Targeting DBS Therapy to the OCD Network Using fMRI and Intracranial Recordings

项目概要/摘要 根据世界卫生组织的数据，强迫症是年轻人残疾的十大原因之一， 患者具有认知疗法和药物疗法难治的严重症状。强迫症被认为是通过 通过锚定在前扣带皮层（ACC）中的皮质-纹状体-丘脑-皮质（CSTC）回路， 眶额皮质（OFC）。脑深部电刺激（DBS）是一种基于靶向电路的治疗方法， 治疗严重的顽固性强迫症然而，DBS的使用仍然有限，因为：1）目前只有50- 60%的患者对治疗有反应，2）DBS程控是一个复杂的试错过程，可能需要 几个月到几年来优化，和3）DBS与不良反应，如睡眠障碍和躁狂症。 我们的目标是克服这些局限性，通过开发方法，DBS治疗的目标是神经回路 潜在的强迫症DBS技术的发展现在允许在DBS被植入的同时执行MR成像。 现在可以从DBS电极导线获取开/关和局部场电位记录，这提供了一个独特的机会 以确定DBS治疗是否在功能上接合预期的OCD电路。在此，我们建议：1） 开发使用基于刺激的fMRI生成个性化空间激活图的协议，以及2） 识别OCD和相关精神症状的个体化电生理生物标志物， 使用颅内记录的DBS。总之，这些成像和电生理学方法可用于 确认DBS正在使用OCD网络。 在我们的试点研究中，我们证明了使用fMRI协议在单个刺激图中生成刺激图的可行性。 受试者，发现OFC和ACC的激活远离经验确定的治疗接触。我们 还描述了在终纹的床核内的抑郁症的伽马生物标志物的鉴定 （BNST），作为一个概念验证，它是可能的，以确定精神疾病的电生理生物标志物。 症状我们目前已获得FDA试验用器械豁免（IDE）批准，可在 OFC和ACC以及标准内囊前肢（ALIC）DBS目标用于OCD。这 该提案旨在确定我们的初步成像结果是否适用于更大的受试者队列， 确定通过进行颅内记录发现新的OCD生物标志物的可行性， OCD网络的关键节点。这些研究提供了一条通往个性化的、基于电路的精确度的道路 改善强迫症DBS的药物。

PROJECT SUMMARY/ABSTRACT According to the WHO, OCD is one of the top ten causes of disability among young adults, and one in ten patients have severe symptoms refractory to cognitive and medical therapies. OCD is thought to be mediated by a cortico-striato-thalamo-cortical (CSTC) circuit anchored in the anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC). Deep brain stimulation (DBS) is a targeted circuit-based treatment that has been used to treat severe, refractory cases of OCD. However, DBS remains limited in its use because: 1) currently only 50- 60% of patients respond to therapy, 2) DBS programming is a complex, trial-and-error process that can take months to years to optimize, and 3) DBS is associated with adverse effects such as sleep disturbance and mania. We aim to overcomes these limitations by developing methods to target DBS therapy to the neural circuits underlying OCD. Developments in DBS technology now allow for MR imaging to be performed while DBS is On/Off and local field potential recordings can now be acquired from DBS leads, providing a unique opportunity to determine whether DBS therapy is functionally engaging the intended OCD circuitry. Here, we propose to: 1) Develop protocols for generating personalized spatial activation maps using stimulation-based fMRI, and 2) Identify individualized electrophysiological biomarkers of OCD and related psychiatric symptoms responsive to DBS using intracranial recordings. Together, these imaging and electrophysiological methods can be used to verify that DBS is engaging the OCD network. In our pilot studies, we demonstrate the feasibility of generating stimulation maps using fMRI protocols in a single subject, finding activation in the OFC and ACC distant from the empirically determine therapeutic contacts. We also describe the identification of a gamma biomarker of depression within the bed nucleus of the stria terminalis (BNST), serving as a proof-of-concept that it is possible to identify electrophysiological biomarkers of psychiatric symptoms. We currently have FDA investigational device exemption (IDE) approval to implant DBS leads in the OFC and ACC in addition to the standard anterior limb of the internal capsule (ALIC) DBS target for OCD. This proposal seeks to determine whether our initial imaging findings will hold in a larger cohort of subjects and to determine the feasibility of discovering novel OCD biomarkers by performing intracranial recordings across critical nodes of the OCD network. These studies provide a path towards personalized, circuit-based precision medicine to improve DBS for OCD.