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Epi-Cease : A Non-Invasive Closed-Loop Transcranial Direct Current Stimulation (tDCS)-based Device for… Adibi, Mohammad Amin; Poologaindran, Anujan Apr 17, 2016

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         Epi-Cease: A Non-Invasive Closed-Loop Transcranial Direct Current Stimulation (tDCS)-based Device for Antiepileptic Drug Resistant Epilepsy  Amin Adibi, Anujan Poologaindran The University of British Columbia April 2016 Final Project - BMEG591P   © Amin Adibi and Anujan Poologaindran, 2016 	 	  2  B. Abstract Epilepsy is a chronic neurological disorder characterized by recurrent and unprovoked seizures due to abnormal electrical activity in the brain. Unfortunately, this disorder affects 50 million people worldwide and of all ages, making it the fourth most common neurological disorder. As a result, epilepsy reduces an individual’s quality of life and provides a challenge for family members and caregivers. Over the last few decades, many advances have been made in effectively treating and controlling epilepsy. Today, a focused history, physical examination, blood work, and video-EEG are all part of the standard protocol in the accurate and timely diagnosis of epilepsy. Once the epileptic etiology is identified, anti-epileptic drugs (AED) represent a first-line pharmacological treatment for these patients. Unfortunately, a portion of patients do not respond to multiple AEDs and may display dose-dependent side effects that warrant AED discontinuation. These patients are considered for neurosurgical intervention after case and extensive review. Many centres, including Vancouver General Hospital, employ temporal lobectomy for focal temporal lobe epilepsies. This procedure is quite effective for a small portion of patients but is highly invasive and can lead to complications in verbal memory in 0.4-4% of patients. More importantly, brain surgery is not for all patients and can only be applied to patients suffering from temporal lobe seizures. The goal of this proposal is to “non-invasively reduce the frequency, duration and/or severity of seizures in drug-resistant focal epilepsy patients”. Particularly, we set out to circumvent the highly invasive nature of brain surgery and its limited widespread use. Moreover, we wished to develop a technology that would non-invasively “abort” seizures in real-time. Our proposed solution, Epi-Cease, is a non-invasive closed-looped system that consists of a wearable head-strap tDCS (transcranial direct-current stimulation) that delivers non-invasive stimulation to abort a seizure. This device will communicate with an Apple Watch that will detect seizures based on motion sensing and physiological data. When detecting the onset of a seizure, the Apple Watch app will signal the tDCS module to deliver stimulation to the brain in real-time in order to suppress/abort seizure initiation.To assess the safety and efficacy of Epi-Cease, we will conduct a two-staged proof-of-concept study. First, we will validate the Apple Watch motion-sensing and physiological data app compared to traditional methods of epilepsy monitoring. Once validated, we will then recruit a small cohort (n=3) of low-risk epilepsy patients to test the technology before expansion. This technology would represent a quantum leap forward in the care of epilepsy patients as it would be the first, real-time non-invasive solution to abort seizures and effectively control focal epilepsies.     3  Table	of	Contents	B.	 Abstract .............................................................................................................................................. 2	C.	 Introduction and Discussion ............................................................................................................ 4	The Clinical Problem ........................................................................................................................................... 4	Current Practice ................................................................................................................................................... 5	Diagnosis ............................................................................................................................................................ 5	Pharmaceutical Treatment .................................................................................................................................. 5	Surgical Treatment ............................................................................................................................................. 6	Challenges to Current Approach ........................................................................................................................ 7	Investigational Products ...................................................................................................................................... 7	Device-Based Treatment of Seizures ................................................................................................................. 7	Device-Based Prediction/Detection of Seizures ................................................................................................ 9	D.	 Addressing the Challenge ............................................................................................................... 10	Objectives of the Proposed Innovation ............................................................................................................. 10	Proposed Solution: Epi-Cease ........................................................................................................................... 10	Technology .......................................................................................................................................................... 11	Preclinical and Clinical Evidence .................................................................................................................... 12	Safety ................................................................................................................................................................ 12	Impact ............................................................................................................................................................... 12	E.	 Future Directions ............................................................................................................................ 13	Proof-of Concept Clinical Study ....................................................................................................................... 13	F.	 References ........................................................................................................................................ 15	        4  C. Introduction and Discussion  Ever since the beginning of recorded history, humans have been fascinated by epilepsy, have written about it, have been affected by it, and have speculated about the causes of it. Our understanding of epilepsy - the disease that was once thought to be a spell from the moon god - has evolved substantially over the last millennia. However, despite tremendous advances in treating epilepsy, millions of people still carry the social, economical, and health-related burdens of the disease.  In this section, we have reviewed basic mechanisms behind seizures and epilepsy syndromes and discussed the current clinical practice, investigational treatments and challenges that remain to be addressed. In the next few sections, we make a case for a novel solution that aims at improving the current practice and addressing its shortcomings.  The Clinical Problem Seizures are disruptions in brain function due to abnormal hypersynchronous firing of neurons in the brain cortex (Miller et al., 2014). Not all seizures are epileptic; psychogenic or pseudo-seizures can result in similar clinical symptoms with no abnormal hypersynchronous neuronal firing. Certain clinical conditions (such as hypoglycemia) may cause seizures in otherwise healthy people (Miller et al., 2014).  Epilepsy is defined as recurrent unprovoked seizures, of which there needs to be at least two before the diagnosis is made. It is important to underscore the heterogeneous nature of epilepsy; it is rather an umbrella term, that refers to a group of diseases with different clinical manifestations, pathophysiology and underlying etiologies (Miller et al., 2014). Traditionally, epileptic seizures have been categorized as either focal or generalized. Focal seizures can be traced back to a localized region in the brain. Naturally, the symptoms will depend on the functions that are controlled by the affected region in the brain. For instance, a seizure arising from the left motor cortex could result in rhythmic jerking in the upper right limb.  Neuronal discharges may remain in the vicinity of the point of origin or spread, locally, or distally. A focal seizure can spread to engulf the entire brain in a process known as secondary generalization (Miller et al., 2014).  In generalized seizures, abnormal firing starts simultaneously in both hemispheres; the resulting clinical presentation could be as subtle as a brief moment of staring and unresponsiveness, as in absence seizures, or as severe as tonic-clonic or grand mal seizures, in which the patient typically loses consciousness and collapses, before undergoing a brief (<60s) episode of muscle stiffening, followed by violent jerking of extremities for another 30-60 seconds (Miller et al., 2014). Seizures are characterized by a post-spell confusion state, known as the post-ictal state, which generally lasts 5-30 minutes (Miller et al., 2014).  Epileptic patients are predisposed to seizures, either genetically or as a result of a structural anomaly - such as a brain tumour or a head trauma- that triggers epileptogenesis, which is the process that turns normal neuronal circuits into hyperexcitable ones (Miller et al., 2014). While we know that   5 epileptogenesis can happen over the course of months to years, details of underlying mechanisms remain poorly understood (Miller et al., 2014).  The pathophysiology of epilepsy involves two hallmark features at neuronal level: hyperexcitability and hypersynchrony. Hyperexcitability - in simplistic terms - results from an imbalance between excitation and inhibition, with the former being abnormally increased and/or the latter decreased (Miller et al., 2014). Both of these etiologies can be caused by a number of pathologies, including but not limited to, mutations in potassium or sodium channels, decreased GABA synthesis, abnormality in inhibitory GABA receptors, abnormal structure of dendrites, and altered neuronal circuits, among others. The choice of AED is based on the specific epilepsy syndrome and its underlying pathophysiology (Miller et al., 2014).   Current Practice  Diagnosis  The current practice for diagnosing epilepsy involves a focused history, blood work, neuroimaging, and physical exam (Engel et al., 1982). A focused history to conducted to determine the onset, past history of seizures, drug and alcohol-induced or exacerbation of seizures, and associated seizure symptoms (Chen et al., 2011). A physical exam is conducted to help further pinpoint a specific epileptic etiology.  Bloodwork is also an important factor in the workup of epilepsy patients in order to identify abnormalities in electrolytes, glucose, ethanol levels and perform toxicology screens. CT/MRI is also completed for seizures without identified cause or known seizure history. Video-EEG is a key mainstay in the characterization of epilepsy and to also localize epileptic foci (Engel et al., 1982) (Wiebe et al., 2001) (Lozano et al., 2009). The importance of accurate diagnosis to to help avoid precipitating factors, guide medical therapy, identify psychosocial issues, and obviate safety concerns such as driving and operating heavy machinery. Most importantly, for treatment-refractory epilepsy patients, accurate diagnosis can result in an early-referral to surgical intervention as well.  Pharmaceutical Treatment Anti epileptic drugs (AED) are often a first-line treatment for epilepsy. The drug of choice depends usually on an accurate diagnosis of the epileptic syndrome, as response to specific anticonvulsants varies among different epileptic etiologies. AEDs may vary based on absence, tonic or atonic, myoclonic, and tonic-clonic seizures. On classification, AEDs can be categorized by their mechanistic properties. Some drugs are blockers of repetitive activation of sodium channels, while others are enhancers of slow inactivation of the sodium channels. There are also AEDs that are channel-specific blockers or enhancers and choice of drug is largely dependent on the type of seizure and etiology (Chen et al., 2011)(Lozano et al., 2009). Generalized-onset and partial-onset seizures are treated by AEDs such as felbamate and lamotrigine. Partial seizures (simple partial, complex partial and secondarily generalized seizures) are treated by carbamazepine and gabapentin (Lozano et al., 2009). It has been noted, however, these drugs may exacerbate generalized seizures. A common problem with these drugs is that they have an increased risk of potentially causing liver failure and thus, limit the drug’s usage for severe epilepsy cases.    6 Surgical Treatment Medically refractory seizures are generally defined as seizures resistant to two first line anti-seizure medications used in succession (Rob et al., 1975)(Engel et al., 1982)(Marks et al., 1992). These patients should be considered for neurosurgical intervention if they meet the appropriate criteria. The goal of epilepsy surgery is to identify an abnormal area of the cortex from which the seizures originate and remove it without causing any functional deficits.  A critical component in the pre-operative stage is to identify the distinct epileptogenic region through clinical history, video-EEG monitoring, MRI, and neuropsychological testing. Other localizing investigations include SPECT, PET, and magnetoencephalography (Lozano et al., 2009). The box below summarizes the 4 questions the surgeon needs to answer during the pre-operative surgical evaluation.  At Vancouver General Hospital, many patients are often videotaped over a period of time in the pre-operative phase to monitor and help localize epileptogenic regions and better guide surgery. If a distinct epileptogenic region cannot be identified, the patient will be considered for a palliative surgical procedure such as corpus callosotomy or hemispherectomy.   Table 1 Major Surgical Questions (Lozano et al, 2009) 1. Are seizures focal or generalized? 2. If focal, are they temporal or extratemporal in origin? 3. Is there a tumour or vascular malformation associated with the seizures? 4. If surgery is undertaken, what functional deficits, if any, might be anticipated?  For adults, resecting the hippocampus and parahippocampal gyrus for mesial temporal lobe epilepsy arising from mesial temporal sclerosis is a safe and established option. For children, resection of an epileptogenic space-occupy lesion, for example temporal lobectomy, results in the most benefit (Chen et al., 2011).  In 2001, a landmark Canadian randomized controlled trial of surgery was conducted to evaluate the efficacy and safety of neurosurgery for temporal lobe epilepsy (Wiebe et al., 2001). 80 patients with poorly controlled temporal lobe epilepsy were randomized for surgery (n=40) or continued pharmaceutical treatment (n=40). The primary endpoint was cessation of seizures that impair awareness of self and surroundings during a period of 12 months post-operatively.  Secondary outcomes included factors such as frequency and severity of seizures, quality of life, disability and death. The results of the trial were practice-changing. The surgical group had higher proportion of patients without seizures impairing awareness compared to the pharmaceutical group (p<0.01). The surgical group also had lower seizure frequency and higher quality of life (p<0.001). Adverse events included thalamic infarct, wound infection, and verbal memory decline in 10% of patients. The authors concluded that temporal lobectomy is superior to prolonged pharmaceutical therapy for temporal-lobe epilepsy.    7 The neurosurgical field has established positive predictive factors for seizure freedom following temporal lobectomy. These factors include hippocampal sclerosis (unilateral), focal localization of interictal epileptic discharges, absence of pre-operative generalized seizures, and complete resection of the lesions (Wiebe et al., 2001). The following chart summarizes outcomes following neurosurgery for epilepsy.  Table 2 Outcomes after Temporal Lobectomy ·      41-79% of adult patients are seizure free for 5 years after temporal lobectomy ·      58-78% of children are seizure free after surgery ·      Interestingly, surgery is associated with improvements in pre-existing psychiatric conditions such as depression and anxiety, as well as improvement in quality of life measures (Chen, 2011) Challenges to Current Approach Keeping with the spirit of BMEG 591, we were tasked to criticize and circumvent the limitations of modern neurosurgery for epilepsy. It is important to view these limitations from both a technical and morbidity point-of-view. First, temporal lobectomy, while effective, is highly invasive and requires long hospitalization. Particularly, recovery from the surgery can take weeks due to the craniotomy and large resection of neural tissue.  Unfortunately, 0.4-4% of surgical patients will have partial hemianopsia, aphasia, motor or sensory deficits, or cranial nerve palsy following temporal lobectomy. Majority of surgical patients will have some decline in verbal memory following dominant temporal lobectomy and in visuospatial memory in non-dominant temporal resection (Chen et al., 2011). It has been promulgated that the degree of memory decline stabilizes after 1-2 years. This deficit might be tolerable in adults but pose a challenge for the developing child. Investigational Products The Epilepsy Foundation estimated more than 100 epilepsy-related products at various pipeline stages (Epilepsy Foundation, 2016). This includes new pharmaceuticals, enhanced drug-delivery methods, novel surgical techniques, dietary supplements and medical devices. Devices can be further categorized into safety and therapeutic devices. While safety devices are aimed at alarming the patient and/or caregivers of an upcoming or ongoing seizure, therapeutic devices focus in delivering some sort of medical intervention - usually in the form of nerve stimuli - to prevent or stop a seizure event.   Device-Based Treatment of Seizures  It is important to underscore that therapeutic medical devices do not cure epilepsy; no medical device has ever made any patient seizure-free; however, some clinical studies have shown significant reduction in number of seizures upon application of certain medical devices. Broadly speaking, therapeutic epilepsy devices fall under two categories: open and closed-loop devices. Open-loop devices generally deliver the intervention either continuously, or at certain predefined time points. In contrast, closed-loop systems utilize a seizure prediction or detection system to deliver their respective intervention only when necessary.    8 Device-based treatment modalities so far have been - for the most part - based on nerve stimulation, applied to either peripheral nerves as in Vagus Nerve Stimulation (VNS) (Gurbani et al., 2016) and external Trigeminal Nerve Stimulation (eTNS), or the brain itself as in Transcranial Magnetic Stimulation (TMS), Deep Brain Stimulation (DBS) (Salanova et al., 2015) or Transcranial Direct Current Stimulation (tDCS). The idea behind brain stimulation is to change tissue excitability. Animal studies have shown that repetitive electrical activation of neurons can cause long lasting alterations in cortical excitability. In case of TMS, it has been suggested that low frequency stimulations inhibit hyperexcitability, while high frequency stimulations enhances it (Nitsche et al., 2009).  Simulation modalities differ in their invasiveness, the complexity of the technology required to deliver them, and the level of clinical evidence that exist for their effectiveness. DBS, for instance, requires neurosurgery for implantation, while the same procedure for VNS is minimally-invasive, and eTNS, TMS and tDCS are non-invasive. Clinical trials of VNS have shown a reduction in seizure frequency, however the efficacy seems to be comparable to that of newer AEDs (Miller et al., 2014). In case of TMS, three randomized controlled trials have been conducted with mixed results: one has shown an improvement in seizure frequency, one has shown only a trend for seizure reduction, and one has shown no efficacy (Nitsche et al, 2009). Trials for DBS have shown statistically significant ~40% reduction in seizure frequency at three months, which improves over time (Fisher, 2012). A number of therapeutic epilepsy devices have been approved and are being marketed in US and elsewhere. Since 1994, Cyberonics have been cleared by the FDA to market its VNS systems as an adjunctive therapy for patients over 12 years of age with partial onset refractory epileptic seizures. The VNS system is a pacemaker-like device that is implanted subcutaneously in the chest area, with lead wires that are connected to the vagus nerve. The implantation is usually done by a general surgeon under general anesthesia. Unlike its predecessors, Cyberonics latest VNS product, the Aspire-SR has a closed-loop system that delivers stimulations to vagus nerve upon the detection of increased heart rate. It is unclear whether this new closed-loop model is any more efficacious than Cyberonics previous open-loop models (Morrel et al., 2016). The RNS system by Neuropace is another implantable closed-loop system in which is implanted subcutaneously under the scalp, with its leads placed inside the brain, at the site of seizure onset. The RNS system continuously monitors brain activities and delivers stimulations upon detection of abnormal electrical waves. The only non-invasive product in the marker is the Monarch eTNS system by Neurosigma, which provides non-invasive stimulations to the V1 branch of the trigeminal nerve through a forehead pad (DeGiorgio, 2006)(Pop et al., 2011). In 2013, results of a randomized active-controlled trial of the eTNS system were published (DeGiorgio, 2013). Fifty patients were randomized to treatment (eTNS at 120 Hz) and control (eTNS at 2 Hz) group, and were evaluated at 6, 12 and 18 weeks. The treatment group showed a non-significant increase in responder rate (defined as the >50% reduction in seizure frequency) (DeGiorgio, 2013). Monarch eTNS is currently approved and being marketed in Canada, Australia and Europe, but not in the US.       9 Table 3-Current Products on the Market Manufacturer Product Mechanism Mechanism Invasiveness Cyberonics Aspire-SR VNS VNS Minimally-invasive Neurosigma Monarch eTNS eTNS Non-invasive NEUROPACE The RNS System DBS DBS Invasive  Device-Based Prediction/Detection of Seizures Seizure prediction/detection devices can serve either as alert systems, to alert the patients themselves or their caregivers of an upcoming or an ongoing seizure, or as a component of a closed-loop therapeutic device that triggers the intervention (e.g. Nerve stimulation) (Ramgopal et al., 2014). A popular approach - both for detection and prediction of seizures - involves real time analysis of EEG (Sierra-Marcos et al., 2014)(Fisher, 2012)(Fürbass, 2015)(Gallagher et al, 2008)(Poh et al., 2012). Other methods include real time video analysis, shake detectors using motion sensors, and analysis of heart rates, for detecting seizures and Near InfraRed Spectroscopy (NIRS) (Gallagher et al, 2008), (Jeppesen et al, 2015b)(Watanabe et al., 2000)(Watanabe et al., 2002)(Zhang et al., 2014)(Machado et al, 2011)(Sokol et al., 2000)(Roche-Labarbe et al., 2010) and Heart Rate Variations (HRV) (Jeppesen et al, 2015a) for predicting seizures (Fisher, 2012),(Van De Vel et al., 2014) (Van De Vel et al., 2015).     10  D. Addressing the Challenge Objectives of the Proposed Innovation Careful problem definition is the first step towards development of any novel treatment.  In doing so, we came up with the following need statement: to non-invasively reduce the frequency, duration and/or severity of seizures in drug-refractory focal epileptic patients.  Following the biodesign process, a set of “must have” and “nice to have” criteria were defined after an elaborate consideration of currently available products and market/treatment gaps (Table 4). These criteria were used to screen initial brainstorming ideas and select the final concept.  Table 4- Biodesign Process Criteria Must have Nice to have Reduce frequency, duration, and/or severity of seizures Closed-loop Non invasive Wearable, with potential integration into currently available wearable technology Feasible Low cost Patentable Collect physiological data for research purposes  Proposed Solution: Epi-Cease  Our proposed solution, Epi-Cease (Figure 1, Next Page) is a non-invasive closed-loop system that consists of: 1) a battery-operated head strap style wearable tDCS module that delivers the stimulation, 2) an accompanying Apple Watch app, which detects seizures based on motion and heart rate data and signals the tDCS module to deliver the stimulation, and 3) the user’s Apple Watch.  The app and the tDCS module communicate through an RFDuino module using bluetooth low energy. The app will use Apple’s CoreMotion framework to access Apple Watch sensor data, HomeKit framework to communicate with the tDCS module, and ResearchKit framework to collect physiological data - upon user’s consent - for clinical research.     11  Figure 1 Epi-Cease- The set-up of a tDCS and Apple Watch to abort focal seizures  Technology The concept behind tDCS is an old one. As far back as in 1960, animal experiment have shown that cortical DC stimulations can inhibit or enhance tissue excitability, depending on the direction of the applied current date (Nitsche et al, 2009). In recent years, tDCS has reemerged as a non-invasive investigational medical intervention with many potentials. Similar to VNS, eTNS, DBS and TMS, tDCS aims at reducing hypersensitivity or interfering with discharges of epileptic brain tissue by delivering extrinsic stimulation (San-Juan et al., 2015).   tDCS is advantageous over other stimulation modalities in a number of way. First and foremost, it is completely non-invasive. This is in contrast with two currently approved stimulation techniques, VNS and DBS, which require invasive procedures for implantation and are associated with various procedure-related risks. Secondly, the manufacturing cost for a tDCS stimulator device can be as low as $20, making it an extremely affordable medical device to make.    12 Preclinical and Clinical Evidence  Potential therapeutic effects of tDCS in preventing epileptic seizures was first studied by Liebetanz and colleagues in a rat model (Liebetanz et al., 2006). In their study, Lievetanz et al used a unilateral epicranial electrode to measure the threshold for inducing focal seizure activity through applying ramp stimulations to the cortex. The authors were able to show that application of 60 minutes of cathodal tDCS at 100 uA results in a significant increase in the threshold for localized seizure activity that lasted more than 2 hours, while anodal tDCS had no effect (Liebetanz et al., 2006). Potential antiepileptic and neuroprotective effects of tDCS has been shown in at least two other animal models (San-Juan et al., 2015).  Results of the first randomized controlled clinical trial of tDCS in patients with refractory epilepsy was published in 2006 (Fregni et al., 2006). In their study, Fregni and colleagues in Harvard Center for Non-invasive Brain Stimulation assigned 19 patients with refractory epilepsy and malformations of cortical development to a treatment (n=10, 20 minutes of stimulation at 1 mA) and a control group (n=9, 5s of stimulation at 1 mA). The cathode placed over the source of epileptogenic activity, and the anode over a non-epileptogenic zone. Results showed a statistically significant 64.3% reduction in the treatment group, compared with a 5.8% reduction in control (Fregni et al., 2006). tDCS was well-tolerated in subjects, with the only reported adverse event being itching in 3 of the treatment and one of the control group subjects (Fregni et al., 2006).   In another randomized clinical trial, Auvichayapat and colleagues studied cathodal tDCS in 36 children (6-15 years old) (Auvichayapat et al., 2013). The treatment group received one session of therapy (20 minutes, 1 mA) with the cathode positioned over the seizure focus, and anode on the contralateral shoulder. Results showed a statistically significant improvement in epileptic discharge frequency immediately, 24 hours and 48 hours post-treatment (Auvichayapat et al., 2013).  Safety Including anecdotal case reports, a total of 65 patients (44 of which between 6 and 15 years old) so far have received tDCS therapy for refractory epilepsy. No major adverse events have been noted in a meta-analysis of all these patients (San-Juan et al, 2015). Impact Epi-Cease has the potential to revolutionize the care of drug-resistant focal epilepsy patients. Post-operative deficits and long hospitalization due to temporal lobectomy can be avoided using this non-invasive, real-time seizure abortion solution. Nearly 50 million individuals worldwide are affected by epilepsy. Of those, up to 30% can be classified as drug-resitant epileptics. Hospital and medical delivery stakeholders would be very interested in this technology as it would be significantly more cost-effective than temporal lobectomy, for example. Furthermore, patients would be strongly in favour of a non-invasive solution to their medical problem that can also be incorporated into their every day lives seamlessly (Figure 2).      13 E. Future Directions  Our first priority, moving forward, is to actively engage with potential users of the this product, that is neurologist, epilepsy patients and their families, to validate the need for such a product and to refine its design. The next step would involve an iterative prototyping, testing and validation process, which involves getting users’ feedback at every stage. At this stage, developing the seizure detection algorithm would be a key step. It would be crucial for the seizure detection algorithm to have high levels of sensitivity; lower levels of specificity, however, might be acceptable given the safety and comfort profile of the device.  Once a working prototype was in place, we will move to file intellectual property around the system and write a business plan with the help of the e@UBC Accelerator Program. In our preliminary patent search, we were able to identify only one granted patent (Patent No. US 7,483,747 B2) and one patent application (Appl. No. 14/349,511) that involved tDCS and epilepsy, not of which seemed to have any claims on our proposed solution. Of course a thorough search of the prior art by a legal patent firm would be needed to confirm novelty and non-obviousness.  We will then start to look for potential investment through grants (provincial and federal programs, The Epilepsy Foundation, etc.) or private investors. The investments would be required for getting the product approved by the FDA and Health Canada for investigational use, contract manufacturing, and planning and conducting required clinical studies. tDCS devices have not been classified by the FDA yet, and fall under “non-classified devices”. TMS devices have been classified as class 2 (Regulation No. 882.5805) and new TMS devices fall under 510(k) submission track. Given the resemblance of the underlying principles of TMS and tDCS, there is a good chance for our proposed device to fall under 510(k), in which case clinical studies would not be required for FDA clearance. Proof-of Concept Clinical Study To assess the safety and efficacy of Epi-Cease, we will conduct a two-staged proof-of-concept study. First, we will determine the accuracy of our Apple Watch motion-sensing and physiological monitoring app in a small cohort (n=3) of low-risk epilepsy patients. We will compare this data to traditional epilepsy monitoring data such as EEG to validate the technique and fine-tune the app and add additional hardware if necessary.  Once the app is validated in a small cohort of patients, we will expand the app for testing in multiple seizure subtypes to ensure further validaity of our app. Ethics approval for such a study will not be difficult due to it’s non-invasive nature and data-gathering stage.   14 The second stage will involve applying this technology in real-time to a small cohort (n=3) of low-risk treatment-resistant epilepsy patients. This study will take place at the bedside in a hospital setting to ensure access to other safety resources.   To conclude, we hope Epi-Cease will represent the first non-invasive real-time seizure aborting solution in epilepsy treatment. Ultimately, we hope this technology is completely wearable and mobile. We envision that the tDCS system can be customized to be installed on the inner surface of a baseball cap. This way seizures can be aborted before they begin even during everyday activities.    Figure 2-Ideal final prototype of Epi-Cease   15 F. 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