人类癫痫海马和边缘系统高频脑电波分析：250-500Hz快涟漪特征

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本文主要探讨了"脑电信号处理"中的一个重要研究领域——高频率振荡（High-Frequency Oscillations, HFOs）在人类癫痫患者海马区（Hippocampus）和内嗅皮层（Entorhinal Cortex）的定量分析。发表于2002年的《神经生理学杂志》（Journal of Neurophysiology, Vol. 88, Issue 4, Pages 1743-1752）的研究由Richard J. Staba、Charles L. Wilson、Anatol Bragin、Itzhak Fried和Jerome Engel Jr.等人进行。研究焦点集中在80-500 Hz范围内的HFOs，其中特别关注了两个关键频段：100-200 Hz的快速振荡（Ripples），在啮齿动物和人类的海马和内嗅皮层区域有记录；以及更高频率的250-500 Hz的快速波动（Fast Ripples, FRs）。这些高频率振荡在引发癫痫的大脑边缘区域（如通过局部海马注射卡胺酸诱发的啮齿动物模型）中也有描述，并且在人类中与癫痫发作起源区域的对侧有所观察。作者们进行了详尽的量化分析，旨在揭示这些高频信号可能与癫痫的病理生理机制、认知功能以及潜在的治疗靶点有关。他们的工作不仅提供了对大脑内部复杂通信的新见解，也促进了我们理解神经元网络如何在健康和疾病状态下调节同步活动。此外，文章引用了多篇相关研究，包括37篇由High Wire平台发布的文章，这些引用有助于扩展了对这一主题的理解。文章中还包含高质量的图表，可以访问《神经生理学杂志》的网站获取更新的信息和服务。该期刊由美国生理学会（The American Physiological Society）出版，提供每月或每年的订阅服务，版权信息表明此研究是截至2013年1月3日的最新研究成果。这篇论文对于理解人类癫痫的高级认知功能障碍，特别是通过高频率脑电信号的分析，具有重要意义，为神经科学领域的进一步探索提供了宝贵的数据和理论支持。

leptogenic areas capable of generating spontaneous seizures

(Bragin et al. 1999b, 2000).

To further study human high-frequency oscillations (HFOs),

we used a quantitative approach to address the following

questions: ﬁrst, is there statistical evidence supporting distinct

modal oscillation frequencies within the frequency band of

80–500 Hz? Second, are there differences other than spectral

frequency, e.g., duration, that distinguish these oscillatory

events? Third, are some oscillations limited to seizure gener-

ating areas? To answer these questions, we studied HFOs in

patients that were surgically implanted with depth electrodes

required for localization of the epileptogenic region. Interictal

wideband EEG was recorded from Hip and EC areas during

overnight polysomnographic sleep studies. HFOs were de-

tected from the sleep EEG recordings using automated tech-

niques and each oscillation was characterized by its peak

spectral frequency, duration, and proximity to seizure-generat-

ing areas.

METHODS

Subjects

Patients with medically intractable complex partial seizures were

implanted with intracerebral clinical depth electrodes for localization

of seizure onset area because noninvasive testing suggested focal

seizure onsets but results were inconclusive. Prior to depth electrode

implantation, patients gave their informed consent for participation in

these research studies under the approval of the Internal Review

Board of the UCLA Ofﬁce for Protection of Research Subjects. Each

patient was surgically implanted with 8–14 ﬂexible polyurethane

clinical depth electrodes stereotactically targeted to clinically relevant

brain areas. EEG from these electrodes was continuously monitored

on the telemetry unit for an average of 2 wk to ﬁnd those brain areas

in which spontaneous seizure activity began ﬁrst (Fried et al. 1999).

Patients in whom a seizure onset area could be localized became

candidates for surgical removal of epileptogenic sites if resection of

the area would not produce unacceptable neurological deﬁcit.

Classiﬁcation of recording site pathology

Identiﬁcation of the epileptogenic region was based primarily on

criteria from electrographic seizure recordings and neuroimaging (En-

gel 1996). Electrographic seizure onsets were recorded during the

patient’s depth electrode telemetry monitoring, and attending neurol-

ogists in the UCLA Seizure Disorders Center identiﬁed locations of

seizure onset based on the recording of multiple seizure occurrences

during the average 2 wk the patients spent in the hospital. In addition,

attending neurologists evaluated each patient’s ﬂuorodeoxyglucose

positron emission tomography scans (FDG-PET) for the presence or

absence of areas of hypometabolism and its predominant location. A

single neuroradiologist at UCLA evaluated every patient’s magnetic

resonance imaging (MRI) scans for the presence or absence of hip-

pocampal atrophy and its location as part of the clinical evaluation.

Recording sites were deﬁned as “ipsilateral” if located in the same

hemisphere as areas where seizure onsets occurred. All Hip and EC

recording sites in patients (n ⫽ 5) with bilateral ictal onsets were

considered ipsilateral to seizure onset. Recording sites were deﬁned as

“contralateral” if located in the hemisphere opposite to that of seizure

initiation.

Electrodes and localization

Wideband EEG was recorded from bundles of nine platinum-

iridium microwires, which were inserted through the lumen of the

seven-contact clinical depth electrodes (1.25-mm diam), so that they

extended 3–5 mm beyond the tip of the clinical electrode (Fried et al.

1999). Microwires were 40

␮

m in diameter with impedances ranging

from 200 to 500 k⍀. Electrode tips were localized using the combined

information from postimplant computed tomography (CT) scans co-

registered with preimplant 1.5T MRI scans (Staba et al. 2002). The

imaging software used (Brain Navigator, Grass-Telefactor, Philadel-

phia, PA) allowed for visualization and highlighting of electrode tip

locations on CT that were automatically registered to the MRI scans.

Anatomical boundaries were based on references of mesial temporal

lobe anatomy by Duvernoy (1998) and Amaral and Insausti (1990).

Only microwires veriﬁed as located in Hip and EC were used in

analyses.

Sleep studies

Sleep studies were conducted on the hospital ward between the

hours of 10

PM and 7 AM. A sleep record was acquired for each patient

to correlate behavioral state with the concurrently recorded wideband

EEG. The sleep record consisted of two electro-ocular channels to

monitor eye movements, two electromyogram channels recording

from the patient’s chin to monitor muscle tone, and two EEG channels

recording from International 10–20 System positions C

and C

(5–10

cm left and right, respectively, of midline at the skull vertex, depend-

ing on cranial size), each referenced to a contralateral auricle site, to

monitor neocortical activity (Jasper 1958). The recording was staged

according to the criteria of Rechtschaffen and Kales (1968) with

stages labeled as waking (Aw), nonrapid eye-movement (NREM)

sleep stages 1–4, and rapid eye-movement (REM) sleep. Episodes of

Aw consisted of patients lying in bed and either sitting quietly with

their eyes opened or engaged in quiet conversation with one of the

investigators. Because the objective of our study was to characterize

HFO activity in relation to areas of epileptogenicity, and the highest

probability of HFO occurrence coincides with NREM episodes (Bra-

gin et al. 1999a; Buzsaki et al. 1992; Suzuki and Smith 1988), the

current paper is limited to the analysis of HFOs that occurred during

episodes of NREM sleep i.e., stages 1–4.

High-frequency recordings and signal analysis

For each patient (n ⫽ 25), 16 channels of wideband (0.1 Hz to 5

kHz) interictal EEG were sampled from intracerebral microwires at 10

kHz with 12-bit precision using an R. C. Electronics EGAA acquisi-

tion system (Santa Barbara, CA). A 10-min NREM sleep-staged

epoch of wideband EEG was visually inspected for the presence of

HFO activity previously described within the non-primate and human

entorhinal-hippocampus axis (Bragin et al. 1999b; Buzsaki et al.

1992; O’Keefe and Nadel 1978). Channels demonstrating oscillations

with large amplitude sinusoid-like waves with frequencies between 80

and 500 Hz that were discernable above background EEG were

selected for analysis.

Between three and ﬁve channels of EEG per patient were selected

for detection and quantiﬁcation of HFO events. The data analyzed for

each patient included only episodes that were recorded during poly-

somnographically deﬁned NREM sleep. Figure 1 illustrates the tech-

nique used to detect HFOs. Each channel of wideband EEG was

digitally band-passed between 100 and 500 Hz (ﬁnite impulse re-

sponse ﬁlter, rolloff, ⫺33 dB/octave), and the root mean square

(RMS; 3-ms sliding window) amplitude of the ﬁltered signal was

calculated (DataPac 2K2, Run Technologies, Mission Viejo, CA).

Multiple ﬁlter cutoff frequencies and roll-off value combinations were

tested to determine ﬁlter settings that would optimally pass the fre-

quencies between 80 and 500 Hz. Successive RMS values with

amplitudes ⬎5 SDs above the mean amplitude of the RMS signal (i.e.,

mean amplitude calculated over the entire length of data ﬁle) longer

than 6 ms in duration were detected and delimited by onset and offset

boundary time markers as putative HFOs. Consecutive events sepa-

1744 STABA, WILSON, BRAGIN, FRIED, AND ENGEL

J Neurophysiol • VOL 88 • OCTOBER 2002 • www.jn.org

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人类癫痫海马和边缘系统高频脑电波分析：250-500Hz快涟漪特征

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