Electroconvulsive therapy (ECT) remains the gold-standard treatment for patients with depressive episodes. During a typical four-week ECT series, most depressive episodes will respond to treatment and people will improve their level of functioning (return to work or family). Independent of the antidepressant effect of ECT, many patients experience transient memory impairment. This investigation will examine the impact of one ECT parameter (pulse amplitude or current) on brain changes (structure of connections within the brain) and clinical outcomes. The goal of this investigation is to determine the optimal parameter for an individual patient that will maintain the clinical response (reduce depression severity) and minimize side effects (eliminate memory issues related to treatment).

Electroconvulsive therapy (ECT) remains the gold-standard treatment for patients with depressive episodes. During a typical four-week ECT series, most depressive episodes remit, and formerly suicidal or psychotically depressed patients will resume their premorbid levels of functioning. Independent of the antidepressant effect of ECT, many patients experience debilitating but transient cognitive effects such as attention and memory deficits. These unwanted side effects are particularly troubling for older patients who are more likely to have existing cognitive deficits. Both the stimulus delivery (electrode placement, pulse amplitude, and pulse width) and seizure induction appear to work in synergy, but the underlying mechanism of action for successful response has yet to be fully elucidated. Moreover, further work is needed to understand the relationship between clinical improvement and cognitive impairment. This investigation will examine the clinical and neurocognitive impact of targeted medial temporal lobe engagement as a function of pulse amplitude, one of several variable factors influencing the ECT charge. The ECT charge is measured in millicoulombs (mC) and derived from multiplying pulse train duration, pulse-pair frequency, pulse width, and pulse amplitude. Pulse amplitude determines the induced electric field strength in the brain and is presently fixed at 900 milliamperes (mA) with no clinical or scientific justification. The central hypothesis of this investigation is that the optimal pulse amplitude for an individual patient will enhance neuroplasticity (clinical response) while minimizing the disruption of dominant hemisphere hippocampal cognitive circuitry (resulting in cognitive stability). The preliminary data informs the dosage range between 600 and 800 mA. Pulse amplitudes outside of this range compromise efficacy (500 mA) or may increase risk of cognitive impairment (900 mA). The first aim of this investigation will identify the electric field strength and neuroplasticity associated with clinical response. Critically, this aim will establish the neuroplasticity threshold, which is defined as the electric field strength necessary to induce neuroplasticity. The second aim will detect the neural correlates of ECT-mediated cognitive changes, which may be related to disrupted dominant hemisphere long-term potentiation. The third aim will use data-driven dual regression to predict the optimal pulse amplitude for an individual patient. This contribution will be significant because the electric field, when manipulated by pulse amplitude, can subsequently maximize hippocampal neuroplasticity (efficacy) and minimize disrupted connectivity (cognitive stability) thus improving clinical outcomes.

Inclusion Criteria:

1. Diagnosis of major depressive disorder (with or without psychotic features)
2. the clinical indications for ECT including treatment resistance or a need for a rapid and definitive response
3. Hamilton Depression Rating Scale 24-item (HDRS-24) > 21
4. age range between 50 and 80 years of age
5. right-handedness

Exclusion Criteria:

1. Defined neurological or neurodegenerative disorder (e.g., history of head injury with loss of consciousness > 5 minutes, epilepsy, Alzheimer's disease)
2. other psychiatric conditions (e.g., schizophrenia, schizoaffective disorder, bipolar disorder)
3. current drug or alcohol use disorder, except for nicotine; and 4) contraindications to MRI.

National Data Archive (NDA)

Clinical, cognitive and MRI data was uploaded to NDA.

per NDA protocol

Each subject was evaluated for adverse effects over the 4-week study protocol.

Subjects discontinued scheduled antidepressant and antipsychotic medications prior to the first imaging assessment, but as-needed medications (lorazepam, quetiapine, trazodone) were permissible with dose restrictions during the ECT series. Second, our study design included a change in pulse width (from 0.3 to 1.0 ms). Each amplitude arm had a very limited number of subjects with brief pulse width. The relationship between amplitude and pulse width will require more research.

Double-blind (participant and outcomes assessor)