Patent Application
20230390554
All publications and patent applications mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.
Electric brain stimulation has been shown to be a potentially effective treatment for a number of brain disorders, including epilepsy, migraine, fibromyalgia, major depression, stroke rehabilitation, and Parkinson's disease. While generally regarded as safe when following standard protocols, electric brain stimulation has been shown to increase the permeability of the blood brain barrier (BBB), allowing otherwise impermeable drugs to reach target areas. Brain endothelial cells, which form the endothelium of cerebral micro vessels, are responsible for the majority of resistance to substances. The integrity of the BBB is essential for the health and proper functioning of brain tissue. However, a temporary breakdown of the BBB and increased permeability may allow for improved advanced drug delivery methods. Electric stimulation may temporarily disrupt the BBB through either the paracellular or transcellular pathway. The type and extent of BBB disruption generally depends on the stimulation parameters, such as location, amplitude, polarity, duration, and frequency. Low frequency high amplitude pulses, applied for a short duration can electroporate endothelial cells, opening transcellular pathways. High frequency low amplitude stimulation applied for a longer duration may disrupt tight junctions, increasing the permeability of the BBB through the paracellular pathway.
Electric brain stimulation has been shown to be effective at treating a variety of Central Nervous System (CNS) disorders. For example, electrochemotherapy, tumor treating fields (TTFields), deep-brain stimulation (DBS), and irreversible electroporation have all shown clinical benefit. Electroporation is predominantly reversible at electric fields less than 400 V cm-1 in the brain and reversibly disrupts the BBB. By combining the benefits of electric brain stimulation with improved drug delivery to target brain regions, it is possible to achieve an additive benefit. A need exists for a method and system that allows targeted brain stimulation to achieve the benefits of neuromodulation, along with drug delivery to that location, and using the electric stimulation to increase permeability of the BBB in that region.
A device for electrical stimulation of a subject's brain is provided, the device comprising: a case comprising electronics configured to generate electrical pulses, the case including an opening that extends through the case; a probe coupled to the case and including a lumen in communication with the opening of the case, wherein the opening and the lumen are configured to receive a drug delivery device to facilitate drug delivery to a target region of the brain; at least one electrode disposed on the probe and configured to deliver electrical stimulation to the target region of the brain, wherein the electrical stimulation increases a permeability of a blood brain barrier in order to increase an effect of the drug on the target region of the brain.
In one aspect, the probe is flexible.
In another aspect, the lumen includes a seal or diaphragm to minimize drug backflow.
In one aspect, the drug delivery device comprises a syringe. In other aspects, the drug delivery device comprises a needle. In another aspect, the drug delivery device comprises a flexible tube.
In some aspects, the drug delivery device is implanted in the patient.
A system for electrical stimulation of a subject's brain is provided, the device comprising: a first case comprising first electronics, the first case including a first opening that extends through the first case; a first probe coupled to the first case and including a first lumen in communication with the first opening of the first case, wherein the first opening and the first lumen are configured to receive a first drug delivery device to facilitate drug delivery to a target region of the brain; at least one electrode disposed on the first probe; a second case comprising second electronics, the second case including a second opening that extends through the second case; a second probe coupled to the second case and including a second lumen in communication with the second opening of the second case; at least one electrode disposed on the second probe; wherein the first and second electronics are configured to generate pulses with opposite polarity such that electric current flows from the first probe through the target region to the second probe.
In one aspect, the electrical current is further configured to flow from the second probe under or through the a scalp to the first case to complete a current loop.
In another aspect, the second opening and the second lumen are configured to receive a second drug delivery device to facilitate drug delivery to the target region of the brain
In one aspect, the system includes a “T” or “Y” shaped coupler having a first branch configured to enter the first opening and a second branch configured to enter the second opening, allowing the drug to be administered through both the first and second lumens the first drug delivery device.
In one aspect, the drug delivery device is implanted in the patient.
A device for electrical stimulation of a subject's brain is provided, the device comprising: a remote pulse generator; a neurostimulator adapted to be implanted in a patient's brain, the neurostimulator being electrically coupled to the remote pulse generator, the neurostimulator comprising: a case including an opening that extends through the case; a probe coupled to the case and including a lumen in communication with the opening of the case, the probe being configured to be implanted in the subject's brain, wherein the opening and the lumen are configured to receive a drug delivery device to facilitate drug delivery to a target region of the brain; at least one electrode disposed on the probe and configured to deliver electrical stimulation to the target region of the brain, wherein the electrical stimulation increases a permeability of a blood brain barrier in order to increase an effect of the drug on the target region of the brain.
In one aspect, the lumen includes a seal or diaphragm to minimize drug backflow.
In another aspect, the remote pulse generator is implanted in the patient.
A device for electrical stimulation of a subject's brain is provided, the device comprising: a remote module comprising a pulse generator and a drug pump; a neurostimulator adapted to be implanted in a patient's brain, the neurostimulator being electrically and fluidly coupled to the remote pulse generator, the neurostimulator comprising: a case including an opening that extends through the case; a probe coupled to the case and including a lumen in communication with the opening of the case, the probe being configured to be implanted in the subject's brain, wherein the opening and the lumen are configured to receive a drug from the remote module to facilitate drug delivery to a target region of the brain; at least one electrode disposed on the probe and configured to deliver electrical stimulation to the target region of the brain, wherein the electrical stimulation increases a permeability of a blood brain barrier in order to increase an effect of the drug on the target region of the brain.
In one aspect, the remote module comprises a controller configured to turn drug delivery on and off.
In another aspect, the remote module comprises a controller configured to adjust a flow rate of the drug.
A system for electrical stimulation of a subject's brain is provided, the system comprising: an endovascular device configured to be fluidly coupled with a blood vessel of the subject, the endovascular device comprising a pulse generator and a drug pump configured to deliver a drug to a first target region in the subject's brain; a neurostimulator adapted to be implanted in a patient's brain, the neurostimulator comprising: a case including an opening that extends through the case; a probe coupled to the case and including a lumen in communication with the opening of the case, the probe being configured to be implanted in the subject's brain; at least one electrode disposed on the probe and configured to deliver electrical stimulation to a second target region of the brain, wherein the electrical stimulation increases a permeability of a blood brain barrier in order to increase an effect of the drug.
In some aspects, the neurostimulator is configured to sense EEG signals from the target region.
In one aspect, the first target region and the second target region are the same.
In another aspect, the first target region and the second target region are different.
A method of treating a target region of a brain of a patient is provided, comprising: implanting a neuro stimulator in the patient's brain such that a case of the neuro stimulator is beneath a scalp but above a skull of the patient and the probe is disposed in the brain with an electrode in or near the target region of the brain; inserting a drug delivery device through a hole in the case and into a lumen of the probe to deliver a drug to the target region of the brain; and delivering electrical stimulation to the target region of the brain with the electrode to increase a permeability of a blood brain barrier.
While certain embodiments have been provided and described herein, it will be readily apparent to those skilled in the art that such embodiments are provided by way of example only. It should be understood that various alternatives to the embodiments described herein may be employed, and are part of the invention described herein.
Provided herein is a method and system whereby a target region in a brain of a person may be electrically stimulated, and that a drug or medication may be administered directly or indirectly to the target region, wherein the electrical stimulation increases a permeability of a BBB in order to increase an effect of the drug on the target region of the brain. The location, amplitude, waveform, and pulse frequency may be configured to optimize the permeability of the BBB. The increase in permeability may be permanent, but preferably the increase in permeability is transient, only lasting approximately as long as the drug or medication is present in the body of the person in sufficient quantity to have the desired effect on the brain, or while the concentration of the drug or medication at or near the target region in the brain is above a prespecified threshold, or while a measured effect of the drug or medication on the brain is above a prespecified threshold.
One example target region comprises a tumor. Another example target region comprises a brain feature, such as the Thalamus, Hippocampus, nucleus accumbens, prefrontal cortex, or some other identifiable component of the brain. Another example target region comprises a lesion that occurs due to a stroke. The target region and the disorder being treated may define which drug is optimal. The invention herein described is applicable regardless of which drug is used. Also, stimulation parameters may vary, depending on the drug or indication. For example, high frequency stimulation affects BBB differently than low frequency stimulation, and this effect may determine the optimal treatment.
Turning to
A first syringe (316) may inject a drug through a needle or catheter (317), which pierces the scalp and enters the hole in the first device (318) and proceeds through the probe tube. The drug exits the needle or catheter, proceeding the rest of the way through the tube, and exiting a hole in the tube which is positioned, on, or near the target region. A second syringe (319) may also be used to inject a drug through a needle or catheter (320), which enters the hole in the second device (321) and proceeds through the probe tube. The drug exits the needle or catheter, proceeding the rest of the way through the tube, and exiting a hole in, on, or near the target region.
Alternately, a single syringe may inject a drug, and the needle or catheter may comprise a “T” or “Y” shaped coupler having a plurality of branches, where each branch enters the hole/lumen in the case of each of the devices, allowing the drug to be administered through both probe tubes via a single syringe.
It may be preferable for the first device or second device to not comprise a pulse generator, and to simply provide an electric connection between the interior and exterior of the skull. In this case, the current pulses may only be generated by one of the two devices, and the other device would act only as a conductive path through the skull, allowing the current loop. Alternately, the first device or second device may not comprise a probe electrode or a case electrode, and may use fluid inside the hollow probe to act as a conductive path for current pulses generated by the other device. In this case, the non-stimulating device may not comprise a diaphragm or seal inside the tube.
In another aspect, the remote module may not comprise a reservoir and pump for the drug, and instead the drug may be injected using a syringe or catheter which goes through the skin and injects the drug directly into the flexible tubing. In an alternate aspect, the reservoir may be refilled with a drug using a needle or catheter which is fluidically coupled to the reservoir.
The electrodes may be incorporated into a stent, which lies on or near the inner surface of a blood vessel in or near the target region. The stent may allow for better securing of the electrodes in place, and may prevent or minimize drift. The drug may be injected using small doses or a low flow rate in order to allow for a greater effect on the target region.
It is not essential that the drug be administered directly to the target region. It may be beneficial to use a separate catheter or syringe to inject the drug into another region of the body, and allow normal circulation to bring the drug to the target region. However, by administering the drug directly to an area in or near the target region, the drug may be in a higher concentration in that area, avoiding the natural dilution of the drug by the circulatory system, thereby increasing the effect and potentially lessening the required dosage, resulting in fewer negative side effects from the drug.
In another aspect, the remote module may not comprise a reservoir and pump for the drug, and instead the drug may be injected using a syringe or catheter which goes through the skin and injects the drug directly into the flexible tubing. In an alternate aspect, the reservoir may be refilled with a drug using a needle or catheter which is fluidically coupled to the reservoir.
In the aforementioned examples, the electrodes were intended to provide stimulation. However, the device may further comprise an electroencephalograph (EEG) amplifier, wherein an EEG recording may be obtained through the electrodes. The device may further comprise a processor, memory, and a means to communicate with an external device. The EEG recording may be streamed or uploaded to the external device for further analysis or potential brain-machine interface (BMI).
The example system in
The endovascular device comprises a pulse generator (713), with a lead (714), which enters a blood vessel (715) at a prespecified location (716). The lead proceeds via the vasculature to a location at or near the target region. The device comprises two electrodes (717, 718) at or near the distal end of the lead. This device may generate stimulation pulses to affect the brain in the target region.
It may be that stimulation by itself may suffice to bring about the desired effect. In one example, the target region is the nucleus accumbens, and stimulation may be intended to treat substance abuse. In another example, the target region is the anterior nucleus of the thalamus, and stimulation may be intended to reduce seizures.
If the stimulation is intended to increase the permeability of the BBB, a syringe (719) may inject a drug through a needle or catheter (720) into a blood vessel in the person. The amount of drug that reaches the target region in this case may be diluted, but the increased permeability in the BBB may significantly improve the efficacy of the drug in or near the target region.
Both the direct stimulation devices and the endovascular device may sense EEG signals from around the target region. The EEG signals would be produced by recording the voltage potential between the two probe electrodes (706, 711), and/or by recording the voltage potential between the two lead electrodes (717, 718). This EEG recording may be used to estimate brain health, brain activity, changes in metabolism, or other biological measurements. The EEG recordings may also be used as part of a Brain-Machine-Interface (BMI). If one or more devices record EEG, the system may additionally comprise an EEG amplifier and an analog-to-digital converter (ADC). The EEG may be stored in memory in the endovascular pulse generator or the direct stimulation generator, or both.
It may be that stimulation of multiple target regions by itself may suffice to bring about the desired effect. In one example, the target region is the nucleus accumbens, and stimulation may be intended to treat substance abuse. In another example, the target region is the anterior nucleus of the thalamus, and stimulation may be intended to reduce seizures.
If the stimulation is intended to increase the permeability of the BBB, a syringe (719) may inject a drug through a needle or catheter (720) into a blood vessel in the person. The amount of drug that reaches the target region in this case may be diluted, but the increased permeability in the BBB may significantly improve the efficacy of the drug in or near the target region. Alternately, the direct stimulation device may comprise a hollow tube with a hole near the distal end so that the drug may be injected directly into the target region. Alternatively, the endovascular stimulation device may comprise a flexible tubing with a hole that allows the drug to be delivered into the bloodstream in or around the second target region.
It may be necessary for the endovascular pulse generator and one or both of the direct stimulation devices to communicate, or for two direct stimulation devices to communicate with each other. For example, it may be advantageous to synchronize pulses so that pulses are delivered at the same time or with a pre-defined offset. In another example, devices may provide battery end-of-life estimates, so that stimulation power may be adjusted to maximize usable life of the devices. The devices could use a wireless transmitter and receiver to communicate. However, since the devices are preferably battery powered, conservation of power is very important. In one aspect the implantable devices may communicate using stimulation pulses to encode data. The system shown in
When a feature or element is herein referred to as being “on” another feature or element, it can be directly on the other feature or element or intervening features and/or elements may also be present. In contrast, when a feature or element is referred to as being “directly on” another feature or element, there are no intervening features or elements present. It will also be understood that, when a feature or element is referred to as being “connected”, “attached” or “coupled” to another feature or element, it can be directly connected, attached or coupled to the other feature or element or intervening features or elements may be present. In contrast, when a feature or element is referred to as being “directly connected”, “directly attached” or “directly coupled” to another feature or element, there are no intervening features or elements present. Although described or shown with respect to one embodiment, the features and elements so described or shown can apply to other embodiments. It will also be appreciated by those of skill in the art that references to a structure or feature that is disposed “adjacent” another feature may have portions that overlap or underlie the adjacent feature.
Terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. For example, as used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms “comprises” and/or “comprising,” when used in this specification, specify the presence of stated features, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, steps, operations, elements, components, and/or groups thereof. As used herein, the term “and/or” includes any and all combinations of one or more of the associated listed items and may be abbreviated as “/”.
Spatially relative terms, such as “under”, “below”, “lower”, “over”, “upper” and the like, may be used herein for ease of description to describe one element or feature's relationship to another element(s) or feature(s) as illustrated in the figures. It will be understood that the spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if a device in the figures is inverted, elements described as “under” or “beneath” other elements or features would then be oriented “over” the other elements or features. Thus, the exemplary term “under” can encompass both an orientation of over and under. The device may be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly. Similarly, the terms “upwardly”, “downwardly”, “vertical”, “horizontal” and the like are used herein for the purpose of explanation only unless specifically indicated otherwise.
Although the terms “first” and “second” may be used herein to describe various features/elements (including steps), these features/elements should not be limited by these terms, unless the context indicates otherwise. These terms may be used to distinguish one feature/element from another feature/element. Thus, a first feature/element discussed below could be termed a second feature/element, and similarly, a second feature/element discussed below could be termed a first feature/element without departing from the teachings of the present invention.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising” means various components can be co-jointly employed in the methods and articles (e.g., compositions and apparatuses including device and methods). For example, the term “comprising” will be understood to imply the inclusion of any stated elements or steps but not the exclusion of any other elements or steps.
As used herein in the specification and claims, including as used in the examples and unless otherwise expressly specified, all numbers may be read as if prefaced by the word “about” or “approximately,” even if the term does not expressly appear. The phrase “about” or “approximately” may be used when describing magnitude and/or position to indicate that the value and/or position described is within a reasonable expected range of values and/or positions. For example, a numeric value may have a value that is +/−0.1% of the stated value (or range of values), +/−1% of the stated value (or range of values), +/−2% of the stated value (or range of values), +/−5% of the stated value (or range of values), +/−10% of the stated value (or range of values), etc. Any numerical values given herein should also be understood to include about or approximately that value, unless the context indicates otherwise. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Any numerical range recited herein is intended to include all sub-ranges subsumed therein. It is also understood that when a value is disclosed that “less than or equal to” the value, “greater than or equal to the value” and possible ranges between values are also disclosed, as appropriately understood by the skilled artisan. For example, if the value “X” is disclosed the “less than or equal to X” as well as “greater than or equal to X” (e.g., where X is a numerical value) is also disclosed. It is also understood that the throughout the application, data is provided in a number of different formats, and that this data, represents endpoints and starting points, and ranges for any combination of the data points. For example, if a particular data point “10” and a particular data point “15” are disclosed, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as well as between 10 and 15. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.
Although various illustrative embodiments are described above, any of a number of changes may be made to various embodiments without departing from the scope of the invention as described by the claims. For example, the order in which various described method steps are performed may often be changed in alternative embodiments, and in other alternative embodiments one or more method steps may be skipped altogether. Optional features of various device and system embodiments may be included in some embodiments and not in others. Therefore, the foregoing description is provided primarily for exemplary purposes and should not be interpreted to limit the scope of the invention as it is set forth in the claims.
The examples and illustrations included herein show, by way of illustration and not of limitation, specific embodiments in which the subject matter may be practiced. As mentioned, other embodiments may be utilized and derived there from, such that structural and logical substitutions and changes may be made without departing from the scope of this disclosure. Such embodiments of the inventive subject matter may be referred to herein individually or collectively by the term “invention” merely for convenience and without intending to voluntarily limit the scope of this application to any single invention or inventive concept, if more than one is, in fact, disclosed. Thus, although specific embodiments have been illustrated and described herein, any arrangement calculated to achieve the same purpose may be substituted for the specific embodiments shown. This disclosure is intended to cover any and all adaptations or variations of various embodiments. Combinations of the above embodiments, and other embodiments not specifically described herein, will be apparent to those of skill in the art upon reviewing the above description.
This patent application claims priority to U.S. provisional patent application No. 63/348,805, titled “BRAIN STIMULATION DEVICE WITH TARGETED INJECTABLE DRUG DELIVERY” and filed on Jun. 3, 2022, which is herein incorporated by reference in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| 63348805 | Jun 2022 | US |
