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

项目摘要/摘要 根据世界卫生组织的数据，强迫症是导致年轻人残疾的十大原因之一，十分之一 患者有严重的症状，对认知和药物治疗无效。强迫症被认为是由 由定位于前扣带回(ACC)的皮质-纹状体-丘脑-皮质(CSTC)回路和 眶前叶皮质(OFC)。脑深部刺激(DBS)是一种已被使用的基于回路的靶向治疗 治疗严重的、难治性的强迫症。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编程是一个复杂的反复试验的过程，可能需要 需要几个月到几年的时间来优化，3)DBS与睡眠障碍和躁狂等不良影响有关。 我们的目标是通过开发针对神经回路的DBS治疗方法来克服这些限制 潜在的强迫症。DBS技术的发展现在允许在DBS进行磁共振成像的同时 现在可以从DBS Leads获取开/关和本地场潜在录音，这提供了一个独特的机会 以确定DBS治疗是否在功能上使用了预期的强迫症电路。在此，我们建议：1) 制定使用基于刺激的功能磁共振成像生成个性化空间激活图的协议，以及2) 确定强迫症的个体化电生理生物标志物和相关的精神症状 DBS使用的是脑部记录。结合起来，这些成像和电生理方法可以用来 验证DBS是否正在使用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 受试者，发现OFC和ACC中的激活远离经验性确定的治疗接触。我们 还描述了终纹床核内抑郁的伽马生物标志物的鉴定。 (BNST)，作为一种概念证明，有可能识别精神疾病的电生理生物标记物 症状。我们目前已获得FDA的调查设备豁免(IDE)批准，可以在 OFC和ACC除标准的内囊前肢(ALIC)外，DBS靶点为强迫症。这 该提案旨在确定我们最初的成像结果是否将适用于更大的受试者队列，并 通过脑部记录确定发现新的强迫症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向个性化、基于电路的精度的道路 改善DBS治疗强迫症的药物。

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.