今天为大家分享的是“景昱—神经科学专栏”第一百零八期，由上海交通大学医学院附属瑞金医院胡柯嘉带来的：“fMRI功能连接预测丘脑前核DBS治疗癫痫的预后”，内容精彩，欢迎阅读。

癫痫是一种常见的全球性残疾和死亡原因，大约20％-40％的癫痫患者属于药物难治性癫痫，目前对此类癫痫机制知之甚少，这使得对其治疗较困难。早期建立的癫痫疾病模型主要集中在采用离散的致癫痫源，但其他多种形式的癫痫，特别是颞叶癫痫（Temporal Lobe Epilepsy，TLE），正日益被认为是具有广泛功能和结构变化的脑网络类疾病。此外，一些癫痫患者可能有多病灶性发作，使局部化的研究策略变得困难。

虽然与对照组相比，癫痫患者的许多脑网络已有不同的变化，但没有一个像默认模式网络（Default Mode Network，DMN）的静息态网络那样被广泛研究过。DMN是一个广泛分布的脑网络，在休息期间优先活跃，在任务介入期间停止活跃。DMN的核心部分包括后扣带皮层（Posterior Cingulate Cortex，PCC），楔前叶，下顶叶（Inferior Parietal Lobule），上顶叶（Superior Parietal Lobe），内侧前额叶皮层（Medial Prefrontal Cortex），压后皮层（Retrosplenial cortex），海马，海马旁皮质（Parahippocampal cortex）和小脑。

之前的研究表明在发作间期癫痫样放电和癫痫发作时候DMN失活或抑制可能与失去意识有关。既往研究涉及了癫痫发作的其他静息状态网络，可能在癫痫的认知效应中发挥作用，例如注意网络和奖励/情感网络，对癫痫的理解从局部转变为网络可能会对治疗结果的变化有所启发。难治性癫痫的一种新兴治疗方法是深部脑刺激（Deep Brain Stimulation，DBS）。目前的靶点包括中心-束旁（Centromedian-parafascicular，Cm-PF）复合体，海马和丘脑前核（Anterior Nucleus of the Thalamus，ANT）。刺激丘脑前核用于治疗癫痫的SANTE（Stimulation of the Anterior Nuclei of Thalamus for Epilepsy）试验结果显示ANT刺激治疗局灶性癫痫的长期疗效和安全性，但结果存在显著的变异。结果变异的一个潜在原因是DBS靶向准确性不足，大约10％的电极不在ANT内。目前已经提出了许多提高ANT靶向定位准确性的改进，但是单纯依靠DBS术中直接定位靶点仍有不足。

为了更好地理解DBS刺激机制和潜在改善疗效，美国Mayo诊所的Erik H. Middlebrooks等研究者评估了ANT DBS治疗与VTA功能连接的相关性，通过评估ANT DBS的组织活化量（Volume of Tissue Activated，VTA）以及静息状态功能连接谱。论文发表于2018年8月的《Neurosurgical Focus》杂志。（REF: Middlebrooks EH, Grewal SS, Stead M, Lundstrom BN, Worrell GA, Van Gompel JJ. Differences in functional connectivity profiles as a predictor of response to anterior thalamic nucleus deep brain stimulation for epilepsy: a hypothesis for the mechanism of action and a potential biomarker for outcomes. Neurosurg Focus. 2018 Aug;45(2):E7.）

该研究回顾性分析包括6名接受ANT-DBS治疗难治性癫痫的患者。根据DBS后癫痫发作减少，患者被分为2类：“响应者”组癫痫发作频率降低≥50％，而“无响应者”组癫痫发作率降低<50％。术后对DBS电极进行定位并根据参数设置计算生成VTA。VTA用作进行的静息状态功能性MRI连接性分析的种子点。在响应者和非响应者组之间评估皮质与VTA的连接的差异。

表1： 6例接受ANT DBS治疗难治性癫痫患者的人口统计学数据和术后结果

图1. 响应者（绿色星号）和无响应者（红色星号）的左侧丘脑（A和B）和右侧丘脑（C和D）内远端阴极接触（K1 / K9）的归一化空间位置。 所有电极均为Medtronic 3389。接触位置记录在DBS内在模板图谱（DISTAL）中，显示与丘脑前核的关系（箭头）。

结果显示，经过平均29.7月的术后随访，共3个无响应者，3个响应者。6名患者中的5个加做了额外双侧靶点（4例海马和1例Cm-PF复合体），而在这5名患者中，4名患者接受两个靶点的刺激（3例ANT +海马和1例ANT + Cm-PF复合体）。 这4患者中，2例在响应组中，2例在无响应组中。

图2：响应者（左）和无响应者（右）的组平均t-分数图显示正相关区域（地图上的红黄色）和反相关（地图上的蓝绿色）。

与无响应者相比，ANT DBS反应者显示出与默认模式网络的更大的正连通性，包括后扣带皮层，内侧前额叶皮层，下顶叶小叶和楔前叶。有趣的是，在响应者的海马体也存在一致的但是是反相关性变化。

图3：响应者中左右半球的连接区域的连通性比无响应者更高。响应者具有更高“正”相关性的区域（以红橙色显示），较高的“负”相关区域蓝绿色显示。地形图由平均组图的差异产生，并且阈值化为p值<0.05，校正自由度。

图4：通过海马体的冠状图像（y = -26；MNI模板空间）显示了无应答者（A）和应答者（B）的平均负相关的程度，（C）显示了两者之间平均差异。 ROI（Region of Interest）分析（下图）显示每位患者的海马MNI坐标为±30 / -26 / -11（平均t评分和ROI内所有非零的体素）。

研究者最后总结，基于他们的初步研究，癫痫患者接受ANT DBS后在默认模式网络中增加了连接性，这增加了癫痫发作的阈值。另外，通过增加的海马γ-氨基丁酸（GABA）浓度介导的对海马的抑制作用可能有助于抑制癫痫发作，而哪些因素是癫痫发作的主要驱动因素，或它们是否是互补效应，需要进一步研究，识别此连接与丘脑VTA相关的概况可能有助于提高ANT DBS术前功能性定位的效率。

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