High Definition Cathodal Transcranial Direct Current Stimulation for Treatment of Refractory Partial Onset Epilepsy

1 Introduction This document is a protocol for a human research study. This study is to be
conducted in accordance with US government research regulations, and applicable international
standards of Good Clinical Practice, and institutional research policies and procedures.

1.1 Background Focal Status epilepticus (FSE) is characterized by a prolonged,
self-sustaining, and anatomically discrete seizures that last longer than one hour (at times
as long as days or weeks) and that are associated with a definable neurologic behavior
(Schomer 2005). Symptoms in FSE can vary according to the function of the brain area
affected, can vary in discharge, and can be as simple as a repetitive limb movement as seen
in epilepsy partialis continua (EPC), or as subtle as an inability to write a command or name
an object. Prevalence of EPC is estimated to be 1 per one million (Cockerell 1996). A large
proportion of FSE episodes are resultant from acute neurologic insult such as stroke or
hemorrhage, although, at times, the cause of FSE remains unknown. FSE treatment should
commence promptly upon its recognition using predefined treatment protocols. The goal of
treatment is the rapid termination of the seizure to minimize the acute and chronic effects
of this emergency and to allow for the prompt assessment and management of the underlying
precipitant (Loddenkemper 2011).

Furthermore, patients may suffer from refractory partial onset epilepsy, and suffer from
frequent seizures despite maximizing medical therapy, which may place them at higher risk of
having FSE or EPC.

Yet many instances of FSE, EPC, and refractory partial onset epilepsy which is resistant to
pharmacotherapy, and require nonpharmacologic treatment.

Accordingly, the investigatorspropose a Phase-1 clinical trial to test the safety and
tolerability of High Definition Transcranial Direct Current Stimulation (HD-tDCS), a
-noninvasive technology with the capacity to suppress seizures in patients with frequent
partial onset seizures, and eventually FSE or EPC. The investigators plan to use the Soterix
HD-tDCS device. The device is a current-controlled source which generates a constant output
current. In other words, the device automatically maintains constant output current by
decreasing or increasing the output voltage needed as long as it does not surpass device
compliance voltage, which provides an added safety measure.

The HD-tDCS device poses a non-significant risk because

1. The device is not an implant with potential for serious risk to health, safety, or
welfare of subject

2. The device is not purported for use supporting or sustaining human life with potential
for serious risk to health safety or welfare of subject

3. The device is not for substantial use in diagnosing, curing, mitigating, or treating
disease or otherwise preventing impairment of human health with a potential for serious
risk to health safety or welfare of subject

4. The device does not otherwise present a serious risk to the health safety or welfare of
a subject.

The investigators anticipate that this will be a step toward eventual wider application of
HD-tDCS.

tDCS Basics: tDCS is a painless and safe method for focal brain stimulation. tDCS is based on
decades-old observations that neuronal firing is modulated by low amplitude electrical direct
current (DC). Specifically, when applied to the cerebral cortex, cathodal DC inhibits
neuronal firing. The mechanisms by which cathodal DC reduces neuronal firing likely relate to
hyper-polarization of the soma membrane which occurs when the apical dendrites neuron are
oriented toward the cathode in a constant electric field. The practical application of tDCS
is simple: low amplitude DC is administered via broad scalp electrodes (typically
saline-saturated sponges) such that the cerebral cortex is exposed to cathodal DC beneath one
of the electrodes - the remaining, (anodal) electrodes can be placed anywhere else on the
body, or as proposed below, circumferentially around the cathode. tDCS methods have also
recently been adapted to rats for experimental work with disease models (Rotenberg 2008;
Kabakov 2012). Over 600 studies have been published using standard tDCS without significant
adverse events. In a recently published safety and tolerability study on 131 subjects
involved in tDCS experiments at the University of Pennsylvania. no significant adverse events
occurred. With commonly reported mild side effects of tingling (76%), itching (68%), burning
(54%), and pain (25%). Direct electrical current stimulation is presently FDA-approved for
extracranial use, FDA applications for cranial stimulation (tDCS) for management of mood
disorder and chronic pain is in progress. Currently, there have been a number of clinical
protocols using tDCS for cranial applications (including previous approved protocols of the
PI), which have considered tDCS a non-significant or minimal risk device (please see attached
documentation).

Figure 1: Principle of tDCS induced reduction in excitability. (left) Cathodal tDCS results
in outward directed cortical current, which hyperpolarizes somatic cell membranes. This in
turn, reduces excitability. Anodal has opposite effects. HD-tDCS technology allows
uni-directional polarization (cathodal/reduced excitability only) as well as stimulation of a
small cortical target. Thus, while leveraging the well-established mechanisms of DC control
and safety of tDCS, HD-tDCS allows us to explore, for the first time, targeted
hyperpolarization for seizure control. (right) As established over decades of research (on
right panel from Purpura and McMurty, 1965) DC current instantly modulates neuronal firing in
a direction specific manner with cathodal stimulation suppressing firing, as well as
epileptiform activity (below).

tDCS Advantages: tDCS units are inexpensive and light-weight. The electrical supply can be
derived from conventional 9-volt batteries. The scalp electrodes can be fastened in seconds.
tDCS can be combined easily with other therapies, such as those that may be required for
resuscitation of an acutely-injured patient. tDCS is presently under investigation as a
treatment for epilepsy, where excess cortical excitability is a prominent feature of the
disease process, and where neuronal inhibition may be beneficial. Thus for SE, tDCS may offer
a practical therapeutic option analogous to hypothermia or pharmacologic suppression of
neuronal activity but with the benefit of easy, rapid and focal application in the setting of
acute seizure or other form of brain injury.

Figure 2: Soterix Medical Inc. (SMI) HD-tDCS system including battery powered base unit, HD
electrodes, and cap. The system has been validated in clinical trials and designated
non-significant-risk by the FDA. SMI develops custom HD electrodes and "cups" which can be
designed to integrate into EEG head-gear. The EASYcap headgear is shown with 4x1 HD electrode
montage. Using the 10/20 system for electrode recording (filled circle) allows interlaced
site for positioning of HD electrodes (open circles). The EASYcap provides for a range of
adult and pediatric sizes. The system is portable, can be deployed simply, and even be
integrated with EEG or used while the subject is moving.

1.2 Preclinical Data Recent clinical studies of cathodal tDCS that focused on chronic
treatment of epilepsy show a mild anti-epileptic effect when tDCS is delivered interictally.
The rationale behind interictal tDCS application is the reliance on the tDCS effects that
outlast stimulation (plasticity). Though results from early animal and clinical studies
suggest that such a plasticity-based approach warrants further consideration, here, the
investigators propose to exploit the well-established acute effects of DC currents. Thus,
what is mechanistically innovative in our approach is leveraging the robust acute effect of
DC polarization (Durand 2001; Kabakov 2012). Refractory partial onset epilepsy represents a
sustained state of brain hyper-excitability (analogous to slice models), which is expected to
be instantly suppressed by weak DC.

High definition transcranial direct current stimulation (HD-tDCS) has an established safety
and tolerability profile and is entering into the clinical arena for treatment of a number of
neurologic disease states, such as mood disorder and chronic pain, and post-stroke motor
deficit, where patients may benefit from focal modulation of cortical excitability. There has
been similar tolerability data in a small number of subjects for HD-tDCS (Minhas 2010). Some
subjects may experience skin irritation or redness after treatment that resolves within
hours. However, in our hands at 1mA per HD electrodes, lasting skin irritations (>24h) have
never been observed (N>100) even in prolonged studies (N>40). Many patients who have received
both standard and HD-tDCS treatments report less sensations from HD-tDCS, likely because the
electrolyte gel produces better contact with the skin compared to saline-soaked pads (Kuo et
al). Indeed a NSR designation for the proposed study was obtained by the FDA (please see
supporting documents)..

Recent studies by our group and others have extended tDCS experiments to preclinical
experiments in rat seizure models, and demonstrated that electrical control with tDCS aborts
ongoing seizures and reduces associated brain injury. Here the investigators propose to apply
cathodal HD-tDCS (Fig 2), the inhibitory variant of this technology, specifically to suppress
cortical excitability and terminate seizures in a well-selected group of patients who
demonstrate frequent focal onset seizures.

Figure 3: Comparison of neuromodulation focality using the HD-tDCS 4x1-Ring deployment vs.
conventional tDCS (left) High-resolution individualized finite element model FEM computer
simulations. (top) Conventional tDCS with large "sponge" pad electrodes results in diffuse
and un-focal brain stimulation, which is bi-directional (both depolarized/activated and
hyperpolarized/inhibited regions). (bottom) In contrast, HD-tDCS Ring stimulation results in
highly targeted cortical area stimulation. Directly under the electrodes this is
unidirectional (hyperpolarization only). These improvements achieved with HD-tDCS are highly
relevant to the clinical aims of this proposal.

Inclusion Criteria:

1. Age 9 to 65 years

2. Focal-onset neocortical epilepsy (as determined by semiology, EEG, and/or MRI)

3. Frequent (>50% of EEG record) focal epileptiform discharges on EEG and/or frequent
(defined as average of ≥2 daily seizures) focal-onset clinical seizure, refractory to
medical anti-epileptic treatment. For the purposes of this study, any patient who has
been treated with three or more AEDs at therapeutic doses for at least four weeks per
drug will be considered medically refractory.

4. Seizure onset must be localizable by clinical semiology, EEG or MRI.

5. Subjects or guardians must be competent to sign an informed consent indicating
awareness of the investigational nature of this study, treatment, benefits and
procedures involved.

Exclusion Criteria:

1. Age over 65 years or under 9 years.

2. Implanted cardiac pacemakers, cochlear implants, implanted medication pump, or
intracardiac line.

3. Within past six months, history of active heart disease, stroke, respiratory disease,
or increased intracranial pressure such as after infarction or trauma.

4. Pregnant women. A urine test will be conducted on all post-menarchal females of
childbearing age and potential to verify they are not pregnant.

5. History of significant head trauma (loss of consciousness >10 minutes) within the past
6 months.

6. Currently taking tricyclic anti-depressants, bupropion, or neuroleptic medications.

7. Intracranial metal (e.g., cortical stimulator, deep brain stimulator, intraventricular
catheter) within 4 cm of optimal stimulation site. Location of cranial metal (e.g.
skull screws) should be carefully documented.

8. Neurodegenerative disease.

9. Radiographic or electrophysiologic evidence for deep structure seizure focus (e.g.,
mesial temporal sclerosis or periventricular heterotopia)

10. Inability to remain seated and relatively still for 30 minutes.

11. Benign rolandic epilepsy.