

In accordance with the present invention, a limited duration treatment program110may effectuate or facilitate at least some degree of permanent, essentially permanent, or long term rehabilitation or restoration of a patient's ability to perform one or more types of physical and/or cognitive functions that had been lost or degraded due to neurological damage or a neurological disorder. A limited duration treatment program110may alternatively or additionally effectuate or facilitate at least some degree of permanent, essentially permanent, or long term development, acquisition, and/or establishment of a patient's ability to perform one or more types of physical and/or cognitive functions that had been at least partially absent or impaired as a result of a neurological malfunction. Therefore, the treatment program110need not be directed toward managing a chronic condition that exists over a very long period of time or throughout a patient's life. Rather, the treatment program110may be applied over a limited time that corresponds to the extent of the patient's recovery or functional gain(s). For example, the treatment program110may occur over a period of six weeks, three months, six months, one year, three years, or another limited timeframe. Alternatively or additionally, the treatment program110may be applied over a predetermined number of treatment sessions, for example, twenty, thirty, fifty, or some other number of treatment sessions in total. Another aspect may limit the duration of the treatment program to an accumulated or aggregate time that stimulation has been applied over some number of treatment sessions. An exemplary treatment program110may include one to four or more hours of electrical stimulation per stimulation session, three to seven stimulation sessions per week, throughout a therapy period of one to six or more weeks. Alternatively, a treatment program110may apply continuous or essentially continuous neural stimulation during one or more portions of a therapy period. The overall length or duration of the treatment program110(i.e., the therapy period), and possibly the type(s) and/or location(s) of applied neural stimulation, may depend upon the nature, number, and/or severity of the patient's functional deficits, as well as a degree of patient recovery or functional development.

The stimulating procedure106may further include an assessing procedure112for determining the extent of the patient's functional rehabilitation, recovery, and/or development at particular intervals or over time. Such intervals may be, for example, every n weeks, or every kth treatment session. The assessing procedure112may involve rating or measuring the patient's physical and/or cognitive abilities in accordance with one or more standard functional measures or tests. Such functional 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. The assessing procedure112may additionally or alternatively include one or more neural imaging procedures. The assessing procedure112can also be used to determine the severity of the patient's functional deficits or other neurological conditions at the beginning and throughout the therapy period.

In one embodiment, the stimulating procedure106may include an analyzing procedure114for examining results obtained from one or more assessing procedures112. The analyzing procedure114may involve data analysis and/or trend analysis techniques. In the event that the patient's functional development and/or recovery has significantly slowed or plateaued, but further recovery may be likely or possible, the stimulating procedure106may include a modification procedure116for changing, adjusting, or adapting the limited duration treatment program110. The treatment program110may be changed, adjusted, or adapted by varying stimulation type(s), stimulation location(s), stimulation parameters, and/or particular synergistic or adjunctive therapies (e.g., behavioral therapies, activities, and/or tasks).

The stimulating procedure106may further include a determining procedure118for deciding whether to continue a treatment program110. In the event that a treatment program110is not yet complete or has been modified or adjusted, the treatment program110may resume or restart. In the event that the patient has functionally developed and/or recovered to an intended, acceptable, or maximum extent, the stimulating procedure106may include a termination procedure120for discontinuing the treatment program110. After the treatment program110is completed or discontinued, the patient's functional recovery or gains in functional ability may persist or be retained on a permanent, essentially permanent, or long term basis without further electrical stimulation therapy.

FIG. 5Dis a flow chart of another embodiment of a stimulating procedure106described above with reference toFIG. 1Cfor applying electrical stimulation to a region of a patient's brain identified in accordance with an associated diagnostic procedure102. The embodiment of the stimulating procedure106shown inFIG. 5Dis similar to the procedure shown inFIG. 5C. The stimulating procedure106show inFIG. 5D, however, further includes a monitoring operation130in which the status of the recovery and/or functional gains is monitored after a period of time to determine whether they have been retained on a permanent or long-term basis without further electrical stimulation therapy. In many applications it is anticipated that the treatment program of procedures110-120over a limited therapy period will be sufficient to retain the recovery or gains in functional ability on a permanent, essentially permanent or long-term basis without further electrical stimulation therapy. The procedure106shown inFIG. 5D, however, is applicable in situations that require further treatment. The stimulation procedure106inFIG. 5Daccordingly further includes a second determining procedure132for deciding whether to restart the treatment program. If the results from the monitoring operation130indicate that the patient has retained an intended, acceptable or maximum recovery in and/or development of a functional ability, then the determining procedure132may proceed to terminate the treatment program. On the other hand, if the monitoring operation130establishes that the recovery in and/or development of functional ability has not been retained or can be further improved, then the determining procedure132restarts the treatment program110. It will be appreciated that this process can include a number of different iterations.

Various embodiments of the electrical stimulation methods described above may be useful for treating brain diseases, such as Alzheimer's, Parkinson's, and other brain diseases. In this application, a stimulation site can be identified by monitoring the neural activity using functional MRI or other suitable imaging techniques over a period of time to determine where the brain is recruiting material to perform the neural activity that is being affected by the disease. It may also be possible to identify a stimulation site by having the patient try to perform an act that the particular disease has affected, and monitoring the brain to determine whether any response neural activity is present in the brain. After identifying where the brain is recruiting additional matter, the electrical stimulation can be applied to this portion of the brain. It is expected that electrically stimulating the regions of the brain that have been recruited to perform the neural activity which was affected by the disease will assist the brain in offsetting the damage caused by the disease.

Various embodiments of the electrical stimulation methods described above are also expected to be useful for treating neurological disorders, such as depression, passive-aggressive behavior, weight control, and other disorders. In these applications, the electrical stimulation can be applied to a stimulation site in the cortex or another suitable part of the brain where neural activity related to the particular disorder is present. The embodiments of electrical stimulation methods for carrying out the particular therapy can be adapted to either increase or decrease the particular neural activity in a manner that produces the desired results. For example, an amputee may feel phantom sensations associated with the amputated limb. This phenomenon can be treated by applying an electrical pulse that reduces the phantom sensations. The electrical therapy can be applied so that it will modulate the ability of the neurons in that portion of the brain to execute sensory functions.

b. Pulse Forms and Potentials

The electrical stimulation methods in accordance with the invention can use several different pulse forms to effectuate the desired neuroplasticity. The pulses can be a bi-phasic or monophasic stimulus that is applied to achieve a desired potential in a sufficient percentage of a population of neurons at the stimulation site. In one embodiment, the pulse form has a frequency of approximately 2-1000 Hz, but the frequency may be particularly useful in the range of approximately 40-200 Hz. For example, initial clinical trials are expected to use a frequency of approximately 50-100 Hz. The pulses can also have pulse widths of approximately 10 μs-100 ms, or more specifically the pulse width can be approximately 20-200 μs. For example, a pulse width of 50-100 μs may produce beneficial results.

It is expected that one particularly useful application of the invention involves enhancing or inducing neuroplasticity by raising the resting membrane potential of neurons to bring the neurons closer to the threshold level for firing an action potential. Because the stimulation raises the resting membrane potential of the neurons, it is expected that these neurons are more likely to “fire” an action potential in response to excitatory input at a lower level.

FIG. 5Eis a graph illustrating applying a subthreshold potential to the neurons N1-N3ofFIG. 1A. At times t1and t2, the excitory/inhibitory inputs from other neurons do not “bridge-the-gap” from the resting potential at −X mV to the threshold potential. At time t3, the electrical stimulation is applied to the brain to raise the resting potential of neurons in the stimulated population such that the resting potential is at −Y mV. As such, at time t4when the neurons receive another excitatory input, even a small input exceeds the gap between the raised resting potential −Y mV and the threshold potential to induce action potentials in these neurons. For example, if the resting potential is approximately −70 mV and the threshold potential is approximately −50 mV, then the electrical stimulation can be applied to raise the resting potential of a sufficient number of neurons to approximately −52 to −60 mV.

The actual electrical potential applied to electrodes implanted in the brain to achieve a subthreshold potential stimulation will vary according to the individual patient, the type of therapy, the type of electrodes, and other factors. In general, the pulse form of the electrical stimulation (e.g., the frequency, pulse width, wave form, and voltage potential) is selected to raise the resting potential in a sufficient number neurons at the stimulation site to a level that is less than a threshold potential for a statistical portion of the neurons in the population. The pulse form, for example, can be selected so that the applied voltage of the stimulus achieves a change in the resting potential of approximately 10%-95%, and more specifically of 60%-80%, of the difference between the unstimulated resting potential and the threshold potential.

In one specific example of a subthreshold application for treating a patient's hand, electrical stimulation is not initially applied to the stimulation site. Although physical therapy related to the patient's hand may cause some activation of a particular population of neurons that is known to be involved in “hand function,” only a low level of activation might occur because physical therapy only produces a low level of action potential generation in that population of neurons. However, when the subthreshold electrical stimulation is applied, the resting membrane potentials of the neurons in the stimulated population are elevated. These neurons now are much closer to the threshold for action potential formation such that when the same type of physical therapy is given, this population of cells will have a higher level of activation because these cells are more likely to fire action potentials.

Subthreshold stimulation may produce better results than simply stimulating the neurons with sufficient energy levels to exceed the threshold for action potential formation. One aspect of subthreshold stimulation is to increase the probability that action potentials will occur in response to the ordinary causes of activation—such as physical therapy. This will allow the neurons in this functional network to become entrained together, or “learn” to become associated with these types of activities. If neurons are given so much electricity that they continually fire action potentials without additional excitatory inputs (suprathreshold stimulation), this will create “noise” and disorganization that will not likely cause improvement in function. In fact, neurons that are “overdriven” soon deplete their neurotransmitters and effectively become silent.

The application of a subthreshold stimulation is very different than suprathreshold stimulation. Subthreshold stimulation in accordance with several embodiments of the invention, for example, does not intend to directly make neurons fire action potentials with the electrical stimulation in a significant population of neurons at the stimulation site. Instead, subthreshold stimulation attempts to decrease the “activation energy” required to activate a large portion of the neurons at the stimulation site. As such, subthreshold stimulation in accordance with certain embodiments of the invention is expected to increase the probability that the neurons will fire in response to the usual intrinsic triggers, such as trying to move a limb, physical therapy, or simply thinking about movement of a limb, etc. Moreover, coincident stimulation associated with physical therapy is expected to increase the probability that the action potentials that are occurring with an increased probability due to the subthreshold stimulation will be related to meaningful triggers, and not just “noise.”

The stimulus parameters set forth above, such as a frequency selection of approximately 50-100 Hz and an amplitude sufficient to achieve an increase of 60% to 80% of the difference between the resting potential and the threshold potential are specifically selected so that they will increase the resting membrane potential of the neurons, thereby increasing the likelihood that they will fire action potentials, without directly causing action potentials in most of the neuron population. In addition, and as explained in more detail below with respect toFIGS. 6-40, several embodiments of stimulation apparatus in accordance with the invention are designed to precisely apply a pulse form that produces subthreshold stimulation by selectively stimulating regions of the cerebral cortex of approximately 1-2 cm (the estimated size of a “functional unit” of cortex), directly contacting the pial surface with the electrodes to consistently create the same alterations in resting membrane potential, and/or biasing the electrodes against the pial surface to provide a positive connection between the electrodes and the cortex.

B. Devices for Electrically Stimulating Regions of the Brain

FIGS. 6-40illustrate stimulation apparatus in accordance with several embodiments of the invention for electrically stimulating regions of the brain in accordance with one or more of the methods described above. The devices illustrated inFIGS. 6-40are generally used to stimulate a region of the cortex proximate to the pial surface of the brain (e.g., the dura mater, the pia mater, the fluid between the dura mater and the pia mater, and a depth in the cortex outside of the white matter of the brain). The devices can also be adapted for stimulating other portions of the brain in other embodiments.

1. Implantable Stimulation Apparatus with Integrated Pulse Systems

FIG. 6is an isometric view andFIG. 7is a cross-sectional view of a stimulation apparatus600in accordance with an embodiment of the invention for stimulating a region of the cortex proximate to the pial surface. In one embodiment, the stimulation apparatus600includes a support member610, an integrated pulse-system630(shown schematically) carried by the support member610, and first and second electrodes660(identified individually by reference numbers660aand660b). The first and second electrodes660are electrically coupled to the pulse system630. The support member610can be configured to be implanted into the skull or another intracranial region of a patient. In one embodiment, for example, the support member610includes a housing612and an attachment element614connected to the housing612. The housing612can be a molded casing formed from a biocompatible material that has an interior cavity for carrying the pulse system630. The housing can alternatively be a biocompatible metal or another suitable material. The housing612can have a diameter of approximately 1-4 cm, and in many applications the housing612can be 1.5-2.5 cm in diameter. The housing612can also have other shapes (e.g., rectilinear, oval, elliptical) and other surface dimensions. The stimulation apparatus600can weigh35g or less and/or occupy a volume of 20 cc or less. The attachment element614can be a flexible cover, a rigid plate, a contoured cap, or another suitable element for holding the support member610relative to the skull or other body part of the patient. In one embodiment, the attachment element614is a mesh, such as a biocompatible polymeric mesh, metal mesh, or other suitable woven material. The attachment element614can alternatively be a flexible sheet of Mylar, a polyester, or another suitable material.

FIG. 7, more specifically, is a cross-sectional view of the stimulation apparatus600after it has been implanted into a patient in accordance with an embodiment of the invention. In this particular embodiment, the stimulation apparatus600is implanted into the patient by forming an opening in the scalp702and cutting a hole704through the skull700and through the dura mater706. The hole704should be sized to receive the housing612of the support member610, and in most applications, the hole704should be smaller than the attachment element614. A practitioner inserts the support member610into the hole704and then secures the attachment element614to the skull700. The attachment element614can be secured to the skull using a plurality of fasteners618(e.g., screws, spikes, etc.) or an adhesive. In an alternative embodiment, a plurality of downwardly depending spikes can be formed integrally with the attachment element614to define anchors that can be driven into the skull700.

The embodiment of the stimulation apparatus600shown inFIG. 7is configured to be implanted into a patient so that the electrodes660contact a desired portion of the brain at the stimulation site. The housing612and the electrodes660can project from the attachment element614by a distance “D” such that the electrodes660are positioned at least proximate to the pia mater708surrounding the cortex709. The electrodes660can project from a housing612as shown inFIG. 7, or the electrodes660can be flush with the interior surface of the housing612. In the particular embodiment shown inFIG. 7, the housing612has a thickness “T” and the electrodes660project from the housing612by a distance “P” so that the electrodes660press against the surface of the pia mater708. The thickness of the housing612can be approximately 0.5-4 cm, and is more generally about 1-2 cm. The configuration of the stimulation apparatus600is not limited to the embodiment shown inFIGS. 6 and 7, but rather the housing612, the attachment element614, and the electrodes660can be configured to position the electrodes in several different regions of the brain. For example, in an alternate embodiment, the housing612and the electrodes660can be configured to position the electrodes deep within the cortex709, and/or a deep brain region710. In general, the electrodes can be flush with the housing or extend 0.1 mm to 5 cm from the housing. More specific embodiments of pulse system and electrode configurations for the stimulation apparatus will be described below.

Several embodiments of the stimulation apparatus600are expected to be more effective than existing transcranial electrical stimulation devices and transcranial magnetic stimulation devices. It will be appreciated that much of the power required for transcranial therapies is dissipated in the scalp and skull before it reaches the brain. In contrast to conventional transcranial stimulation devices, the stimulation apparatus600is implanted so that the electrodes are at least proximate to the pial surface of the brain708. Several embodiments of methods in accordance with the invention can use the stimulation apparatus600to apply an electrical therapy directly to the pia mater708, the dura mater706, and/or another portion of the cortex709at significantly lower power levels than existing transcranial therapies. For example, a potential of approximately 1 mV to 10 V can be applied to the electrodes660; in many instances a potential of 100 mV to 5 V can be applied to the electrodes660for selected applications. It will also be appreciated that other potentials can be applied to the electrodes660of the stimulation apparatus600in accordance with other embodiments of the invention.

Selected embodiments of the stimulation apparatus600are also capable of applying stimulation to a precise stimulation site. Again, because the stimulation apparatus600positions the electrodes660at least proximate to the pial surface708, precise levels of stimulation with good pulse shape fidelity will be accurately transmitted to the stimulation site in the brain. It will be appreciated that transcranial therapies may not be able to apply stimulation to a precise stimulation site because the magnetic and electrical properties of the scalp and skull may vary from one patient to another such that an identical stimulation by the transcranial device may produce a different level of stimulation at the neurons in each patient. Moreover, the ability to focus the stimulation to a precise area is hindered by delivering the stimulation transcranially because the scalp, skull and dura all diffuse the energy from a transcranial device. Several embodiments of the stimulation apparatus600overcome this drawback because the electrodes660are positioned under the skull700such that the pulses generated by the stimulation apparatus600are not diffused by the scalp702and skull700.

2. Integrated Pulse Systems for Implantable Stimulation Apparatus

The pulse system630shown inFIGS. 6 and 7generates and/or transmits electrical pulses to the electrodes660to create an electrical field at a stimulation site in a region of the brain. The particular embodiment of the pulse system630shown inFIG. 7is an “integrated” unit in that is carried by the support member610. The pulse system630, for example, can be housed within the housing612so that the electrodes660can be connected directly to the pulse system630without having leads outside of the stimulation apparatus600. The distance between the electrodes660and the pulse system630can be less than 4 cm, and it is generally 0.10 to 2.0 cm. The stimulation apparatus600can accordingly provide electrical pulses to the stimulation site without having to surgically create tunnels running through the patient to connect the electrodes660to a pulse generator implanted remotely from the stimulation apparatus600. It will be appreciated, however, that alternative embodiments of stimulation apparatus in accordance with the invention can include a pulse system implanted separately from the stimulation apparatus600in the cranium or an external pulse system. Several particular embodiments of pulse systems that are suitable for use with the stimulation apparatus600will now be described in more detail.

FIGS. 8 and 9schematically illustrate an integrated pulse system800in accordance with one embodiment of the invention for being implanted in the cranium within the stimulation apparatus600. Referring toFIG. 8, the pulse system800can include a power supply810, an integrated controller820, a pulse generator830, and a pulse transmitter840. The power supply810can be a primary battery, such as a rechargeable battery or another suitable device for storing electrical energy. In alternative embodiments, the power supply810can be an RF transducer or a magnetic transducer that receives broadcast energy emitted from an external power source and converts the broadcast energy into power for the electrical components of the pulse system800. The integrated controller820can be a wireless device that responds to command signals sent by an external controller850. The integrated controller820, for example, can communicate with the external controller850by RF or magnetic links860. The integrated controller820provides control signals to the pulse generator830in response to the command signals sent by the external controller850. The pulse generator830can have a plurality of channels that send appropriate electrical pulses to the pulse transmitter840, which is coupled to the electrodes660. Suitable components for the power supply810, the integrated controller820, the pulse generator830, and the pulse transmitter840are known to persons skilled in the art of implantable medical devices.

Referring toFIG. 9, the pulse system800can be carried by the support member610of the stimulation apparatus600in the manner described above with reference toFIGS. 6 and 7. The external controller850can be located externally to the patient500so that the external controller850can be used to control the pulse system800. In one embodiment, several patients that require a common treatment can be simultaneously treated using a single external controller850by positioning the patients within the operating proximity of the controller850. In an alternative embodiment, the external controller850can contain a plurality of operating codes and the integrated controller820for a particular patient can have an individual operating code. A single controller850can thus be used to treat a plurality of different patients by entering the appropriate operating code into the controller850corresponding to the particular operating codes of the integrated controllers820for the patients.

FIG. 10is a schematic view illustrating a pulse system1000and an external controller1010for use with the stimulation apparatus600in accordance with another embodiment of the invention. In this embodiment, the external controller1010includes a power supply1020, a controller1022coupled to the power supply1020, and a user interface1024coupled to the controller1022. The external controller1010can also include a pulse generator1030coupled to the power supply1020, a pulse transmitter1040coupled to the pulse generator1030, and an antenna1042coupled to the pulse transmitter1040. The external controller1010generates the power and the pulse signal, and the antenna1042transmits a pulse signal1044to the pulse system1000in the stimulation apparatus600. The pulse system1000receives the pulse signal1044and delivers an electrical pulse to the electrodes. The pulse system1000, therefore, does not necessarily include an integrated power supply, controller and pulse generator within the housing610because these components are in the external controller1010.

FIG. 11is a schematic view illustrating an embodiment of the pulse system1000in greater detail. In this embodiment, the pulse system1000is carried by the support member610of the stimulation apparatus600. The pulse system1000can include an antenna1060and a pulse delivery system1070coupled to the antenna1060. The antenna1060receives the pulse signal1044from the external controller1010and sends the pulse signal1044to the pulse delivery system1070, which transforms the pulse signal1044into electrical pulses. Accordingly, the electrodes660can be coupled to the pulse delivery system1070. The pulse delivery system1070can include a filter to remove noise from the pulse signal1044and a pulse former that creates an electrical pulse from the pulse signal1044. The pulse former can be driven by the energy in the pulse signal1044, or in an alternative embodiment, the pulse system1000can also include an integrated power supply to drive the pulse former.

FIG. 12is a schematic view illustrating an embodiment of pulse system1200for use in an embodiment of the stimulation apparatus600, and an external controller1210for controlling the pulse system1200remotely from the patient using RF energy. In this embodiment, the external controller1210includes a power supply1220, a controller1222coupled to the power supply1220, and a pulse generator1230coupled to the controller1222. The external controller1210can also include a modulator1232coupled to the pulse generator1230and an RF generator1234coupled to the modulator1232. In operation, the external controller1210broadcasts pulses of RF energy via an antenna1242.

The pulse system1200can be housed within the stimulation apparatus600(not shown). In one embodiment, the pulse system1200includes an antenna1260and a pulse delivery system1270. The antenna1260incorporates a diode (not shown) that rectifies the broadcast RF energy from the antenna1242. The pulse delivery system1270can include a filter1272and a pulse former1274that forms electrical pulses which correspond to the RF energy broadcast from the antenna1242. The pulse system1200is accordingly powered by the RF energy in the pulse signal from the external controller1210such that the pulse system1200does not need a separate power supply carried by the stimulation apparatus600.

FIG. 13is a cross-sectional view of a pulse system1300for use in another embodiment of the implantable stimulation apparatus600, together with an external controller1310for remotely controlling the pulse system1300externally from the patient using magnetic energy. In this embodiment, the external controller1310includes a power supply1320, a controller1322coupled to the power supply1320, and a user interface1324coupled to the controller1322. The external controller1310can also include a pulse generator1330coupled to the controller1332, a pulse transmitter1340coupled to the pulse generator1330, and a magnetic coupler1350coupled to the pulse transmitter1340. The magnetic coupler1350can include a ferrite core1352and a coil1354wrapped around a portion of the ferrite core1352. The coil1354can also be electrically connected to the pulse transmitter1340so that electrical pulses applied to the coil1354generate changes in a corresponding magnetic field. The magnetic coupler1350can also include a flexible cap1356to position the magnetic coupler1350over the implanted stimulation apparatus600.

The pulse system1300can include a ferrite core1360and a coil1362wrapped around a portion of the ferrite core1360. The pulse system1310can also include a pulse delivery system1370including a rectifier and a pulse former. In operation, the ferrite core1360and the coil1362convert the changes in the magnetic field generated by the magnetic coupler1350into electrical pulses that are sent to the pulse delivery system1370. The electrodes660are coupled to the pulse delivery system1370so that electrical pulses corresponding to the electrical pulses generated by the pulse generator1330in the external controller1310are delivered to the stimulation site on the patient.

FIGS. 14-24illustrate electrodes in accordance with various embodiments of the invention that can be used with the stimulation apparatus disclosed herein.FIGS. 14-22illustrate embodiments of electrodes configured to apply an electrical current to a stimulation site at least proximate to the pial surface of the cortex, andFIGS. 23 and 24illustrate embodiments of electrodes configured to apply an electrical current within the cortex or below the cortex. It will be appreciated that other configurations of electrodes can also be used with other implantable stimulation apparatus.

FIG. 14is a bottom plan view andFIG. 15is a cross-sectional view of a stimulation apparatus1400in accordance with an embodiment of the invention. In this embodiment, the stimulation apparatus1400includes a first electrode1410and a second electrode1420concentrically surrounding the first electrode1410. The first electrode1410can be coupled to the positive terminal of a pulse generator1430, and the second electrode1420can be coupled to the negative terminal of the pulse generator1430. Referring toFIG. 15, the first and second electrodes1410and1420generate a toroidal electric field1440.

FIG. 16is a bottom plan view andFIG. 17is a cross-sectional view of a stimulation apparatus1600in accordance with another embodiment of the invention. In this embodiment, the stimulation apparatus1600includes a first electrode1610, a second electrode1620surrounding the first electrode1610, and a third electrode1630surrounding the second electrode1620. The first electrode1610can be coupled to the negative terminals of a first pulse generator1640and a second pulse generator1642; the second electrode1620can be coupled to the positive terminal of the first pulse generator1640; and the third electrode1630can be coupled to the positive terminal of the second pulse generator1642. In operation, the first electrode1610and the third electrode1630generate a first toroidal electric field1650, and the first electrode the1610and the second electrode1620generate a second toroidal electric field1660. The second toroidal electric field1660can be manipulated to vary the depth that the first toroidal electric field1650projects away from the base of the stimulation apparatus1600.

FIG. 18is a bottom plan view andFIG. 19is a cross-sectional view of a stimulation apparatus1800in accordance with yet another embodiment of the invention. In this embodiment, the stimulation apparatus1800includes a first electrode1810and a second electrode1820spaced apart from the first electrode1810. The first and second electrodes1810and1820are linear electrodes which are coupled to opposite terminals of a pulse generator1830. Referring toFIG. 19, the first and second electrodes1810and1820can generate an approximately linear electric field.

FIG. 20is a bottom plan view of a stimulation apparatus2000in accordance with still another embodiment of the invention. In this embodiment, the stimulation apparatus2000includes a first electrode2010, a second electrode2020, a third electrode2030, and a fourth electrode2040. The first and second electrodes2010and2020are coupled to a first pulse generator2050, and the third and fourth electrodes2030and2040are coupled to a second pulse generator2060. More specifically, the first electrode2010is coupled to the positive terminal and the second electrode2020is coupled to the negative terminal of the first pulse generator2050, and the third electrode2030is coupled to the positive terminal and the fourth electrode2040is coupled to the negative terminal of the second pulse generator2060. The first and second electrodes2010and2020are expected to generate a first electric field2070, and the third and fourth electrodes2030and2040are expected to generate a second electric field2072. It will be appreciated that the ions will be relatively free to move through the brain such that a number of ions will cross between the first and second electric fields2070and2072as shown by arrows2074. This embodiment provides control of electric field gradients at the stimulation sites.

FIG. 21is a bottom plan view of another embodiment of the stimulation apparatus2000. In this embodiment, the first electrode2010is coupled to the positive terminal and the second electrode2020is coupled to the negative terminal of the first pulse generator2050. In contrast to the embodiment shown inFIG. 20, the third electrode2030is coupled to the negative terminal and the fourth electrode2040is coupled to the positive terminal of the second pulse generator2070. It is expected that this electrode arrangement will result in a plurality of electric fields between the electrodes. This allows control of the direction or orientation of the electric field.

FIG. 22is a bottom plan view that schematically illustrates a stimulation apparatus2200in accordance with still another embodiment of the invention. In this embodiment, the stimulation apparatus2200includes a first electrode2210, a second electrode2220, a third electrode2230, and a fourth electrode2240. The electrodes are coupled to a pulse generator2242by a switch circuit2250. The switch circuit2250can include a first switch2252coupled to the first electrode2210, a second switch2254coupled to the second electrode2220, a third switch2256coupled to the third electrode2230, and a fourth switch2258coupled to the fourth electrode2240. In operation, the switches2252-2258can be opened and closed to establish various electric fields between the electrodes2210-2240. For example, the first switch2252and the fourth switch2258can be closed in coordination with a pulse from the pulse generator2242to generate a first electric field2260, and/or the second switch2254and the third switch2256can be closed in coordination with another pulse from the pulse generator2242to generate a second electric field2270. The first and second electric fields2260and2270can be generated at the same pulse to produce concurrent fields or alternating pulses to produce alternating or rotating fields.

FIG. 23is a bottom plan view andFIG. 24is a side elevational view of a stimulation apparatus2300in accordance with another embodiment of the invention. In this embodiment, the stimulation apparatus2300has a first electrode2310, a second electrode2320, a third electrode2330, and a fourth electrode2340. The electrodes2310-2340can be configured in any of the arrangements set forth above with reference toFIGS. 14-22. The electrodes2310-2340also include electrically conductive pins2350and/or2360. The pins2350and2360can be configured to extend below the pial surface of the cortex. For example, because the length of the pin2350is less than the thickness of the cortex709, the tip of the pin2350will accordingly conduct the electrical pulses to a stimulation site within the cortex709below the pial surface. The length of the pin2360is greater than the thickness of the cortex709to conduct the electrical pulses to a portion of the brain below the cortex709, such as a deep brain region710. The lengths of the pins are selected to conduct the electrical pulses to stimulation sites below the pia mater708. As such, the length of the pins2350and2360can be the same for each electrode or different for individual electrodes. Additionally, only a selected portion of the electrodes and the pins can have an exposed conductive area. For example, the electrodes2310-2340and a portion of the pins2350and2360can be covered with a dielectric material so that only exposed conductive material is at the tips of the pins. It will also be appreciated that the configurations of electrodes set forth inFIGS. 14-22can be adapted to apply an electrical current to stimulation sites below the pia mater by providing pin-like electrodes in a matter similar to the electrodes shown inFIGS. 23 and 24.

Several embodiments of the stimulation apparatus described above with reference toFIGS. 6-24are expected to be more effective than existing transcranial or subcranial stimulation devices. In addition to positioning the electrodes under the skull, many embodiments of the stimulation apparatus described above also accurately focus the electrical energy in desired patterns relative to the pia mater708, the dura mater706, and/or the cortex709. It will be appreciated that transcranial devices may not accurately focus the energy because the electrodes or other types of energy emitters are positioned relatively far from the stimulation sites and the skull diffuses some of the energy. Also, existing subcranial devices generally merely place the electrodes proximate to a specific nerve, but they do not provide electrode configurations that generate an electrical field in a pattern designed for the stimulation site. Several of the embodiments of the stimulation apparatus described above with reference toFIGS. 6-24overcome this drawback because the electrodes can be placed against the neurons at the desired stimulation site. Additionally, the electrode configurations of the stimulation apparatus can be configured to provide a desired electric field that is not diffused by the skull700. Therefore, several embodiments of the stimulation apparatus in accordance with the invention are expected to be more effective because they can accurately focus the energy at the stimulation site.

4. Implantable Stimulation Apparatus with Biasing Elements

FIGS. 25-30illustrate several embodiments of stimulation apparatus having a biasing element in accordance with a different aspect of the invention. The stimulation apparatus shown inFIGS. 25-30can be similar to those described above with reference toFIGS. 6-24. Therefore, the embodiments of the stimulation apparatus shown inFIGS. 25-30can have the same pulse systems, support members and electrode configurations described above with reference toFIGS. 6-24.

FIG. 25is an isometric view andFIG. 26is a cross-sectional view of a stimulation apparatus2500in accordance with an embodiment of the invention. In one embodiment, the stimulation apparatus2500includes a support member2510, a pulse-system2530carried by the support member2510, and first and second electrodes2560coupled to the pulse system2530. The support member2510can be identical or similar to the support member610described above with reference toFIGS. 6 and 7. The support member2510can accordingly include a housing2512configured to be implanted in the skull700and an attachment element2514configured to be connected to the skull700by fasteners2518(FIG. 2), an adhesive, and/or an anchor. The pulse system2530can be identical or similar to any of the pulse systems described above with reference toFIGS. 6-13, and the first and second electrodes2560can have any of the electrode configurations explained above with reference toFIGS. 14-24. Unlike the stimulation apparatus described above, however, the stimulation apparatus2500includes a biasing element2550coupled to the electrodes2560to mechanically bias the electrodes2560away from the support member2510. In an alternative embodiment, the biasing element2550can be positioned between the housing2512and the attachment element2514, and the electrodes2560can be attached directly to the housing2512. As explained in more detail below, the biasing element2550can be a compressible member, a fluid filled bladder, a spring, or any other suitable element that resiliently and/or elastically drives the electrodes2560away from the support member2510.

FIG. 26illustrates an embodiment of the stimulation apparatus2500after it has been implanted into the skull700of a patient. When the fasteners2518are attached to the skull700, the biasing element2550should be compressed slightly so that the electrodes2560contact the stimulation site. In the embodiment shown inFIG. 26, the compressed biasing element2550gently presses the electrodes2560against the surface of the pia mater708. It is expected that the biasing element2550will provide a uniform, consistent contact between the electrodes2560and the pial surface of the cortex709. The stimulation apparatus2500is expected to be particularly useful when the implantable device is attached to the skull and the stimulation site is on the pia mater708or the dura mater706. It can be difficult to position the contacts against the pia mater708because the distance between the skull700, the dura mater706, and the pia mater708varies within the cranium as the brain moves relative to the skull, and also as the depth varies from one patient to another. The stimulation apparatus2500with the biasing element2550compensates for the different distances between the skull700and the pia mater708so that a single type of device can inherently fit several different patients. Moreover, the stimulation apparatus2500with the biasing element2550adapts to changes as the brain moves within the skull. In contrast to the stimulation apparatus2500with the biasing element2550, an implantable device that does not have a biasing element2550may not fit a particular patient or may not consistently provide electrical contact to the pia mater.

FIGS. 27 and 28are cross-sectional views of stimulation apparatus in which the biasing elements are compressible members.FIG. 27, more specifically, illustrates a stimulation apparatus2700having a biasing element2750in accordance with an embodiment of the invention. The stimulation apparatus2700can have an integrated pulse system2530and electrodes2560coupled to the pulse system2530in a manner similar to the stimulation apparatus2500. The biasing element2750in this embodiment is a compressible foam, such as a biocompatible closed cell foam or open cell foam. As best shown inFIG. 27, the biasing element2750compresses when the stimulation apparatus2700is attached to the skull.FIG. 28illustrates a stimulation apparatus2800having a biasing element2850in accordance with another embodiment of the invention. The biasing element2850can be a compressible solid, such as silicon rubber or other suitable compressible materials. The electrodes2560are attached to the biasing element2850.

FIG. 29is a cross-sectional view of a stimulation apparatus2900having a biasing element2950in accordance with another embodiment of the invention. The stimulation apparatus2900can have a support member2910including an internal passageway2912and a diaphragm2914. The biasing element2950can include a flexible bladder2952attached to the support member2910, and the electrodes2560can be attached to the flexible bladder2952. In operation, the flexible bladder2952is filled with a fluid2954until the electrodes2560press against the stimulation site. In one embodiment, the flexible bladder2952is filled by inserting a needle of a syringe2956through the diaphragm2914and injecting the fluid2954into the internal passageway2912and the flexible bladder.

FIG. 30is a cross-sectional view of a stimulation apparatus3000having a biasing element3050in accordance with another embodiment of the invention. In this embodiment, the biasing element3050is a spring and the electrodes2560are attached to the spring. The biasing element3050can be a wave spring, a leaf spring, or any other suitable spring that can mechanically bias the electrodes2560against the stimulation site.

Although several embodiments of the stimulation apparatus shown inFIGS. 25-30can have a biasing element and any of the pulse systems set forth above with respect toFIGS. 6-13, it is not necessary to have a pulse system contained within the support member. Therefore, certain embodiments of implantable stimulation apparatus in accordance with the invention can have a pulse system and/or a biasing member in any combination of the embodiments set forth above with respect toFIGS. 6-30.

5. Implantable Stimulation Apparatus with External Pulse Systems

FIGS. 31-35are schematic cross-sectional views of various embodiments of implantable stimulation apparatus having external pulse systems.FIG. 31, more specifically, illustrates an embodiment of a stimulation apparatus3100having a biasing element3150to which a plurality of electrodes3160are attached in a manner similar to the stimulation apparatus described above with reference toFIGS. 25-30. It will be appreciated that the stimulation apparatus3100may not include the biasing element3150. The stimulation apparatus3100can also include an external receptacle3120having an electrical socket3122and an implanted lead line3124coupling the electrodes3160to contacts (not shown) in the socket3122. The lead line3124can be implanted in a subcutaneous tunnel or other passageway in a manner known to a person skilled and art.

The stimulation apparatus3100, however, does not have an internal pulse system carried by the portion of the device that is implanted in the skull700of the patient500. The stimulation apparatus3100receives electrical pulses from an external pulse system3130. The external pulse system3130can have an electrical connector3132with a plurality of contacts3134configured to engage the contacts within the receptacle3120. The external pulse system3130can also have a power supply, controller, pulse generator, and pulse transmitter to generate the electrical pulses. In operation, the external pulse system3130sends electrical pulses to the stimulation apparatus3100via the connector3132, the receptacle3120, and the lead line3124.

FIGS. 32 and 33illustrate an embodiment of a stimulation apparatus3200for use with an external pulse system in accordance with another embodiment of the invention. Referring toFIG. 33, the stimulation apparatus3200can include a support structure3210having a socket3212, a plurality of contacts3214arranged in the socket3212, and a diaphragm3216covering the socket3212. The stimulation apparatus3200can also include a biasing element3250and a plurality of electrodes3260attached to the biasing element3250. Each electrode3260is directly coupled to one of the contacts3214within the support structure3210. It will be appreciated that an alternative embodiment of the stimulation apparatus3200does not include the biasing element3250.

Referring toFIGS. 32 and 33together, the stimulation apparatus3200receives the electrical pulses from an external pulse system3230that has a power supply, controller, pulse generator, and pulse transmitter. The external pulse system3230can also include a plug3232having a needle3233(FIG. 33) and a plurality of contacts3234(FIG. 33) arranged on the needle3233to contact the internal contacts3214in the socket3212. In operation, the needle3233is inserted into the socket3212to engage the contacts3234with the contacts3214, and then the pulse system3230is activated to transmit electrical pulses to the electrodes3260.

FIGS. 34 and 35illustrate additional embodiments of stimulation apparatus for use with external pulse systems.FIG. 34illustrates an embodiment of a stimulation apparatus3400having electrodes3410coupled to a lead line3420that extends under the scalp702of the patient500. The lead line3420is coupled to an external pulse system3450.FIG. 35illustrates an embodiment of a stimulation apparatus3500having a support member3510, electrodes3512coupled to the support member3510, and an external receptacle3520mounted on the scalp702. The external receptacle3520can also be connected to the support member3510. The external receptacle3520can have a socket3522with contacts (not shown) electrically coupled to the electrodes3512. The stimulation apparatus3500can be used with the external pulse system3130described above with reference toFIG. 31by inserting the plug3132into the socket3522until the contacts3134on the plug3132engage the contacts within the socket3522.

6. Alternate Embodiments of Implantable Stimulation Apparatus

FIG. 36is a schematic cross-sectional view of an implantable stimulation apparatus3600in accordance with another embodiment of the invention. In one embodiment, the stimulation apparatus3600has a support structure3610and a plurality of electrodes3620coupled to the support structure3610. The support structure3610can be configured to be implanted under the skull700between an interior surface701of the skull700and the pial surface of the brain. The support structure3610can be a flexible or compressible body such that the electrodes3620contact the pia mater708when the stimulation apparatus3600is implanted under the skull700. In other embodiments, the support structure3610can position the electrodes3620so that they are proximate to, but not touching, the pia mater708.

In one embodiment, the stimulation apparatus3600can receive electrical pulses from an external controller3630. For example, the external controller3630can be electrically coupled to the stimulation apparatus3600by a lead line3632that passes through a hole711in the skull700. In an alternative embodiment, the stimulation apparatus3600can include an integrated pulse system similar to the pulse systems described above with reference toFIGS. 6-13. Such an embodiment of the stimulation apparatus3600can accordingly use a wireless external control unit. It will be appreciated that the electrodes3620of the stimulation apparatus3600can have several of the electrode configurations described above with reference toFIGS. 14-24.

FIGS. 37 and 38illustrate one embodiment of the implantable stimulation apparatus3600. Referring toFIG. 37, the support structure3610can be a flexible substrate and the electrodes3620can be conductive elements that are printed onto the flexible substrate. The stimulation apparatus3600, for example, can be manufactured in a manner similar to flexible printed circuit assemblies that are used in electrical components. The stimulation apparatus3600can be implanted under the skull700using an insertion tool3700. In one embodiment, the insertion tool3700has a handle3702and a shaft3704projecting from the handle3702. The shaft3704can have a slot3706configured to receive a flat portion of the support member3610. Referring toFIG. 38, the support member3610is wrapped around the shaft3704, and then the stimulation apparatus3600is passed to a tube3720positioned in the hole711through the scalp700and the dura mater706. After the stimulation apparatus3600has been passed through the tube3720, it is unfurled to place the electrodes3620at least proximate to the pia mater708. The electrodes3620can be coupled to an external controller by the lead lines3632.

FIG. 39illustrates another embodiment of an implantable stimulation apparatus3900that is also configured to be positioned between the skull700and the pia mater708. In one embodiment, the stimulation apparatus3900can include a support member3910and a plurality of electrodes3920coupled to the support member3910. The electrodes3920can be coupled to individual lead lines3922to connect the electrodes3920to an external pulse system. In an alternative embodiment, an integrated pulse system3930can be carried by the support member3910so that the electrodes3920can be coupled directly to the integrated pulse system3930without external lead lines3922. The support member3910can be a resiliently compressible member, an inflatable balloon-like device, or a substantially solid incompressible body. In the particular embodiment shown inFIG. 39, the support member3910is an inflatable balloon-like device that carries the electrodes3920. In operation, the stimulation apparatus3900is implanted by passing the distal end of the support member3910through the hole711in the skull700until the electrodes3920are positioned at a desired stimulation site.

FIG. 40is a schematic illustration of a stimulation apparatus4000together with an internal pulse system4030in accordance with another embodiment of the invention. The stimulation apparatus4000can include a support member4010, a biasing element4015carried by the support member4010, and a plurality of electrodes4020carried by the biasing element4015. The internal pulse system4030can be similar to any of the integrated pulse systems described above with reference toFIGS. 6-13, but the internal pulse system4030is not an integrated pulse system because it is not carried by the housing4010. The internal pulse system4030can be coupled to the electrodes4020by a cable4034. In a typical application, the cable4034is implanted subcutaneously in a tunnel from a subclavicular region, along the back of the neck, and around the skull. The stimulation apparatus4000can also include any of the electrode configurations described above with reference toFIGS. 14-24.

FIG. 41Ais a schematic view illustrating a stimulation apparatus4100suitable for performing the stimulation procedures106described above with reference toFIGS. 5C and 5D. The stimulation apparatus4100includes a housing4102that is configured to be implanted in or otherwise attached to the patient. The housing4102, for example, can be any of the structures described above for being implanted in the patient's cranium or another area located above the patient's neck. In other embodiments, the housing4102can be configured to be implanted below the patient's neck, such as a subclavicular or abdominal location.

The stimulation apparatus4100illustrated inFIG. 41Aincludes a controller4110, a power supply4120, and a signal or pulse generator4130. The power supply4120and the signal generator4130are coupled to the controller4110, and the signal generator4130is also coupled to the power supply4120. The stimulation apparatus4100further includes a limiting module4112that can be a component of the controller4110or a separate standalone component. The limiting module4112prevents stimulation signals generated by the signal generator4130from being provided to an electrode array after expiration of a therapy period. As explained above, the therapy period is the period of one or more therapy sessions that constitute a complete therapy treatment for effectuating recovery of a functional ability corresponding to an impaired neural function.

The limiting module4112provides a limited duration treatment that terminates operation of the signal general4130or otherwise disconnects the signal generator4130from either the power supply4120or the electrode array. The limiting module4112can be a hardware or software switch. In one embodiment, the limiting module causes the controller4110to deactivate the signal generator4130so that the signal generator4130does not produce signals after expiration of the therapy period. The limiting module4112can also be a hardware or software switch in the controller4110that disconnects the power supply4120from the signal generator4130. In another embodiment, the limiting module4112can be a hardware or software switch that disconnects the signal generator4130from the electrode array.

FIG. 41Bis a schematic view illustrating particular examples of several embodiments of the stimulation apparatus4100. In this embodiment, the limiting module comprises one or more switches4142,4144and/or4146that are operated by the controller4110. For example, the limiting module can include a switch4142between the power supply4120and the pulse generator4130. The controller4110opens the switch4142to disconnect the power supply4120from the pulse generator4130. In another embodiment, the limiting module can include a switch4144and/or a switch4146that disconnects the pulse generator4130from the electrode array. In any of these embodiments, the controller4110can operate these switches, or the switches can be operated by another mechanism that is either a component of the stimulation apparatus4100or an external devices. For example, the switches4142,4144, and/or4146can be operated telemetrically by a magnetic source or an RF source external to the patient for manual operation of the limiting module.