Interictal discharge events: from physiological effects to cognitive consequences

描述（由申请人提供）：发作间期放电事件：从生理效应到认知后果。许多癫痫患者更有可能表现出学习障碍，在学校表现不如同龄人，智商分数分布较低。此外，许多癫痫受试者患有重要的共病，其通常导致学习障碍，包括自闭症谱系障碍、情绪障碍、睡眠障碍和精神病。最近，除了癫痫发作事件本身，人们的注意力已经投入到发作间期放电事件中流行的一大部分癫痫科目。在癫痫发作事件之间，癫痫受试者的颅内场电位记录通常以称为发作间期放电事件（IIDE）的内部刺激事件为特征。我们的建议旨在了解内侧颞叶（MTL）负责学习的神经元回路如何受到癫痫临床和亚临床表现的影响。来自神经学、电生理学、影像学、电刺激和分子研究的汇聚证据指出海马和相关MTL结构在学习中的突出作用。我们的建议是基于四个具有丰富癫痫患者工作经验的PI之间的合作努力（Kreiman，Ph.D.，安德森，医学博士，哲学博士、Loddenkemper，医学博士和Madsen，M.D.）。我们研究了顽固性癫痫患者，植入电极以定位致痫区域进行切除。预防这一过程中的不良反应需要了解致痫区域的生理和行为功能。因此，除了解决有关学习的关键问题外，我们的工作可能会直接使那些接受手术治疗的患者受益。我们的电生理记录为我们提供了一个独特的机会，以高空间和时间分辨率检查人类MTL电路。虽然已经提出，IIDE可能在几个癫痫患者中观察到的认知缺陷中发挥重要作用，但IIDE与认知之间的联系仍然知之甚少。这个提议的目的是进一步了解IIDE引起的生理变化及其在认知功能中的作用。我们假设，与其他人一样，内侧颞叶区域（包括海马和周围结构）的IIDE在癫痫受试者普遍存在的认知障碍中起着重要作用。我们将测试的假设，IIDE的影响学习成绩和颞叶的生理反应。我们将进一步评估IIDE的潜在调节或破坏作用的空间和时间特异性。该提案的目标旨在通过结合生理，计算和行为工具来测试这一假设。具体目标是：2.1具体目标1：描述发作间期放电事件对生理活动的影响2.2具体目标2：评价发作间期放电事件对认知的影响 公共卫生相关性：发作间期放电事件：从生理影响到认知后果癫痫儿童表现出学习障碍，在学校表现不如同龄人。癫痫合并症的预防和治疗是脑研究的一个紧迫主题。我们的目的是了解癫痫的临床和亚临床表现如何影响负责学习和记忆形成的神经元回路。我们的团队包括神经学家，神经外科医生和认知神经科学家，并结合生理，计算和认知技术，以帮助解决癫痫患者的认知挑战。

DESCRIPTION (provided by applicant): Interictal discharge events: from physiological effects to cognitive consequences. Many epileptic subjects are more likely to show learning disabilities, perform less well than peers at school and have a lower distribution of IQ scores. Additionally, many epileptic subjects suffer from important co-morbidities that often lead to learning impairments including autistic spectrum disorder, mood disorders, sleep disorders and psychosis. Recently, in addition to seizure events themselves, attention has been devoted to the interictal discharge events prevalent in a large fraction of epileptic subjects. Between seizure events, intracranial field potential recordings in epilepsy subjects are often characterized by internal stimulation events denominated interictal discharge events (IIDEs). Our proposal aims to understand how the neuronal circuits in the medial temporal lobe (MTL) responsible for learning are affected by clinical and subclinical manifestations of epilepsy. Converging evidence from neurology, electrophysiology, imaging, electrical stimulation and molecular studies point to the prominent role of the hippocampus and related MTL structures in learning. Our proposal is based on a collaborative effort between four PIs with extensive experience in working with epileptic patients (Kreiman, Ph.D., Anderson, M.D., Ph.D., Loddenkemper, M.D. and Madsen, M.D.). We study patients with intractable epilepsy implanted with electrodes to localize epileptogenic areas for resection. Preventing adverse effects in this procedure requires understanding the physiological and behavioral functions of the epileptogenic areas. Thus, in addition to addressing key questions about learning, our work may directly benefit those patients undergoing surgical treatment. Our electrophysiological recordings provide us with a unique opportunity to examine the human MTL circuitry at high spatial and temporal resolution. Although it has been proposed that IIDEs may play an important role in the cognitive deficits observed in several epileptic patients, the link between IIDEs and cognition remains only poorly understood. The goal of this proposal is to further our understanding of the physiological changes evoked by IIDEs and their consequent roles in cognitive function. We hypothesize, with others, that IIDEs in medial temporal lobe areas including the hippocampus and surrounding structures play an important role in the cognitive impairments prevalent in epileptic subjects. We will test the hypothesis that IIDEs influence learning performance and physiological responses in the temporal lobe. We will further assess the spatial and temporal specificity of potential modulatory or disruptive effects by IIDEs. The goals of this proposal aim to test this hypothesis by combining physiological, computational and behavioral tools. The specific aims are: 2.1 Specific Aim 1: Characterize the effects of interictal discharge events on physiological activity 2.2 Specific Aim 2: Evaluate the effects of interictal discharge events on cognition PUBLIC HEALTH RELEVANCE: Interictal discharge events: from physiological effects to cognitive consequences Children with epilepsy show learning disabilities and perform less well than peers at school. The prevention and treatment of the co-morbidities associated with epilepsy is an urgent theme of brain research. We aim to understand how clinical and subclinical manifestations of epilepsy affect the neuronal circuits responsible for learning and memory formation. Our team includes neurologists, neurosurgeons and cognitive neuroscientists and combines physiological, computational and cognitive techniques to help address the cognitive challenges in subjects with epilepsy.