Coupling between slow waves and sharp-wave ripples engages distributed neural activity during sleep in humans

Hippocampal-dependent memory consolidation during sleep is hypothesized to depend on the synchronization of distributed neuronal ensembles, organized by the hippocampal sharp-wave ripples (SWRs, 80 to 150 Hz), subcortical/cortical slow-wave activity (SWA, 0.5 to 4 Hz), and sleep spindles (SP, 7 to 15 Hz). However, the precise role of these interactions in synchronizing subcortical/cortical neuronal activity is unclear. Here, we leverage intracranial electrophysiological recordings from the human hippocampus, amygdala, and temporal and frontal cortices to examine activity modulation and cross-regional coordination during SWRs. Hippocampal SWRs are associated with widespread modulation of high-frequency activity (HFA, 70 to 200 Hz), a measure of local neuronal activation. This peri-SWR HFA modulation is predicted by the coupling between hippocampal SWRs and local subcortical/cortical SWA or SP. Finally, local cortical SWA phase offsets and SWR amplitudes predicted functional connectivity between the frontal and temporal cortex during individual SWRs. These findings suggest a selection mechanism wherein hippocampal SWR and cortical slow-wave synchronization governs the transient engagement of distributed neuronal populations supporting hippocampal-dependent memory consolidation.

Memory consolidation involves the transformation of newly encoded representations into long-term memory (1–3). During non-rapid eye movement (NREM) sleep, hippocampal representations of recent experiences are reactivated (4, 5), along with transient synchronization of distributed subcortical and cortical neuronal populations (6, 7). It is hypothesized that the oscillatory synchrony facilitates connections between the neuronal ensembles, stabilizing memory representations (8). The selection and synchronization of distant neuronal populations that participate in hippocampal-dependent memory consolidation are proposed to depend on the interaction between hippocampal sharp-wave ripples (SWRs, 80 to 150 Hz), traveling subcortical/cortical slow-wave activity (SWA, 0.5 to 4 Hz), and sleep spindles (SP, 7 to 15Hz), but the underlying mechanisms subserving this network engagement are unclear. Here, we investigated how hippocampal SWRs and subcortical/cortical slow waves and spindles coordinate distributed neuronal populations during memory consolidation in NREM sleep.Hippocampal SWRs are transient local field potential oscillations (20 to 100 ms; 80 to 150 Hz in humans) implicated in planning, memory retrieval, and memory consolidation (9). Several lines of evidence highlight the role of SWRs in sleep-dependent memory consolidation. First, memory reactivation in the hippocampus, cortical, and subcortical structures peaks during SWRs (4–7, 10, 11). Second, hippocampal–subcortical/cortical functional connectivity, the prerequisite for binding of anatomically distributed reactivated memory traces is enhanced around SWRs (7, 12–15). Finally, SWR suppression interferes with, while prolongation of SWR duration improves hippocampal-dependent memory consolidation (16, 17).While research converges on the notion that SWR output modulates neuronal activity across brain regions during NREM sleep, SWR events are temporally biased by phases of SWA and SWA-nested SP (18–20). SWA and SP are present in cortical and subcortical structures (21, 22), originate in frontal areas, and traverse in an orderly succession to temporal lobes and subcortical structures, including the hippocampus (18, 22–24). Indeed, SWA synchrony increases following learning, and the reduction of SWA synchrony is correlated with memory impairment (25). Finally, although SWA is ubiquitous, individual SWA trajectories are usually limited to a subset of cortical/subcortical areas, with ∼80% of these events detected in less than half of recorded locations in humans (22). Therefore, each SWR-associated SWA event could recruit and index a unique sequence of cortical and subcortical populations.In this study, we used the broadband high-frequency activity (HFA, 70 to 200 Hz) recorded from human intracranial electrodes as a metric of subcortical/cortical activity. HFA is an indirect measure of multiunit spiking from the population surrounding the electrode contact (26), estimated in the range of several hundred thousand neurons. Consistent with the hypothesized role of SWR in synchronizing distributed memory traces, we found HFA power modulation during hippocampal SWR events in ∼30% of extrahippocampal recording sites. Given the critical role of SWA in facilitating hippocampal-dependent memory consolidation (13) and their confinement to local regions (22), we hypothesize that interplay between SWA and SWRs organizes hippocampal–cortical and cortical–cortical interactions during SWR events. Indeed, we found a strong association between SWR phase locking to extrahippocampal SWA or SP and HFA modulation in the same recording site. Interestingly, while the SWR–SWA phase locking was present bilaterally, the SWR–SP phase locking was limited to the hemisphere of SWR origin. These findings suggest that coupling between the hippocampal SWRs and extrahippocampal SWA/SP drives the selection of cortical populations to participate in hippocampal–cortical communication. In addition, theoretical constructs of memory consolidation predict transient synchronization of neuronal populations in distant cortical regions during hippocampal SWRs. Based on the widespread presence of SWA during NREM sleep, SWA–SWR temporal coupling, and ability of SWA to synchronize large cortical areas, we hypothesized that the pairwise phase relation between the SWA in different cortical locations could predict the functional coupling between the local cortical populations during SWR windows. In support of the cooperative role of SWR and SWA in orchestrating cortical–cortical communication, we found that SWA phase alignments between two distant cortical sites predicted their neuronal population synchronization during individual SWR windows, manifested by temporal HFA power correlations. The amplitude of individual SWRs was another strong predictor of cortico–cortical coupling, while the combination of SWA phase difference and SWR amplitude outperformed the predictive accuracy of the phase difference or SWA amplitude individually. These results imply a recruitment mechanism by which interplay of SWA and SWRs provides communication windows for long-range interactions between distributed neuronal populations, critical for hippocampal-dependent memory consolidation.     

Spontaneous neural activity during human slow wave sleep

Slow wave sleep (SWS) is associated with spontaneous brain oscillations that are thought to participate in sleep homeostasis and to support the processing of information related to the experiences of the previous awake period. At the cellular level, during SWS, a slow oscillation (<1 Hz) synchronizes firing patterns in large neuronal populations and is reflected on electroencephalography (EEG) recordings as large-amplitude, low-frequency waves. By using simultaneous EEG and event-related functional magnetic resonance imaging (fMRI), we characterized the transient changes in brain activity consistently associated with slow waves (>140 μV) and delta waves (75–140 μV) during SWS in 14 non-sleep-deprived normal human volunteers. Significant increases in activity were associated with these waves in several cortical areas, including the inferior frontal, medial prefrontal, precuneus, and posterior cingulate areas. Compared with baseline activity, slow waves are associated with significant activity in the parahippocampal gyrus, cerebellum, and brainstem, whereas delta waves are related to frontal responses. No decrease in activity was observed. This study demonstrates that SWS is not a state of brain quiescence, but rather is an active state during which brain activity is consistently synchronized to the slow oscillation in specific cerebral regions. The partial overlap between the response pattern related to SWS waves and the waking default mode network is consistent with the fascinating hypothesis that brain responses synchronized by the slow oscillation restore microwake-like activity patterns that facilitate neuronal interactions.     

Peripheral sensory stimulation elicits global slow waves by recruiting somatosensory cortex bilaterally

Slow waves (SWs) are globally propagating, low-frequency (0.5- to 4-Hz) oscillations that are prominent during sleep and anesthesia. SWs are essential to neural plasticity and memory. However, much remains unknown about the mechanisms coordinating SW propagation at the macroscale. To assess SWs in the context of macroscale networks, we recorded cortical activity in awake and ketamine/xylazine-anesthetized mice using widefield optical imaging with fluorescent calcium indicator GCaMP6f. We demonstrate that unilateral somatosensory stimulation evokes bilateral waves that travel across the cortex with state-dependent trajectories. Under anesthesia, we observe that rhythmic stimuli elicit globally resonant, front-to-back propagating SWs. Finally, photothrombotic lesions of S1 show that somatosensory-evoked global SWs depend on bilateral recruitment of homotopic primary somatosensory cortices. Specifically, unilateral lesions of S1 disrupt somatosensory-evoked global SW initiation from either hemisphere, while spontaneous SWs are largely unchanged. These results show that evoked SWs may be triggered by bilateral activation of specific, homotopically connected cortical networks.

Slow waves (SWs) are the predominant cortical rhythm during nonrapid eye movement sleep and anesthesia (1, 2). Since they were first characterized three decades ago, SWs have been linked to a variety of brain functions, including memory consolidation (3–6), homeostatic synaptic plasticity (7), and grouping of other oscillatory events (8–10). Macroscopic recordings (scalp electroencephalogram [EEG]) have revealed that spontaneous global SWs occur approximately once per second (∼1 Hz) and propagate in a stereotypical front-to-back topography through the entire cortex (11). Local electrophysiology has demonstrated that virtually every cortical neuron participates in traveling SWs, exhibiting phase-locked alternation between depolarization (up-state) and hyperpolarization (down-state) (12, 13). During low arousal states, global SWs occur spontaneously but may also be evoked by peripheral sensory stimulation, as well as direct electromagnetic and optogenetic stimulation of the cortex (14–18). However, much remains unknown about the large-scale circuits supporting SW generation and propagation.Here, we investigate the role of the primary somatosensory cortex and its interhemispheric connections in the initiation and propagation of somatosensory-evoked SWs. To this end, we performed widefield optical imaging of cortical dynamics in awake and anesthetized mice expressing fluorescent calcium indicator GCaMP6f in pyramidal neurons. High-resolution mesoscopic imaging across the whole dorsal neocortex allows for a more-precise characterization of globally coherent waves of neural activity than conventional approaches for recording SWs (EEG or local electrophysiology). We demonstrate that unilateral somatosensory stimulation elicits bilateral waves that propagate in opposite directions depending on state (awake versus ketamine/xylazine anesthesia). Further, we show that the imposed rhythm of stimulation induces resonant activity locally in sensorimotor areas that remains focal in awake animals. In contrast, in anesthetized animals, rhythmic stimulation subsequently elicits SWs that spread globally in a front-to-back trajectory across the cortex. Finally, we use a photothrombotic stroke model to show that somatosensory-evoked global SWs depend on engagement of both ipsilateral and contralateral somatosensory cortex (S1). Unilateral photothrombosis of S1 disrupts global SWs evoked by peripheral stimulation of either hemisphere but spares the global spatiotemporal structure of spontaneous SWs outside of the perilesional area. These findings suggest a key role for bilateral recruitment of homotopically connected somatosensory cortices in initiating somatosensory-evoked global SWs and suggest potential mechanisms by which focal cortical injuries may influence global brain dynamics.     

Fasting and postprandial small intestinal slow waves non-invasively measured in subjects with total gastrectomy

BACKGROUND AND AIM: Slow wave is essential to initiate gastrointestinal tract motility. Subjects with total gastrectomy (TG) provide an opportunity to study small intestinal slow wave in the absence of stomach interference. The aims of this study were to determine the origin of 3 cycles per min (cpm) slow wave recorded via electrogastrogram (EGG) and the characteristics of putative small intestinal slow waves in TG subjects. METHODS: Thirty-three subjects with TG (25 male, age: 44-83 years) were consecutively enrolled. In each subject, the myoelectricity-like signals of the gastrointestinal tract were recorded using 3-channel EGG. Fourier transform-based spectral analysis was performed to derive the EGG parameters including dominant frequency/power, % normal rhythm (2-4 cpm), and power ratio. RESULTS: Neither visual nor spectral analysis of the EGG revealed any waves at a frequency of about 3 cpm. The most frequently observed peaks in the power spectra of all subjects were those at approximately 1, approximately 6 and approximately 11 cpm with occurrences of 97%, 6.1% and 90.9%, respectively. Based on visual analysis of all recorded signals, the approximately 11 cpm signal was exactly rhythmically recorded rather than the approximately 1 cpm. The recorded approximately 11 cpm wave had a frequency of 10.9 +/- 1.0 cpm in the fasting state and 10.9 +/- 1.3 cpm in the fed state (NS), and a power of 31.5 +/- 3.2 dB in the fasting state and 35.2 +/- 3.8 dB in the fed state (P < 0.0001). None of other factors, including sex, age, and body mass index, had any impact on this approximately 11 cpm wave. CONCLUSIONS: Small intestinal slow wave can be recorded non-invasively using EGG via cutaneous electrodes in TG subjects. Sex, age and body mass index have no effect on the intestinal slow waves. The power rather than frequency of intestinal slow wave is increased after a solid meal.     

显著性概率地形图一些基础问题再探讨──老年组谱参量的性别差异和正态转换

目的显著性概率地形图（ＳＰＭ）临床应用有一些先决条件。我们重点探讨老年人脑电地形图（ＢＥＡＭ）谱参量有无性别差异，以及其中哪些参量近正态分布。方法对４３名老年右利健康人头部取５对（１０个）样点，将各点功率、相对功率Ⅰ和Ⅱ的四个经典频段（δ、θ、α、β）检测性别差异；然后将各参量进行Ｘ，Ｌｎ（Ｘ）、Ｌｏｇ（Ｘ）转换，用正态性Ｄ检验方法观察各参量转换前后的分布状态。结果功率有明显的性别差异（主要为δ和β频段及枕部α频段），相对功率则差别较少。转换前相对功率（尤以Ⅰ）近正态分布较佳，功率多数参量呈非正态；转换后相对功率的正态性改进不显，经Ｌｏｇ（Ｘ）转换则有明显改进，但仍不能完全满足统计学要求。结论老年人功率ＢＥＡＭ有明显的性别差异，功率Ⅰ大多数多量近正态分布，功率经Ｌｏｇ（Ｘ）转换后有一半参量分布转为正态。     

儿童癫痫伴慢波睡眠期持续棘慢波综合征临床特征及预后

目的 加强对癫痫伴慢波睡眠期持续棘慢波(CSWS)临床、脑电图特征的认识,强调早期诊断及治疗的重要性.方法 回顾性分析5例CSWS患者临床、脑电图特征及治疗情况,并对患者进行6个月～1.5a随访.结果 5例患者,男3例、女2例,癫痫起病年龄1岁1个月～7岁8个月.2例存在脑部静止性病变,3例头影像学未见异常.4例患者以夜间发作首发,1例以清醒期全面强直阵挛发作起病,逐渐出现全面性脑功能减退,脑电图具备特征性慢波睡眠期持续性放电.4例在激素治疗3个月后临床症状及脑电图明显改善,1例激素治疗6个月后复发.结论 CSWS早期表现不典型,早期诊断及激素治疗可改善患者认知.     

From the Cover: Sleep homeostasis in the rat is preserved during chronic sleep restriction

Sleep is homeostatically regulated in all animal species that have been carefully studied so far. The best characterized marker of sleep homeostasis is slow wave activity (SWA), the EEG power between 0.5 and 4 Hz during nonrapid eye movement (NREM) sleep. SWA reflects the accumulation of sleep pressure as a function of duration and/or intensity of prior wake: it increases after spontaneous wake and short-term (3–24 h) sleep deprivation and decreases during sleep. However, recent evidence suggests that during chronic sleep restriction (SR) sleep may be regulated by both allostatic and homeostatic mechanisms. Here, we performed continuous, almost completely artifact-free EEG recordings from frontal, parietal, and occipital cortex in freely moving rats (n = 11) during and after 5 d of SR. During SR, rats were allowed to sleep during the first 4 h of the light period (4S⁺) but not during the following 20 h (20S⁻). During the daily 20S⁻ most sleep was prevented, whereas the number of short (<20 s) sleep attempts increased. Low-frequency EEG power (1–6 Hz) in both sleep and wake also increased during 20S⁻, most notably in the occipital cortex. In all animals NREM SWA increased above baseline levels during the 4S⁺ periods and in post-SR recovery. The SWA increase was more pronounced in frontal cortex, and its magnitude was determined by the efficiency of SR. Analysis of cumulative slow wave energy demonstrated that the loss of SWA during SR was compensated by the end of the second recovery day. Thus, the homeostatic regulation of sleep is preserved under conditions of chronic SR.     

外源性胃电刺激对犬胃慢波的作用

目的探讨外源性胃电刺激完全控制胃慢波的最佳刺激方法和最佳刺激参数。方法在8条比格犬的胃大弯浆膜层埋植4对电极,分4组:单导联刺激组、两导联刺激组、三导联刺激组和三导联延迟刺激组。多导联电刺激器与距胃窦上6、10和14cm的浆膜电极相连并输入不同宽度和振幅的脉冲以控制胃慢波。运用多导联胃电记录仪记录胃肌电活动。观察实验中胃慢波、脉冲宽度和振幅。结果长脉冲胃电刺激能控制胃慢波。单导联刺激组所需的最佳刺激能量最小(51.25±12.46,P<0.01)。三导联刺激组较其延迟刺激组所需的最佳刺激能量值低(P<0.01)。刺激前后胃肌电活动的主功和胃慢波的传播速度差异无统计学意义(P>0.05)。结论长脉冲胃电刺激能控制胃慢波,但对胃肌电活动的主功和传播速度无作用。单导联胃电刺激控制胃慢波所需的刺激能量最小。导联之间的延迟时间能增加控制胃慢波所需的最佳刺激能量。     

An assembled electrogastrographic device to examine the meal effect on gastric slow wave

We have assembled an electrogastrographic device based on the main components of amplifiers, a band-pass filter, an analogue/digital converter, low band-pass digital filters and a personal computer. The analysis software uses autoregressive moving average modelling to compute the frequency of slow waves and uses fast Fourier transformation for power spectral computation. Twenty healthy young male volunteers were enrolled in the study to test meal-elicited responses of the slow wave. Subjects underwent a 15 min recording while fasting and then a standard breakfast, which included 250 mL milk and a cake with a total of 1.45 kj, was ingested within 5 min. The post-prandial 15 min recording was immediately resumed after the meal. A slight but significant increase in the frequency of slow waves was seen in post-prandial measurements (mean ± s.d., 0.0506±0.0005 vs 0.0497±0.0005 Hz; P<0.0001). Moreover, a significant enhancement of the power of slow waves was elicited following the meal (36.0±3.1 vs 27.6±3.1 dB; P<0.0001). We conclude that this assembled electrogastrographic device is a reliable means of monitoring gastric myoelectrical activity because the phenomenon of post-prandial responses of slow waves in either frequency or power is well demonstrated.     

Real-time display of the stomach slow wave and its parameters in a newly designed electrogastrographic system

We designed a new three-channel electrogastrographic (EGG) system, which was easily operated on the Windows 95 platform and could automatically provide slow wave parameters. The purpose of the present study was to test its reliability and accuracy in clinical recording. The system included a signal acquisition device assembled on a printed circuit board. Recorded myoelectrical signals were filtered, amplified, digitized, and transmitted via this device into a notebook personal computer (PC). Based on the short-term Fourier transform the software could transfer the time domain of the signal into the frequency domain. Real-time displayed slow wave parameters, including dominant frequency/power, percent of normal frequency (2–4 cpm), instability coefficient in frequency/power, and power ratio, were automatically renewed every 64 s. Twenty healthy subjects (M/F, 12/8; age, 23–51 years) were enrolled to measure both fast and postprandial myoelectrical activities for each 30-min recording. Our results indicated that meal ingestion significantly increased dominant frequency (3.15 ± 0.20 vs 3.23 ± 0.23 cpm; P < 0.05) and power (26.1 ± 3.8 vs 28.4 ± 3.9 dB; P < 0.05). The power ratio of the meal effect was 2.02 ± 2.07. Other parameters, including instability coefficient and percent of normal frequency, remained similar despite food ingestion. This newly designed EGG system is acceptable for clinically measuring gastric myoelectrical activity; the real-time display of many EGG parameters is an advantage with this new system. Received: May 1, 2000 / Accepted: July 28, 2000     

交感神经和肌间神经丛在胃电刺激调控胃慢波中的作用

目的研究胃交感神经及肌间神经丛在电刺激调控胃慢波活动中的作用,确定胃电起博的神经机制和作用环节,为今后起搏器的深入研究打下基础。方法10只雄性wistar大鼠随机分为对照组和电刺激组,各5只。全部大鼠植入浆膜电极,电刺激组大鼠行胃电刺激至胃慢波被完全控制。植入电极组不行电刺激。采用免疫组化S P法检测并比较两组大鼠胃窦肌间神经丛和脊髓后角C fos蛋白表达。结果电刺激组大鼠胃慢波全部被完全控制,所需能量为2 70±80 .6ms ,2mA。2组大鼠脊髓中间内侧核,中间外侧核均未见C fos阳性神经元,而后角浅层均见散在C fos表达,比较无显著性差异(P >0 .0 5 )。植入电极组胃窦肌间神经丛未见C fos阳性神经元,电刺激组胃窦肌间神经丛可见C fos阳性神经元。结论适宜参数的胃电刺激可完全控制大鼠胃慢波。肌间神经丛参与胃电刺激调控胃慢波,而交感神经则无明显作用。     

Roles of putative neurotransmitters in the regulation of gastric and intestinal slow waves in conscious dogs

BACKGROUND AND AIMS: Slow waves play an important role in controlling the frequency and propagation of gastrointestinal contractions. However, mechanisms involved in the modulation of slow wave activity in vivo are still unclear. In this study, the roles of different neurotransmitters in the regulation of gastrointestinal slow waves were investigated in conscious dogs. METHODS: Female dogs implanted with electrodes in the stomach and the small bowel were used in a seven-session study. Gastrointestinal myoelectrical activity was recorded at baseline and after i.v. saline, atropine, atropine methyl nitrate, guanethidine, Nomega-nitro-L-arginine (L-NNA), ondansetron or naloxone. RESULTS: Both atropine and atropine methyl nitrate induced tachygastria, bradygastria and arrhythmia. No difference was noted in the effects between atropine and atropine methyl nitrate. L-NNA increased the dominant frequency of small-intestinal slow waves but had no effect on gastric slow waves. Guanethidine, ondansetron and naloxone did not affect the dominant frequency, power or percentage of normal gastrointestinal slow waves. CONCLUSION: Acetylcholine acting at muscarinic receptors seems to play an important role in the regulation of gastric slow waves. Nitric oxide may play a role in modulating intestinal slow waves but not gastric slow waves. Sympathetic pathways, 5-HT(3) receptors and opioid receptors (especially micro-opioid receptors) do not play a role in the regulation of gastric or intestinal slow waves under normal physiological conditions.     

NO参与了胃起搏调控胃慢波活动

目的观察NOS抑制剂L-NAME对胃慢波以及刺激能量的影响,旨在探讨胃起搏作用机制。方法通过手术建立Wistar大鼠胃起搏模型,随机分为4组(每组8只),分别腹腔给予不同剂量L-NAME,以生理盐水作对照。应用多导胃肠电记录仪记录胃慢波,L-NAME对胃慢波的影响应用频谱分析方法进行分析。结果大剂量(50mg/kg)注射时,L-NAME能引起胃电紊乱。正常慢波百分比明显降低(55.3%±4.0%),与对照组(91.7%±3.0%)比较,P<0.001。胃起搏仍能纠正胃电紊乱,正常慢波百分比得到改善(90.9%±2.5%),且所需的EPS较对照组明显升高(878.1±11.4vs537.5±91.6ms×mA,P<0.001)。L-NAME诱发的胃电节律失常以胃电过缓多见(41.3%±1.8%)。但给小剂量L-NAME(12.5mg/kg、25mg/kg)时,正常慢波百分比变化不明显(87.4%±4.9%、86.3%±5.6%),与对照组比较(91.7%±3.0%)差异无显著性;其慢波被控制时所需EPS分别为(487.5±64.1、550±53.5ms×mA),与对照组比较(537.5±91.6ms×mA),P>0.05。结论NOS抑制剂L-NAME能引起大鼠胃电紊乱,增大刺激能量能纠正之,表明NO可能参与了胃起搏对胃慢波活动的调控作用。     

Selective changes of resting-state networks in individuals at risk for Alzheimer's disease

Alzheimer''s disease (AD) is a neurodegenerative disorder that prominently affects cerebral connectivity. Assessing the functional connectivity at rest, recent functional MRI (fMRI) studies reported on the existence of resting-state networks (RSNs). RSNs are characterized by spatially coherent, spontaneous fluctuations in the blood oxygen level-dependent signal and are made up of regional patterns commonly involved in functions such as sensory, attention, or default mode processing. In AD, the default mode network (DMN) is affected by reduced functional connectivity and atrophy. In this work, we analyzed functional and structural MRI data from healthy elderly (n = 16) and patients with amnestic mild cognitive impairment (aMCI) (n = 24), a syndrome of high risk for developing AD. Two questions were addressed: (i) Are any RSNs altered in aMCI? (ii) Do changes in functional connectivity relate to possible structural changes? Independent component analysis of resting-state fMRI data identified eight spatially consistent RSNs. Only selected areas of the DMN and the executive attention network demonstrated reduced network-related activity in the patient group. Voxel-based morphometry revealed atrophy in both medial temporal lobes (MTL) of the patients. The functional connectivity between both hippocampi in the MTLs and the posterior cingulate of the DMN was present in healthy controls but absent in patients. We conclude that in individuals at risk for AD, a specific subset of RSNs is altered, likely representing effects of ongoing early neurodegeneration. We interpret our finding as a proof of principle, demonstrating that functional brain disorders can be characterized by functional-disconnectivity profiles of RSNs.     

Self-organization of the phosphatidylinositol lipids signaling system for random cell migration

Phosphatidylinositol (PtdIns) lipids have been identified as key signaling mediators for random cell migration as well as chemoattractant-induced directional migration. However, how the PtdIns lipids are organized spatiotemporally to regulate cellular motility and polarity remains to be clarified. Here, we found that self-organized waves of PtdIns 3,4,5-trisphosphate [PtdIns(3,4,5)P₃] are generated spontaneously on the membrane of Dictyostelium cells in the absence of a chemoattractant. Characteristic oscillatory dynamics within the PtdIns lipids signaling system were determined experimentally by observing the phenotypic variability of PtdIns lipid waves in single cells, which exhibited characteristics of a relaxation oscillator. The enzymes phosphatase and tensin homolog (PTEN) and phosphoinositide-3-kinase (PI3K), which are regulators for PtdIns lipid concentrations along the membrane, were essential for wave generation whereas functional actin cytoskeleton was not. Defects in these enzymes inhibited wave generation as well as actin-based polarization and cell migration. On the basis of these experimental results, we developed a reaction-diffusion model that reproduced the characteristic relaxation oscillation dynamics of the PtdIns lipid system, illustrating that a self-organization mechanism provides the basis for the PtdIns lipids signaling system to generate spontaneous spatiotemporal signals for random cell migration and that molecular noise derived from stochastic fluctuations within the signaling components gives rise to the variability of these spontaneous signals.     

Identification of the slow conduction zone in a macroreentry circuit of verapamil-sensitive idiopathic left ventricular tachycardia using electroanatomic mapping

Identification of the Slow Conduction Zone in a Macroreentry. Background: Although idiopathic left ventricular tachycardia (ILVT) has been shown to possess a slow conduction zone (SCZ), the details of the electrophysiological and anatomic aspects are still not well understood. Objective: We hypothesized that the SCZ can be identified using a 3‐dimensional electroanatomic (EA) mapping system. Methods : Ten patients with ILVT were mapped using a 3‐dimensional electroanatomic (EA) mapping system. After a 3‐dimensional endocardial geometry of the left ventricular was created, the conduction system with left Purkinje potential (PP) and the SCZ with diastolic potential (DP) in LV were mapped during sinus rhythm (SR) and ventricular tachycardia (VT) and were tagged as special landmarks in the geometry. The electrophysiological and anatomic aspects of it were investigated. Results: EA mapping during SR and VT was successfully performed in 7 patients, during VT in 3 patients. The SCZ with DPs located at the inferoposterior septum was found in 7 patients during SR and all patients during VT. The length of the SCZ was 25.2 ± 2.3 mm with conduction velocity 0.08 ± 0.01 m/s. No differences in these parameters were found between patients during SR and VT (P > 0.05). An area with PP was found within the posterior septum. A crossover junction area with DP and PP was found in 7 patients during SR and VT. This area with DP and PP during SR coincided or were in proximity to such area during VT and radiofrequency ablation targeting the site within the area abolished VT in all patients. Conclusion: The ILVT substrate within the junction area of the SCZ and the posterior fascicular can be identified and can be used to guide the ablation of ILVT. (J Cardiovasc Electrophysiol, Vol. 23, pp. 840‐845, August 2012)     

Sleep,Brain, and Cognition Special Feature: Understanding the roles of central and autonomic activity during sleep in the improvement of working memory and episodic memory

The last decade has seen significant progress in identifying sleep mechanisms that support cognition. Most of these studies focus on the link between electrophysiological events of the central nervous system during sleep and improvements in different cognitive domains, while the dynamic shifts of the autonomic nervous system across sleep have been largely overlooked. Recent studies, however, have identified significant contributions of autonomic inputs during sleep to cognition. Yet, there remain considerable gaps in understanding how central and autonomic systems work together during sleep to facilitate cognitive improvement. In this article we examine the evidence for the independent and interactive roles of central and autonomic activities during sleep and wake in cognitive processing. We specifically focus on the prefrontal–subcortical structures supporting working memory and mechanisms underlying the formation of hippocampal-dependent episodic memory. Our Slow Oscillation Switch Model identifies separate and competing underlying mechanisms supporting the two memory domains at the synaptic, systems, and behavioral levels. We propose that sleep is a competitive arena in which both memory domains vie for limited resources, experimentally demonstrated when boosting one system leads to a functional trade-off in electrophysiological and behavioral outcomes. As these findings inevitably lead to further questions, we suggest areas of future research to better understand how the brain and body interact to support a wide range of cognitive domains during a single sleep episode.     

Rapid eye movement and slow-wave sleep rebound after one night of continuous positive airway pressure for obstructive sleep apnoea

Background and objective: Rebound of slow‐wave sleep (SWS) and rapid eye movement (REM) sleep is observed in patients who are on continuous positive airway pressure (CPAP) therapy for obstructive sleep apnoea (OSA); but, neither have been objectively defined. The pressure titration study often represents the first recovery sleep period for patients with OSA. Our aim was to objectively define and identify predictors of SWS and REM sleep rebound following CPAP titration. Methods: Paired diagnostic polysomnography and pressure titration studies from 335 patients were reviewed. Results: The mean apnoea‐hypopnoea index was 40.7 ± 26.1, and minimum oxygen saturation was 76 ± 14.4%. Comparing eight incremental thresholds, a rebound of 20% in REM sleep and a 40% increase in SWS allowed the best separation of prediction models. A 20% rebound in REM sleep was predicted by REM sleep %, non‐REM arousal index (ArI) and total sleep time during diagnostic polysomnography, and male gender (R² = 35.3%). A 40% rebound in SWS was predicted by SWS %, total ArI and REM sleep % during diagnostic polysomnography, and body mass index (R² = 45.4%). Conclusions: A 40% rebound in SWS, but only a 20% rebound in REM sleep on the pressure titration study, is predicted by abnormal sleep architecture and sleep fragmentation prior to the commencement of treatment.     

干细胞因子对糖尿病小鼠小肠平滑肌细胞慢波的影响

目的:探讨外源性干细胞因子(stem cell factor,SCF)对糖尿病(diabetes mellitus,DM)小鼠小肠动力障碍时小肠平滑肌细胞慢波的影响.方法:♂Balb/c小鼠一次性腹腔注射(ip)链脲佐菌素(STZ,150 mg/kg)造模,将小鼠分为正常组、DM组、DM+外源性SCF组(DM+SCF组);DM+SCF组ip SCF 0.20 μg/(kg·d),正常组和DM组每天ip等量的磷酸盐缓冲液(pH7.40).所有小鼠干预6 wk结束后,给予印度墨水灌胃测定小肠传输速率,用微电极细胞内记录仪记录各组小鼠十二指肠平滑肌细胞内慢波的变化.结果:DM组小肠推进率比正常组的明显降低(44.05%±5.48% vs 82.75%±6.56%,P<0.01);DM+SCF组比DM组的小肠推进率显著增加(75.89%±3.61% vs 44.05%±5.48%,P<0.01).但比正常组的降低(75.89%±3.619% vs 82.75%±6.56%,P<0.05);DM组与正常小鼠相比,十二指肠平滑肌细胞内慢波频率明显减慢(13.33±4.27 vs 30.67±3.33,P<0.01),波幅明显减小(15.17±3.71 vs 35.17±3.71,P<0.01).且波形杂乱不规则.DM+SCF组小鼠十二指肠平滑肌细胞内慢波频率和波幅比DM组增加(26.50±1.87 vs 13.33±4.27;27.50±2.26 vs 15.17±3.71,均P<0.01),但比正常组减慢和降低(26.50±1.87 vs 30.67±3.33,P<0.05;27.50±2.26 vs 35.17±3.71,P<0.01).结论:外源性SCF对DM小鼠的小肠动力障碍有一定的改善作用.     

Sleep,Brain, and Cognition Special Feature: Hippocampal gamma and sharp wave/ripples mediate bidirectional interactions with cortical networks during sleep

Hippocampus–neocortex interactions during sleep are critical for memory processes: Hippocampally initiated replay contributes to memory consolidation in the neocortex and hippocampal sharp wave/ripples modulate cortical activity. Yet, the spatial and temporal patterns of this interaction are unknown. With voltage imaging, electrocorticography, and laminarly resolved hippocampal potentials, we characterized cortico-hippocampal signaling during anesthesia and nonrapid eye movement sleep. We observed neocortical activation transients, with statistics suggesting a quasi-critical regime, may be helpful for communication across remote brain areas. From activity transients, we identified, in a data-driven fashion, three functional networks. A network overlapping with the default mode network and centered on retrosplenial cortex was the most associated with hippocampal activity. Hippocampal slow gamma rhythms were strongly associated to neocortical transients, even more than ripples. In fact, neocortical activity predicted hippocampal slow gamma and followed ripples, suggesting that consolidation processes rely on bidirectional signaling between hippocampus and neocortex.

Spontaneous activity during quiescent periods and sleep is likely to be crucial for a multitude of cognitive functions. Functional connectivity studies from human neuroimaging and other brain monitoring modalities have identified several “resting-state networks” whose activity fluctuations are coordinated. One of them, the default mode network (DMN), increases its activity when the brain does not actively drive overt behavior and is involved in functions such as imagery, planning, self-reflection, and memory mechanism (1, 2). The dynamical interplay between hippocampus and the neocortex is another hallmark of the spontaneous activity during behavioral idleness. Hippocampal sharp waves/ripples (SWRs) (3), bursts of hippocampal activity, have attracted most attention as a conduit for this interplay, as they modulate neocortical activity (4–6). Interestingly, the DMN areas are among those most strongly activated at SWR times (7). SWRs are also linked to the bulk of memory replay in the hippocampus, which is the spontaneous repetition of neural activity patterns that were initially elicited during experience (8, 9). Replay has been observed also in many cortical areas (see, e.g., refs. 10–13), most strongly in correspondence with hippocampal SWRs.The interaction between the hippocampus and the neocortex figures prominently in most theories of explicit memory: The hippocampus is seen as rapidly forming rapid memories and “index codes” that summarize and point to activity patterns (14) that simultaneously (albeit more slowly) form in the neocortex and elsewhere in the brain. At memory retrieval, and during offline periods, those codes would propagate to the neocortex. Here, they would help seamlessly updating a large memory repository, as postulated by the complementary learning systems theory (15), or would create new, multiple memory traces [MMT theory (16)] with either similar content or semantic, gist-like representations (17).According to all of these theoretical accounts, however, cortico-hippocampal interplay likely involves the entirety of the neocortex. Yet, previous work has concentrated mostly on single neocortical areas, chosen among those with strongest anatomical links to the hippocampus. Functional magnetic resonance imaging (fMRI) (5) and voltage-sensitive imaging data (18) highlight the global character of neocortical activity modulations related to SWR, with a prominent role of the DMN (7), but how information propagates in neocortical networks is not known yet.During sleep cortical networks are capable of self-sustained high activity transients (UP states, periods of neuronal activation) delimited by silent periods (DOWN states, periods of neuronal silence) (19), generated by recurrent excitation across cortical neurons (20, 21). UP/DOWN state fluctuations have often been described as traveling waves (22–25), but little is known about the structure of each transient activation. Here, with voltage imaging in neocortex of mice combined with layer-resolved hippocampal local field potentials (LFPs), we characterize the probability distribution of transient sizes, showing that it approximates a power-law shape, signature of a near-critical state (in which long-range spatial and temporal correlation are maximized, facilitating global brain coordination), thought to maximize information transmission between far apart cortical sites (26, 27). Thus, these dynamics may be an effective support for the formation of neocortical memory traces.We further delineate the structure of activity transients in a data-driven manner and we find three functional networks centered respectively on the retrosplenial cortex and medial cortical bank of the cortex, on somatosensory cortex, and on lateral cortex. These networks closely match the results of a large anatomical projections dataset (28). Crucially, we show that they are differentially involved in hippocampal communication, with a “retrosplenial” network, overlapping with the standard DMN playing a prominent role.All the theoretical accounts mentioned above emphasize the hippocampal influence on the neocortex and a unidirectional flow from the hippocampus to neocortex, embodied in SWRs. Our data from voltage imaging and LFPs from hippocampal subfield CA1 suggest two refinements of this picture. First, the strongest correlate of cortical activity transients is the slow gamma rhythm (20 to 50 Hz), even outpacing SWRs. Slow gamma has been linked with the routing of information from hippocampal subfields CA3 to CA1. The CA3 subfield is rich in recurrent connections, features of an auto-associative memory (29–31). During sleep, increased slow gamma during SWR events correlates with greater replay (32). Furthermore, using pseudocausality analysis we show here that cortical transients in the DMN/retrosplenial network precede bouts of hippocampal slow gamma.Together, these data point toward a bidirectional interaction as a constituent of the overall architecture of cortico-hippocampal interactions, which provides a potential dynamical scenario. This picture opens up a theoretical view explaining the involvement of the DMN in memory and the two-way exchanges between hippocampus and neocortex, regions crucial for memory and cognition.