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

个人简介(由申请人提供)：我(应聘者)是成人癫痫学的早期学术人员，曾在牛津大学担任罗兹奖学金获得者，曾受过很强的临床训练，并拥有应用数学博士学位。我致力于以患者为中心的研究，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授予的Milken Family Foundation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(氧气增强磁共振成像；OE-MRI)来诊断局灶性癫痫。2010年，我参与了休斯顿大学休斯顿临床与翻译科学中心的种子基金，以探索功能激活条件下的OE-MRI。这些小规模的奖励产生了耐人寻味且前景看好的试验数据。现在，我希望在资深研究人员的指导下，节省时间，为癫痫神经成像的长期研究奠定坚实的基础。我的研究项目将推动OE-MRI(通过受试者在扫描过程中呼吸100%氧气实现)的应用，以更好地对局灶性癫痫进行解剖学诊断，并对口才皮层进行非侵入性识别。在局灶性癫痫患者，尤其是那些计划进行癫痫手术的患者的检查中，确定影像病变仍然是至关重要的。然而，高达30%的难治性局灶性癫痫患者的成像正常，即使在常规临床使用的最先进技术(高场强MRI和PET)下也是如此。在最近发表的试点研究中(Kalamangalam等人(2011)，癫痫研究-手稿附后)，我已经证明了OE产生强大的、对诊断有用的对比MRI信号，实现了对颞叶癫痫的诊断和定侧，具有良好的灵敏度和完美的特异度。特别是，在完全没有MRI或PET异常的情况下，OE可以偏侧化。我希望将这些令人兴奋的发现在更长期的前瞻性基础上推广到更大的同时患有颞叶和新皮质癫痫的患者群体(特定目标I)。癫痫手术患者的一个重要但不同的问题是口才皮质的精确定位(主要是语言、运动功能和记忆偏侧性)。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%氧气产生的强烈对比信号表明，在OE条件下，应用经典的fMRI方法检测口才皮质将提供更多信息，导致对口才皮质面积的无创估计比迄今可能的更好。我与正常受试者的初步数据表明，这一前提可能是正确的。我希望在我们的癫痫手术患者(特定目标II)的长期前瞻性基础上探索这些有趣的结果。该奖项的培训和职业发展方面将包括对现代神经成像的全面基础，重点是磁共振成像和功能磁共振成像、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。培训将通过与我的主要导师、具有国际声誉的核磁共振科学家Ponnada A Narayana博士的授课课程和参加国家培训研讨会来实现。我还将完成UTHSC研究生院提供的高级神经科学方面的精选课程。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有组织的培训，培训将由我的合作导师詹姆斯·A·费伦德利博士监督，他是我们的前主席和美国癫痫学会的前主席。通过核磁共振研究部和休斯顿大学休斯顿临床与翻译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-包括德克萨斯大学内科医生的门诊环境和赫尔曼纪念医院的癫痫住院监测单元-每年跟踪&gt；1500名患者，为我的研究招募研究对象提供了足够的患者基础。我的系主任詹姆斯·格罗塔博士保证75%的受保护时间用于我的研究，此外还提供所需的任何秘书和行政支持。我也有一群在职业生涯各个阶段都支持我的教员同事，包括NIH资助的高级临床研究人员。在K23授权期结束时，我将是申请NIH RO1拨款的理想人选，以追求癫痫神经成像方面的独立临床研究生涯。这样做，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中。

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.