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

Objective Despite advances in antidepressant interventions, none has replaced electroconvulsive therapy (ECT) in its acute efficacy and spectrum of action in severely depressed patients, including in psychotic depression, catatonia, and acutely suicidal patients. However, ECT carries a risk of significant adverse effects including cognitive and physiological side effects, some of which can be long term. The side effects are thought to be related to stimulation of brain areas beyond those implicated in depression, so called non-target regions. While these advances have improved the safety and tolerability of seizure therapy, a risk of cognitive side effects remains, and none of the currently used procedures individualize the current amplitude for each patient despite knowledge that anatomical variation significantly impacts the strength of the current delivered to the brain. We propose a first-in-human safety and feasibility study of this approach (termed individualized low amplitude seizure therapy , or iLAST). iLAST introduces three areas of improvement over conventional ECT: 1. use of a multi-electrode array to selectively target different regions of the brain coupled with computational electric field modeling on an individual patient basis to examine the current flow in the brain. 2. an alternative dosing strategy in which the stimulus is titrated in the current amplitude domain. 3. use of high-density EEG electrodes that are weaved into the multi-stimulation electrode array so that topographical ictal EEG is recorded. As mandated by the US FDA, a first in human (FIH) study is a type of study in which a device for a specific indication is evaluated for the first time in human subjects. We propose a FIH study of iLAST in 10 subjects. If safety and feasibility of iLAST are supported, this could lead to the development of a practical and safer alternative to ECT that could be rapidly disseminated through modification of ECT devices already cleared by the FDA, lowering regulatory barriers and development cost. If the aims are not supported, this would provide further support that development of the magnetic approach to seizure therapy is warranted. 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 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 (STa), 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 (0.25 ms) seizure therapy conditions. As per conventional ECT treatment schedule, treatments will be delivered on a 3 per week schedule. This will be followed by a repeat of the baseline assessment. 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 and b) neurocognitive 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 may receive optional post- course measures including: clinical rating scales, neurocognitive testing, neuroimaging, and a neuroplasticity battery. 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.