Title: Safety and Feasibility of Individualized Low Amplitude Seizure Therapy (iLAST)

The primary aim of the current protocol is to evaluate the safety and feasibility of iLAST in
10 adults with major depressive episode (unipolar) eligible for ECT. We hypothesize that both
iLAST will result in superior neurocognitive outcomes than conventional ECT. In addition, we
will evaluate the feasibility of alternative methods to individualize the pulse amplitude.
The approach to individualizing pulse amplitude is to apply trains of pulses of increasing
amplitude until a seizure is induced. To be practical in the clinical setting, the motor
threshold (MT) procedure will be completed rapidly to minimize time under anesthesia. To this
end, we will evaluate a rapid- estimation motor thresholding algorithm under anesthesia. This
will allow us to determine the relationships among measured amplitude-titrated seizure
threshold (ST), measured MT, and simulated MT derived from electric field modeling. Our
hypothesis is that both measured and simulated MT are correlated with STa, thus providing a
clinically useful predictor of current amplitude necessary to perform seizure therapy under
the time-constraints of anesthesia.

Study Population

The study will consist of 10 individuals between 22 and 70 years old, with a major depressive
disorder.

Study Design

This is a within-subject safety and feasibility study that comprises three phases. Phase I
includes medication taper (as clinically indicated), and baseline assessments.

In Phase II, patients will receive the 7 ultrabrief pulse width (0.3 ms) seizure therapy
conditions. As treatments will be delivered on a 3 per week schedule.

On each experimental condition day, patients will undergo a number of procedures to assess
clinical status and safety. Post procedure acute battery assessments will include: a) side
effect questionnaire, b) neurocognitive battery, and c) neuroplasticity battery.

In Phase III, patients will be offered routine clinical management consisting of a
conventional ECT course (typically 6 12 treatments) based on clinical need. Patients will
receive pre- and post- course measures including: clinical rating scales, neurocognitive
testing, neuroimaging, and a neuroplasticity battery.

Patients will also receive optional TMS EEG and ictal EEG recording at the 2nd, 8th or final
treatment.

Outcome Measures

Primary Outcome measures: successful seizure induction as measured by topographical EEG and
motor manifestations, vital signs, ECG, subjective side effect scale, and adverse
events/significant adverse events.

Secondary Outcome measures: Neurocognitive battery known to be sensitive to the cognitive
effects of ECT, with alternative versions to avoid practice effects; and, Amplitude-titrated
seizure threshold (STa), measured electrical MT, and simulated MT derived from realistic head
modeling.

- INCLUSION CRITERIA:

- Male and female, 22 70 years old

- Use of effective method of birth control for women of childbearing capacity. Women who
are able to get pregnant must be willing to use at least one form of effective birth
control during the entire period of study participation (or until last clinical labs
and rating) and have a negative pregnancy test at screening.

- DSM-5 diagnosis of major depressive disorder, confirmed by the MINI

- Eligible for ECT, including patients receiving maintenance ECT

- Each subject must have a level of understanding sufficient to agree to all required
tests and examinations and sign an informed consent document

- Subjects are willing and able to adhere to the intensive treatment schedule and all
required study procedures

EXCLUSION CRITERIA:

- Pregnant or nursing women or women who plan to become pregnant.

- Current or recent (within the past 6 months) substance abuse or dependence (excluding
nicotine and caffeine)

- Current serious medical illness judged to be clinically significant, such as high
blood pressure, diabetes, heart or lung disease

- History of seizure except those therapeutically induced by ECT (childhood febrile
seizures are acceptable and these subjects may be included in the study), history of
epilepsy in self or first degree relatives, stroke, brain surgery, concussion resulted
in loss of consciousness or hospitalization, cranial metal implants, known structural
brain lesion, devices that may be affected by TMS or MRI (pacemaker, medication pump,
cochlear implant, implanted brain stimulator, vagus nerve stimulator)

- Diagnosed with the following conditions (current unless otherwise stated):

- Any other current primary Axis I mood, anxiety, or psychotic disorder

- Depression secondary to a general medical condition, or substance-induced

- Psychotic disorder (lifetime), including schizoaffective disorder, or major
depression with psychotic features in the current episode

- Eating disorder (current or within the past year)

- Obsessive compulsive disorder (current or within the past year)

- Post-traumatic stress disorder (current or within the past year)

- ADHD (currently being treated)

- Subjects meeting criteria based upon DSM-5 criteria, which in the judgment of the
Investigator, may hinder the subjects in completing the procedures required by
the study protocol

- Actively suicidal

- Increased risk of seizure for any reason, including prior diagnosis of increased
intracranial pressure (such as after large infarctions or trauma), or currently taking
medication that lowers the seizure threshold

- Subjects with a clinically defined neurological disorder including, but not limited
to:

- Any condition likely to be associated with increased intracranial pressure

- Space occupying brain lesion

- History of stroke

- Transient ischemic attack within two years

- Cerebral aneurysm

- Dementia

- Mini Mental Status Exam (MMSE) score < 24

- Parkinson s disease

- Huntington s disease

- Multiple sclerosis

- Subjects with any of the following treatment histories:

- Failure to respond to TMS or ECT treatment (i.e., consistent with ATHF confidence
level 3 or higher) in this or any previous episode

- Lifetime history of treatment with Deep Brain Stimulation or Vagus Nerve
Stimulation

- Use of any investigational drug or device within 4 weeks of the screening

- MRI contraindications (any metal in the body, claustrophobia, etc.)

- Current visual, auditory, or motor impairment that compromises ability to complete
evaluations

- Positive HIV test

- NIMH employees and staff and their immediate family members will be excluded from the
study per NIMH policy