Abstract

Electroconvulsive therapy (ECT) pulse amplitude, which dictates the induced electric field (E-field) magnitude in the brain, is presently fixed at 800 or 900 milliamperes (mA) without clinical or scientific rationale. We have previously demonstrated that increased E-field strength improves ECT’s antidepressant effect but worsens cognitive outcomes. Amplitude-determined seizure titration may reduce the E-field variability relative to fixed amplitude ECT. In this investigation, we assessed the relationships among amplitude-determined seizure-threshold (ST_a), E-field magnitude, and clinical outcomes in older adults (age range 50 to 80 years) with depression. Subjects received brain imaging, depression assessment, and neuropsychological assessment pre-, mid-, and post-ECT. ST_a was determined during the first treatment with a Soterix Medical 4×1 High Definition ECT Multi-channel Stimulation Interface (Investigation Device Exemption: G200123). Subsequent treatments were completed with right unilateral electrode placement (RUL) and 800 mA. We calculated E_brain defined as the 90th percentile of E-field magnitude in the whole brain for RUL electrode placement. Twenty-nine subjects were included in the final analyses. E_brain per unit electrode current, E_brain/I, was associated with ST_a. ST_a was associated with antidepressant outcomes at the mid-ECT assessment and bitemporal electrode placement switch. E_brain/I was associated with changes in category fluency with a large effect size. The relationship between ST_a and E_brain/I extends work from preclinical models and provides a validation step for ECT E-field modeling. ECT with individualized amplitude based on E-field modeling or ST_a has the potential to enhance neuroscience-based ECT parameter selection and improve clinical outcomes.

Discussion

This investigation used a unique design with amplitude-determined seizure titration at the first treatment followed by fixed 800 mA for subsequent treatments. Pulse number (20 Hz frequency and 8 s pulse train duration) was held constant at 160 pulse pairs for the ST_a titration and the 800 mA treatments. Both ST_a and E_brain/I had a wide range, which challenges the long-standing use of fixed amplitude ECT. ST_a increased with age, which is consistent with the observations made by Liberson when “brief stimulus therapy” was first experimented in the 1940s [49]. The relationship between ST_a and E_brain/I extends work from preclinical models [15, 16] and provides a validation step for ECT E-field modeling. Despite their relationship, ST_a and E_brain/I had different relationships with antidepressant and cognitive outcomes. The antidepressant and cognitive outcomes in relation to ST_a may be understood as a ratio between ST_a and subsequent 800 mA treatments (800 mA/STa) (Fig. 1B). Lower ratios (e.g., 800 mA/686 mA) may be inadequate to achieve the necessary “suprathreshold” dosing for antidepressant response. Higher ST_a (and hence lower 800 mA/ST_a ratio) was associated with the BT switch at V2 as determined by <25% change from baseline depression severity. Higher E_brain/I was associated with worse cognitive outcomes as measured by longitudinal change in category fluency. E_brain/I at the mid-point of the distribution (0.15 V/m/mA) differentiated cognitive impairment with 800 mA amplitude. ST_a and treatment number interaction was related to right hippocampal volume change, and right hippocampal volume change was associated with antidepressant outcomes (bitemporal switch and RUL response). In the following sections, we provide context for these findings, strengths and limitations of this approach, and potential implications for the practice of ECT dosing.

Antidepressant outcomes

Our antidepressant results demonstrated improved efficacy with “suprathreshold” treatments. In current clinical practice, suprathreshold treatments are defined in the context of pulse number (i.e., pulse train duration and frequency). The minimum number of pulses for a fixed amplitude and pulse width determines the seizure threshold. The suprathreshold multiplier (typically six-times seizure threshold for RUL ECT) determines the individualized pulse number necessary for antidepressant efficacy [50]. In contrast, the suprathreshold specifier can also be applied to the stimulus current amplitude. Our findings indicate that for ECT with 800 mA fixed amplitude to be effective, the inflection point for ST_a is approximately 330 mA, corresponding to fixed amplitude/ST_a ratio of 800 mA/330 mA or ~2.5. Higher ST_a (>330 mA) is associated with inadequate antidepressant response with subsequent treatments completed at 800 mA resulting in a protocol-determined switch to BT electrode placement. When the ST_a is greater than 330 mA, increased amplitude (>800 mA) may improve antidepressant efficacy. Alternatively, an electrode placement switch from RUL to bitemporal may also provide the necessary suprathreshold dose for antidepressant efficacy in the context of high ST_a.

Previous research with E-field strength and antidepressant outcomes has been mixed [14, 17, 51]. In this current study sample, E_brain/I was unrelated to antidepressant outcomes. We also did not replicate the previously identified relationship between right hippocampal E-field strength (E_hippo/I) and right hippocampal volume change [14]. Differences between these two investigations include the focus on RUL (previous investigation included RUL and BT) and 800 mA (previous investigation included 600 and 700 mA). Despite not demonstrating the E_brain/I and hippocampal volume relationship, right hippocampal volume change was associated with antidepressant outcome including response criteria and bitemporal electrode placement switch. Larger investigations are necessary to disentangle the effect of E_brain/I from ECT treatment number and other parameters (i.e., pulse width, stimulation time) on hippocampal volume change and to explore potential moderating effects of structural and functional changes between E_brain/I and antidepressant outcomes. In contrast, ST_a may capture additional information such as cortical excitability not included in E_brain/I that strengthens the relationships to antidepressant outcomes [52] or age-related changes in conductivity (i.e., white matter disease) not presently included in E-field modeling approaches [53].

Cognitive outcomes

The DKEFS Category and Letter Fluency tests were sensitive to RUL-mediated changes in cognitive performance. Higher E_brain/I was associated with worse category fluency performance. In contrast, ST_a was unrelated with cognitive outcomes. The strong association between E_brain/I and cognitive outcomes replicates our previous work and adds support for the role of E_brain/I in ECT dosing [14, 54]. In this sample, an E_brain/I of 0.15 V/m/mA was the maximal associated with stable cognitive performance with traditional fixed amplitude 800 mA dosing. When E_brain/I is greater than 0.15 V/m/mA (120 V/m at 800 mA), decreased amplitude (<800 mA) may reduce cognitive risk. The widespread right hemisphere associations between E_brain/I and cognitive outcomes did not identify a specific anatomic “anti-target” amenable to changes in electric field geometry to improve the focality of treatment to prevent cognitive impairment. In contrast, an individualized stimulus amplitude determined prior to treatment initiation has the potential to improve cognitive outcomes.

Source: Nature