Rational Dosing for Electric and Magnetic Seizure Therapy

电和磁癫痫治疗的合理剂量

• 批准号: 8246645
• 负责人: Sarah H Lisanby
• 金额: $ 33.51万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8246645
• 关键词: Rational; Dosing; Electric; Magnetic; Seizure

DESCRIPTION (provided by applicant): This translational project will develop a novel framework to optimize the dosing of seizure therapies for the treatment of medication resistant disorders. Despite advances in antidepressant interventions, none has replaced electroconvulsive therapy (ECT) in its acute efficacy and spectrum of action. However, ECT carries the risk of significant cognitive side effects, some of which are lasting. Major improvements in the risk/benefit ratio of ECT have been made over the past few decades, including the introduction of more focal stimulation with magnetic seizure therapy (MST), yet our knowledge of the optimal dosing of seizure therapies remains relatively rudimentary. Lacking an understanding of the biophysical and physiological mechanisms, refinements in ECT/MST technique must rely exclusively on time-consuming and costly clinical trials. Consequently, key questions remain unanswered, such as: (1) how to position the electrode or coil to TARGET stimulation to specific brain areas, (2) how best to INDIVIDUALIZE the dosage for each patient, and (3) how to OPTIMIZE stimulus parameters for efficient seizure induction. Answers to these questions could lead to substantial advances in the tolerability of the treatment and would inform clinical decision-making. Addressing this knowledge gap, we propose a new platform for the rational dosing of electric and magnetic seizure therapy that couples computational modeling with empirical validation to inform the targeting, individualization, and optimization of ECT/MST technique. This 5-year collaborative project spanning the disciplines of engineering and psychiatry entails two interrelated lines of work: computational modeling, and in vivo testing to physiologically calibrate the model and empirically determine the dynamic interaction between pulse train characteristics and seizure initiation. This proposal has 3 aims: (AIM 1) to inform TARGETING, we will simulate the strength and focality of neural stimulation as a function of ECT electrode and MST coil configuration using realistic head models calibrated through empirical neural threshold measurement in vivo; (AIM 2) to guide the INDIVIDUALIZATION of dosage, we will titrate pulse amplitude for efficient seizure induction in vivo and evaluate it as a means of controlling the focality of stimulation; and (AIM 3) to OPTIMIZE train parameters, we will empirically determine the most efficient frequency and directionality of pulse trains for seizure induction. This approach accounts for tissue conductivity and the anisotropy of white matter as measured by diffusion tensor imaging, it includes physiological calibration of field maps relative to neural activation thresholds, and it evaluates relatively ignored parameters which are central to controlling the focality and physiological action of seizure therapies. Pilot data supporting each of the aims demonstrate that lowering pulse amplitude improves focality and seizure induction is more efficient with lower frequencies and unidirectional pulse trains. This work provides a basis for rational dosing of seizure therapies that could help improve their risk/benefit ratio and guide the development of safer alternatives for severely ill patients. PUBLIC HEALTH RELEVANCE: Clinical depression affects upwards of 34 million US citizens, but only about one third of those are effectively treated with medications. For the remainder, electroconvulsive therapy (ECT) is an effective option but it carries a risk of side effects. This project couples state-of-the-art engineering methods with the latest developments in clinical psychiatry to inform the dosing of existing and novel seizure therapies so that persons with severe depression and other disabling disorders will have more effective and safer treatment options.

描述（由申请人提供）：该转化项目将开发一个新的框架来优化癫痫治疗的剂量，以治疗耐药性疾病。尽管抗抑郁干预措施取得了进展，但在其急性疗效和作用范围方面，还没有一种药物能够取代电休克疗法 (ECT)。然而，ECT 存在显着的认知副作用的风险，其中一些副作用是持久的。过去几十年来，ECT 的风险/效益比取得了重大改进，包括通过磁癫痫治疗 (MST) 引入更多局灶性刺激，但我们对癫痫治疗最佳剂量的了解仍然相对初级。由于缺乏对生物物理和生理机制的了解，ECT/MST 技术的改进必须完全依赖于耗时且昂贵的临床试验。因此，关键问题仍然没有得到解答，例如：（1）如何定位电极或线圈以将刺激瞄准特定的大脑区域，（2）如何最好地为每个患者个性化剂量，以及（3）如何优化刺激参数有效诱导癫痫发作。这些问题的答案可能会大大提高治疗的耐受性，并为临床决策提供信息。为了解决这一知识差距，我们提出了一个用于合理剂量电和磁癫痫治疗的新平台，该平台将计算模型与经验验证相结合，为 ECT/MST 技术的靶向、个体化和优化提供信息。这个跨越工程和精神病学学科的为期 5 年的合作项目需要两个相互关联的工作领域：计算建模和体内测试，以生理校准模型并凭经验确定脉冲串特征和癫痫发作之间的动态相互作用。该提案有 3 个目标：（目标 1）为了告知目标，我们将使用通过体内经验神经阈值测量校准的真实头部模型来模拟神经刺激的强度和焦点作为 ECT 电极和 MST 线圈配置的函数； （目标 2）为了指导剂量的个体化，我们将滴定脉冲幅度以在体内有效诱导癫痫发作，并将其作为控制刺激焦点的手段进行评估； （目标 3）为了优化序列参数，我们将根据经验确定用于癫痫发作诱导的脉冲序列的最有效频率和方向性。这种方法解释了通过扩散张量成像测量的组织电导率和白质的各向异性，它包括相对于神经激活阈值的场图的生理校准，并且它评估相对被忽视的参数，这些参数对于控制癫痫的焦点和生理作用至关重要疗法。支持每个目标的试点数据表明，降低脉冲幅度可以提高焦点，并且在较低频率和单向脉冲序列下，癫痫发作诱导更加有效。这项工作为癫痫治疗的合理剂量提供了基础，有助于提高其风险/效益比，并指导为重症患者开发更安全的替代方案。 公共卫生相关性：临床抑郁症影响着超过 3,400 万美国公民，但其中只有约三分之一能得到有效的药物治疗。对于其余患者，电休克疗法（ECT）是一种有效的选择，但它存在副作用的风险。该项目将最先进的工程方法与临床精神病学的最新发展相结合，为现有和新型癫痫疗法的剂量提供信息，从而使患有严重抑郁症和其他致残性疾病的患者获得更有效和更安全的治疗选择。