Drug Treatment of Nervous System Dysfunction

Abstract

The subject watches or interacts with an audio / video-based task on an electronic display to intentionally trigger the release of a neurological disease therapeutic agent in a targeted region of the subject's brain by a drug delivery system (DDS). The DDS is adjusted to release the neurological disease therapeutic agent based on a specific pH, lactate level, blood flow, temperature, magnetic field, specific molecules released by brain cells, or other physiological factors in the targeted region. The interactive task produces physiological factors in the specific lesioned region in the brain for which the drug is prescribed, thus limiting drug delivery to areas not affected by the disease that may disrupt normal function, cause problematic side effects, and prevent optimal dose levels to affect the target. Feedback from the interactive task and associated cognitive probes can also adapt the interactive task or suggest new pharmacological agents as the extent or primary focus of the brain lesion changes during the course of treatment.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 159,228, filed March 10, 2021, which is incorporated by reference herein in its entirety for all purposes.

[0002] STATEMENT REGARDING RIGHTS TO INVETIONS MADE UNDER FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT Not applicable

[0003] Embodiments of the present invention generally relate to controlling the release of a drug delivery system (DDS) of a neurological drug using deliberate cognitive or motor stimulation of a subject to alter, for example, the chemistry of targeted neurofunctional systems in the subject's brain. [Background technology]

[0004] Schizophrenia and depression are chronic, debilitating central nervous system (CNS) disorders that affect millions of people worldwide. With onset in the second and third decades of life, schizophrenia is estimated to cost individuals, families, and societies $60 billion annually in medical costs and lost productivity in the United States alone. Currently available pharmacotherapy (drugs) are partially effective, but their use and effectiveness are severely limited by the side effects of drugs. Side effects are the main reason why the life expectancy of people with schizophrenia is reduced by 15 years, and also negatively affect the quality of life of people suffering from schizophrenia. Furthermore, some studies have shown that although higher than usual doses can increase symptom reduction, the associated side effects make such doses unsafe and unacceptable to the majority of subjects. Side effects may not only limit the maximum dosage, but may also prevent a candidate drug from being approved in the first place. For example, side effects may cause safety issues, which may prevent the drug from gaining approval from the Food and Drug Administration (FDA). Alternatively, side effects may limit the dosage to sub-therapeutic levels. That is, side effects may make such drugs unsafe or ineffective. Of the candidate drugs developed in preclinical trials for CNS disorders, 93% fail clinical trials. The main cause of all these limitations is the fact that drugs are delivered through the blood throughout the brain, rather than being delivered specifically to the location where the therapeutic action is needed. Thus, the drug chemical comes into contact with more areas than the intended area, or the drug chemical is not dispensed in sufficient amounts to the targeted area. Essentially, all drugs currently used for schizophrenia work by blocking dopamine D2 receptors in the substantia nigra, a structure in the basal ganglia of the midbrain that provides, among other things, reward information. 1A-1B are positron emission tomography (PET) images showing blockade of D2 receptors in the substantia nigra by prior art antipsychotics. Each figure shows levels 102A-B of radiolabel uptake into D2 receptors in the substantia nigra of subjects with schizophrenia. FIG. 1A shows levels 102A of uptake before treatment, and FIG. 1B shows levels 102B corresponding to reduced uptake after treatment with antipsychotics that occupy receptors and prevent dopamine uptake (i.e., dopamine blockade). The reduction in uptake caused by drug-induced blockade of D2 receptors in association subdivisions of the substantia nigra is the primary therapeutic benefit of antipsychotics, but there are other subdivisions of the substantia nigra that are similarly affected by drugs.

[0005] There are three functionally distinct subdivisions of the substantia nigra: motor (MSN), associative (ASN) and reward / motivation (RMSN). Midbrain dopamine neurons are the source of dopamine projections to the striatum in primates, and these structures are shared with other animals such as rodents. In primates, the limbic system originates from the dorsal part of the substantia nigra. In rodents, the limbic system originates from the ventral tegmental area, which is located medial to the substantia nigra. Projections from the midbrain to the association and sensorimotor striatum follow a dorsomedial vs. ventrolateral topology. When a drug is administered, it travels through all of these regions. Side effects arise for at least two reasons: 1) D2 receptors are located in many parts of the brain independent of where the therapeutic action is needed, including parts of the substantia nigra, and are independent of the function of these other areas affected by the drug; and 2) available D2 receptor blocking drugs also affect receptors for other neuromodulators throughout the brain, and these effects result in additional undesirable side effects. Side effects of drugs for schizophrenia include abnormal movements (called extrapyramidal effects) that affect up to 35% of subjects depending on the specific drug, including stiffness, parkinsonian bradykinesia and rigidity, tremor of the hands, and involuntary repetitive movements of the mouth, head, or arms. The repetitive movements may persist even after the drug is stopped. This sequela is described in the literature as tardive dyskinesia. Tardive dyskinesia is caused by D2 blockade in the substantia nigra (MSN) division associated with motor control, adjacent to the therapeutic area of ​​action in the ASN.

[0006] Other side effects include endocrine side effects, which occur in 20-40% of subjects and are related to elevated prolactin levels caused by D2 blockade in the pituitary gland. Side effects include breast enlargement and sexual dysfunction in men, and breast pain and lactation in women. The major contributing factors in shortened life span are weight gain and metabolic side effects. It is not uncommon for subjects to gain 50 pounds or more on these drugs. This is due in part to D2 blockade in other divisions of the substantia nigra associated with reward and appetitive behaviors, regions adjacent to the site of therapeutic action in the ASN. Weight gain is also due to the effects of antipsychotic drugs on histamine Hi and serotonin 5-HT2C receptors that may not be related to clinical benefit. Side effects may also include secondary negative symptoms associated with D2 blockade in the temporal and insular cortices, and parts of the substantia nigra associated with reward and motivation, including dysphoria and a complex of subjective experiences of "low subjective well-being", including reduced cognitive function, emotional regulation, physical function and social integration. Sedation, one of the most problematic side effects in terms of quality of life, is also associated with histamine H1 antagonism. Cognitive dysfunction, dry eyes and mouth, urinary retention, and constipation are all attributed to anticholinergic effects due to blockade of muscarinic receptors. Given this background of side effects of neurological drugs and their physiological causes, it is clear that there is a need in the art for more brain-targeted treatments for schizophrenia and other central nervous system disorders. Summary of the Invention

[0007] Typically, a neurological disease therapeutic is attached to a drug delivery system (DDS) that releases the drug in the presence of a local physiological factor in the subject's brain. The local physiological factor is deliberately and intentionally created by the subject as the subject performs a predetermined task or challenge. The task or challenge is presented through an audio or video display or in an immersive virtual reality (VR) environment. The task or challenge can include video games, puzzles, matching or contrast problems, or other challenges. The local physiological factor in the brain can include changes in pH, lactate levels, blood flow, temperature, local magnetic fields, and other such factors. Although subtle, these factors are measurably affected by the subject performing the task and are used to trigger the release of the drug by the DDS.

[0008] Neurosystem dysfunction in individual subjects can be continuously and non-invasively assessed by computer monitoring and intervention systems before, during, or after treatment to identify neurosystem dysfunction and drug therapy targets for each individual. Furthermore, assessment of neurosystem function by intervention systems can be continued throughout the course of treatment to modify drug therapy targets, release set points of DDS to enhance the sensitivity or specificity of neural system targeting, and drug therapy agents. Drugs delivered by DDS that are sensitive to physiological changes associated with local neural system activity may themselves be sustained release structures to allow for continuation of localized pharmacological effects after cessation of external neural activation designed to produce localized drug release.

[0009] Some embodiments of the invention relate to a method of activating a neurological pharmacotherapy by a targeted activation task by a subject, the method comprising the steps of administering to the subject a drug delivery system (DDS), the DDS carrying a neurological pharmacotherapy, the drug delivery system being configured to release the neurological pharmacotherapy when it encounters a predetermined pH, lactate level, blood flow, temperature, magnetic field, or a specific molecule released by a brain cell; presenting a targeted activation task to the subject, the targeted activation task being selected to change the pH, lactate level, blood flow, temperature, magnetic field, or concentration of the specific molecule at a physical location of a predetermined neurological functional system of the subject's brain; and releasing the neurological pharmacotherapy from the DDS at the physical location of the neurological functional system in the brain based on the change in pH, lactate level, blood flow, temperature, magnetic field, or concentration of the specific molecule caused by the targeted activation task.

[0010] The targeted activation function may be a sensory-motor brain activation task, and presenting the targeted activation task may include instructing the subject to move an appendage. The moving may include rhythmically moving the appendage. The instructing may include starting or stopping the moving. The targeted activation function may be a cognitive neuroscience task, and presenting the targeted activation task may include displaying an interactive game or challenge on a video display, and receiving interactive input from the subject and updating the video display in response to the interactive input. The video display may include virtual reality goggles. The step of presenting the targeted activation task may include playing an audible game or challenge over a speaker, and receiving interactive input from the subject, and updating the audible game or challenge in response to the interactive input. The method may include measuring the releasing step with a sensor and adjusting the length or intensity of the targeted activation task in response to the value obtained by the measuring step. The method may include adapting the targeted activation task based on changes in pH, lactate level, blood flow, temperature, magnetic field, or concentration of a particular molecule in the subject's brain, and stopping the targeted activation task when a predetermined dose of the neurological disease therapeutic agent is estimated to be released. The method may include waiting a predetermined time for the drug delivery system to cross the subject's blood-brain barrier before presenting the targeted activation task.

[0011] The drug delivery system may be selected from the group consisting of deoxyribonucleic acid (DNA) nanocages, cell delivery systems, microelectromechanical (MEM)-based devices, polymer matrices, and gene delivery systems. Releasing the drug may include dissociating or exposing an active region of the neurological disease therapeutic. The subject may be a human or other mammal. The human may be a human suffering from a central nervous system disorder. The central nervous system disorder may be a psychiatric disorder. [Brief description of the drawings]

[0012] [Figure 1A] 1 is a positron emission tomography (PET) image of a subject with schizophrenia before treatment with a prior art antipsychotic. [Figure 1B] PET image of the subject from FIG. 1A following treatment with an antipsychotic. [Figure 2A] FIG. 1 illustrates a deoxyribonucleic acid (DNA) nanocage drug carrier according to an embodiment. [Figure 2B] FIG. 1 illustrates a deoxyribonucleic acid (DNA) nanocage drug carrier according to an embodiment. [Figure 2C] FIG. 1 illustrates a deoxyribonucleic acid (DNA) nanocage drug carrier according to an embodiment. [Figure 2D]FIG. 1 illustrates a deoxyribonucleic acid (DNA) nanocage drug carrier according to an embodiment. [Figure 2E] FIG. 1 illustrates a deoxyribonucleic acid (DNA) nanocage drug carrier according to an embodiment. [Figure 2F] FIG. 1 illustrates a deoxyribonucleic acid (DNA) nanocage drug carrier according to an embodiment. [Figure 3A] FIG. 1 illustrates additional deoxyribonucleic acid (DNA) nanocage drug carriers according to certain embodiments. [Figure 3B] FIG. 1 illustrates additional deoxyribonucleic acid (DNA) nanocage drug carriers according to certain embodiments. [Figure 3C] FIG. 1 illustrates additional deoxyribonucleic acid (DNA) nanocage drug carriers according to certain embodiments. [Figure 4] FIG. 1 illustrates a universal pH-sensitive DNA nanocage drug delivery system according to an embodiment. [Diagram 5] FIG. 1 illustrates a carrier prodrug drug delivery system according to an embodiment. [Figure 6] FIG. 1 illustrates a subject undergoing a digital neurotherapy procedure using a video display according to one embodiment. [Figure 7] FIG. 1 illustrates the effects on the brain of a subject performing a targeted activation task using a video display according to an embodiment. [Figure 8] FIG. 1 illustrates the effects on the brain of a subject performing a targeted activation task according to an embodiment. [Figure 9] FIG. 13 illustrates the effects on the brain of a subject performing another targeted activation task according to an embodiment. [Figure 10] FIG. 1 illustrates a flow chart of a process for focal activation in the brain of neurological disease medication through a subject-based task, according to an embodiment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] Many important targets for drug therapy are present in the body, and most pharmacological agents are delivered to the desired site of action through the blood after oral ingestion or by being introduced intravenously. This creates problems in that the blood circulates and delivers the drug to all parts of the body, many or even most of which are not the site of the disease. These other parts may be affected by the drug, which may result in side effects that limit the ultimate benefit of the drug, may present safety concerns that prevent the drug from being approved in the first place, and may limit the maximum dose of the drug to a level that is too low to affect the target disease.

[0014] To address these issues, drug delivery systems have been developed that carry drugs in the blood in an inactive form and then activate the drug in response to some property at the site of the lesion. For example, the drug can be transported in a "container" that becomes porous and releases the drug in response to physiological factors in the local environment of the targeted lesion. Alternatively, the drug can be biochemically linked to another molecule that renders the drug inactive but is cleaved in response to local factors. The local factors are generally those related to metabolic activity, such as pH, blood flow, metabolic by-products, temperature, magnetic fields, and / or other factors. Drug delivery systems have been pioneered to deliver anti-cancer drugs. Cancer tumors themselves have distinct metabolic characteristics, such as a temperature that differs from that of surrounding healthy tissue. Thus, the higher temperature of the tumor can trigger drug release. In some other cases, external light is applied through the skin to reach a location inside the body to trigger the photosensitive mechanism of the drug delivery system to release the drug. "Drug delivery system" (DDS) includes systems engineered or known in the art for administering pharmaceutical compounds to a subject. The term encompasses macroscopic devices such as patches and microneedles, as well as nanoscale particles (e.g., DNA nanocages), bacteria, viruses, or other microscopic carriers.

[0015] Microscopic "drug delivery systems" (DDS) include engineered carriers made of liposomes, proliposomes, microspheres, gels, prodrugs, cyclodextrins, or other materials that can be attached to drug compounds and targeted to specific parts of the body, or as known in the art. Once present at the target, the drug delivery systems are configured to unmask, expose, or otherwise release the cargo drug in response to local factors such as pH, lactate levels, blood flow, temperature, magnetic fields, and / or other factors. "Releasing" a cargo drug from a drug delivery system includes unblocking the drug, or a portion of it, freeing the drug, liberating the drug, activating the drug, or allowing the drug to perform its intended therapeutic function in a subject where the drug delivery system would otherwise prevent the drug from performing its function, or as known in the art. For example, the drug delivery system can encapsulate the drug and then become porous and release the drug in response to physiological factors in the local environment of the targeted lesion. Alternatively, the drug can be biochemically bound to another molecule of the drug delivery system that renders the drug inactive but is cleaved in response to local factors.

[0016] DDS appears not to have been used before to treat psychiatric and other central nervous system (CNS) disorders, which together constitute a major cause of global disease burden. The inability to apply this approach to CNS disorders, despite widespread need, and the severely limited efficacy of current treatments, demonstrate the lack of a way to provide a physiological or local trigger to activate drugs at the desired site of their impact. The brain is somewhat fluidically isolated from the rest of the body, and is naturally well protected, sensitive, and difficult to explore using common surgical tools.

[0017] However, digitally delivered neurotherapeutic acts presented through audio / visual displays that increase neuronal activity and function in targeted neural systems compromised by disease can produce localized physiological changes sufficient to trigger DDS-mediated release of therapeutically active drugs, allowing for highly focused, directed drug delivery to specific dysfunctional neural systems in individual subjects, increasing efficacy and reducing side effects. For example, a neurotherapeutic approach may allow for the selective delivery of D2 antagonists to the associated substantia nigra to maximize the beneficial effects of the drug and minimize side effects. This approach addresses several limitations that may hinder enhanced pharmacological treatment of psychiatric and other CNS disorders, including: Many psychiatric and CNS disorder drugs work by blocking or enhancing neuronal signaling through synapses. This can be done, for example, by blocking access to specific postsynaptic receptors, by directly activating postsynaptic receptors, or by preventing the degradation of endogenously released neurotransmitters, increasing their concentration and increasing their effect on postsynaptic receptors. The problem is that the same individual neurotransmitters function throughout the brain. As a result, drugs delivered throughout the brain via the bloodstream affect the function of many neurological systems, resulting in many significant side effects.

[0018] Furthermore, CNS dysfunction in psychiatric and other diseases is associated with the alteration of multiple neurotransmitters and modulators.The first-generation drug theory of action for disorders such as schizophrenia and depression focuses on the impairment of a single neurotransmitter, while second- and third-generation drugs have proven more effective, but they generally focus on multiple neurotransmitters and modulators.This increases the potential for more widespread brain effects and associated side effects, especially when high doses are attempted on partially or non-responsive subjects.

[0019] Moreover, current clinical diagnostic categories include individuals with different brain lesions and different mixes of neurosystem dysfunction. Brain imaging and genetic risk studies have established that individuals with the same diagnosis may have completely different underlying brain dysfunctions, and subjects with different diagnoses may share certain underlying brain dysfunctions. For these reasons, there is a growing recognition that to improve efficacy, CNS diseases should be individualized far beyond any guidance provided by diagnosis. Thus, the research theory and priorities of the US National Institutes of Health (NIH) are shifting to focus on aspects of function across all diagnostic categories. However, there is no practical device or system that translates this perspective into treatment for individual subjects. The combination approach, in which the drug delivery system is used in conjunction with the subject performing a task to stimulate the neurofunctional regions of his / her brain, provides a specific procedure that dramatically increases the specificity of treatment for psychiatric and CNS disorders in two dimensions.First, the combination approach serves the scope of targeted drug therapy of specific disease-related brain functional systems, rather than exposing the entire brain to drug effects.Second, the combination approach allows for personalized treatment of nervous system dysfunction specific to each subject.That is, personalized audiovisual presentations can be provided based on how the subject is diagnosed and how the subject responds in real time.

[0020] The system may include determining the specific disease-related brain functional systems in a particular individual. This determination may use sensory detection and information processing probe tests to identify the dysfunction in each individual and to monitor the improvement or shift of the dysfunction over the course of treatment. Visual and auditory probes may be digitally presented and rapidly adapted to efficiently focus and further identify the dysfunction. In some cases, olfactory, gustatory, or somatosensory probes are used. The system can assist in the delivery of drug therapy to specific disease-related brain functional systems. The system can use existing or modified DDSs that have already proven effective in providing targeted drug therapy for cancer and other body disorders, but have not been used previously for psychiatric or CNS disorders. It is also possible to develop novel DDSs. Based on the set of identified dysfunctions, the system can create custom targeted activation tasks, such as a series of visually presented digital cognitive games, to attract and induce increased neuronal firing in the dysfunctional system. Activation of the DDS is triggered by local physiological changes associated with increased targeted local neuronal firing, such as the accompanying metabolic activity and energy expenditure. 2A-4 illustrate several DNA nanocage drug carrier drug delivery systems (DDS) 210a, 210b, 210c, 210d, 210e, 210f, 310a, 310b, 310c, and 410 according to certain embodiments. There are several methods and materials to construct DDS. As an example, DNA nanocages provide a highly versatile carrier that can cross the blood-brain barrier and can be triggered to open and release the drug or expose the active region of the drug by various local physiologically based ligands, biomolecules, changes in temperature, changes in lactate levels, changes in blood flow, changes in magnetic field, or changes in pH.

[0021] pH-sensitive systems are of particular interest because they can be constructed with various set points of release tuned by the chemical nature of the hydrogen-bonding groups on the nanocages. Alternative DDSs can be constructed with release set points at different pH levels, for example using mesoporous silica nanoparticles. By applying different numbers of layers of poly(allylamine hydrochloride) and poly(styrene sulfonate) to the mesoporous silica nanoparticles, the pH-sensitive release point can be tuned. Additionally, ethylenediamine (EN) can be used in pH-responsive nanocages, as exemplified by DDS 410 in FIG. 4.

[0022] In an exemplary embodiment, the DDS can deliver an antipsychotic drug, such as haloperidol, in an inactive form through the systemic and cerebral bloodstream, and release the drug from the DDS in an active form in response to a trigger present at the site of desired therapeutic action. 5 illustrates a carrier prodrug DDS 510 according to one embodiment. DDS 510 includes a neurological disorder therapeutic agent 512, a linker 513, and a carrier 514. When carrier 514 is linked to neurological disorder therapeutic agent 512, neurological disorder therapeutic agent 512 is inactive. However, carrier 514 can be cleaved from neurological disorder therapeutic agent 512, for example, by an enzyme or other biomolecule, thereby activating neurological disorder therapeutic agent 512. Although Figures 2A-5 depict DNA nanocages and carrier prodrugs, other examples of DDS can include cell delivery systems, microelectromechanical (MEM)-based devices, polymer matrices, and gene delivery systems. FIG. 6 illustrates a subject 602 performing a digital neurotherapy action using an audio / video (A / V) display, according to an embodiment. A targeted activation task 604 triggers drug release from a DDS 610 in a targeted neurofunctional system. For example, the targeted activation task 604 can be a cognitive neuroscience task or a sensory-motor brain activation task. A cognitive neuroscience task can involve the display of an interactive game or cognitive task with which the subject 602 interacts. The display can be updated based on the interaction with the subject 602. In some cases, the display can be comprised of a computer or virtual reality goggles. Another example of a cognitive neuroscience task can involve a speaker playing an audible game or cognitive task. The subject 602 can interact with the speaker to provide interactive input, which then updates the audible game or cognitive task. A sensory-motor brain activation task can involve instructing the subject 602 to move a limb. The moving may involve rhythmic periodic moving, such as periodically tapping a hand at a specified frequency (e.g., once per second). The targeted activation task 604 may instruct the subject 602 to start and / or stop moving. Before presenting the targeted activation task 604 to the subject 602, a predetermined time may be waited for the DDS 610 to cross the subject's blood-brain barrier 602.

[0023] For example, the ASN, an association subdivision of the substantia nigra, is strongly activated during tasks that require behavioral adaptability. The ASN is particularly well suited for testing neurological drugs targeted with DDS, since it is the only known common area required for goal-directed behavior that is sensitive to outcome devaluation and sequential reversal learning in both animal and human studies. These functions are impaired in subjects with schizophrenia.

[0024] In the case of targeted delivery of D2 antagonist drugs to treat schizophrenia, the targeted activation task 604 performed by the subject 602 may involve devaluation of results and continuous reversal learning tasks presented in a user interface (UI) application module at least in daily "drug activation sessions." Each drug activation session using the UI application may include 30 minutes of task performance, with the difficulty of the task being continuously adjusted based on monitoring of the accuracy of performance to maintain performance within a particular range, e.g., 75%-90% accuracy. The particular range may be selected to ensure that the ASNs are attracted and stimulated. One or more task parameters may be adjusted to individualize the difficulty to maintain a desired level of performance. These parameters may include, for example, the degree of similarity between the high-value and low-value stimuli (e.g., two types of cookies vs. cookies and apples), the inherent attractiveness of the low-value stimulus relative to the high-value stimulus (e.g., ice cream vs. apples), the duration of exposure to the stimuli and the time between successive stimuli, the percentage of foils that are reversed, the frequency with which learned associations or combinations of stimulus components are reversed, and the provision of cues and strategy suggestions.

[0025] UI applications may include software instructions executed by a general purpose or other computer, the software being stored in volatile or non-volatile memory or loaded over a computer network. The software may include interactive elements such as those supported by Microsoft Windows, Apple macOS, Google Chrome, or other operating systems. They may be entirely browser-based or loaded as a program on the local computer.

[0026] Example workflow: What subjects and doctors do An example of a workflow for a physician and a subject is described here. First, a physician can perform a clinical evaluation, assign a diagnosis, and prescribe medication. Second, a subject is registered in the system by hospital or clinic staff as one of the physician's patients with a unique user name and a personal password. Third, a subject can log into the system from a computer or tablet in the ward if treated as an inpatient, or in the office or at home if treated as an outpatient, and complete a cognitive function assessment to identify "localizer" cognitive dysfunctions related to the subject's CNS disorder. The identified cognitive dysfunction reflects the specific neural system that has dysfunction. This becomes the target location for drug release. Fourth, the system can design, select, and / or create a targeted activation task "game" that can activate the target neural system dysfunction to cause a localized change in pH, lactate level, blood flow, temperature, magnetic field, or concentration of a specific molecule to release a neurological disease therapeutic at the physical location of the neural function system. Fifth, the subject may be instructed and then reminded by the system to play a cognitive game appropriate for the pharmacokinetics of the orally ingested neurological disease therapeutic drug over a period of time, for example, approximately 20-60 minutes, following oral ingestion of the neurological disease therapeutic drug. The purpose is to wait a sufficient length of time after oral ingestion for approximately peak blood levels of the neurological disease therapeutic drug to be achieved. Sixth, the procedure may be repeated twice per day in conjunction with each dose of the neurological disease therapeutic drug. Seventh, the system may repeat the cognitive assessment periodically throughout the course of treatment to monitor improvements in the function of the target system and to detect other dysfunctions that need to be targeted. It may be common to identify more than one cognitive dysfunction "localizer" and to include more than one targeted activation task "game" for targeted drug delivery. 7 illustrates the effect on a subject's brain 702 performing a targeted activation task 704 using a video display, according to an embodiment. The targeted activation task 704 may be a cognitive neuroscience task or a sensory-motor brain activation task, and is selected based on a determined dysfunction of a neural functional system of the subject 702. As illustrated in FIG. 7, the neural functional system may be accompanied by a physical location 706 corresponding to an area of ​​the brain where a neurological disease therapeutic agent is released based on the dysfunction of the neural functional system of the subject 702.

[0027] As an example, a DDS 710A can be administered to a subject 702. The DDS 710A carries a neurological disorder therapeutic agent 712A and is configured to release the neurological disorder therapeutic agent 712 in response to an increase in lactate release and a decrease in pH levels. The subject 702 can perform a targeted activation task 704, which results in an increase in neuronal firing at a physical location 706 in the brain, causing an increase in lactate release and a decrease in pH levels at the physical location 706. Based on the increase in lactate release and the decrease in pH levels at the physical location 706, the neurological disorder therapeutic agent 712A can be released from the DDS 710A. Thus, the neurological disorder therapeutic agent 712A is received at the physical location 706, but not at other locations in the brain where an increase in neuronal firing has not occurred as a result of the targeted activation task 704.

[0028] As another example, DDS 710B can be administered to subject 702. DDS 710B includes a carrier 714 linked to a neurological disease therapeutic 712B. Carrier 714 can be cleaved from neurological disease therapeutic 712B in response to increased release of a protease, thus resulting in activation of neurological disease therapeutic 712B. Thus, subject 702 can perform a targeted activation task 704, resulting in increased neuronal firing at physical location 706, causing release of a protease at physical location 706. Based on the release of the protease at physical location 706, neurological disease therapeutic 712B can be released from DDS 710B. As a result, neurological disease therapeutic 712B is received at physical location 706, but not at other locations of the brain where increased neuronal firing has not occurred as a result of targeted activation task 704.

[0029] As yet another example, a DDS 710C can be administered to a subject 702. The DDS 710C carries a neurological disease therapeutic agent 712C and is configured to release the neurological disease therapeutic agent 712C in response to an increase in blood flow, a decrease in deoxyhemoglobin, and an increase in temperature. Thus, the subject 702 can perform a targeted activation task 704, which results in an increase in neuronal firing at the physical location 706, causing an increase in blood flow, a decrease in deoxyhemoglobin, and an increase in temperature at the physical location 706. Based on the increase in blood flow, the decrease in deoxyhemoglobin, and the increase in temperature at the physical location 706, the neurological disease therapeutic agent 712C can be released from the DDS 710C. Thus, the neurological disease therapeutic agent 712C is received at the physical location 706, but not at other locations of the brain where an increase in neuronal firing has not occurred as a result of the targeted activation task 704. 8 illustrates the effects on the brain 808 of a subject 802 performing a targeted activation task, according to one embodiment. The targeted activation task involves a video display 803 displaying an interactive game or cognitive task. The subject 802 provides interactive input, which updates the video display 803 in response. For example, if the subject 802 has schizophrenia, the targeted activation task can be a cognitive task designed to activate the associated striatum, where the effects of medication for schizophrenia are desired.

[0030] A first phase 804A of the targeted activation task is illustrated as involving presenting the subject 802 with a series of words on a video display 803. After a period of time, a second phase 804B of the targeted activation task involves the subject 802 selecting a location where one word in the series of words was located during the first phase 804A. For example, if the location word is "boat" and the series of words in the first phase 804A was presented as "car-boat-dog-hat," then to successfully complete the targeted activation task, the subject 802 should select "2" during the second phase 804B. The number "2" is the location of the second word "boat" in the series of words. The subject 802 is repeatedly shown different series of words and allowed to select the location of the word within the series of words. The targeted activation task can be sustained long enough to induce a desired change in a physical location 806 corresponding to the relevant striatum of the subject's 802 brain 808, such as a predetermined pH, lactate level, blood flow, temperature, magnetic field, or change in specific molecules released by brain cells.

[0031] The targeted activation task can be adjusted over time based on the subject's 802 response to the neurological disease therapeutic agent or to improve the specificity of the neurological disease therapeutic agent released in response to the targeted activation response. For example, during the targeted activation task, sensors such as functional magnetic resonance imaging (fMRI) can be used to measure areas of brain activation and indicate that other locations of the brain 808 other than the physical location 806 where therapeutic drug release is desired are affected by the targeted activation task while the subject 802 is performing the targeted activation task. As a result, the neurological disease therapeutic agent is also released at other locations that may not be the desired location. Thus, the targeted activation task can be adjusted in response to the fMRI. For example, if it is determined that the physical location 806 is activated and produces the desired physiological change after the subject 802 performs the targeted activation task for 1 minute, and that other locations are activated and produce the desired physiological change after the subject 802 performs the targeted activation task for 10 minutes, the length of the targeted activation task can be reduced to 7 minutes so that the neurological disease therapeutic agent is released locally at the physical location 806. Adjusting the targeted activation task may additionally or alternatively involve adjusting the intensity, eg, speed, difficulty, etc., of the targeted activation task.

[0032] The measured release of the neurological disorder therapeutic agent may also be used to adapt the targeted activation task based on changes in pH, lactate levels, blood flow, temperature, magnetic field, or concentrations of specific molecules in the brain 808 of the subject 802. For example, the targeted activation task may be adapted so that the first and second stages 804A, 804B are displayed more quickly for different sequences of words. Sensors may be used to continuously measure the degree of activation of the desired therapeutic target location, and the targeted activation task may be stopped once the sensors determine that a predetermined dose of the neurological disorder therapeutic agent is estimated to be released. 9 illustrates the effects on a brain 908 of a subject 902 performing another targeted activation task 904 according to an embodiment. The targeted activation task 904 involves a video display 903 displaying an interactive game or cognitive challenge. The subject 902 provides interactive input, which updates the video display 903 in response. For example, if the subject 902 has depression, the targeted activation task can be a cognitive task designed to activate the middle frontal gyrus of the brain 908, where the effects of medication for depression are desired.

[0033] The targeted activation task 904 is illustrated as involving presenting the subject 902 with a sentence on a video display 903. The subject 902 inputs a "yes" or "no" selection to indicate the subject's agreement with the sentence. For example, for the sentence "I like chicken wings," the subject 902 can select "yes" to indicate that he likes chicken wings or "no" to indicate that he does not like chicken wings. The subject 902 can be repeatedly shown various sentences and asked to select whether he agrees with the sentence. The middle frontal gyrus can be activated by the subject 902 thinking about and responding to the sentence, since the frontal lobe in which it is located is associated with controlling personality. The targeted activation task 904 can be sustained long enough to induce a desired change in a physical location 906 corresponding to the middle frontal gyrus of the subject's 902 brain 908, such as a predetermined pH, lactate level, blood flow, temperature, magnetic field, or change in a particular molecule released by brain cells.

[0034] The targeted activation task can be adjusted over time based on the subject's 902 response to the neurological disease therapeutic as determined by improvement in function of the target region initially impaired by the disease. This can be in the form of, for example, measuring improvement in performance on a cognitive neuroscience task, a sensory task, or a motor task used to determine the target for therapeutic drug release. Based on the measurements, the length, intensity, or other adjustments to the targeted activation task 904 can be made. 10 illustrates a flow chart of a process for focal activation in the brain of a neurological disease drug therapy through a task by a subject, according to an embodiment. In operation 1002, a DDS carrying a neurological disease drug is administered to the subject. The DDS can be selected from the group consisting of a DNA nanocage, a cell delivery system, a MEMs-based device, a polymer matrix, and a gene delivery system. The DDS is configured to release the neurological disease drug when it encounters a predetermined pH, lactate level, blood flow, temperature, magnetic field, or a specific molecule released by brain cells.

[0035] In operation 1004, a selection of a targeted activation task is performed on the subject. The targeted activation task is selected to change pH, lactate levels, blood flow, temperature, magnetic field, or concentration of a particular molecule at a physical location of a given neurofunctional system of the subject's brain. The targeted activation task may include a cognitive neuroscience task or a sensory-motor brain activation task. The cognitive neuroscience task involves an audio game or cognitive task or an interactive game or cognitive task. The sensory-motor brain activation task may involve the subject moving a limb. The targeted activation task may be a task that activates a physical location of a neurofunctional system. For example, a first targeted activation task may be selected if the neurofunctional system is associated with the striatum of the brain or if the neurofunctional system is associated with the middle frontal gyrus of the brain. In operation 1006, a targeted activation task is presented to the subject. Presenting the targeted activation task may involve displaying an interactive game or cognitive challenge on a video display, which may include virtual reality goggles. Presenting the targeted activation task may additionally or alternatively involve playing an audible game or cognitive challenge over a speaker. Before presenting the targeted activation task, a predetermined time may be waited to allow the drug delivery system to cross the subject's blood-brain barrier. In operation 1008, the neurological disease therapeutic agent is released from the DDS at a physical location of a neurological functional system in the subject's brain. Depending on the DDS, the release of the neurological disease therapeutic agent may involve dissociating or exposing an active region of the neurological disease therapeutic agent. The neurological disease therapeutic agent is released based on the physical location where the targeted activation task causes a change in pH, lactate level, blood flow, temperature, magnetic field, or concentration of a specific molecule. That is, because the targeted activation task causes a predetermined physiological change at a physical location related to a neurological functional system, the neurological disease therapeutic agent is released at the physical location, rather than throughout the subject's brain, thereby reducing potential side effects of the neurological disease therapeutic agent.

[0036] How to test the prototype The method can be tested and refined, first in cell culture and then in mice. Mouse neuronal cells can be cultured on 60-channel 8 × 8 microelectrode arrays (MEAs). Experimental procedures can be followed in which a network of selected cultured cells in the MEA is "trained" to promote the growth of synaptic connections and the enhancement of synaptic-mediated responses to probe stimulation. Such trained systems have been demonstrated to be sensitive to inhibition of synaptic transmission by applying pharmacological agents to the culture medium. The system can be used to demonstrate pH-dependent local release from a DDS of drugs that reduce synaptic transmission and neuronal firing, such as the N-methyl-D-aspartate (NMDA) antagonist ketamine. Release from three variations of the DDS with different set points for pH-sensitive release can be compared. Local changes in pH associated with synaptic transmission and neuronal activity can also be measured.

[0037] In one experiment, 10 MEAs can be created for each experimental condition. Signals for spike detection can be recorded from each electrode at a rate of 25 kHz using a 300 Hz to 3 kHz bandpass filter. The spike detection threshold can be set to 5 times the standard deviation of the base noise level for 500 ms for each recording electrode individually. A subset of the electrode stimulation sites in an "L" configuration can be used to deliver probe stimulation to assess neuronal responsiveness before and after the presentation of training stimuli through the same electrodes. The probe pulse can include a 0.5 Hz biphasic pulse, 200 microsecond pulse duration with an amplitude of 900 mV. The training pulse can include a 40 pulse train, each containing 100 biphasic pulses with an interpulse period of 4 ms, a 200 microsecond pulse duration, and a pulse amplitude of 900 mV. Spike frequencies can be counted 50 ms after the stimulation pulse and divided into 10 ms bins with the following conditions (10 MEAs / condition): i. No training and no drug control MEA ii. Trained MEAs, no drugs iii. Using trained MEA and drug-free DDS iv. Use trained MEA, DDS+ketamine, but set the pH release sensitivity of the DDS well beyond the predicted range v. Trained MEA, using the drug ketamine vi. Using trained MEAs, DDS+ketamine, low DDS pH release sensitivity vii. Trained MEA, DDS+ketamine, using medium DDS pH release sensitivity viii. Using trained MEA, DDS+ketamine, high DDS pH release sensitivity

[0038] Conditions ii-iv may show higher spike counts than condition i, but no difference between conditions ii-iv. The difference between ii and i may demonstrate the validity of the training paradigm. The similarity of conditions ii, iii, and iv may demonstrate that the DDS alone or unreleased ketamine is inactive. Condition v, and conditions vi and / or vii and / or vii may show lower spike counts than condition ii. This indicates that the drug is successfully released from the DDS at one or more of the pH release sensitivities of the above conditions. The differences between conditions vi, vii, and viii provide important information for balancing the specificity and sensitivity of DDS release.

[0039] Testing and refinement in mice In vivo experiments in mice can be performed to demonstrate both the efficacy and specificity of localized drug release induced by localized neuronal activity associated with auditory or visual sensory stimulation. Using simple auditory or visual stimulation to induce localized release of drugs may not be limiting, but perhaps only to establish a prototype. Neural systems involved in cognitive processing or other brain functions can also be activated to induce localized release of drugs. In these experiments, cell firing and local pH in the auditory and visual cortex can be measured while the animals are receiving auditory or visual stimulation. Measurements can be designed to show drug release by the DDS associated with pH changes in the auditory cortex but not in the visual cortex with auditory stimulation, and conversely, pH changes in the visual cortex but not in the auditory cortex with visual stimulation. pH can be measured at single cell resolution using a surface-enhanced Raman scattering (SERS) optical physiological probe or another suitable method.

[0040] There are several well-established methods for measuring single neuron spike trains and small network activation in mice, each of which provides different types of additional information of potential added value. For example, one method combines patch clamp recordings using a commercially available recording system to measure spontaneous and evoked spike trains from individual neurons with ribonucleic acid (RNA)-based subtyping of individual neurons. Another method uses a wireless miniature fluorescent microscope capable of recording neuronal activity with single-cell resolution in freely moving mice. Synaptic agonists and / or antagonists delivered by pH-sensitive DDS to auditory or visual neural processing systems activated by sensory stimulation can be measured in groups of 5-10 mice. Neuronal activity can be measured in auditory and visual processing areas before and after auditory or visual stimulation under five pharmacological conditions: placebo, free drug, and drug in three DDSs with different pH release set points from 1 to 3. Sensory stimulation protocols are well established to elicit neural activity in the mouse auditory and visual cortex. Pulsed noise trains and pulsed visual stimuli can be used to increase extracellular lactate and alter extracellular pH.

[0041] Although specific embodiments of the present invention have been described, various modifications, variations, alternative constructions, and equivalents are also encompassed within the scope of the present invention. The embodiments of the present invention are not limited to operation in any particular specific environment, but are free to operate in multiple environments. Furthermore, while the embodiments of the method of the present invention are described using a particular sequence of operations and steps, it should be apparent to one skilled in the art that the scope of the present invention is not limited to the sequence of operations and steps described. Additionally, while embodiments of the present invention are described using a particular combination of hardware, it should be understood that other combinations of hardware are also within the scope of the present invention.

[0042] Accordingly, the specification and figures are to be regarded in an illustrative rather than a restrictive sense, but it will be apparent that additions, subtractions, deletions and other modifications and changes may be made therein without departing from the broader spirit and scope.

Claims

1. 1. A drug delivery system for use in a method for focally activating a neurological disease medication in the brain through a task by a subject, comprising: The drug delivery system has a drug for treating neurological diseases. the drug delivery system is configured to release a neurological disease therapeutic agent when encountering a predetermined pH, lactate level, blood flow, temperature, magnetic field, or specific molecules released by brain cells; The method is administering the drug delivery system to a subject; selecting a targeted activation task for the subject, the targeted activation task comprising a cognitive neuroscience task or a sensorimotor brain activation task; Presenting a subject with a targeted activation task, the targeted activation task being selected to change pH, lactate levels, blood flow, temperature, magnetic field, or concentration of a particular molecule at a physical location of a given neurological functional system in the subject's brain; and Releasing a neurological disease therapeutic from the drug delivery system at a physical location of a neurological functional system in the brain based on the physical location where the targeted activation task causes a change in pH, lactate level, blood flow, temperature, magnetic field, or concentration of a particular molecule. A drug delivery system comprising:

2. 2. The drug delivery system of claim 1, wherein the targeted activation task is a sensorimotor brain activation task, and the step of presenting the targeted activation task comprises instructing the subject to move a limb.

3. The drug delivery system of claim 2 , wherein the moving comprises rhythmically moving the drug.

4. The drug delivery system of claim 2 , wherein instructing comprises starting or stopping the moving.

5. The targeted activation task is a cognitive neuroscience task, and presenting the targeted activation task comprises: displaying interactive games or cognitive challenges on a video display; receiving interactive input from the subject; and Updating a video display in response to interactive input The drug delivery system of claim 1 , comprising:

6. The drug delivery system of claim 5 , wherein the video display comprises virtual reality goggles.

7. The targeted activation task is a cognitive neuroscience task, and presenting the targeted activation task comprises: playing an audible game or cognitive challenge over a speaker; and Receiving interactive input from a subject wherein the audible game or cognitive challenge is updated in response to interactive input. The drug delivery system of claim 1.

8. The method comprising: Measuring the releasing step with a sensor; and adjusting the length or intensity of the targeted activation task in response to values ​​obtained from the measuring step. The drug delivery system of claim 1 further comprising:

9. The method comprising: Adapting the targeted activation task based on changes in pH, lactate levels, blood flow, temperature, magnetic field, or concentrations of specific molecules in the subject's brain; and Stopping the targeted activation task when a predetermined dose of the neurological disorder therapeutic agent is estimated to be released.

9. The drug delivery system of claim 8, further comprising:

10. The drug delivery system of claim 1, wherein the method further comprises waiting a predetermined time for the drug delivery system to pass through the subject's blood-brain barrier before presenting the targeted activation task.

11. The drug delivery system of claim 1, selected from the group consisting of deoxyribonucleic acid (DNA) nanocages, cell delivery systems, microelectromechanical (MEM)-based devices, polymer matrices, and gene delivery systems.

12. 2. The drug delivery system of claim 1, wherein the step of releasing the neurological disease therapeutic agent comprises dissociating or exposing an active region of the neurological disease therapeutic agent.

13. The drug delivery system of claim 1 , wherein the subject is a human.

14. The drug delivery system of claim 13, wherein the human is suffering from a central nervous system disorder.

15. The drug delivery system of claim 14, wherein the central nervous system disease is a psychiatric disease.

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