Electroconvulsive therapy amplitude titration for improved clinical outcomes in late-life depression

电休克治疗（ECT）刺激参数的选择反映了疗效和 认知不良影响。ECT刺激参数与更多抗抑郁疗效相关（非局灶性 电极放置、较长的脉冲宽度）与认知不良影响的风险增加相关。 在标准临床实践中，振幅目前固定在800或900毫安（mA），没有临床或 科学依据振幅决定电场（E场）空间分布的强度。与 固定的颅外振幅，由于解剖结构的不同，由E场表示的ECT“剂量”是高度可变的。 皮肤头骨体液和脑组织的差异这种解剖变异性在老年人（50岁以上）中很突出。 抑郁症患者，并可能损害抗抑郁药的疗效（情绪相关的刺激不足， 电路）和安全性（由于过度刺激认知相关电路而引起认知障碍）。 正如当前提案中提出的那样，振幅滴定可以减少与固定振幅相关的变异性 剂量和优化临床和认知结果。这个项目的目标是改变标准ECT 从固定幅度到个性化和经验确定的幅度的参数选择。实现 为了实现这一目标，我们将重点关注振幅滴定和治疗反应性变化之间的关系， 海马神经可塑性与RUL固定振幅ECT。固定振幅ECT导致可变电场或 ECT剂量。在ECT系列的过程中，可变ECT剂量将导致 海马神经可塑性相反，翻译前的研究表明， 滴定导致一致的电场或ECT“剂量”。癫痫发作滴定幅度（基于历史数据，233至 544 mA）低于FDA批准的ECT设备的幅度范围（500至900 mA）， 适配器以降低输出振幅（试验用器械豁免）。振幅滴定也将低于 海马神经可塑性阈值和抗抑郁反应不足。的区别 RUL振幅滴定和RUL固定振幅（800 mA）ECT将确定目标接合程度 与海马体有关。为了说明，使用~250 mA（800/250，高固定/滴定）的低振幅滴定的受试者 振幅比）将在海马神经可塑性中具有显著的变化。高振幅受试者 滴定~500 mA（800/500，低固定/滴定比）对海马神经可塑性的影响最小。 振幅滴定和固定振幅海马神经可塑性之间的关系将用于 开发一致和临床有效的ECT剂量所需的振幅乘数。一项随机 然后，对照试验将比较海马神经可塑性，抗抑郁药和认知结果， 使用神经可塑性倍增器（固定脉冲数）和传统固定振幅ECT的振幅滴定 (800 mA，可变脉冲数）。

Electroconvulsive therapy (ECT) stimulation parameter selection reflects a balance between efficacy and cognitive adverse effects. ECT stimulation parameters associated with more antidepressant efficacy (non-focal electrode placement, longer pulse width) are associated with increased risk of cognitive adverse effects. Amplitude is currently fixed at 800 or 900 milliamperes (mA) in standard clinical practice with no clinical or scientific basis. Amplitude determines the intensity of the spatial distribution of the electric field (E-field). With a fixed extracranial amplitude, the ECT “dose” as represented by the E-field is highly variable due to anatomic differences in skin, skull, fluid, and brain tissue. This anatomic variability is prominent in older (age 50+) depressed patients and can compromise both antidepressant efficacy (insufficient stimulation of mood-related circuitry) and safety (inducing cognitive impairment due to excessive stimulation of cognitive related circuitry). Amplitude titration, as proposed in this current proposal, can reduce the variability related to fixed amplitude dosing and optimize clinical and cognitive outcomes. The goal of this project is to change standard ECT parameter selection from a fixed amplitude to an individualized and empirically determined amplitude. To achieve this goal, we will focus on the relationship between amplitude titration and treatment-responsive changes in hippocampal neuroplasticity with RUL fixed amplitude ECT. Fixed amplitude ECT results in variable E-field or ECT dose. Over the course of an ECT series, the variable ECT dose will result in inconsistent changes in hippocampal neuroplasticity. In contrast, pre-translational investigations have demonstrated that amplitude titration results in a consistent E-field or ECT “dose”. Seizure titration amplitudes (based on historic data, 233 to 544 mA) are below the amplitude range of FDA-approved ECT devices (500 to 900 mA) and will require an adaptor to reduce the output amplitude (Investigational Device Exemption). Amplitude titration will also be below the hippocampal neuroplasticity threshold and insufficient for antidepressant response. The difference between RUL amplitude titration and RUL fixed amplitude (800 mA) ECT will determine the degree of target engagement with the hippocampus. To illustrate, subjects with low amplitude titration of ~250 mA (800/250, high fixed/titration amplitude ratio) will have significant changes in hippocampal neuroplasticity. Subjects with high amplitude titration ~500 mA (800/500, low fixed/titration ratio) will have minimal changes in hippocampal neuroplasticity. The relationship between amplitude titration and fixed amplitude hippocampal neuroplasticity will be used to develop the amplitude multiplier required for consistent and clinically effective ECT dosing. A randomized controlled trial will then compare hippocampal neuroplasticity, antidepressant, and cognitive outcomes between amplitude titration with neuroplasticity multiplier (fixed pulse number) and traditional fixed amplitude ECT (800 mA, variable pulse number) in older depressed subjects.