THE results of the experiments in which purified lecithine from two sources, egg yolk and fresh beef liver, has been shown to prevent deposition of fat in the livers of normal rats [Best, Hershey and Huntsman, 1932] have led us to study the effects of feeding various components of lecithine. It appeared possible that the oleic or other unsaturated fatty acid, the glycerophosphate, the choline, some combination of two or more of these factors, or the whole lecithine molecule, might be the active agent. The general procedure in this series of experiments has been to substitute for the lecithine in the daily diet of each rat the amounts of glycerophosphate, oleate, or choline, which it is calculated might be derived from 0 5 g. of purified lecithine. This amount of lecithine was previously found to be effective in preventing the deposition of fat in the livers of normal white rats, each of which ingested daily for 3 weeks approximately 2x5 g. of fairly well-saturated fat.

Digital health technologies for people with epilepsy (PWE) include internet-based resources and mobile apps for seizure management. Since non-pharmacological interventions, such as listening to specific Mozart's compositions, cognitive therapy, psychosocial and educational interventions were shown to reduce epileptic seizures, these modalities can be integrated into mobile software and delivered by mobile medical apps as digital therapeutics. Herein, we describe: (1) a survey study among PWE about preferences to use mobile software for seizure control, (2) a rationale for developing digital therapies for epilepsy, (3) creation of proof-of-concept mobile software intended for use as an adjunct digital therapeutic to reduce seizures, and (4) broader applications of digital therapeutics for the treatment of epilepsy and other chronic disorders. A questionnaire was used to survey PWE with respect to preferred features in a mobile app for seizure control. Results from the survey suggested that over 90% of responders would be interested in using a mobile app to manage their seizures, while 75% were interested in listening to specific music that can reduce seizures. To define digital therapeutic for the treatment of epilepsy, we designed and created a proof-of-concept mobile software providing digital content intended to reduce seizures. The rationale for all components of such digital therapeutic is described. The resulting web-based app delivered a combination of epilepsy self-care, behavioral interventions, medication reminders and the antiseizure music, such as the Mozart's sonata K.448. To improve long-term patient engagement, integration of mobile medical app with music and multimedia streaming via smartphones, tablets and computers is also discussed. This work aims toward development and regulatory clearance of software as medical device (SaMD) for seizure control, yielding the adjunct digital therapeutic for epilepsy, and subsequently a drug-device combination product together with specific antiseizure medications. Mobile medical apps, music, therapeutic video games and their combinations with prescription medications present new opportunities to integrate pharmacological and non-pharmacological interventions for PWE, as well as those living with other chronic disorders, including depression and pain.

THE very interesting effects of some component of crude lecithine upon the condition of diabetic animals have been discussed in previous communications from this laboratory [Hershey, 1930;Hershey and Soskin, 1931;Best and Hershey, 1932]. The symptoms exhibited by these animals and the autopsy findings indicate that the characteristic condition is largely attributable to failure of liver function. The results of these studies suggested that an investigation of the effect of lecithine on deposition of fat in the livers of normal animals might be profitable. 'The literature relevant to this subject has been reviewed in the monographs byLeathes and Raper [1925] and byMacLean and MacLean [1927]. As far as we know, the particular problem in which we are interested has not been investigated by previous workers. The experiments -were planned with a view to obtaining deposition of large amounts of fat in the livers of a group of control animals. This was accomplished by feeding a diet high in fairly saturated fats. A second group of animals comparable in every way, as far as we could determine, with the controls, received the same amount of fat as those in the control group and in izdition varying amounts of crude or purified lecithine. The results demonstrate, among other points, that crude and purified lecithine influence the accumulation of fat in the livers of the test group of animals. METHODS.White rats of the Wistar strain, weighing between 150 and 230 g., were used as test animals. Previous to the experiment they had been receiving a stock diet which was adequate in all respects. All the animals used in the experiment were apparently healthy, and great care was taken to ensure that the various groups into which they were divided for any one experiment were as similar as possible. Much time was wasted

Digital therapeutics (software as a medical device) and mobile health (mHealth) technologies offer a means to deliver behavioral, psychosocial, disease self-management and music-based interventions to improve therapy outcomes for chronic diseases, including pain and epilepsy. To explore new translational opportunities in developing digital therapeutics for neurological disorders, and their integration with pharmacotherapies, we examined analgesic and antiseizure effects of specific musical compositions in mouse models of pain and epilepsy. The music playlist was created based on the modular progression of Mozart compositions for which reduction of seizures and epileptiform discharges were previously reported in people with epilepsy. Our results indicated that music-treated mice exhibited significant analgesia and reduction of paw edema in the carrageenan model of inflammatory pain. Among analgesic drugs tested (ibuprofen, cannabidiol (CBD), levetiracetam, and the galanin analog NAX 5055), music intervention significantly decreased paw withdrawal latency difference in ibuprofen-treated mice and reduced paw edema in combination with CBD or NAX 5055. To the best of our knowledge, this is the first animal study on music-enhanced antinociceptive activity of analgesic drugs. In the plantar incision model of surgical pain, music-pretreated mice had significant reduction of mechanical allodynia. In the corneal kindling model of epilepsy, the cumulative seizure burden following kindling acquisition was lower in animals exposed to music. The music-treated group also exhibited significantly improved survival, warranting further research on music interventions for preventing Sudden Unexpected Death in Epilepsy (SUDEP). We propose a working Metcalf et al. Music-Enhanced Analgesic and Antiseizure Activities model of how musical elements such as rhythm, sequences, phrases and punctuation found in K.448 and K.545 may exert responses via parasympathetic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis. Based on our findings, we discuss: (1) how enriched environment (EE) can serve as a preclinical surrogate for testing combinations of non-pharmacological modalities and drugs for the treatment of pain and other chronic diseases, and (2) a new paradigm for preclinical and clinical development of therapies leading to drug-device combination products for neurological disorders, depression and cancer. In summary, our present results encourage translational research on integrating non-pharmacological and pharmacological interventions for pain and epilepsy using digital therapeutics.

IN previous communications from this department and from the School of Hygiene, the effect of choline in preventing the deposition of fat in the liver of the white rat has been discussed. In this paper the action of choline in accelerating the removal of fat from the livers of these animals will be reported. Choline is found to be effective in curing as well as preventing the condition in white rats, as it does in the diabetic dog [Best, Ferguson and Hershey, 1933]. Not only does the fat disappear from the liver but there is definite improvement in the histological appearance of the liver cells [Best and MacL ean, 1934]. The significance of the presence of choline, or of substances with similar action on liver fat, in feeding experiments with rats, will be made clear. METHODS.The white rats were of the Wistar strain which we have used previously, and were supplied from the Connaught Laboratories' colony The fatty livers were produced by feeding the stock diet of mixed grains to which beef fat had been added. This diet was the same as that used in previous experiments. The choline and the casein free from vitamins and from fat were obtained from the British Drug Houses. In the absence of sufficient amounts of a more satisfactory choline-free carbohydrate, commercial sucrose was used. The vitamin A, B1 and D preparations were provided by Ayerst, McKenna and Harrison, Ltd. The total choline estimations were made by acetylation of the choline after acid hydrolysis of the mixture containing it and comparison of the acetylcholine with standard acetylcholine, using the isolated intestine of the rabbit. Liver and body fat was estimated by the saponification procedure. The iodine numbers were determined by the R osenmund-Kuh nhenn method. PH. LXXXIII. 17