Advancing Diagnosis and Functional Localization in Focal Epilepsy with Oxygen-Enh

利用 Oxygen-Enh 推进局灶性癫痫的诊断和功能定位

• 批准号: 8352557
• 负责人: Giridhar Padmanabhan Kalamangalam
• 金额: $ 17.33万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8352557
• 关键词: Adult; Affect; American; Area; Attention; Award; Biometry; Brain; Brain scan; Breathing; Chairperson; Clinical; Clinical Research; Clinical Sciences; Clinical Services; Data; Data Analyses; Diagnosis; Diagnostic; Disease; Doctor of Philosophy; Educational workshop; Electric Stimulation; Electroencephalography; Environment; Epidemiologic Methods; Epilepsy; Equipment; Evidence Based Medicine; Excision; Faculty; Family; Foundations; Functional Imaging; Functional Magnetic Resonance Imaging; Funding; Goals; Gold; Grant; Handedness; Hospitals; Human Resources; Image; Imaging Techniques; Inpatients; International; Investigation; Language; Lesion; Location; Magnetic Resonance Imaging; Manuscripts; Maps; Mathematics; Measures; Memory; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Metabolic; Metabolism; Methods; Modality; Monitor; Motor; Neurosciences; Operative Surgical Procedures; Outcome; Outpatients; Oxygen; Partial Epilepsies; Patients; Pattern; Physicians; Pilot Projects; Positron-Emission Tomography; Postoperative Period; Publishing; Refractory; Reporting; Research; Research Infrastructure; Research Methodology; Research Personnel; Research Project Grants; Scanning; Schools; Scientist; Seeds; Signal Transduction; Site; Societies; Solid; Specificity; Staging; Structure; Study Subject; Sum; Syndrome; Techniques; Temporal Lobe; Temporal Lobe Epilepsy; Testing; Time; Training; Translational Research; United States National Institutes of Health; Universities; Work; base; career; career development; cohort; cost; design; imaging modality; improved; neocortical; neuroimaging; novel; outcome forecast; patient oriented research; patient population; population based; prospective; radioligand; research study; skills; success

DESCRIPTION (provided by applicant): I (the candidate) am an early stage academic faculty in adult epileptology, with strong clinical training and a PhD doctorate in applied mathematics from Oxford University where I was a Rhodes Scholar. I have a career commitment to patient-oriented research, and have achieved preliminary success in applying my skills to important scientific problems in epilepsy. In 2007 I was awarded a Milken Family Foundation Early Career Award from the American Epilepsy Society that enabled me to commence work on a promising and novel imaging technique (oxygen-enhanced MRI; OE-MRI) for the diagnosis of focal epilepsy. In 2010, I was co-PI on a seed grant from the Center for Clinical and Translational Sciences at UTHSC-Houston to explore OE-MRI under conditions of functional activation. These small awards have resulted in intriguing and promising pilot data. I now wish to protect my time to build the solid foundation of a long-term research career in epilepsy neuroimaging, under the mentorship of senior established investigators. My research project will advance the application of OE-MRI (achieved by subjects breathing 100% oxygen during scanning) for better anatomical diagnosis of focal epilepsy, and for noninvasive identification of eloquent cortex. Identifying an imaging lesion remains crucial in the workup of focal epilepsy patients, particularl those for whom epilepsy surgery is planned. Yet up to 30% of all refractory focal epilepsy patients have normal imaging, even with the most advanced techniques in routine clinical use (high-field strength MRI and PET). In recently published pilot studies (Kalamangalam et al (2011), Epilepsy Research - manuscript appended), I have demonstrated that OE produces a robust and diagnostically useful contrast MRI signal that achieves diagnosis and lateralization of temporal lobe epilepsy with good sensitivity and perfect specificity. In particular, OE can be lateralizing in the complete absence of MRI or PET abnormalities. I wish to extend these exciting findings on a longer term prospective basis to larger patient groups with both temporal lobe and neocortical epilepsies (Specific Aim I). An important, though different, concern in epilepsy surgery patients is the precise localization of eloquent cortex (mainly language, motor function and memory laterality). The gold standard tests for all these modalities are invasive (electrical stimulation mapping for language and motor, and the Wada test for memory). However, the strong contrast signal produced by 100% oxygen suggested that classical fMRI methods applied to detect eloquent cortex would be more informative under OE conditions, leading to improved noninvasive estimates of eloquent cortical areas than has been possible hitherto. My preliminary data with normal subjects indicates that this premise may be true. I wish to explore these intriguing results on a long-term prospective basis in our epilepsy surgery patients (Specific Aim II). The training and career development aspects of the award will comprise a thorough grounding in modern neuroimaging, focusing on MRI and fMRI, experiment design, data analysis and interpretation. I will also complete training in general clinical researc methods. Training will be achieved with mix of didactic sessions with my primary mentor, Dr Ponnada A Narayana, an MRI scientist of international standing, and attendance at national training workshops. I will also complete selected courses in advanced neuroscience offered at UTHSC's graduate school. I will also receive structured training in biostatistics, translational research and epidemiologic methods offered by the Center for Clinical Research and Evidenced-Based Medicine, which will be supervised by my co-mentor Dr James A Ferrendelli, our former Chairman and past President of the American Epilepsy Society. The institutional facilities and infrastructure available to me via the MRI Research Division and the Center for Clinical and Translational Sciences at UTHSC-Houston are the ideal setting in which to accomplish my goals. Our epilepsy clinical service - comprising the outpatient environment of UT Physicians and the inpatient Epilepsy Monitoring Unit of Memorial Hermann Hospital - follows >1500 patients yearly, providing a sufficient patient population base for recruitment of study subjects for my research. My department Chair, Dr James Grotta, guarantees 75% protected time for my research, in addition to providing any secretarial and administrative support required. I also have a supportive cohort of faculty colleagues at all career stages, including senior NIH-funded clinical researchers. At the end of the K23 award period I will be ideally placed to apply for an NIH RO1 grant to pursue an independent clinical research career in epilepsy neuroimaging. In doing so, I will be firmly on the path of my long-term goal of a clinical research career in academic epileptology. PUBLIC HEALTH RELEVANCE: MRI of the brain is the most important investigation in patients with refractory epilepsy, a condition affecting one million Americans (and 15 million worldwide). A visualized abnormality on imaging enormously improves the chances of epilepsy surgery helping the patient. Yet, a substantial fraction of refractory epilepsy patients are 'nonlesional' i.e., have normal brain scans. My project will advance the application of a novel, low-cost, and easily-implemented method of MRI brain scanning - while the patient inhales 100% oxygen - to identify imaging abnormalities in nonlesional patients, so that epilepsy surgery can be performed with greater success. The method has been successful in my pilot studies, and will be extended to better define important brain areas for language, motor and memory function, so that epilepsy surgery is also safer in these patients.

描述（由申请人提供）：我（候选人）是成人癫痫学的早期学术教师，接受过严格的临床训练，并获得牛津大学应用数学博士学位，我是该校的罗德学者。我的职业生涯致力于以患者为导向的研究，并将我的技能应用于癫痫的重要科学问题，并取得了初步成功。 2007 年，我获得了美国癫痫协会颁发的米尔肯家庭基金会早期职业奖，这使我能够开始研究一种有前景的新型成像技术（氧增强 MRI；OE-MRI），用于诊断局灶性癫痫。 2010 年，我作为共同 PI 获得了 UTHSC-Houston 临床和转化科学中心的种子资助，以探索功能激活条件下的 OE-MRI。这些小奖项带来了有趣且有希望的试点数据。现在，我希望利用自己的时间，在资深研究人员的指导下，为癫痫神经影像学的长期研究生涯打下坚实的基础。我的研究项目将推进 OE-MRI（通过受试者在扫描过程中呼吸 100% 氧气来实现）的应用，以更好地对局灶性癫痫进行解剖诊断，并对口才皮层进行无创识别。识别影像学病变对于局灶性癫痫患者的检查仍然至关重要，特别是那些计划进行癫痫手术的患者。然而，即使采用常规临床使用的最先进技术（高场强 MRI 和 PET），仍有高达 30% 的难治性局灶性癫痫患者的影像学表现正常。在最近发表的试点研究（Kalamangalam 等人（2011），癫痫研究 - 手稿附后）中，我证明了 OE 产生了强大的、诊断上有用的对比 MRI 信号，能够以良好的灵敏度和完美的特异性实现颞叶癫痫的诊断和偏侧化。特别是，在完全没有 MRI 或 PET 异常的情况下，OE 可能会偏向一侧。我希望将这些令人兴奋的发现在长期前瞻性的基础上扩展到更大的颞叶和新皮质癫痫患者群体（具体目标 I）。癫痫手术患者的一个重要但不同的问题是口才皮层的精确定位（主要是语言、运动功能和记忆偏侧性）。所有这些方式的黄金标准测试都是侵入性的（语言和运动的电刺激映射，以及记忆的 Wada 测试）。然而，100% 氧气产生的强对比信号表明，用于检测雄辩皮层的经典功能磁共振成像方法在 OE 条件下将提供更多信息，从而比迄今为止可能的方式改进雄辩皮层区域的无创估计。我对正常受试者的初步数据表明这个前提可能是正确的。我希望在我们的癫痫手术患者中长期前瞻性地探索这些有趣的结果（具体目标 II）。该奖项的培训和职业发展方面将包括现代神经影像学的全面基础，重点是 MRI 和 fMRI、实验设计、数据分析和解释。我还将完成一般临床研究方法的培训。培训将通过我的主要导师 Ponnada A Narayana 博士（一位具有国际声誉的 MRI 科学家）的教学课程以及参加国家培训研讨会来实现。我还将完成 UHSC 研究生院提供的高级神经科学精选课程。我还将接受临床研究和循证医学中心提供的生物统计学、转化研究和流行病学方法方面的结构化培训，这些培训将由我的共同导师 James A Ferrendelli 博士（我们的前主席和美国前任主席）进行监督。癫痫学会。 UTHSC-休斯顿分校的 MRI 研究部和临床与转化科学中心为我提供的机构设施和基础设施是实现我的目标的理想环境。我们的癫痫临床服务 - 包括 UT 医生的门诊环境和纪念赫尔曼医院的住院癫痫监测单位 - 每年追踪超过 1500 名患者，为我的研究招募研究对象提供足够的患者群体基础。我的系主任 James Grotta 博士除了提供所需的任何秘书和行政支持外，还保证我的研究有 75% 的受保护时间。我还有一群在职业生涯各个阶段支持我的教职同事，包括美国国立卫生研究院资助的高级临床研究人员。在 K23 奖励期结束时，我将非常有资格申请 NIH RO1 拨款，以从事癫痫神经影像学方面的独立临床研究职业。通过这样做，我将坚定地走在学术癫痫学临床研究职业的长期目标的道路上。 公共卫生相关性：脑部 MRI 是对难治性癫痫患者最重要的检查，这种疾病影响着 100 万美国人（以及全世界 1500 万）。影像学上的可视化异常极大地提高了癫痫手术帮助患者的机会。然而，相当一部分难治性癫痫患者是“无病变”的，即脑部扫描结果正常。我的项目将推进一种新型、低成本且易于实施的 MRI 脑部扫描方法的应用 - 当患者吸入 100% 氧气时 - 识别非病变患者的影像学异常，从而使癫痫手术能够取得更大的成功。该方法在我的试点研究中取得了成功，并将扩展到更好地定义语言、运动和记忆功能的重要大脑区域，从而使这些患者的癫痫手术也更加安全。