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.
Highlights
Electroconvulsive therapy (ECT) remains the gold-standard treatment for patients with depressive episodes [1]
We assessed the relationship between right hippocampal electric field (E-field) strength (Er-hippo) and right hippocampal volume change, (ΔVolr-hippo/Pre-ECT-Volr-hipp) with a linear regression analysis controlling for sex, age, pulse width and number of treatments
Because of the mid-series electrode placement switch and the large difference in the left hippocampal E-field between the right unilateral (RUL) and BT electrode placements, we focused on the right hippocampus
Summary
Electroconvulsive therapy (ECT) remains the gold-standard treatment for patients with depressive episodes [1]. Independent of the antidepressant effect of ECT, many patients experience transient but debilitating cognitive side effects such as attention and memory impairment [2, 3]. ECT-mediated hippocampal neuroplasticity has been implicated in both antidepressant and cognitive outcomes [4, 5]. Neuroplasticity refers to the brain’s ability to restructure itself by forming new neural connections [6] and appears to be a common mechanism shared by both ECT and chemical antidepressant treatments [7]. Some investigations demonstrated a direct relationship between hippocampal neuroplasticity and antidepressant response [8,9,10,11,12,13], but other investigations were negative [14,15,16,17,18,19,20,21]. The rapid hippocampal volume increase involves extensive remodeling and may be related to procedure-related cognitive impairment [22, 23]
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