MULTIMODAL MAPPING OF SUBCORTICAL AND CORTICAL FUNCTIONAL NETWORK DISTURBANCES IN FOCAL EPILEPSY

癫痫影响1%的人口，导致显著的发病率和死亡率。在局灶性癫痫中，癫痫发作起源于致痫区（EZ），手术切除导致许多患者无癫痫。然而，局灶性癫痫的有害影响超出了解剖学EZ，包括弥漫性灰质萎缩，新皮质代谢减退和神经认知功能受损。以往的发作间期（癫痫发作之间）脑磁图局灶性癫痫患者的功能连接的研究表明，减少连接的关联新皮层，是直接相关的频率的意识损害（但不是意识保留）癫痫发作。此外，先前的发作（癫痫发作期间）皮质电图（ECoG）研究表明，在局灶性癫痫的意识损害（但不是意识保留）癫痫发作期间，新皮质活动受到抑制。本建议的中心假设是，随着时间的推移，局灶性癫痫的复发性发作导致皮质下激活结构（例如，丘脑，基底前脑）和联合皮质，导致新皮质连接性降低，可能导致神经认知功能障碍。为了解决这一假设，本研究将使用功能性磁共振成像（fMRI）来测量术前局灶性癫痫患者与对照组（目标1）的皮层下激活结构和关联新皮层之间的发作间期功能连接。连接模式将与癫痫发作类型/频率和神经认知参数相关。为了确定一旦患者术后实现癫痫发作自由，功能连接扰动是否可逆，将在术后≥ 1年的患者中重复进行皮质下-皮质连接的fMRI分析和神经心理学测试（目标2）。最后，为了确定意识损害性癫痫发作（发作）期间的异常新皮层节律是否直接导致新皮层连通性（发作间期）的长期降低，将使用ECoG在癫痫发作之前、期间和之后测量连通性的动态变化（目标3）。预计与非癫痫对照相比，局灶性癫痫患者在发作间期fMRI上表现出皮质下-皮质连接性降低，这与意识损害性癫痫发作和神经认知功能障碍的频率相关（目的1）。然而，预计在癫痫手术后无癫痫发作的患者中，皮质下-皮质功能连接紊乱将得到改善（目标2）。最后，预计动态功能连接的ECoG研究将证明与基线相比，在意识损害癫痫发作期间，新皮层连接的发作减少，表明癫痫发作活动与改变的新皮层连接之间存在直接联系（目的3）。通过这些研究获得的局灶性癫痫中皮质下-皮质网络功能障碍的详细了解可能会导致基于神经调节的治疗的新靶点，改善手术患者的选择和结果预测，以及预防这种毁灭性疾病的神经认知后遗症的更好策略。

Epilepsy affects 1% of the population, leading to significant morbidity and mortality. In focal epilepsy, seizures originate from an epileptogenic zone (EZ), and surgical resection leads to seizure-freedom in many patients. However, deleterious effects of focal epilepsy extend beyond the anatomic EZ, including diffuse gray matter atrophy, neocortical hypometabolism, and impaired neurocognitive function. Previous interictal (between seizures) magnetoencephalography studies of functional connectivity in focal epilepsy patients have demonstrated decreased connectivity in association neocortex that is directly related to frequency of consciousness-impairing (but not consciousness-sparing) seizures. Furthermore, prior ictal (during seizures) electrocorticography (ECoG) studies have demonstrated depressed neocortical activity during consciousness-impairing (but not consciousness-sparing) seizures in focal epilepsy. The central hypothesis of the present proposal is that over time, recurrent seizures in focal epilepsy lead to aberrant connections between subcortical activating structures (e.g., thalamus, basal forebrain) and association cortex, resulting in depressed neocortical connectivity that may contribute to neurocognitive dysfunction. To address this hypothesis, the present studies will use functional magnetic resonance imaging (fMRI) to measure interictal functional connectivity between subcortical activating structures and association neocortex in pre-operative focal epilepsy patients vs. controls (Aim 1). Connectivity patterns will be related to seizure type/frequency and neurocognitive parameters. To determine if functional connectivity perturbations are reversible once patients achieve seizure freedom after surgery, fMRI analyses of subcortical-cortical connectivity and neuropsychological tests will be repeated in patients ≥ 1 year post-operatively (Aim 2). Finally, to determine whether abnormal neocortical rhythms during consciousness-impairing seizures (ictal) lead directly to long-term reductions in neocortical connectivity (interictal), dynamic changes in connectivity will be measured before, during, and after seizures using ECoG (Aim 3). It is anticipated that compared to non-epileptic controls, focal epilepsy patients will exhibit reduced subcortical-cortical connectivity on interictal fMRI, which will be related to frequency of consciousness-impairing seizures and neurocognitive dysfunction (Aim 1). However, it is expected that subcortical-cortical functional connectivity perturbations will improve in patients who become seizure free after epilepsy surgery (Aim 2). Finally, it is anticipated that ECoG studies of dynamic functional connectivity will demonstrate ictal reductions in neocortical connectivity during consciousness-impairing seizures compared to baseline, suggesting a direct link between seizure activity and altered neocortical connectivity (Aim 3). A detailed understanding of subcortical-cortical network dysfunction in focal epilepsy gained through these studies may lead to novel targets for neuromodulation-based treatment, improvements in surgical patient selection and outcome prediction, and better strategies to prevent neurocognitive sequelae in this devastating disorder.