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

描述（申请人提供）：我（候选人）是一名早期成人癫痫学学术人员，具有较强的临床训练，并获得牛津大学应用数学博士学位，并获得罗德奖学金。我的职业致力于以患者为导向的研究，并在将我的技能应用于癫痫的重要科学问题方面取得了初步成功。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途的新型成像技术（氧增强MRI； OE-MRI），用于诊断局灶性癫痫。2010年，我是UTHSC-Houston临床与转化科学中心（Center for Clinical and Translational Sciences）种子基金的共同负责人，研究功能激活条件下的e - mri。这些小奖励产生了有趣而有前途的试点数据。我现在希望保护我的时间，在资深研究人员的指导下，为癫痫神经影像学的长期研究奠定坚实的基础。我的研究项目将推动e - mri（通过受试者在扫描过程中呼吸100%氧气来实现）在局灶性癫痫的更好的解剖诊断和对流利皮层的无创识别方面的应用。在局灶性癫痫患者的检查中，确定影像学病变仍然是至关重要的，特别是那些计划进行癫痫手术的患者。然而，高达30%的难治性局灶性癫痫患者成像正常，即使使用常规临床使用的最先进技术（高场强度MRI和PET）也是如此。在最近发表的试点研究中（Kalamangalam et al (2011)， Epilepsy Research -手稿附后），我已经证明OE产生了一个强大的、诊断上有用的MRI对比信号，以良好的敏感性和完美的特异性实现了颞叶癫痫的诊断和侧化。特别是，在完全没有MRI或PET异常的情况下，OE可以侧化。我希望将这些令人兴奋的发现在长期的前瞻性基础上扩展到更大的颞叶和新皮层癫痫患者群体（具体目标1）。在癫痫手术患者中，一个重要但不同的问题是雄辩皮质的精确定位（主要是语言、运动功能和记忆侧性）。所有这些模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，在OE条件下，用于检测雄辩皮层的经典fMRI方法将提供更多信息，从而提高了迄今为止对雄辩皮质区域的无创估计。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的长期前瞻性基础上探索这些有趣的结果（Specific Aim II）。该奖项的培训和职业发展方面将包括现代神经成像的全面基础，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。培训将与我的主要导师Ponnada A Narayana博士（一位具有国际地位的核磁共振科学家）一起进行教学，并参加国家培训讲习班。我还将在研究生院完成高级神经科学的选修课。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，该中心将由我的共同导师、美国癫痫学会前主席和前会长James A Ferrendelli博士监督。休斯敦休斯敦大学核磁共振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目标的理想环境。我们的癫痫临床服务包括UT医师门诊环境和纪念赫尔曼医院住院癫痫监测单元，每年随访患者约1500例，为我的研究招募研究对象提供了充足的患者人群基础。我的系主任James Grotta博士保证75%的保护时间用于我的研究，此外还提供必要的秘书和行政支持。我在各个职业阶段都有一群支持我的同事，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，我将理想地申请NIH RO1资助，以追求癫痫神经成像的独立临床研究事业。在这样做的过程中，我将坚定地走在我的长期目标的道路上，在学术癫痫学的临床研究生涯。

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.