Electroconvulsive therapy, electric field, neuroplasticity, and clinical outcomes

Abstract

Electroconvulsive therapy (ECT) remains the gold-standard treatment for patients with depressive episodes, but the underlying mechanisms for antidepressant response and procedure-induced cognitive side effects have yet to be elucidated. Such mechanisms may be complex and involve certain ECT parameters and brain regions. Regarding parameters, the electrode placement (right unilateral or bitemporal) determines the geometric shape of the electric field (E-field), and amplitude determines the E-field magnitude in select brain regions (e.g., hippocampus). Here, we aim to determine the relationships between hippocampal E-field strength, hippocampal neuroplasticity, and antidepressant and cognitive outcomes. We used hippocampal E-fields and volumes generated from a randomized clinical trial that compared right unilateral electrode placement with different pulse amplitudes (600, 700, and 800 mA). Hippocampal E-field strength was variable but increased with each amplitude arm. We demonstrated a linear relationship between right hippocampal E-field and right hippocampal neuroplasticity. Right hippocampal neuroplasticity mediated right hippocampal E-field and antidepressant outcomes. In contrast, right hippocampal E-field was directly related to cognitive outcomes as measured by phonemic fluency. We used receiver operating characteristic curves to determine that the maximal right hippocampal E-field associated with cognitive safety was 112.5 V/m. Right hippocampal E-field strength was related to the whole-brain ratio of E-field strength per unit of stimulation current, but this whole-brain ratio was unrelated to antidepressant or cognitive outcomes. We discuss the implications of optimal hippocampal E-field dosing to maximize antidepressant outcomes and cognitive safety with individualized amplitudes.

Fig. 1. Overall study design.

After randomization to either 600, 700, or 800 mA amplitudes, subjects received antidepressant ratings, neuropsychological assessments, and imaging pre-ECT (Visit 1 or “V1”), mid-ECT (V2), and post-ECT (V3). If subjects failed to respond to their assigned amplitude at the V2 assessment (defined as <25% reduction in pre-ECT HDRS₂₄), subjects completed the protocol with bitemporal electrode placement.

Fig. 2. Hippocampal E-field variability and implications for ECT dosing.

A Right and left hippocampal E-field strengths across the three amplitude arms. B Individualized amplitudes have the potential to create accurate and precise E-field dosing.

Fig. 3. E-field and right hippocampal neuroplasticity.

Right hippocampal E-field was associated with right hippocampal neuroplasticity (t₄₆ = 2.59, p = 0.01) controlling for age, sex, pulse width and number of treatments.

Fig. 4. Hippocampal neuroplasticity and clinical outcomes.

A Right hippocampal E-field was not related to antidepressant outcomes (t₄₆ = −0.62, p = 0.54). B Right hippocampal neuroplasticity had a relationship with antidepressant outcomes (t₄₆ = −3.12, p = 0.003). C Structural equation modeling showed that right hippocampal neuroplasticity mediated the relationship between right hippocampal E-field strength and antidepressant response. D Right hippocampal E-field was associated with change in DKEFS Letter Fluency (t₄₄ = −2.44, p = 0.02). E Right hippocampal neuroplasticity was not related to change in DKEFS Letter Fluency (t₄₄ = −0.68, p = 0.50). F Structural equation modeling showed that right hippocampal neuroplasticity did not mediate the direct effect of right hippocampal E-field and change in DKEFS Letter Fluency. G Receiver operator characteristic curve analysis comparing right hippocampal E-field and cognitive outcome (change in DKEFS Letter Fluency > −3) revealed an area under the curve of 0.78 (95% CI: 0.64–0.93) and maximal sensitivity and specificity of 112.5 V/m.

Fig. 5. Right hippocampal E-field (E_r-hippo), ratio of the induced E-field in the brain per unit of stimulation current (E_brain/I_electrode), antidepressant, and cognition outcomes.

A E_r-hippo had a direct relationship with E_brain/I_electrode (t₄₈ = 8.19, p < 0.001). B E_brain/I_electrode was not associated with %∆HDRS (t₄₇ = −0.40, p = 0.69). C E_brain/I_electrode was not associated with ∆DKEFS Letter Fluency (t₄₅ = −1.66, p = 0.10).