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

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，具有强大的临床培训和牛津大学应用数学博士学位，我是罗兹学者。我有一个以病人为导向的研究的职业承诺，并已取得初步成功，运用我的技能在癫痫的重要科学问题。2007年，我获得了美国癫痫协会授予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休斯顿临床和转化科学中心种子基金的共同PI，以探索功能激活条件下的OE-MRI。这些小奖项产生了有趣和有前途的试点数据。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生涯奠定坚实的基础。我的研究项目将推进OE-MRI的应用（扫描过程中受试者呼吸100%氧气），以更好地解剖诊断局灶性癫痫，并无创识别功能皮层。识别影像学病灶在局灶性癫痫患者的检查中仍然至关重要，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的成像正常，即使在常规临床使用的最先进的技术（高场强MRI和PET）。在最近发表的初步研究（Kalamangalam等人（2011），癫痫研究-随附手稿）中，我已经证明OE产生了一种稳健且诊断上有用的对比MRI信号，可实现颞叶癫痫的诊断和定侧，具有良好的灵敏度和完美的特异性。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扩展到更大的颞叶和新皮质癫痫患者群体（具体目标I）。一个重要的，虽然不同的，关注癫痫手术患者是精确定位的功能皮层（主要是语言，运动功能和记忆偏侧）。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%氧气产生的强对比度信号表明，经典的功能磁共振成像方法应用于检测功能皮层将在OE条件下提供更多的信息，从而改善非侵入性估计功能皮层区域比迄今为止可能。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（特定目标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。培训将通过与我的主要导师Ponnada A Narayana博士（一位具有国际地位的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UTHSC研究生院提供的高级神经科学课程。我还将接受由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的结构化培训，这将由我的共同导师James A Ferrendelli博士监督，他是我们的前任主席和美国癫痫协会的前任主席。通过UTHSC休斯顿的MRI研究部门和临床和转化科学中心提供给我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-每年随访> 1500名患者，为我的研究招募研究受试者提供了足够的患者人群基础。我的系主任James Grotta博士保证75%的研究时间受到保护，此外还提供所需的任何秘书和行政支持。我还有一群支持我的同事，他们来自各个职业阶段，包括NIH资助的高级临床研究人员。在K23奖期间结束时，我将理想地申请NIH RO1补助金，以追求癫痫神经影像学的独立临床研究生涯。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.