The present invention is directed generally toward methods and apparatuses for treating neurological disorders by electrically stimulating cells implanted in the nervous system.
A wide variety of mental and physical processes are controlled or influenced by neural activity in particular regions of the brain. For example, various physical or cognitive functions are directed or affected by neural activity within the various regions of the cerebral cortex. For most individuals, particular areas of the brain appear to have distinct functions. In most people, for example, the areas of the occipital lobes relate to vision; the regions of the left inferior frontal lobes relate to language; portions of the cerebral cortex appear to be involved with conscious awareness, memory, and intellect; and particular regions of the cerebral cortex as well as the basal ganglia, the thalamus, and the motor cortex cooperatively interact to facilitate motor function control.
Many problems or abnormalities with body functions can be caused by damage, disease and/or disorders of the nervous system, which includes the brain, the spinal cord and peripheral nerves. A stroke, for example, is one very common condition that damages the brain. Strokes are generally caused by emboli (e.g., vascular obstructions), hemorrhages (e.g., vascular ruptures) or thrombi (e.g., vascular clots) in a specific region of the cortex, which in turn generally causes a loss or impairment of a neural function (e.g., neural functions related to face muscles, limbs, speech, etc.). Stroke patients are typically treated using physical therapy to rehabilitate the loss of function of a limb or other affected body part. For most patients, little can be done to improve the function of the affected limb beyond the recovery that occurs naturally without intervention.
One existing physical therapy technique for treating stroke patients constrains or restrains the use of a working body part of the patient to force the patient to use the affected body part. For example, the loss of use of a limb is treated by restraining the other limb. Although this type of physical therapy has shown some experimental efficacy, it is expensive, time-consuming and little-used. Stroke patients can also be treated using physical therapy plus adjunctive therapies. For example, some types of drugs, such as amphetamines, that increase the activation of neurons in general, appear to enhance neural networks; these drugs however, have limited efficacy because they are very non-selective in their mechanisms of action and cannot be delivered in high concentrations directly to the site where they are needed. Therefore, there is a need to develop effective treatments for rehabilitating stroke patients and patients having other types of neurological disorders. Such disorders include Alzheimer's disease, Parkinson's disease, Hodgkins disease, Huntington's disease, essential tremor motion, and language disorders, such as aphasias.
Two additional approaches for addressing the loss of neural functionality include electrical stimulation of nerve cells and replacement of nerve cells. These two approaches have also been combined. For example, U.S. Pat. No. 6,095,148 to Shastri et al. (“Shastri”) discloses a method for electrically stimulating nerve cells prior to or after implantation in the body, using electrically conductive polymers as a substrate. This technique may be unnecessarily invasive. For example, it may be difficult to remove the substrate from the patient after the cells have been regenerated, differentiated, or altered with the electrically conductive polymer. Furthermore, the replacement cells may not grow in the desired directions to complete functional connections with other cells.
The following disclosure describes several methods for treating neurological disorders and/or dysfunctions by implanting and/or electrically stimulating cells that have and/or develop neural characteristics. For example, methods in accordance with some embodiments of the invention include preparing at least partially undifferentiated cells for implantation, implanting the cells within a patient's skull cavity, and differentiating the cells to have increased neural characteristics by applying an electrical potential to at least one electrode in electrical communication with the cells. The cells can be implanted at a variety of locations, depending on the patient's disorder. For example, when the patient has suffered a stroke, the cells can be implanted at an infarct or peri-infarct region of the brain. If the patient suffers from movement disorders, the cells can be implanted at the motor cortex, basal ganglia, thalamus, or other centers of the brain responsible for controlling the patient's movements. If the patient suffers from language disorders, the cells can be implanted at or near the language centers of the brain.
In further embodiments, the process of increasing the neural characteristics and/or functionality of the cells can be enhanced by exposing the cells to growth factors, for example, IGF and/or GDNF. In other embodiments, aspects of the manner in which the electrical stimulation is applied to the cells can be controlled to enhance the neuronal development of the cells. Such characteristics include the voltage of the electrical stimulation, the current of the electrical stimulation, the pulse width, the pulse pattern, and/or the frequency or frequencies at which the electrical stimulation is varied.
In still further embodiments, the electrical stimulation can be used to alter characteristics of fully differentiated neural cells. For example, stimulation can be applied to fully differentiated, implanted cells to enhance connections between those cells and native cells of the patient. Such techniques can also be used to direct the growth of fully differentiated cells, for example, by directing an electrical current through the tissues surrounding the fully differentiated neural cells.
The specific details of certain embodiments of the invention are set forth in the following description and in
The cells are then implanted at an implantation site within the patient's skull cavity while the cells are in the first state (process portion 103). In a particular aspect of this embodiment, the cells are implanted without support from a substrate. At least one electrode is positioned in electrical communication with the implantation site in process portion 104. In process portion 105, the neural dysfunction of and/or damage to the patient's nervous system at least proximate to the implantation site is at least partially corrected or reversed by differentiating the cells at least until the cells achieve a second state. In the second state, the cells have an increased level of differentiation and increased neural characteristics when compared to the cells in the first state. The correction or reversal is obtained at least in part by applying an electrical potential to the at least one electrode while the electrode is in electrical communication with the implantation site.
As used herein, the term “at least partially undifferentiated” when identifying a cell characteristic, includes a cell capable of differentiating or further differentiating from an initial state into a cell (such as a neuron) that exhibits increased signaling characteristics (e.g., increased electrical and/or chemical signaling characteristics) when compared to the cell in its initial state. The signaling characteristics can include action potential characteristics. An action potential occurs when a membrane potential of the cell (e.g., the resting membrane potential) surpasses a threshold level. When this threshold level is reached, and “all-or-nothing” action potential is generated. For example, once the threshold level is reached in a neuron, the neuron can “fire” an action potential, which propagates down the length of the axon of the neuron to cause the release of neurotransmitters from that neuron that will further influence adjacent neurons.
At least partially undifferentiated cells can include stem cells, progenitor cells, precursor cells, and cells having stem cell-like characteristics (e.g., blood cells that are modified to have such characteristics). Stem cells are characterized as being completely undifferentiated; they can divide without limit and when they divide each daughter cell can remain a stem cell or assume the physical and/or functional characteristics of a cell that it is replacing. For example, stem cells are capable of differentiating into neurons or glial cells. In one embodiment, a progenitor cell can be partially undifferentiated and can therefore have a more restricted potential cellular purpose than a stem cell. For example, some progenitor cells may only develop into neurons or glia. In one embodiment, a precursor cell can be even more differentiated than a progenitor cell and can have even more restricted cellular purposes. For example, a neuroblast can only become a neuron. In other embodiments, the at least partially undifferentiated cells can include other cell types. Accordingly, stem cells, progenitor cells, and precursor cells are representative examples, rather than an exhaustive list of at least partially undifferentiated cells.
Referring now to
The growth, differentiation and/or development of the implanted cells 113 can be encouraged by other agents in addition to the electrical current described above. For example, the implanted cells 113 can be exposed to growth factors including IGF and/or GDNF, after implantation and/or before implantation. The growth factors can be introduced to the implanted cells 113 by existing techniques, for example, by virus transport, as disclosed by Lauerman in “Brain Work This Week,” v. 1, No. 30, incorporated herein in its entirety by reference.
One feature of an embodiment of the foregoing arrangement is that the implanted cells 113 can be introduced directly into the surrounding native tissue and stimulated either directly or via the surrounding tissue. Accordingly, this arrangement does not require an implanted substrate that supports the implanted cells and transmits electrical signals to the implanted cells. An advantage of this approach when compared with some conventional arrangements (such as that disclosed by Shastri in U.S. Pat. No. 6,095,148) is that it can reduce the complexity of the stimulation system 120 and the amount of non-native material that must be implanted in the patient P. For example, this approach does not require the implanted cells to be introduced into the brain on a conductive polymer substrate, which can be difficult if not impossible to remove from the patient's brain after the implanted cells 113 are fully developed and/or differentiated. Instead, electrical stimulation is provided by a device that can be removed from the brain with relative ease when it is no longer needed.
One procedure for identifying an implantation site includes generating the intended neural activity remotely, 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 the signal to be sent to the brain. For example, in the case of a patient who has lost the use of a limb, the affected limb is moved and/or stimulated while the brain is scanned, using a known imaging technique that can detect neural activity. Such imaging techniques include functional magnetic resonance imaging (fMRI) techniques, magnetic resonance imaging (MRI) techniques, computed tomography (CT) techniques, single photon emission computed tomography (SPECT) techniques, positron emission tomography (PET) techniques and/or other techniques.
In one specific embodiment, the affected limb can be moved by the practitioner or the patient, stimulated by a sensory test (e.g., a pricking test), or subjected 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 any of the foregoing imaging techniques. By peripherally generating the intended neural activity, this embodiment may accurately identify where the brain has recruited matter to perform the intended neural activity associated with the neural function. This location can be selected as a site for implanted cells.
Another method for identifying the implantation site includes identifying a location of the brain where the neural activity has changed in response to a change in the neural function of the patient. This embodiment 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 the 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, as explained above.
In still another embodiment, the implantation and stimulation site can be identified at a location of the brain where the intended neural activity is developing. This technique can be generally similar to other embodiments described above but can be used to identify stimulation site at (a) the normal region of the brain where the intended neural activity is expected to occur, in accordance with 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 includes 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 implantation/stimulation sites can be defined by the areas of the brain where the neural activity has the highest intensity, the greatest increase, and/or other parameters that indicate areas of the brain that are being used to perform the particular task.
In other embodiments, similar techniques are used to identify areas of the brain for implantation and stimulation to correct other neural dysfunctions. For example, imaging techniques including MRI techniques can be used to locate infarct regions caused by strokes or other conditions. Cells can be implanted directly at the infarct regions, and/or at surrounding peri-infarct regions. In still further embodiments, the areas of the brain selected for implantation and stimulation are identified with reference to the patient's anatomical features.
In certain embodiments, a set of implantation and/or stimulation sites may be identified through an acquisition, measurement, generation, and/or analysis of electrophysiologically-based signals, such as coherence and/or partial coherence signals. Coherence may provide a measure of rhythmic or synchronous neural activity that may result from oscillatory signaling behavior associated with various neural pathways or loops. In general, coherence may be defined as a frequency-domain measure of synchronous activity and/or linear association between a first and a second signal. The first and second signals may be identical or different signal types. For example, depending upon embodiment details, a coherence measurement may be based upon two EMG signals; two EEG signals; two ECoG signals; two MEG signals; an EMG signal and an EEG, ECoG, or MEG signal; an EMG, EEG, ECoG, or MEG signal and a functional correlate signal (e.g., an accelerometer signal); or two functional correlate signals; or other signal type pairs. Particular manners of making and/or interpreting coherence measurements are described in detail in “Defective cortical drive to muscle in Parkinson's disease and its improvement with levodopa,” Stephan Salenius et al., Brain (2002), Vol. 125, p. 491-500; and “Intermuscular coherence in Parkinson's disease: relationship to bradykinesia,” Peter Brown et al., NeuroReport, Vol. 12, No. 11, Aug. 8, 2001. Those skilled in the art will understand that measurement or determination of coherence may involve multiple signal acquisitions, measurements, and/or recordings, potentially separated by quiescent intervals, and possibly mathematical procedures upon such signals, which may comprise for example, filtering, averaging, transform, statistical operations, and spectral analysis operations.
In yet further embodiments, generally similar techniques can be used to identify areas of the brain targeted for implantation and stimulation to correct language-based disorders, such as aphasias.
To identify the particular portion of the brain to be targeted for implantation and stimulation, the practitioner can direct the patient to perform a language-based task that generates a neural response which can be made visible using any of the imaging techniques described above. In a particular aspect of this embodiment, the language-based task performed by the patient does not require the patient to actually vocalize. Instead, the patient can be directed to merely think of a word, letter, phrase or other language component. For example, the patient can be directed to silently generate a verb associated with a common noun, silently repeat a noun, silently retrieve a word based on a letter cue, or silently retrieve a word based on a visual cue. In any of these embodiments, the patient need not use motor neurons to execute the selected task. Accordingly, this technique can reduce or eliminate the recorded activity of motor neurons, which might otherwise clutter or obscure the cognitive, language-based information of interest. Further details of methods for obtaining such information are included in co-pending U.S. application Ser. No. ______ (Attorney Docket No. 33734.8055US01) entitled “Methods for Treating and/or Collecting Information Regarding Neurological Disorders, Including Language Disorders,” filed Dec. 10, 2003, and incorporated herein in its entirety by reference.
In some cases, only a site identified by the foregoing techniques is selected for implantation and stimulation. In other cases, a contralateral site (e.g., the corresponding site on the opposite hemisphere of the brain 150) is selected, in addition to or in lieu of the identified site. The selection of a particular site or contralateral site can depend upon the type of disorder treated and/or the overall condition of the patient's brain 150. In any of the foregoing embodiments, the practitioner can select a plurality of implantation and/or stimulation sites for a single patient. For example, the practitioner can select multiple sites if it is initially unclear which site will provide a benefit (and/or the greatest benefit) to the patient, and/or if it is determined that implantation and/or stimulation at a plurality of sites provides a greater benefit than implantation and/or stimulation at a single site.
Once the appropriate information regarding the patient's neural activity (or lack of neural activity) has been collected, the at least partially undifferentiated cells can be implanted in the brain 150 in a manner generally similar to that described above. In some embodiments, the implantation and stimulation may take place at more than one location of the brain 150. Accordingly, a stimulation system 420 having an elongated support 421 with multiple electrodes 422 can be positioned in the brain 150 to stimulate a variety of locations. An advantage of this arrangement is that a practitioner can stimulate multiple sites of the brain 150 (either simultaneously or sequentially) with a single system 420. In one embodiment, the practitioner can stimulate multiple sites (rather than a single site) to produce enhanced benefits for the patient. In another embodiment, the practitioner can use a stimulation system 420 having an array of electrodes 422 when it is initially uncertain which area(s) of the patient's brain 150 should be stimulated to produce the most beneficial effect. Accordingly, the practitioner can stimulate a particular area of the brain 150 with one or more of the electrodes 422, observe the effect on the patient and, if the effect is not the desired effect, stimulate another area of the brain 150 with another of the electrodes 422 and observe the resulting effect, all with a single implanted stimulation system 420.
In still another embodiment, the practitioner can apply stimulation to different sites for different lengths of time, and/or the practitioner can independently vary other stimulation parameters supplied to the electrodes 422. In any of these embodiments, any characteristic or combination of characteristics of the signal applied to the electrodes 422 can be varied randomly, pseudo-randomly, aperiodically or approximately aperiodically. Further details of the signals applied to the electrodes 422 are described below with reference to
In one embodiment, the electrical signals can be applied to a single one of the electrodes 522 to provide a unipolar pulse of current to a small area of the brain 150. Accordingly, the system 520 can include a return electrode, which can be a portion of the pulse generator 540, or a separate electrode implanted elsewhere in the patient P (e.g., on the other side of the patient's brain 150 or at a subclavicular location). In other embodiments, electrical current can be passed through all of the electrodes 522 or only a subset of the electrodes 522 to stimulate larger or different populations of implanted cells and/or native neurons. In one aspect of these embodiments, the potential applied to the electrodes 522 can be the same across all of the activated electrodes 522 to provide unipolar stimulation at the stimulation site. In other embodiments, some of the electrodes 522 can be biased with a positive polarity and other electrodes 522 can be biased with a negative polarity at any given point in time. This embodiment provides a bipolar stimulation to the brain 150. The particular configuration of the electrodes 522 activated during treatment can be optimized after implantation to provide the most efficacious therapy for the patient P.
The particular waveform of the applied stimulus depends upon the symptoms of the patient P. In one embodiment, the stimulus includes a series of biphasic, charge balanced pulses. In one aspect of this embodiment, each phase of the pulse is generally square. In another embodiment, the first phase can include a generally square wave portion representing an increase in current above a reference level, and a decrease below the reference level. The second phase can include a gradual rise back to the reference level. The first phase can have a pulse width ranging from about 25 microseconds to about 400 microseconds. In particular embodiments, the first phase can have a pulse width of 100 microseconds or 250 microseconds. The total pulse width can range up to 500 milliseconds.
The voltage of the stimulus can have a value of from about 0.25 V to about 10.0 V. In further particular embodiments, the voltage can have a value of from about 0.25 V to about 5.0 V, about 0.5 V to about 3.5 V, about 2.0 V to about 3.5 V or about 3 V. The voltage can be selected to correspond in some manner to the target or actual action potential of the stimulated cells. For example, if the stimulated cells have differentiated to the point that they exhibit action potentials, the applied voltage can be correlated with the exhibited threshold potential. If the stimulated cells do not yet exhibit action potentials, the applied voltage can be correlated to the desired threshold potential. In either embodiment, the selected voltage can be below a level that causes movement, speech or sensation in the patient (e.g., subthreshold) or above such a level (e.g., suprathreshold). Accordingly, the threshold level is generally correlated with generating electrophysiologic signals associated with a neural function. In one embodiment, the subthreshold voltage can be from about 10% to about 50% less than the threshold voltage. In another embodiment, the subthreshold voltage can have other ranges, for example, from about 10% to about 95%, about 10% to about 60%, about 20% to about 60%, about 30% to about 60%, about 25% to about 50%, about 60% to about 80%, or about 50% to about 80% less than the threshold voltage. In certain embodiments, the practitioner may control the current applied to the patient, in addition to or in lieu of controlling the voltage applied to the patient. Once the implanted cells begin to exhibit action potentials, the voltage and/or current applied to the cells can be reduced, or in further particular embodiments, the electrical stimulation can cease.
In particular embodiments, the voltage of the stimulus (or any other characteristic of the stimulus) is adjusted and/or selected based on a response by and/or characteristic of the implanted cells. Techniques (e.g., fMRI techniques) can be used to isolate the response and/or characteristic as being attributed to the implanted cells. In other embodiments, the response and/or characteristic may be attributed to native cells and this attribution can be made on the basis of similar techniques. In still further embodiments, the response and/or characteristic may be attributed to both native cells and implanted cells. In yet further embodiments, it is not necessary to attribute the response and/or characteristic to a particular type of cell (e.g., native cell and/or implanted cell). The implanted cells may develop functionality via excitatory and/or inhibitory pathways. Native cells, though possibly damaged, may influence the functionality (e.g., the ability to generate action potentials) of the implanted cells. In any of the foregoing embodiments, the response and/or characteristic of the cells can be determined on the basis of the cells' action potentials (or lack of action potentials) or by other techniques, for example, specific and/or general aspects of the patient's response to the stimulation.
The frequency of the stimulus can have a value of from about 2 Hz to about 250 Hz. In particular embodiments, the frequency can have a value of from about 50 Hz to about 150 Hz, or about 100 Hz. The stimulation can be applied for a period of 0.5 hour-4.0 hours, and in many applications the stimulation can be applied for a period of approximately 0.5 hour-2.0 hours, either during therapy (e.g., physical therapy or language comprehension training) or before, during and/or after such therapy. In other embodiments, the stimulation can be applied continuously, or only during waking periods but not during sleeping periods. In particular aspects of this embodiment, the characteristics (e.g., current, voltage, waveform, pulse duration, frequency) are different depending on whether the stimulation is applied before, during or after the therapy. In still further embodiments, the stimulation can be applied while a selected drug (e.g., an amphetamine or other neuroexcitatory agent) is active. In other embodiments, such drugs are not administered. Examples of specific electrical stimulation protocols for use with an electrode array at an epidural stimulation site are as follows:
An electrical stimulus having a current of from about 3 mA to about 10 mA, an impedance of 500 to 2000 Ohms, a pulse duration of 160 microseconds, and a frequency of approximately 100 Hz. The therapy is not applied continuously, but rather during 30-120 minute intervals, associated with therapy.
The stimulus has a current of from about 3 mA to about 6 mA, a pulse duration of approximately 150-180 microseconds, and a frequency of approximately 25 Hz-31 Hz. The stimulus is applied continuously during waking periods, but it is discontinued during sleeping periods to conserve battery life of the implanted pulse generator.
The stimulus has a current of from about 3 mA to about 6 mA, a pulse duration of approximately 90 microseconds, and a frequency of approximately 30 Hz. This stimulus is applied continuously during waking and sleeping periods, but it can be selectively discontinued during sleeping periods.
Treatment programs in accordance with several embodiments of the invention can include electrical stimulation by itself, and/or electrical stimulation in conjunction or association with one or more synergistic or adjunctive therapies, such as behavioral therapies, activities, and/or tasks. Such behavioral therapies, activities, and/or tasks can 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; an imagination or visualization task; and/or other therapies or activities. Other synergistic or adjunctive therapies can include, for example, drug therapies, such as treatment with amphetamines. The electrical stimulation and synergistic or adjunctive therapies can be performed simultaneously and/or serially.
In one aspect of embodiments of the systems described above with reference to
The support member 621 can be configured to be implanted in the skull 110 or another region of a patient P above the neckline. In one embodiment, for example, the support member 621 includes a housing 625 and an attachment element 623 connected to the housing 625. The housing 625 can be a molded casing formed from a biocompatible material, and can have an interior cavity for carrying the pulse system 640 and a power supply. The housing 625 can alternatively be a biocompatible metal or another suitable material. The housing 625 can have a diameter of approximately 1-4 cm, and in many applications the housing 625 can be 1.5-2.5 cm in diameter. The thickness T of the housing 625 can be approximately 0.5-4 cm, and can more generally be about 1-2 cm. The housing 625 can also have other shapes (e.g., rectilinear, oval, elliptical) and/or other surface dimensions. The stimulation system 620 can weigh 35 g or less and/or can occupy a volume of 20 cc or less. The attachment element 623 can include a flexible cover, a rigid plate, a contoured cap, or another suitable element for holding the support member 621 relative to the skull 110 or other body part of the patient P. In one embodiment, the attachment element 623 includes a mesh, e.g., a biocompatible polymeric mesh, metal mesh, or other suitable woven material. The attachment element 623 can alternatively be a flexible sheet of Mylar, polyester, or another suitable material.
In one aspect of an embodiment shown in
The embodiment of the stimulation system 620 shown in
The configuration of the stimulation system 620 is not limited to the embodiment shown in
The pulse system 640 shown in
In one aspect of an embodiment shown in
To implant the stimulation apparatus 820, a burr hole 815 is cut completely through the skull 110 of the patient P at a predetermined location identified according to the methods set forth above. The burr hole 815 can also pass through the dura mater (not shown
Still further embodiments of the invention use electrical stimulation in conjunction with fully differentiated implanted cells. For example, referring first to
In another embodiment, shown in a flow diagram in
In a further particular embodiment, the growth of the fully differentiated, implanted neural cells can be directed by applying electrical current from a device having a plurality of electrodes, for example, a device generally similar to the stimulation system 520 described above with reference to
From the foregoing, it will be appreciated that specific embodiments of the invention have been described herein for purposes of illustration, but that various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.
The present application is a continuation-in-part of pending U.S. application Ser. No. 10/261,116 filed Sep. 30, 2002 and incorporated herein in its entirety by reference.
Number | Date | Country | |
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Parent | 10261116 | Sep 2002 | US |
Child | 10842052 | May 2004 | US |