Insular lobe epilepsy is one of the least understood focal epilepsies. This is attributable to the difficulty to explore insular epileptic foci and, consequently, to the slow accumulation of clinical experience. Stereo-electroencephalography (SEEG) has played a critical role for identifying insular lobe seizures (Isnard et al., 2000, Isnard et al., 2004, Ryvlin et al., 2006), allowing definitive spatiotemporal segregation of insular seizures with respect to those originating from other brain regions. To date, clinico-electrophysiological features of the insular lobe epilepsy have not been fully established. Previous reports consist of classic case description and interpretation of clinical data set (Dobesberger et al., 2008, Isnard et al., 2000, Isnard et al., 2004, Montavont et al., 2015, Nguyen et al., 2009, Ryvlin et al., 2006, von Lehe et al., 2009). Seizure propagation and related semiologies of the insular lobe epilepsy have not been linked by objective indices.
岛叶癫痫是人们了解最少的局灶性癫痫之一。这是由于难以探索岛状癫痫病灶，因此，缓慢积累的临床经验。立体脑电图(SEEG)在识别岛叶癫痫发作方面发挥了关键作用(Isnard 等，2000，Isnard 等，2004，Ryvlin 等，2006) ，允许岛状癫痫发作的明确时空分离来自其他大脑区域。迄今为止，岛叶癫痫的临床电生理特征尚未完全确定。以前的报告包括经典病例描述和临床数据集的解释(Dobesberger 等，2008，Isnard 等，2000，Isnard 等，2004，Montavont 等，2015，Nguyen 等，2009，Ryvlin 等，2006，von Lehe 等，2009)。脑岛叶癫痫的发作传播与相关的符号学尚未用客观指标联系起来。
In principle, identification of seizure focus largely relies on interpretation of clinical presentation, which proved useful in epilepsies of frontal (Bonini et al., 2014), temporal (Dupont et al., 2015, Marks and Laxer, 1998), parietal (Francione et al., 2015), and occipital (Appel et al., 2015) lobe origins. Recently, however, exploration with SEEG enabled identification of the insular origin of seizures in patients with various extra-insular semiologies, mimicking temporal (Isnard et al., 2004, Nguyen et al., 2009, Ostrowsky et al., 2000), frontal (Dobesberger et al., 2008, Nguyen et al., 2009, Ryvlin et al., 2006), and parietal (Montavont et al., 2015, Nguyen et al., 2009) lobe epilepsies. These evidences suggest a potential risk for diagnostic error when relying on clinical presentation especially in MRI-negative focal epilepsies.
原则上，癫痫发作焦点的识别很大程度上依赖于临床表现的解释篇，这在额叶癫痫(Bonini et al。 ，2014) ，颞叶癫痫(Dupont et al。 ，2015，Marks and Laxer，1998) ，顶叶癫痫(Francione et al。 ，2015)和枕叶起源(Appel et al。 ，2015)。然而，最近，SEEG 的探索使得能够鉴定各种岛外符号学患者癫痫发作的岛状起源，模拟时间(Isnard 等，2004，Nguyen 等，2009，Ostrowsky 等，2000) ，额叶(Dobesberger 等，2008，Nguyen 等，2009，Ryvlin 等，2006)和顶叶(Montavont 等，2015，Nguyen 等，2009)叶癫痫。这些证据表明，当依赖于临床表现，特别是在 MRI 阴性的局灶性癫痫时，存在潜在的诊断错误风险。
However, understanding the association between an insular-origin seizure and a clinical presentation of frontal epilepsy is not straightforward. The involvement of mesial frontal cortex during propagation of insular seizures has been suggested by several studies based on electro-clinical analysis of intra-cerebral recordings (Dobesberger et al., 2008, Dylgjeri et al., 2014, Nguyen et al., 2009, Proserpio et al., 2011, Ryvlin et al., 2006). However the recording of cortico-cortical evoked potentials (CCEPs) failed to demonstrate direct functional connections between the insula and mesial frontal cortex (Almashaikhi et al., 2014); furthermore the strength and directionality of functional coupling between these two regions have not been quantified during insular seizures. In the current study, we analyzed ictal SEEG in five patients with insular onset seizures presenting with elementary motor/hypermotor seizures in three, and with an insular semiology in two. We aimed at assessing the functional coupling pattern during seizures propagation associated with a frontal presentation and at understanding the reason for the semiological difference between these two types of seizures.
然而，理解岛源性癫痫发作与额叶癫痫临床表现之间的关系并非易事。基于脑内记录的电子临床分析的几项研究(Dobesberger 等，2008，Dylgjeri 等，2014，Nguyen 等，2009，Proserpio 等，2011，Ryvlin 等，2006)提示了内侧额叶皮层在岛状癫痫发作传播过程中的参与。然而，皮层诱发电位(CCEPs)的记录未能证明岛叶和内侧额叶皮层之间的直接功能连接(Almashaikhi 等，2014) ; 此外，这两个区域之间功能耦合的强度和方向性尚未在岛状癫痫发作期间进行量化。在目前的研究中，我们分析了5例岛状发作癫痫患者的发作性 SEEG，其中3例表现为初级运动/运动亢进性癫痫，2例表现为岛状符号学。我们的目的是评估与额叶呈现相关的癫痫发作传播过程中的功能耦合模式，并了解这两种类型癫痫发作之间存在符号学差异的原因。
Five insular lobe epilepsy patients were analyzed in this study (Table 1). These patients met the following criteria: (1) their ictal onset zones were localized to the insula by clinical interpretation of SEEG based on low-voltage fast discharge (LVFD); (2) Regions explored by SEEG included the insula as well as the mesial frontal/cingulate regions; (3) Radiofrequency-thermocoagulation (Catenoix et al., 2008, Guénot et al., 2004) targeted at the insula achieved more than 50% reduction of seizure frequency. The five patients represented 21.7% of twenty-three patients diagnosed with insular lobe epilepsy in our department over the 2000–2015 period, of whom six patients presented seizures with a predominant frontal lobe semiology. The first three patients (the patients 1–3) represented each different type of frontal semiology in this population.
本研究分析了5例岛叶癫痫患者(表1)。这些患者符合以下标准: (1)通过基于低电压快速放电(LVFD)的 SEEG 临床解释，他们的发作区域定位于脑岛; (2) SEEG 探索的区域包括脑岛以及内侧额叶/扣带回区域; (3)靶向脑岛的射频热凝(Catenoix 等，2008，Guénot 等，2004)实现了超过50% 的癫痫发作频率降低。在2000-2015年期间，我们部门诊断为岛叶癫痫的23例患者中，5例患者占21.7% ，其中6例患者表现为癫痫发作，额叶符号学占主导地位。前三位患者(患者1-3)代表了这一人群中每一种不同类型的额叶符号学。
Table 1. Clinical features.
表1. 临床特征。
| Patients 病人 | Patient 1 1号病人 | Patient 2 2号病人 | Patient 3 3号病人 | Patient 4 4号病人 | Patient 5 5号病人 |
|---|---|---|---|---|---|
| Gender 性别 | M | M | F | F | M |
| Age at SEEG monitoring (y) 接受 SEEG 监测的年龄(y) | 17 | 18 | 24 | 49 | 22 |
| Epilepsy onset (y) 癫痫发作(y) | 9 | 5 | 5 | 39 | 21 |
| Seizure frequency 癫痫发作频率 | S/D (mostly nocturnal) S/D (多为夜间活动) | S/D (nocturnal S/D (夜间 > diurnal) 日记) | S/D (mostly nocturnal) S/D (多为夜间活动) | S/D | S/D |
| Seizure semiology 癫痫符号学 | (for diurnal seizures) R-sided paresthesia sparing the face and trunk → Tonic contraction in the R arm and leg (slightly earlier in the leg), then elevation and abduction of the R arm (±leg) | A brief mechanical sound, reminiscent of a hammer stroke above the head → Symmetric axial-dominant tonic posture (marked in the neck and upper part of the trunk, resulting in hyperextension) | Fear 恐惧 → Rocking of the pelvis, agitation with frightened facial and verbal expressions, and ambulation | Laryngeal constriction, a metallic taste, and a Bil cold sensation in thighs | L-sided painful sensation sparing the head 左侧疼痛感使头部免受伤害 |
| MRI 核磁共振 | N | N | N | Slight thickening with T2-high signal in the R insula | Cortical dysplasia in the R posterior insula |
| FDG-PET (hypometabolism) (低代谢) | L peri-sylvian | N | R insula R 岛 | R infero-posterior insula 下后脑岛 | R insula R 岛 |
| Ictal SPECT 发作性 SPECT (hyperperfusion) (高灌注) | NP | R posterior insula 后脑岛 R | NP | R infero-posterior insula 下后脑岛 | NP |
| MEG | L peri-sylvian | N (no spikes) N (无峰值) | N (no spikes) N (无峰值) | NP | NP |
| Scalp EEG 头皮脑电图 | |||||
| Interictal abnormalities 发作间期异常 | L fronto-central L 前中心 | R centro-parietal 右中顶叶 | R fronto-central R 前中心 | R temporal R 是暂时的 | R centro-temporal 中央-颞叶 |
| Ictal discharge 发作性放电 | Bil supra-sylvian | Bil fronto-central (R > L) | R fronto-central R 前中心 | R/L temporal 临时登记册 | R temporal R 是暂时的 |
| SEEG | |||||
| Interictal abnormalities 发作间期异常 | L anterior insula 左前脑岛 | R posterior insulo-opercular region, posterior cingulate 后扣带回 | R anterior insulo-opercular region 前胰岛盖区 | R infero-posterior insula 下后脑岛 | R posterior insula 后脑岛 R |
| Ictal onset 发作 | L MSG and PSG L 味精和 PSG | R ALG and PLG R ALG 和 PLG | R ASG 美国空军司令部 | R PLG and insular central sulcus 岛状中央沟 | R ALG |
S/D, several times a day; N, normal; NP, not performed; R, right; L, left; Bil, bilateral; ASG, the anterior short gyrus of the insula; MSG, the middle short gyrus of the insula; PSG, the posterior short gyrus of the insula; ALG, the anterior long gyrus of the insula; PLG, the posterior long gyrus of the insula.
S/D，每天数次; N，正常; NP，未执行; R，右; L，左; Bil，双侧; ASG，岛叶前短回; MSG，岛叶中短回; PSG，岛叶后短回; ALG，岛叶前长回; PLG，岛叶后长回。
Patient 1 was a 17-year-old male with age of epilepsy onset at 9. His ictal semiology consisted of initial right-sided paresthesia sparing the face and trunk, and tonic contraction in the right leg and later also in the right arm, accompanied by elevation and abduction of the right arm. The seizures occurred several times a day and mostly during sleep. Scalp EEG showed bilateral diffuse supra-sylvian theta activity at the end of seizures. While there was no abnormality on MRI, FDG-PET demonstrated hypometabolism in the peri-sylvian region, and inter-ictal MEG also pointed to a peri-sylvian origin of seizure. Ictal SEEG disclosed LVFD in the middle and posterior short gyri (MSG and PSG) of the left insula. He remained free of seizure for 9 months after thermo-coagulation.
患者1为17岁男性，9岁开始发作癫痫。他的发作符号学包括最初的右侧感觉异常保留面部和躯干，并在右腿强直收缩，后来也在右臂，伴随着抬高和右臂外展。癫痫每天发作几次，大多发生在睡眠时。癫痫发作结束时头皮脑电图显示双侧侧裂上 θ 波弥漫性活动。虽然在 MRI 上没有异常，FDG-PET 显示在外侧脑室周围区域的低代谢，发作间 MEG 也指出了癫痫发作的外侧脑室周围起源。发作性 SEEG 显示左侧脑岛中部和后部短回(MSG 和 PSG)有 LVFD。他在热凝术后9个月内没有癫痫发作。
Patient 2 was an 18-year-old male with epilepsy onset at 5. He presented axial-dominant, almost symmetric tonic contraction preceded by an auditory hallucination (a very brief mechanical sound, as “sound of a hammer stroke” above his head) several times a day. His scalp EEG during seizures revealed a diffuse depression followed by bilateral fronto-central rhythmic theta activity, which was slightly lateralized to the right. His MRI did not show any abnormality. On the contrary, ictal SPECT demonstrated hyperperfusion in the right posterior insula. Ictal SEEG revealed LVFD in the anterior and posterior long gyri (ALG and PLG) of the right insula. Direct cortical stimulation of the PLG reproduced the full sequence of his seizures. Thermo-coagulation resulted in a 1.5-month seizure freedom and in an 80% reduction in seizures frequency afterward.
2号病人为18岁男性，5岁时发作癫痫。他表现出轴向主导的、几乎对称的紧张性收缩，之后是幻听(一种非常短暂的机械声，如头顶上方的“锤击声”) ，每天好几次。癫痫发作期间，他的头皮脑电图显示弥漫性抑郁，随后双侧额-中央节律性 θ 活动，稍偏向右侧。他的核磁共振没有显示任何异常。相反，发作性 SPECT 显示右后脑岛高灌注。发作期 SEEG 显示右侧脑岛前后长回(ALG 和 PLG)存在 LVFD。PLG 直接皮层刺激重现了他癫痫发作的全过程。热凝导致1.5个月的癫痫发作自由，并在80% 减少癫痫发作频率之后。
Patient 3 was a 24-year-old female with epilepsy onset at 5. Fear and hyperkinesia were the prominent features of her seizures. Her hyperkinesia was initially expressed as proximal-stereotypy (rocking) of the pelvis. Then she became progressively agitated with frightened facial and verbal expressions, and eventually she ambulated. Ictal scalp EEG showed a right frontal theta activity after the onset of hyperkinesia. Brain MRI was negative, and MEG was also not informative because of lack of inter-ictal spike. However, FDG-PET showed right insular hypometabolism. Ictal SEEG demonstrated LVFD in the anterior short gyrus (ASG) of the right insula. Thermo-coagulation resulted in one-month seizure freedom. Her seizure reappeared gradually but the frequency was decreased from several a day to a few per month.
患者3为24岁女性，5岁时发作癫痫。恐惧和运动亢进是她癫痫发作的显著特征。她的运动亢进最初表现为骨盆的近端刻板印象(摇摆)。然后她变得越来越激动，面部表情和语言表情受到惊吓，最后她走动了。发作性头皮脑电图显示运动亢进发作后右额叶脑电活动。脑部 MRI 为阴性，MEG 也因为缺乏发作间峰而无法提供信息。然而，FDG-PET 显示右侧岛叶低代谢。发作性 SEEG 显示右侧脑岛前短回(ASG)有 LVFD。热凝导致一个月的癫痫发作自由。她的癫痫发作逐渐再次出现，但发作频率从每天几次下降到每月几次。
Patient 4 was a 49-year-old female who started having seizures at age 39. She reported during her seizures a sensation of strangulation, a metallic taste in the mouth, and a cold sensation in both thighs. Her seizure occurred multiple times a day. Although ictal scalp EEG did not disclose any abnormalities at seizure onset (only right or left temporal slow activity was suspected at the end of seizures), her MRI showed a slight cortical thickening with T2-enhanced signal in the right insula. FDG-PET as well as ictal SPECT also indicated a focal region of functional abnormality in the right infero-posterior insula. Her ictal SEEG revealed LVFD in the right insula, most predominantly in the PLG and insular central sulcus. Only the cold sensation was reported 2–3 times a week after thermo-coagulation.
4号病人是49岁的女性39岁开始癫痫发作。她说在癫痫发作期间有一种窒息的感觉，嘴里有一种金属的味道，两条大腿都有一种冰冷的感觉。她的癫痫一天发作好几次。尽管发作性头皮脑电图没有显示癫痫发作时的任何异常(在癫痫发作结束时仅怀疑右侧或左侧时间缓慢活动) ，但是她的 MRI 显示右脑岛中 T2增强信号的轻微皮质增厚。FDG-PET 和发作性 SPECT 也显示右下后脑岛功能异常的局灶性区域。发作期 SEEG 显示右侧脑岛有 LVFD，主要位于 PLG 和岛状中央沟。热凝术后每周仅有2-3次的寒冷感。
Patient 5 was a 22-year-old male who started having painful seizures of the whole left side of the body, sparing the head, 8 months before admission. Although his ictal scalp EEG did not indicate origin of seizures, his brain MRI suggested a cortical dysplasia in the posterior insula. His Ictal SEEG demonstrated LVFD in the ALG of the right insula. Stimulation using the insular contact reproduced his painful sensation. Thermo-coagulation led to a 2-year seizure freedom. The detailed electro-clinical data in this patient have been already published (Isnard et al., 2011).
病人5是一名22岁的男性，在入院前8个月开始出现全身左侧疼痛性癫痫发作，保留了头部。虽然他的发作性头皮脑电图没有显示癫痫的起源，但是他的脑部磁共振成像显示他的后脑岛有皮质发育不良。他的发作性 SEEG 显示右脑岛 ALG 有 LVFD。使用隔离接触的刺激重现了他的痛苦感觉。热凝导致2年的癫痫自由发作。该患者的详细电子临床数据已经发表(Isnard 等，2011)。
The intracerebral recordings were performed with the orthogonally-oriented implantation method in Talairach space. Each single electrode placement was guided by pre-surgical video-scalp EEG and other non-invasive investigations. Clinical surveillance and interpretation of SEEG traces were conducted on a video-EEG monitoring system (Micromed, Italy). All signals were sampled at a frequency of 256 Hz and were analyzed in a bipolar montage using pairs of neighboring contacts on the same electrode.
脑内记录是在 Talairach 空间用正交定向植入法进行的。每个单个电极的放置都由术前视频头皮脑电图和其他非侵入性检查指导。临床监测和 SEEG 痕迹的解释进行了视频脑电监测系统(Micromed，意大利)。所有的信号都以256赫兹的频率采样，并使用同一电极上的相邻触点对以双极蒙太奇方式进行分析。
Fundamentals and methodology of NLA have been introduced by Pijn and Lopes da Silva (Lopes da Silva et al., 1989, Pijn and Lopes da Silva, 1993), and subsequently Wendling et al. (2001) added a measure of directionality. This directed coupling measure detects both linear and non-linear correlations. The latter type of correlation is crucial for seizure propagation analysis, since a significant proportion of propagation can be expressed as a non-linear association (Wendling et al., 2001). NLA is a well-established directed functional coupling measure incorporating non-linear feature and the most extensively used for understanding propagation pathways during SEEG-recorded seizures. In fact, NLA has long been adopted for analyzing seizures propagation within mesial temporal structures (Bartolomei et al., 2001, Bartolomei et al., 2004, Bartolomei et al., 2005, Wendling et al., 2001), temporo-thalamic and thalamo-parietal network in temporal lobe epilepsy (Arthuis et al., 2009, Guye et al., 2006), and prefronto-parietal network in parietal and frontal lobe epilepsies (Bonini et al., 2016, Lambert et al., 2012).
Pijn 和 Lpes da Silva (Lope da Silva 等，1989，Pijn 和 Lope da Silva，1993)介绍了 NLA 的基础和方法，随后 Wendling 等(2001)增加了方向性的量度。这种定向耦合度量同时检测线性和非线性相关性。后一种类型的相关性对于癫痫发作的传播分析是至关重要的，因为传播的很大一部分可以表示为非线性关联(Wendling et al。 ，2001)。NLA 是一个完善的定向功能耦合措施，结合非线性特征，最广泛地用于了解传播途径在 SEEG 记录癫痫发作。事实上，长期以来，NLA 一直被用于分析内侧颞叶结构内的癫痫发作传播(Bartolomei 等，2001，Bartolomei 等，2004，Bartolomei 等，2005，Wendling 等，2001) ，颞-丘脑和丘脑-顶叶网络(Arthuis 等，2009，Guye 等，2006) ，以及顶叶和额叶癫痫的前额-顶叶网络(Bonini 等，2016，Lambert 等，2012)。
The basic code for implementing this analysis on Matlab® has been provided in a previous study (Westmijse et al., 2009). NLA yields a functional coupling index h2 and a directionality index D. The computation of h2 and D was performed using broadband signals (only highpass filter of 1.5–5 Hz was applied, depending on the background activity) and 4-s time window sliding by steps of 250 ms (Bartolomei et al., 2004, Guye et al., 2006). Concerning h2, a maximum value was obtained by simulating a delay between signals recorded at two distinct sites. Since the delay should be within a physiological range, we employed twelve times the sampling interval (i.e., 1/256 Hz) as the maximal delay (approximately 47 ms), which was determined with reference to the latency of CCEPs (∼50 ms) (Almashaikhi et al., 2014). In accord with the previous studies, we analyzed the clonic phase of ictal discharges with sustained rhythmic spiking activity, since LVFD at seizure onset can result in a strong diminution of h2 due to functional decoupling (Bartolomei et al., 2004, Wendling et al., 2003). To isolate significant h2, a mean plus two times the standard deviation of h2 (calculated from the baseline period: a 20-s inter-ictal period without paroxysmal abnormalities, which was at least several minutes before ictal events) was defined as the threshold (h2BL). Positive value of the directionality index D ≥ 0.2 signifies that a reference region sends signals to a target region (vice versa for D ≤ −0.2) (Bartolomei et al., 2001, Bartolomei et al., 2005, Wendling et al., 2001), and the intermediate value signifies bidirectional transfer, only if h2 takes a significant value (Bartolomei et al., 2001, Bartolomei et al., 2005, Wendling et al., 2001).
在 Matlab 上实现这种分析的基本代码已经在之前的研究中提供了(Westmijse et al。 ，2009)。NLA 产生一个函数耦合指数 h2和一个方向性指数 D。使用宽带信号(仅应用1.5 -5 Hz 的高通滤波器，取决于背景活动)和4s 时间窗滑动250ms (Bartolomei 等，2004，Guye 等，2006)进行 h2和 D 的计算。对于 h2，通过模拟在两个不同位置记录的信号之间的延迟获得最大值。由于延迟应该在生理范围内，我们采用了12倍的采样间隔(即1/256Hz)作为最大延迟(约47ms) ，这是根据 CCEP 的潜伏期(something 50ms)确定的(Almashaikhi 等，2014)。根据以前的研究，我们分析了发作性放电的阵发性阶段，具有持续的节律性脉冲活动，因为发作发作时的 LVFD 可能由于功能解耦而导致 h2的强烈减少(Bartolomei 等，2004，Wendling 等，2003)。为了分离出显著的 h2，将平均值加上 h2标准差的两倍(从基线期计算: 发作间期为20秒，没有阵发性异常，在发作事件发生前至少几分钟)定义为阈值(h2BL)。方向性指数 D ≥0.2的正值表示参考区域向目标区域发送信号(对于 D ≤ -0.2，反之亦然)(Bartolomei 等，2001，Bartolomei 等，2005，Wendling 等，2001) ，中间值表示双向转移，仅当 h2取得显着值(Bartolomei 等，2001，Bartolomei 等，2005，Wendling 等，2001)。
To analyze all possible pairs of anatomical regions, sensors of interest were selected for every single electrode track. Specifically, one neighboring pair of contact from a deep end (i.e., mesial hemispheric regions, limbic structures, and the insula) and another pair of contact from a superficial end (i.e., lateral cortical regions) were chosen for each electrode track.
为了分析所有可能的解剖区域对，为每个电极轨迹选择感兴趣的传感器。具体而言，为每个电极轨迹选择来自深端(即，内侧半球区域，边缘结构和脑岛)的一个相邻对接触和来自表面端(即，外侧皮质区域)的另一对接触。
The classical presentation of results (Bartolomei et al., 2001, Bartolomei et al., 2004, Bartolomei et al., 2005, Guye et al., 2006, Wendling et al., 2001) did not provide a combined view of directionality (D) and functional coupling (h2). It is important to interpret both of them at the same time, because the index D can be accompanied by various levels of h2. In addition, sustained shifts of D should be distinguished from brief intermittent shifts, because the former indicate more significant involvement in seizure propagation and stable hierarchy. Thus, we implemented the following functional coupling- and continuity-weighting procedures in order to identify robust and sustained directed couplings. Firstly, the index D was multiplied by a Z-score of h2 (h2z) for each sliding step only in case h2 exceeds h2BL, and it was summed over a time window of interest. The time window of interest was set at a clonic period of discharge (10–20 s) centered at a time with elementary motor/hypermotor seizures for the three patients and insular semiology for the other two. Here, the definition of time window of interest was driven by two factors: functional decoupling, which precluded the LVFD period, and the aim of obtaining robust correlation between semiology and functional coupling pattern. Secondly, a coefficient C was determined by adding 1 for each consecutive sliding step (i.e., 250 ms) only when the duration of significant elevation of h2 (>h2BL) exceeded 5 s (C = 1 for less than 5 s; e.g., if duration was 7 s, C = 1 + (7 − 5)/0.25 = 9). Thirdly, the summed value was multiplied by C, and a square root transformation was performed to obtain a value that followed a normal distribution. Lastly, a ratio was calculated by dividing the actual value by an estimated value of complete directed functional coupling (where h2 = 1, D = 1 (−1), and a maximum value of C (i.e., continuous for the clonic period)). We defined the ratio as the continuity-weighted directed coupling index (cDCI):(1)where the small letter e denotes the values used for the estimation.
结果的经典表示(Bartolomei 等，2001，Bartolomei 等，2004，Bartolomei 等，2005，Guye 等，2006，Wendling 等，2001)没有提供方向性(D)和功能耦合(h2)。同时解释这两个指数是很重要的，因为指数 D 可以伴随不同水平的 h2。此外，D 的持续变化应该与短暂的间歇性变化区分开来，因为前者表明癫痫发作的传播和稳定的等级制度更重要的参与。因此，我们实现了以下功能耦合和连续性加权程序，以确定稳健和持续的定向耦合。首先，只有在 h2超过 h2BL 的情况下，将指数 D 乘以每个滑动步骤的 h2(h2z)的 Z 分数，并将其相加在感兴趣的时间窗内。感兴趣的时间窗设置在以三名患者的初级运动/运动过度癫痫发作和其他两名患者的岛状符号学为中心的阵发性放电期(10-20秒)。在这里，感兴趣的时间窗口的定义是由两个因素驱动的: 功能解耦，这排除了 LVFD 周期，以及获得稳健的相关性之间的符号学和功能耦合模式的目标。其次，只有当 h2(> h2BL)的显着升高持续时间超过5s (C = 1，持续时间小于5s; 例如，如果持续时间为7s，则 C = 1 + (7-5)/0.25 = 9) ，通过对每个连续滑动步骤(即250ms)加1来确定系数 C。再次，将求和值乘以 C，然后进行平方根变换得到一个遵循正态分布的值。最后，通过将实际值除以完全定向功能耦合的估计值(其中 h2 = 1，D = 1(- 1)和 C 的最大值(即克隆期连续))来计算比率。我们将比率定义为连续加权有向耦合指数(cDCI) : (1)其中小写字母 e 表示用于估计的值。
The cDCI was obtained for both directions, and a subtraction was carried out in order to determine dominant direction. Results from all the possible pairs of contact were aligned in a matrix. Then, we compared mean cDCIs among all the rows using one-way ANOVA with multiple comparison test (the Tukey–Kramer method as a post hoc test). Although bidirectional transfer was not accounted for by the above calculation, this comparison enabled identification of a leading region during seizure propagation. Bidirectional transfer was separately identified in case significant elevation of h2 (>h2BL) with intermediate values of the index D (i.e., −0.2 < D < 0.2) continued more than 5 s. P < 0.05 was considered significant.
获得了两个方向的 cDCI，并进行减法以确定优势方向。所有可能的接触对的结果都排列在一个矩阵中。然后，我们使用单因素方差分析和多重比较检验(Tukey-Kramer 方法作为事后检验)比较所有行之间的平均 cDCI。虽然上述计算没有考虑到双向转移，但这种比较能够在癫痫发作传播过程中识别主要区域。在 h2显着升高(> h2BL)的情况下，分别鉴定了双向转移，指数 D 的中间值(即 -0.2 < D < 0.2)持续超过5秒，P < 0.05被认为是显着的。
The patient 1 showed LVFD at ictal onset, followed by clonic discharge starting at around 20 s from the onset (20-s duration for calculating cDCI) (Fig. 1A). Regions involved by the ictal event consisted of the MSG and PSG of insula, pre-SMA, SMA, midcingulate, posterior midcingulate, middle frontal gyrus (premotor area), and the parietal operculum. The PSG showed positive cDCIs towards most regions (Fig. 1B, the 1st row), and consequently showed significantly the highest mean cDCI among all regions. Although the parietal operculum also showed positive cDCIs towards the SMA and midcingulate region (Fig. 1B, the 7th row), the PSG showed positive cDCI towards the parietal operculum (Fig. 1B, the 1st row). Likewise, although there were positive cDCIs between the mesial hemispheric regions (e.g., from pre-SMA to SMA; Fig. 1B, the 2nd row), the PSG showed markedly positive cDCIs towards those regions (Fig. 1B, the 1st row). The PSG was the only region showing positive cDCI towards the pre-SMA. Taken together, the PSG was the primary region driving the mesial hemispheric regions (Fig. 1C for a schematic illustration of intra-insular and insula-to-mesial hemispheric couplings).
患者1在发作时显示 LVFD，随后在发作后20秒左右开始阵挛性放电(计算 cDCI 的持续时间为20秒)(图1A)。发作事件涉及的区域包括岛叶、前 SMA、 SMA、中扣带回、后扣带回、中额回(运动前区)和顶叶岛盖的 MSG 和 PSG。PSG 对大多数区域呈阳性 cDCI (图1B，第1行) ，因此在所有区域中显示出最高的平均 cDCI。虽然顶叶岛盖对 SMA 和中扣带回区域显示阳性 cdCI (图1B，第7行) ，但 PSG 对顶叶岛盖显示阳性 cdCI (图1B，第1行)。同样，尽管在内侧半球区域(例如，从前 SMA 到 SMA; 图1B，第2行)之间存在阳性 cDCI，但 PSG 对这些区域显示出明显的阳性 cDCI (图1B，第1行)。在 SMA 前期，PSG 是唯一显示 cDCI 为阳性的区域。综上所述，PSG 是驱动内侧半球区域的主要区域(图1C 为岛内和岛叶-内侧半球耦合的示意图)。
Fig. 1. Patient 1. (A) Original SEEG trace of regions involved in elementary motor seizure. (B) Matrix view of cDCI. Only positive values (positive directionality) and those higher than 0.1 are displayed. Each row shows a reference region. The insular row (i.e., the PSG of the insula) indicated by an arrow head has statistically the highest mean cDCI in comparison to other rows (P < 0.05). This indicates that the PSG is connected in a positive direction to the largest number of regions (each column represents a target region). See text for detailed explanation. (C) Schematic view of seizure propagation from the PSG to the mesial frontal and cingulate regions. Intra-insular propagation is also displayed.
图1。1号病人。(A)初级运动性癫痫发作相关区域的原始 SEEG 痕迹。(B) cDCI 的矩阵视图。只显示正值(正方向性)和大于0.1的值。每行显示一个引用区域。与其他行相比，箭头指示的岛行(即岛屿的 PSG)具有统计学上最高的平均 cDCI (P < 0.05)。这表明 PSG 是以正方向连接到最大数量的区域(每列代表一个目标区域)。详细说明见正文。(C)癫痫发作从 PSG 向内侧额叶和扣带回区域传播的示意图。还显示了岛内传播。
The patient 2 showed LVFD lasting around 8 s and a subsequent period of clonic discharge (10-s duration for cDCI) (Fig. 2A). Those ictal discharges were observed in the ASG, ALG, PLG, pre-SMA, SMA, posterior cingulate, middle frontal gyrus (premotor area), and the parietal operculum. The PLG showed positive cDCIs towards the other insular regions, pre-SMA/SMA, and the parietal operculum (Fig. 2B, the 1st row). The statistical comparison showed that the PLG had significantly higher mean cDCI compared to the other regions, except for the posterior cingulate region. The posterior cingulate exhibited bidirectional coupling with the PLG (Fig. 2B, the 1st and 3rd rows). Concerning the pre-SMA and SMA, both the PLG and posterior cingulate showed positive cDCIs towards these regions (Fig. 2B, the 1st and 3rd rows). The parietal operculum also showed weakly positive cDCI towards the pre-SMA (Fig. 2B, the 5th row), while the PLG showed strongly positive cDCI towards the parietal operculum (Fig. 2B, the 1st row). As a whole, the bidirectional coupling between PLG and posterior cingulate played a principal role in generating the mesial frontal propagation (Fig. 2C).
患者2显示 LVFD 持续约8秒，随后出现阵挛性放电(cDCI 持续10秒)(图2A)。这些发作性放电分布在 ASG、 ALG、 PLG、前扣带回、前扣带回、后扣带回、中额回(前运动区)和顶叶岛盖。PLG 显示其他岛状区域，前 SMA/SMA 和顶叶岛盖的 cdcI 呈阳性(图2B，第一行)。统计学比较显示，除后扣带区外，PLG 的平均 cDCI 显著高于其他区域。后扣带回表现出与 PLG 的双向耦合(图2B，第1行和第3行)。关于前 SMA 和 SMA，PLG 和后扣带回对这些区域显示阳性 cDCI (图2B，第1和第3行)。顶叶岛盖对于前 SMA 也显示出弱阳性 cdCI (图2B，第5行) ，而 PLG 对于顶叶岛盖显示出强阳性 cdCI (图2B，第1行)。作为一个整体，PLG 和后扣带回之间的双向耦合在产生内侧额叶传播中起主要作用(图2C)。
Fig. 2. Patient 2. (A) Original SEEG trace of regions involved in elementary motor seizure. (B) Matrix view of cDCI. The PLG has a significantly higher mean cDCI than other regions (P < 0.05), except for the posterior cingulate gyrus. Functional coupling between the PLG and posterior cingulate gyrus is bidirectional. Therefore, both the PLG and posterior cingulate are indicated by arrow heads. (C) Schematic view of intra-insular and mesial frontal/cingulate propagation originating from the PLG and posterior cingulate gyrus.
图2。2号病人。(A)初级运动性癫痫发作相关区域的原始 SEEG 痕迹。(B) cDCI 的矩阵视图。除后扣带回外，PLG 的平均 cDCI 显著高于其他区域(P < 0.05)。PLG 和后扣带回之间的功能性耦合是双向的。因此，PLG 和后扣带回都用箭头表示。(C)起源于 PLG 和后扣带回的岛内和内侧额叶/扣带回传播的示意图。
Concerning the patient 3, her ictal activity consisted of LVFD intermixed with clonic spiking in its middle to the end (9 s from the onset; 10-s duration for cDCI) (Fig. 3A). The ictal activity was observed in the ASG, MSG, ALG, medial/lateral orbitofrontal regions, anterior cingulate regions, and the frontal operculum. The ASG showed positive cDCIs towards most regions (Fig. 3B, the 1st row). The statistical comparison proved that the ASG had the highest mean cDCI compared to all the other regions. While the medial orbitofrontal region showed positive cDCIs towards the anterior cingulate regions (Fig. 3B, the 2nd row), the ASG showed positive cDCI towards the medial orbitofrontal region (Fig. 3B, the 1st row). The cDCIs towards and from the frontal operculum were under the detection level (Fig. 3B, the 1st and 6th rows). Therefore, the ASG was the leader region for the mesial frontal/cingulate propagation (Fig. 3C).
关于患者3，她的发作活动包括 LVFD 与中间至终点的阵挛性加压(发病后9秒; cDCI 持续时间10秒)(图3A)。在 ASG、 MSG、 ALG、眶额内/外侧区、前扣带回区和额盖区观察到发作活动。ASG 对大多数区域显示阳性 cDCI (图3B，第1行)。统计学比较证明 ASG 的平均 cDCI 高于其他所有区域。虽然内侧眶前区域对前扣带回区域显示阳性 cDCI (图3B，第2行) ，但 ASG 对内侧眶前区域显示阳性 cDCI (图3B，第1行)。来自额盖的 cDCI 低于检测水平(图3B，第1排和第6排)。因此，ASG 是内侧额叶/扣带回传播的前导区域(图3C)。
Fig. 3. Patient 3. (A) Original SEEG trace of regions involved in hypermotor seizure. (B) Matrix view of cDCI. The ASG has the highest mean cDCI among all the regions (P < 0.05). (C) Schematic view of intra-insular and mesial frontal/cingulate propagation originating from the ASG.
图3。3号病人。(A)运动性癫痫发作相关区域的原始 SEEG 痕迹。(B) cDCI 的矩阵视图。在所有地区中，ASG 的平均 cDCI 最高(P < 0.05)。(C)源自 ASG 的岛内和内侧额叶/扣带传播的示意图。
Ictal event of the patient 4 started with LVFD lasting around 16 s, followed by a clonic discharge period (10-s duration for cDCI) (Fig. 4A). Those ictal discharges were observed in the MSG, PSG, insular central sulcus, PLG, posterior midcingulate, and the peri-sylvian precentral gyrus. Statistically, the insular central sulcus had the highest mean cDCI in comparison to all the other regions. The positive cDCIs were demonstrated towards the PSG, posterior midcingulate, and the peri-sylvian precentral gyrus (Fig. 4B, the 1st row). The MSG and PLG showed bidirectional couplings with the insular central sulcus (Fig. 4B, the 1st row). The peri-sylvian precentral gyrus did not show functional coupling with the posterior midcingulate region. Therefore, the posterior midcingulate regions coupled exclusively with the insular central sulcus (Fig. 4C).
患者4的发作事件始于 LVFD 持续约16秒，随后是阵挛性放电期(cDCI 持续10秒)(图4A)。这些发作性放电在 MSG、 PSG、岛状中央沟、 PLG、后中扣带回和侧裂前中央回均可观察到。统计学上，与所有其他区域相比，岛状中央沟具有最高的平均 cDCI。阳性 cDCI 表现为 PSG、后扣带回和外侧中央前回(图4B，第1行)。MSG 和 PLG 显示与岛状中央沟的双向耦合(图4B，第1行)。侧裂前中央回与后扣带中央区没有功能性耦合。因此，后中扣带区仅与岛状中央沟相连(图4C)。
Fig. 4. Patient 4. (A) Original SEEG trace showing ictal discharge accompanied with insular semiology (laryngeal constriction). (B) Matrix view of cDCI. Only the insular central sulcus shows the positive cDCIs and has the highest mean cDCI compared to all the others (P < 0.05). (C) Schematic view of intra-insular and mesial frontal/cingulate propagation originating from the insular central sulcus.
图4。4号病人。(A)显示发作性放电伴有岛状符号学(喉收缩)的原始 SEEG 痕迹。(B) cDCI 的矩阵视图。只有岛状中央沟 cDCI 呈阳性，平均 cDCI 最高(P < 0.05)。(C)起源于岛内中央沟的岛内和内侧额叶/扣带传播的示意图。
The patient 5 showed LVFD and a repetitive after-discharge period (approximately 17 s after the seizure onset; 20-s duration for cDCI) (Fig. 5A). The seizure activity occurred in the MSG, PSG, insular central sulcus, ALG, anterior cingulate, posterior midcingulate, dorsal posterior cingulate, and the parietal operculum. The ALG showed positive cDCIs towards the other regions, and significantly higher mean cDCI than all the others (Fig. 5B, the 1st row). The parietal operculum also showed positive cDCIs towards the anterior cingulate and dorsal posterior cingulate regions (Fig. 5B, the 5th row), but the ALG showed positive cDCI towards the parietal operculum (Fig. 5B, the 1st row). The ALG was the only region showing positive cDCI towards the posterior midcingulate region (Fig. 5B, the 1st row). Accordingly, the ALG was considered responsible for driving the cingulate regions (Fig. 5C).
患者5显示 LVFD 和重复的出院后期(癫痫发作后约17秒; cDCI 持续20秒)(图5A)。癫痫活动发生在味精、 PSG、岛状中央沟、 ALG、前扣带回、后扣带回、后扣带回和顶叶岛盖。ALG 对其他区域呈阳性 cDCI，平均 cDCI 显著高于其他区域(图5B，第1行)。顶叶岛盖对前扣带回和背后后扣带回区域也显示出阳性 cdCI (图5B，第5行) ，但是 ALG 对顶叶岛盖显示出阳性 cdCI (图5B，第1行)。ALG 是唯一向后扣带回区显示阳性 cDCI 的区域(图5B，第1行)。因此，ALG 被认为是负责驱动扣带回区域(图5C)。
Fig. 5. Patient 5. (A) Original SEEG trace showing ictal discharge accompanied with insular semiology (persistent left-sided pain). (B) Matrix view of cDCI. The ALG has the highest mean cDCI among all the regions (P < 0.05). (C) Schematic view of intra-insular and mesial frontal/cingulate propagation originating from the ALG.
图5。5号病人。(A)显示发作性放电伴有岛状符号学(持续性左侧疼痛)的原始 SEEG 痕迹。(B) cDCI 的矩阵视图。在所有地区中，ALG 的平均 cDCI 最高(P < 0.05)。(C)起源于 ALG 的岛内和内侧额叶/扣带传播的示意图。
Our results demonstrated significant functional coupling between the insula and mesial frontal/cingulate regions during insular seizures. The insular regions were clearly driving the seizures propagation towards the mesial frontal regions, whereas extra-insular regions were scarcely involved in this propagation.
我们的研究结果表明，在岛状癫痫发作期间，岛叶和内侧额叶/扣带回区之间存在显著的功能耦合。海岛区明显地驱动癫痫发作向内侧额叶区的传播，而海岛外区很少参与这种传播。
As shown in our first three patients, the insular seizures could mimic mesial frontal seizures. The patient 1 would have been diagnosed as having a mesial peri-rolandic origin of seizures (Bonini et al., 2014) with secondary involvement of the SMA, unless functional imaging and the spatially-fragmented sensory manifestations suggested a possible operculo-insular involvement. The NLA analysis in this patient objectified that the PSG of the left insula was driving the pre-SMA/SMA and midcingulate regions. Similarly to the patient 1, non-invasive investigations in the patient 2 suggested a dorsomedial frontal origin of seizures. The symmetric axial-dominant tonic posture during seizures in combination with the bilateral fronto-central rhythmic theta was compatible with an origin of seizure in the SMA (Bonini et al., 2014), and only auditory hallucination and the insular hyperperfusion on ictal SPECT oriented towards the operculoinsular region. The NLA analysis proved the functional couplings among the PLG, posterior cingulate region, and the pre-SMA/SMA, the latter two being driven by the PLG. A propagation to the SMA was initially suggested for seizures originating from the antero-superior portion of the insula (Ryvlin et al., 2006), but later studies demonstrated a more posterior origin of these seizures in the insula (Dylgjeri et al., 2014, Proserpio et al., 2011), a clinical observation that was substantiated by our NLA results in the patients 1 and 2. In contrast to these patients, the patient 3 demonstrated a more anteriorly distributed type of propagation, corresponding to that suggested by electro-clinical analysis of SEEG in the earliest study (Ryvlin et al., 2006). The ictal semiology in this patient suggested that the epileptogenic zone could be located in the ventromedial prefrontal and orbitofrontal cortices with a possible involvement of the anterior cingulate gyrus (Bonini et al., 2014). However, prior studies of non-lesional frontal lobe epilepsy (Dobesberger et al., 2008, Nguyen et al., 2009, Ryvlin et al., 2006) justified the exploration of the insula, which in fact enabled us to identify the ASG as the origin of seizure. The NLA results objectified the dissociation between the origin and clinical presentation in the form of significant functional coupling between the ASG and antero-mesial frontal regions, with the ASG being the leader region. To the best of our knowledge, such precise electro-chronological inter-relationship during insular seizure has not been demonstrated in previous studies. Our study thus provides firm evidence for the frontal presentation of insula lobe epilepsy.
如前三位病人所示，岛叶癫痫可以模仿内侧额叶癫痫。除非功能成像和空间碎片化的感觉表现提示可能的操作性岛叶受累，否则患者1将被诊断为具有 SMA 继发性癫痫发作的内侧周围起源(Bonini 等，2014)。该患者的 NLA 分析显示左侧脑岛的 PSG 驱动前 SMA/SMA 和中扣带回区域。与患者1相似，患者2的非侵入性检查提示癫痫发作的背内侧额叶起源。癫痫发作期间对称的轴向主导性强直姿势与双侧额中心节律 θ 相结合，与 SMA 中癫痫发作的起源相一致(Bonini 等，2014) ，只有发作性 SPECT 的幻听和岛状高灌注朝向操作岛状区域。NLA 分析证实了 PLG、后扣带回区和前 SMA/SMA 之间存在功能耦合，后两者由 PLG 驱动。最初建议将癫痫发作传播到 SMA (Ryvlin 等，2006) ，但后来的研究表明这些癫痫发作在脑岛中更后来的起源(Dylgjeri 等，2014，Proserpio 等，2011) ，临床观察证实了我们的 NLA 结果患者1和2。与这些患者相反，患者3表现出更向前分布的繁殖类型，与最早的研究(Ryvlin 等，2006)中 SEEG 的电子临床分析所提示的相对应。该患者的发作符号学提示癫痫发作区可能位于腹内侧前额叶和眶额叶皮质，可能涉及前扣带回(Bonini 等，2014)。然而，之前对非病变性额叶癫痫的研究(Dobesberger 等，2008，Nguyen 等，2009，Ryvlin 等，2006)证明了对脑岛的探索，这实际上使我们能够确定 ASG 作为癫痫发作的起源。NLA 结果以 ASG 和前内侧额叶区之间显著的功能耦合的形式客观化了起源和临床表现之间的分离，ASG 是前内侧额叶区的主导区域。据我们所知，这种精确的电-时间相互关系在岛叶癫痫发作期间尚未证实以前的研究。因此，我们的研究为脑岛叶癫痫的额叶表现提供了坚实的证据。
We also analyzed propagation in seizures with semiologies highly suggestive of insular involvement (patients 4 and 5) (Isnard et al., 2004, Isnard et al., 2011). Consistent with their clinical presentation, the NLA analysis proved the insular origin of their seizures. The semiology of patient 4 was characterized by laryngeal constriction and gustatory hallucination. Those manifestations were once described as symptomatic of mesial temporal and parietal opercular seizures, but were later shown to be significant manifestations of insular lobe epilepsy (Isnard et al., 2004, Nguyen et al., 2009). The results of patient 4 consolidated the primary involvement of the insula in the development of these symptoms. The patient 5, who was previously reported as having painful seizure of the posterior insular origin, demonstrated significant positive directed coupling towards the midcingulate and parietal operculum. The intra-insular directed coupling also confirmed the primary role of the posterior insula in the genesis of ictal painful sensation, that was recently shown using SEEG in patients with painful somatosensory seizures (Montavont et al., 2015). The current results also confirmed the result of previous time–frequency analysis in this patient that suggested the ictal involvement of the pain matrix, composed of the posterior insula, parietal operculum and midcingulate gyrus, in the genesis of ictal pain (Isnard et al., 2011). The results in the last two patients thus underpin our prior knowledge of insular seizures symptoms.
我们还分析了癫痫发作中的传播，符号学高度提示孤立受累(患者4和5)(Isnard 等，2004，Isnard 等，2011)。与他们的临床表现一致，NLA 分析证实了他们癫痫发作的岛状起源。病人4的症状是拥有属性喉收缩和味觉幻觉。这些表现一度被描述为内侧颞叶和顶叶癫痫发作的症状，但后来被证明是岛叶癫痫的显着表现(Isnard 等，2004，Nguyen 等，2009)。患者4的结果巩固了脑岛在这些症状发展中的主要参与。病人5之前被报道有后脑岛源性疼痛性癫痫发作，表现出明显的向扣带中央和顶叶岛盖的定向偶联。岛内定向偶联也证实了后脑岛在发作性疼痛感觉发生中的主要作用，最近在疼痛体感癫痫发作患者中使用 SEEG 显示了这一点(Montavont 等，2015)。目前的研究结果也证实了该患者之前的时频分析结果，即疼痛基质(由后脑岛、顶叶岛盖和中扣带回组成)在发作性疼痛发生中的参与(Isnard et al。 ，2011)。最后两例患者的结果支持了我们对岛状癫痫症状的早期认识。
Importantly, there were significant directed couplings from the insula to mesial hemispheric regions even in seizures with typical manifestations of insular epilepsy: the patients 4 and 5 demonstrated that the insula could drive the cingulate regions. This signifies that the insula-to-mesial frontal/cingulate propagation is common in the insular lobe epilepsy. However, the reason for a frontal presentation while almost lacking the insular semiology remains to be addressed. A possible explanation is that the boisterous frontal semiology overwhelms the insular symptoms. A similar propensity for the frontal semiology to be predominant has been demonstrated in temporal and parietal lobe epilepsies (Alqadi et al., 2016, Staack et al., 2011). Although limited in spatial sampling, our study suggests that the insular semiology can be a dominant feature only when the mesial hemispheric propagation is limited to the limbic portion of the mesial frontal lobe (i.e., cingulate regions), whereas once the propagation intensively drives the pre-SMA/SMA and medial orbitofrontal region the somatosensory and viscero-sensory features of insular semiology can easily pass unnoticed because of the aggressive and rapidly-evolving motor-dominant frontal semiology.
重要的是，即使在具有典型岛状癫痫表现的癫痫发作中，从脑岛到内侧半球区域也存在显着的定向偶联: 患者4和5表明脑岛可以驱动扣带回区域。这意味着脑岛-内侧额叶/扣带回传播在脑岛叶癫痫中很常见。然而，正面介绍的原因，而几乎缺乏岛屿符号学仍有待解决。一个可能的解释是，喧闹的额叶符号学压倒了孤岛症状。在颞叶和顶叶癫痫中已经证实了额叶符号学占主导地位的类似倾向(Alqadi 等，2016，Staack 等，2011)。尽管在空间采样方面受到限制，但我们的研究表明，岛状符号学仅当内侧半球传播限于内侧额叶的边缘部分(即扣带区域)时才可能是主要特征，而一旦传播强烈驱动前 SMA/SMA 和内侧眶额区域岛状符号学的躯体感觉和内脏感觉特征可以很容易地被忽视，因为侵略性和快速发展的运动主导的额叶符号学。
The frontal presentation in seizures with insular origin has been recognized only since 2006 (Ryvlin et al., 2006). In other words, the insula had never been explored in patients with frontal lobe epilepsy before 2006, resulting in the small number of patients in this study. We suggest that seizures of insular origin are potentially missed in some cases with cryptogenic mesial frontal lobe epilepsy.
脑岛源性癫痫发作的额叶表现仅在2006年被认可(Ryvlin et al。 ，2006)。换句话说，脑岛在2006年之前从未在额叶癫痫患者中被探索过，因此本研究中的患者数量很少。我们认为，在一些隐源性额叶内侧癫痫的病例中，岛源性癫痫发作可能被忽略。
We found significant propagation of insular seizures to the pre-SMA/SMA and cingulate areas, where the previous intracranial study using direct insular stimulation could not identify functional connections based on CCEPs (Almashaikhi et al., 2014). In contrast to CCEPs, our study is based on the analysis of seizures propagation, which is a pathological condition, thereby possibly disclosing different information in this respect. Nevertheless, the non-human primate studies have demonstrated that the pre-SMA and SMA receive inputs from the dysgranular and granular insula, respectively (Augustine, 1996, Nieuwenhuys, 2012). The human insula retains similar gradient of cyto-architectonic divisions, with a difference that the dysgranular division covers a larger area of the insula (one-third of the total surface in monkeys versus a half in humans), extending more posteriorly (Morel et al., 2013). Therefore, the seizure origins of the patients 1 and 2 could have connections both to the pre-SMA and SMA. Functional imaging studies using resting-state fMRI are in favor of these connections, with the middle to posterior part being more strongly connected to the sensorimotor regions, including the pre-SMA/SMA (Cauda et al., 2011, Deen et al., 2011). Afferents to the cingulate gyrus also show the anterior-to-posterior gradient with respect to the insular cyto-architectonic divisions (Augustine, 1996, Nieuwenhuys, 2012); the anterior cingulate region is connected to the anterior insula (the agranular and adjacent dysgranular insula), whereas a more extensive region of the cingulate gyrus, including the middle and posterior cingulate regions, is connected to the posterior insula (granular insula). Resting-state fMRI studies (Cauda et al., 2011, Deen et al., 2011, Taylor et al., 2009) and a recent tractography study (Ghaziri et al., 2015) confirmed this organization of cingulate connections. On the basis of these anatomo-functional evidence, it is more than probable that the mesial hemispheric propagation of insular seizure is mediated by the functional connectivity between the insula and mesial frontal/cingulate regions.
我们发现岛状癫痫发作显着传播到 SMA/SMA 前和扣带回区域，其中以前使用直接岛状刺激的颅内研究不能鉴定基于 CCEP 的功能连接(Almashaikhi 等，2014)。与 CCEPs 相反，我们的研究是基于癫痫发作传播的分析，这是一种病理状态，从而可能披露不同的信息在这方面。尽管如此，非人类灵长类动物研究已经证明，前 SMA 和 SMA 分别从颗粒状和颗粒状脑岛接受输入(Augustine，1996，Nieuwenhuys，2012)。人类脑岛保留了类似的细胞结构分裂梯度，差异在于不规则分裂覆盖了更大的脑岛面积(猴子总表面的三分之一与人类的一半) ，向后延伸更多(Morel 等，2013)。因此，患者1和2的癫痫发作起源可能与 SMA 前期和 SMA 有关。使用静息状态 fMRI 的功能成像研究有利于这些连接，中后部与感觉运动区域(包括前 SMA/SMA)更强烈地连接(Cauda 等，2011，Deen 等，2011)。扣带回的传入点也显示了相对于岛状细胞结构分区的前后梯度(Augustine，1996，Nieuwenhuys，2012) ，前扣带回区域与前脑岛(无颗粒和相邻的不颗粒脑岛)相连，而更广泛的扣带回区域，包括中间和后扣带回区域，与后脑岛(颗粒脑岛)相连。静息状态 fMRI 研究(Cauda 等，2011，Deen 等，2011，Taylor 等，2009)和最近的纤维束成像研究(Ghaziri 等，2015)证实了这种扣带连接的组织。根据这些解剖功能证据，岛状癫痫的内侧半球传播很可能是由岛叶和内侧额叶/扣带回区域之间的功能连接介导的。
The current study is the first to employ NLA for analyzing propagation of seizures originating from the insular cortex. The most important reservation of NLA is the length of the analyzed time window required to achieve stable results. Although we analyzed the correlation within a maximal delay of 47 ms between the insula and other regions, our results may represent the overall direction of signal transfer mixing direct with indirect connections. However, the propagation trajectories in our patients were well supported by the neuroanatomical and functional imaging studies. Another methodological point to discuss is that unequivocal directed coupling results can be obtained only for the organized discharge period that follows the period of LVFD, which is usually the focus of attention in SEEG interpretation. However, this is not a methodological limitation. LVFD is relatively focal and oscillates in less synchronous manner due to functional decoupling (Bartolomei et al., 2004, Wendling et al., 2003). Conversely, the organized discharge period, which is more broadly distributed and consists of synchronized oscillations, allows to have an entire view of regions involved in the completion of seizure and can be viewed as an appropriate target for understanding the organization of particular type of seizures. Consequently, the temporal correlation between the insula and mesial frontal/cingulate regions was well established with stable directionality during this period, with paucity of participation of extra-insular regions.
目前的研究是第一次使用 NLA 来分析起源于岛叶皮层的癫痫发作的传播。NLA 最重要的保留是获得稳定结果所需的分析时间窗的长度。尽管我们分析了脑岛与其他区域之间最大延迟47ms 内的相关性，但我们的结果可能代表了直接与间接连接的信号传输混合的整体方向。然而，神经解剖学和功能影像学研究很好地支持了我们患者的传播轨迹。需要讨论的另一个方法学问题是，只有在 LVFD 之后的有组织排放期才能获得明确的定向耦合结果，这通常是 SEEG 解释中的关注焦点。然而，这并不是一个方法上的限制。由于功能解耦，LVFD 是相对局灶性的，并且以不太同步的方式振荡(Bartolomei 等，2004，Wendling 等，2003)。相反，有组织排放期分布更为广泛，由同步振荡组成，可以全面了解参与完成发作的区域，并可被视为了解特定类型发作的组织情况的适当目标。因此，脑岛和内侧额叶/扣带回区之间的时间相关性在这一时期具有稳定的方向性，而岛外区域的参与很少。
The directed functional coupling analysis in the current study proved specific association between the insula and mesial frontal/cingulate regions during the propagation of insular seizures. Investigating the possible insular origin of seizures should be considered in cryptogenic mesial frontal epilepsies even in the absence of ictal clinical manifestations of insular lobe involvement.
目前研究中的定向功能耦合分析证实了岛叶癫痫发作传播过程中岛叶和内侧额叶/扣带回区之间的特异性联系。在隐源性内侧额叶癫痫中，即使没有发作性脑叶受累的临床表现，也应考虑研究癫痫发作的可能岛源性。
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