Hippocampal oscillations, interictal discharges, and memory formation

 描述（由申请人提供）： 目的：这项研究将探讨癫痫患者的记忆缺陷与脑电图（EEG）异常电活动之间的关系。颞叶癫痫（TLE）患者通常在智力正常的情况下表现出记忆功能障碍。这一发现与建立新记忆在很大程度上取决于海马和其他内侧颞叶结构的功能的理论是一致的，这是一个已知在TLE中功能失调的网络。先前的研究发现认知任务表现的中断与发作间期癫痫样放电（IED）的存在之间存在关联。简易爆炸装置是反映异常神经元放电的间歇性尖峰或尖波，但不会组织成癫痫发作。嵌入IED中的可能是病理性高频伽马振荡（HFO），与被认为是记忆形成基础的正常高频活动不同。在临床实践中，IED仅被认为是癫痫的标志物，不能用药物抑制。然而，关于对认知功能构成最大风险的简易爆炸装置的特性或简易爆炸装置引起认知缺陷的机制，人们知之甚少。本研究探讨了在编码过程中使用简易爆炸装置对刺激项目后续记忆的影响。该研究的第一个目的是确定海马内IED的空间和时间特征，这将预测延迟回忆和识别较差，以及确定嵌入的病理性HFO的影响。第二个目标是确定简易爆炸装置中断内存编码的机制。假设简易爆炸装置破坏了记忆形成的正常脑电图节律。更具体地说，预测是，简易爆炸装置将导致记忆编码期间诱发的正常高频伽马活动量减少。此外，有人提出，简易爆炸装置及其相关的病理性HFO会破坏整个海马体正常伽马振荡的同步定时或“一致性”。研究计划/方法：为了检验这些假设，TLE受试者将在颅内EEG记录期间完成记忆任务。测试将包括语言和非语言编码，工作记忆，延迟回忆和识别任务。在可能的切除性癫痫手术之前，将电极植入海马内或海马旁进行临床评价。将通过人工审查识别简易爆炸装置，使用Neuroscan软件量化时间和空间特性。将使用光谱分析评估HFO功率和相干性。临床相关性：简易爆炸装置对正常脑电图振荡的中断有助于解释该患者人群的短暂和长期记忆功能障碍。拟议的研究还将确定简易爆炸装置内的病理性HFO是否有助于其不良认知影响。简易爆炸装置破坏记忆编码所必需的电活动的证据可能表明需要抑制放电或为记忆功能障碍的新疗法指明方向。这些发现可以指导未来的研究，旨在通过改变异常振荡活动来改善癫痫患者的认知能力。

 DESCRIPTION (provided by applicant): Objective: The proposed study will investigate the relationship between memory deficits and abnormal electrical activity seen on electroencephalography (EEG) in patients with seizures. Patients with temporal lobe epilepsy (TLE) often demonstrate memory dysfunction in the setting of otherwise normal intelligence. This finding is consistent with the theory that establishing new memories is dependent to a large extent on the function of the hippocampus and other mesial temporal lobe structures, a network known to be dysfunctional in TLE. Prior studies found an association between disruptions of cognitive task performance and the presence of interictal epileptiform discharges (IEDs). IEDs are intermittent spikes or sharp waves that reflect abnormal neuronal firing, but do not organize into a seizure. Embedded within the IEDs may be pathological high frequency gamma oscillations (HFOs), distinct from the normal high frequency activity that is thought to underlie memory formation. In clinical practice, IEDs are considered only to be markers of epilepsy and are not suppressed with medications. Little is known, however, regarding the properties of IEDs that pose the greatest risk to cognitive function or the mechanism by which IEDs cause cognitive deficits. The present study examines the effects of IEDs during encoding on subsequent memory for the stimulus items. The first aim of the study is to determine the spatial and temporal characteristics of IEDs within the hippocampus that will predict poorer delayed recall and recognition, as well as identify the effect of embedded pathological HFOs. The second aim is to identify the mechanism by which IEDs interrupt memory encoding. The hypothesis is that IEDs disrupt the normal EEG rhythms that underlie memory formation. More specifically, the prediction is that IEDs will cause a decrease in the amount of normal high frequency gamma activity induced during memory encoding. Furthermore, it is proposed that IEDs and their associated pathological HFOs will disrupt the synchronous timing, or "coherence," of normal gamma oscillations throughout the hippocampus. Research Plan/Methods: To test these hypotheses, subjects with TLE will complete memory tasks during intracranial EEG recordings. Testing will include verbal and non-verbal encoding, working memory, and delayed recall and recognition tasks. The electrodes will be implanted within or alongside the hippocampus for clinical evaluations prior to possible resective epilepsy surgery. IEDs will be identified by manual review, with temporal and spatial properties quantified using Neuroscan software. HFO power and coherence will be assessed using spectral analysis. Clinical Relevance: The interruption of normal EEG oscillations by IEDs would help to explain both transient and long-term memory dysfunction in this patient population. The proposed study will also determine if pathological HFOs within the IEDs contribute to their adverse cognitive effects. Evidence that IEDs disrupt electrical activity necessary for memory encoding may indicate the need for suppression of discharges or point the way to new treatments for memory dysfunction. These findings could direct future investigations aimed at therapeutic approaches to improve cognition in epilepsy patients by alteration of abnormal oscillatory activity.