Combining Non-Pharmacological Treatments with Pharmacotherapies for Neurological Disorders: A Unique Interface of the Brain, Drug–Device, and Intellectual Property

Mobile medical applications (mHealth), music, and video games are being developed and tested for their ability to improve pharmacotherapy outcomes and medication adherence. Pleiotropic mechanism of music and gamification engages an intrinsic motivation and the brain reward system, supporting therapies in patients with neurological disorders, including neuropathic pain, depression, anxiety, or neurodegenerative disorders. Based on accumulating results from clinical trials, an innovative combination treatment of epilepsy seizures, comorbidities, and the medication non-adherence can be designed, consisting of antiepileptic drugs and disease self-management software delivering clinically beneficial music. Since creative elements and art expressed in games, music, and software are copyrighted, therefore clinical and regulatory challenges in developing copyrighted, drug–device therapies may be offset by a value proposition of the exclusivity due to the patent–independent protection, which can last for over 70 years. Taken together, development of copyrighted non-pharmacological treatments (e-therapies), and their combinations with pharmacotherapies, offer incentives to chronically ill patients and outcome-driven health care industries.


INTRODUCTION
Mobile medical applications (mHealth apps) emerge as daily companions to help patients, clinicians, and pharmacists (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). There is a growing number of self-management applications including those for chronic pain (11,12), asthma (13), or mental health (14,15). One example of an FDA-cleared mobile therapy is Blue-Star®, the clinical and behavioral self-management platform for patients with type 2 diabetes, which was shown to improve control of glucose blood levels (16)(17)(18). Mobile medical applications cleared by the FDA range from diagnostic and monitoring platforms to a sound therapy or interactive medication reminders (19). The FDA intends to exercise enforcement discretion for mobile medical applications, which aim to help patients with disease selfmanagement or medication adherence, while those intended to perform medical device functions, may require approval or clearance (2). The exponential growth of mobile medical applications has resulted in a lag of reports from larger scale, randomized controlled trials (RCTs) to support their clinical utilities (3,20).
Interactive technologies targeting healthy behaviors and therapy outcomes include video games (21). Clinical utility of serious video games (e-therapies or therapeutic games) has been studied in patients with various chronic conditions including depression, Abbreviations: AEDs, antiepileptic drugs; FDA, Food and Drug Administration; IP, intellectual property; NSAIDS, non-steroidal anti-inflammatory drugs; PMA, premarket approval; RCTs, randomized controlled trials.
Parkinson's disease, asthma, diabetes, cancer, or stroke (22)(23)(24)(25)(26). Table S1 in Supplementary Material provides examples of mobile apps and games for the treatment of depression, anxiety, dementia, pain, attention deficit hyperactivity disorder (ADHD), and cerebral palsy. One example of a serious video game is "Re-Mission," a game specifically designed for cancer patients and shown to improve behavioral outcomes, cancer-related knowledge, and medication adherence during chemotherapy in adolescent patients with acute leukemia, lymphoma, and soft-tissue sarcoma (27,28). In RCTs, playing video games was found to be clinically effective in treating depression (25,29). The use of video games to modulate the brain neuroplasticity also improved age-related neuronal deficits and enhanced cognitive functions in older adults (30). Video games are explored as a preventive medicine strategy against HIV infections (31), or obesity (32). Fun and game-based principles (gamification) in serious video games are important elements when targeting intrinsic motivation to improve health behaviors (21). In 2014, the FDA cleared a motion-capture video game, developed by Jintronix as a rehabilitation system for stoke patients, or those with traumatic brain injury.
Music has been applied as a non-pharmacological treatment mainly for neurological conditions. The pleiotropic nature of music is mediated by neurochemical changes in the brain, endocrinological, and immune systems (33)(34)(35). A therapeutic potential of music to treat psychiatric disorders was recently reviewed (33). Recent studies show clinical applications of music for epilepsy patients (36,37), including listening to the Mozart K.448 sonata, which was shown to reduce frequency of epileptiform discharges (38)(39)(40)(41)(42)(43), and to reduce seizure frequencies (40,43,44). Music-supported therapies include indications such as pain (45)(46)(47)(48), stroke (49,50), dementia (51,52), depression (53), or anxiety (54,55). A therapeutic music video intervention was shown to improve resilience in cancer patients being treated with hematopoietic stem cells (56). Given popularity and convenience of listening to music, this non-pharmacological treatment can be easily incorporated into mobile medical applications.
Over the last decade, it has been recognized that a significant number of patients with chronic diseases fail to take medications as prescribed (57,58). Medication non-adherence is considered as a serious global health care problem (59). While clinical aspects of medication adherence are studied, economic costs of medication non-adherence are estimated as $100-290 billion per year in additional medical spending paid by the US health care (57) and $564 billion in lost revenues of the global pharmaceutical industry (60). Current strategies to improve medication adherence include less frequent dosing, extended-release formulations, novel drug delivery devices, providing external incentives, or support-based interventions. Medication non-adherence is a patient behavioral aspect associated with all chronic diseases. Health care industry is embracing gamification and electronic platforms in patient care (61). Clinical studies of mobile medical applications, serious video games, or music show their promise as tools to improve therapy outcomes, disease self-management, or medication adherence for chronically ill patients ( Figure 1A). This article discusses opportunities for creating and clinical development of non-pharmacological treatments, which can be integrated into specific combination therapies for chronic diseases.

INTEGRATING GAMIFICATION AND MUSIC INTO THERAPIES -DOPAMINERGIC CONNECTIONS
FDA-cleared mobile and video game therapies, such as BlueStar® and Jintronix Rehabilitation System, show new opportunities to integrate drugs with devices, thereby bridging pharmacotherapies with disease self-management. Figure 1B shows an example of pharmacotherapy in combination with a mobile platform for the treatment of diabetes. Since studies encourage clinical use of music for pain relief (48,62,63), parallel needs for more personalized treatments of neuropathic pain and for improving pain relief (64) can be addressed by a combination of an appropriate analgesic and pain self-management platforms with music and games for pain relief. Therapeutic interactive voice response has been shown to reduce use of opioids and non-steroidal antiinflammatory drugs (NSAIDs) (65). Cancer patients may benefit from combining chemotherapy with a serious video game, such as "Re-Mission" (27,28) or the Patient Empowerment Exercise Video Game (22) which target comorbidities including depression, anxiety, or fatigue. Gamification is a tool to engage intrinsic motivation using such features as choice and decision-making, levels and challenge, fantasy and curiosity (66). Therapeutic video games and self-acquired rewards engage the brain reward system in active players (67, 68), therefore integrating gamification into self-management platforms is also useful for motivating and

FIGURE 1 | Examples of drug-device interfaces created by mobile medical applications, serious video games, or music. (A)
Electronic devices are used to provide music, games, and mobile medical applications, while also becoming delivery systems for disease self-management platforms. (B) An example of combining pharmacotherapies with medical devices for the treatment of diabetes. Mobile therapies, such as BlueStar®, can support disease-specific, healthy behaviors of a patient, and remind about taking prescribed medications on-time.
rewarding patients while learning and reinforcing disease-specific healthy habits.
Studies on physiological effects of music and games begin to indicate multiple effects on the nervous and endocrine systems, including music-induced modulation of various neurotransmitters and hormones (34,35). An overlapping mechanism of gaming and music includes activation of the mesolimbic system and dopaminergic neurotransmission in the brain (67)(68)(69)(70)(71)(72). Game-or music-evoked dopamine release involving dopamine D2 receptors was shown by positron emission tomography using 11C-labeled raclopride (69,71). Table S2 in Supplementary Material provides examples of functional magnetic resonance imaging (fMRI) studies aimed to elucidate music or games mechanism of actions. Both gaming and music activate nucleus accumbens in the mesolimbic reward circuitry, as well as parts of prefrontal cortex (67,68,72,73). Mesolimbic dopamine plays important roles in learning and motivation (74,75), thus activation of the dopaminergic signaling by therapeutic games or/and tailored music can facilitate behavioral and pharmacological interventions in patients. Targeting the dopamine system by playing video games improved symptoms in schizophrenia patients (76), whereas clinical studies of games for depression (25) or Parkinson's disease (24,77), encourage similar strategies for migraines or addiction. Taken Frontiers in Neurology | Epilepsy together, the dopaminergic mechanisms of music and games offer opportunities for coupling the pleasurable brain reward system with intrinsic motivation and the formation of healthy habits, resulting in unique disease self-management platforms. Given pleiotropic effects of music and games, mechanism-based combinations of these non-pharmacological treatments with specific drugs can improve therapy outcomes for various neurological diseases.

REDEFINING A COMBINATION THERAPY FOR EPILEPSY
Designing innovative drug-device combination therapies can be illustrated using the treatment of epilepsy. Managing epilepsy is challenging due to: (i) significant resistance to antiepileptic drugs (AEDs), (ii) compromised medication adherence, and (iii) significant prevalence of comorbidities, such as anxiety or depression (78). Despite many AEDs approved for the treatment of epilepsy (Figure 2A), estimated 25-40% of patients with epilepsy are refractory to current AEDs (79). An approximate 50-60% medication adherence rate among epilepsy patients results in increased risks of seizures and mortality (80)(81)(82), while the main comorbidity, depression, is also difficult to treat with antidepressant drugs (83). To help epilepsy patients with disease selfmanagement, currently available mobile devices include a Smart-Watch, which is capable of detecting movements associated with seizures, as well as mobile applications helping to self-report and record seizures, manage medications, or learn more facts about epilepsy.
Accumulating clinical evidence suggests that listening to the Mozart's K.448 results in reduction of generalized and focal seizures in epilepsy patients (36,37). The K.448 was also effective in reducing seizure frequencies in children with pharmacoresistant epilepsy (84), and in patients following their first unprovoked seizures (43). Using simultaneous electroencephalogram and electrocardiogram recordings, the reduction of epileptiform discharges by K.448 and K.545 was shown to be accompanied by activation of the parasympathetic system (42). While an anticonvulsant mechanism of action for audiogenic stimulation remains unknown, reports also suggest a role of mirror neurons or/and neurotransmitters pathways including the dopaminergic system (36,37). Genetic, pharmacological, and imaging studies support the dopamine signaling in epilepsy and epileptogenesis, including D2 receptors (85)(86)(87)(88).
To improve pharmacotherapy, manage comorbidities and medication adherence for epilepsy patients, the drug-device combination therapy can include a specific AED and a matching medical device delivering non-pharmacological elements ( Figure 2B). The most apparent non-pharmacological component could be music, which reduces seizures [such as the Mozart's K.448 or K.545 (41)]. To treat symptoms of depression or anxiety, often experienced by epilepsy patients, the self-management platform can include a game comprising cognitive behavioral therapy elements (29), or even a combination of music and games as musical games. Such platforms may also help manage seizure-precipitating stress by modulating cortical responses (89). Noteworthy, a longterm stimulation of nucleus accumbens can decrease seizure severity (90), while integrating music into the treatments of

FIGURE 2 | Integrating antiepileptic drugs into a copyrighted combination therapy for the treatment of epilepsy. (A) Examples of generic antiepileptic drugs. (B)
Designing an integrated combination therapy consisting of antiepileptic drugs and copyrighted non-pharmacological components delivered by an electronic device. While antiepileptic drugs and music can treat epileptic seizures, a self-management digital platform can include specifically designed games for the treatment of depression or anxiety. epilepsy comorbidities was recently emphasized (91). Additional non-pharmacological components delivered by the medical device can include medication adherence reminders and other features to self-report and track seizures. This integrated treatment may appeal to pediatric epilepsy patients, since non-adherence to AEDs within the first 6 months significantly affects long-term rates of becoming seizure-free (92).
Creating therapeutic music to reduce epileptic seizures extends to translational research, since music can be subject to preclinical screening [for example, in such indications as addiction (93)]. In animal testing, exposure to the Mozart K.448 resulted in: (i) reduction of spontaneous absence seizure and high-voltage rhythmic spike discharges in Long Evans rats (94), (ii) increased dopamine levels in rat brains (95), and (iii) decreased corticosterone (95,96). Positive effects of the K.448 music on spatial-temporal learning were reported for rats and mice (97)(98)(99). Since clinical data suggest that K.448 can reduce seizures in patients with refractory epilepsy (84), studies on interactions between K.448 and AEDs in animal models of epilepsy may help to elucidate the mechanism of action of K.448 while increasing the potency of the AEDs. Comparing preclinical and clinical effects of music in other medical indications, such as depression, anxiety, addiction, or neurodegenerative disorders may validate the translational research for using specific auditory stimulations with drugs.

COPYRIGHTS AS INCENTIVES FOR CREATING NON-PHARMACOLOGICAL TREATMENTS
An incentive for creating and clinical development of nonpharmacological therapies can be their copyrighted works, which are protected by the intellectual property (IP) law. Unlike patents protecting ideas, copyright protects the expression of an idea found in creative elements and art found in digital media, software, electronic games, and music. In the US, the Copyright Act of 1976 offers the benefit a long-term protection lasting not less than 70 years, and up to 120 years. Copyright protection is automatic as soon as it is created, although a copyright registration offers legal advantages in case of any future infringements. Furthermore, copyright is recognized and protected in most countries under national and international law through the Universal Copyright Convention and the Berne Convention which the US joined as a member in 1955 and 1989, respectively.
In a web-based era, developing games or music intended for clinical use create opportunities for "off-label" uses, whereas classical music which exists in public domain (such as Mozart's K.448 or K.545 sonatas) presents the exclusivity challenge. Re-recording of specific pieces of classical music may offer recording copyrights, while re-composing and modifying individual pieces of publicdomain music intended for clinical development may offer an additional level of protection before evaluating therapeutic claims. The copyright protection for the music created, re-composed, and recorded "for hire" can last 120 years. Clinically validated music can be used as a "stand-alone" non-pharmacological therapy, or can be integrated into disease self-management digital platforms or therapeutic games (Figure 2B). The Digital Millenium Copyright Act from 1998 is the law protecting copyrighted art and works used in digital media against infringement and piracy. In contrast to music, electronic and video games pose complex copyright challenges due to multiple components of art involved in digital technologies (100).

OPPORTUNITIES AND CHALLENGES OF THE COPYRIGHTED COMBINATION THERAPIES
Using mobile applications, playing electronic games, or listening to music are daily practices of many patients taking medications. As mentioned earlier, games and music target intrinsic motivation and the reward system, becoming useful "personalized medicine" tools to improve patient compliance with their prescribed pharmacotherapies. For chronically ill patients at risk for medication non-adherence, gamification strategies are alternatives to providing external incentives to reinforce taking drugs as prescribed, given that patient motivation may decrease once incentives are discontinued (101). Combination of pharmacotherapy and gamification can improve treatments for chronic diseases with inflammatory components (such as rheumatoid arthritis), which can be lessen by behavioral changes and self-management platforms (102). Given advances in genomics, individuals carrying mutations in susceptibility genes for chronic diseases may benefit from non-pharmacological and behavioral interventions. In addition to encouraging development of preventive medicine strategies, copyrights can also provide incentives to create innovative treatments for rare genetic disorders, for example epileptic encephalopathies.
Since medication non-adherence affects approximately half of the prescribed therapeutics for chronic disorders, drug discovery and clinical development efforts will benefit from applications of the copyrighted combination therapies due to integration of pharmacotherapy outcomes and medication adherence. This aspect becomes important when translating discoveries of new molecular targets into combination therapies: for example, the treatment of epilepsy emphasize needs for network-based polypharmacies (103). Copyrighted therapies may also encourage clinical development of new combination therapies with clinically beneficial compounds existing in public domain (e.g., curcumin), due to the IP exclusivity under the premarket approval (PMA) application. Copyrighted combination products may appeal to developing therapies for neurodegenerative diseases. For example, having 70 years protection of the copyrighted combination therapy for the Alzheimer disease would facilitate balancing decisions between clinical and business objectives related to lengthy clinical trials. Pharmaceutical industry is recognizing both opportunities and challenges in applying mobile medical applications and gamification in patient care (104,105). Since changing patent guidelines can affect drug discovery efforts (106), copyrights can provide incentives to transform generic drugs into innovative treatments of chronic diseases with improve medication adherence and outcomes.
Herein, it is prudent to emphasize challenging times for the regulatory agencies and for those who seek approval/clearance of mobile medical applications and their combinations with pharmacotherapies (1,107). Integrating drugs with devices is commonly associated with combination products such as pen injectors and insulin, transdermal patches, drug-eluting stents, or drug creams with light sources (108,109). The long-term prospects of the copyrighted combination therapies include becoming the combination products. For example, given advancements in medical technologies at the interface of drugs and devices, the FDA established the Office of Combination Products (110,111). Efforts to reach PMA applications for the copyrighted combination products may be incentivized by the long-term exclusivity of specific medical treatment due to the copyright protection. Creation, translational research, and clinical validation of copyrighted non-pharmacological treatments is a long and challenging frontier, requiring cross-technological interactions among pharmaceutical-biotech companies, electronic and mobile devices, and those providing the creative works such as software, video games, or music.
Clinical development of the non-pharmacological therapies like therapeutic games or music, and their combinations with the pharmacotherapies, carry inherent risks related to safety (adverse effects) and efficacy (tolerance, addiction). Developing tolerance to non-pharmacological treatments is unknown, whereas addictive properties of gaming can be addressed by appropriate design features. Current understanding of mechanisms of musicogenic seizures and photosensitive epilepsy can facilitate designing music and games to avoid proconvulsant properties. Incorporation of features such as patient preference to have choices in selecting music for the therapy is offset by unknown variables in response to music due to differences in a patient genetics and personality [for example individual responses to music for pain treatment Frontiers in Neurology | Epilepsy were reported (63)]. Large-scale RCTs will test therapeutic utility of non-pharmacological treatments and their combinations with drugs, and will advance clinical knowledge and design of such innovative treatments for neurological and other chronic medical conditions.

CONCLUSION
Taken together, creating and developing copyrighted music, games, and medical software to be combined with pharmacotherapies provides an opportunity to deliver novel treatments for patients with neurological and other chronic diseases. Neurosciencecentered, innovative drug-device platforms can facilitate delivery of more personalized and integrated treatments of the target disease and associated comorbidities, resulting in improved therapy outcomes and medication adherence. Mechanism-based combinations of pharmacotherapies with non-pharmacological treatments offer win-win solutions for all health care stake-holders.

ACKNOWLEDGMENTS
The NIH Grant U01 NS 066991 is acknowledged during Grzegorz Bulaj's sabbatical leave. I would like to thank my colleagues involved in discussions about non-pharmacological treatments in clinical and pharmacy practices. I thank Professors Julie Korenberg, Mark Munger, Harold Wolf, and Steve White, and attorneys Seth Mailhot and Bradley Sanders for their feedback and helpful comments on the manuscript. I thank my family and friends.