基于方剂构成信息的知识发现和关联网络构建挖掘海洋中药海马历代用药经验＊

目的 通过对含海马方剂构成信息进行数据挖掘和知识发现，构建关联网络，分析海马的历代应用情况，挖掘海马用药配伍经验，发现海马潜在功效和主治病症，为海马的临床应用和开发提供依据。方法 以《中医方剂大辞典》《中国药典》《中华医典》等多部著作为方源，收集含有海马的相关方剂，并进行频数分析、关联规则挖掘和关联网络的构建。结果 共筛选有文献记载的含海马方剂154首。从剂型看，大多为散剂，从方剂分布年代来看，海马的应用虽然有很长历史，但是古代应用并不广泛，现代应用较多。通过对配伍药物进行分析发现，与海马配伍频率较高的是“鹿茸”、“熟地黄”、“肉苁蓉”等补益药物。从功效主治方面看，大多数方剂具有“补肾”、“温阳”、“益精”等传统功效外，还具有健脑等功效；主治病症中，除“阳痿”、“癥瘕”、“疔疮”等《中国药典》所记载的疾病之外，还可治疗“虚劳”、“健忘”、“瘿病”、“不寐”、“痹证”、“小便淋沥或不通”等。对其进行关联关系分析发现，海马配伍补肾温阳的效果较为明显，多用于治疗阳痿，且腰痛、虚劳、遗精、健忘、不育等疾病的治疗与补肾关系密切；在治疗癥瘕时，多与醋、樗鸡、干漆、硇砂、斑蝥、水蛭、没药、当归配伍。结论 该研究不仅发现了含海马方剂的常用剂型、分布年代和药物配伍规律，发现了历代医家应用海马的临床经验，还探索了海马的潜在应用价值。海马作为一味海洋中药，具有温、补、托、消等特性，除常用于治疗阳痿外，还可用于治疗腰痛、健忘、瘿病、不寐、痹证等病症，这些研究结果可为拓展海马的临床应用提供理论基础及依据。     

Neurofeedback and neuroplasticity of visual self-processing in depressed and healthy adolescents: A preliminary study

Adolescence is a neuroplastic period for self-processing and emotion regulation transformations, that if derailed, are linked to persistent depression. Neural mechanisms of adolescent self-processing and emotion regulation ought to be targeted via new treatments, given moderate effectiveness of current interventions. Thus, we implemented a novel neurofeedback protocol in adolescents to test the engagement of circuits sub-serving self-processing and emotion regulation.MethodsDepressed (n = 34) and healthy (n = 19) adolescents underwent neurofeedback training using a novel task. They saw their happy face as a cue to recall positive memories and increased displayed amygdala and hippocampus activity. The control condition was counting-backwards while viewing another happy face. A self vs. other face recognition task was administered before and after neurofeedback training.ResultsAdolescents showed higher frontotemporal activity during neurofeedback and higher amygdala and hippocampus and hippocampi activity in time series and region of interest analyses respectively. Before neurofeedback there was higher saliency network engagement for self-face recognition, but that network engagement was lower after neurofeedback. Depressed youth exhibited higher fusiform, inferior parietal lobule and cuneus activity during neurofeedback, but controls appeared to increase amygdala and hippocampus activity faster compared to depressed adolescents.ConclusionsNeurofeedback recruited frontotemporal cortices that support social cognition and emotion regulation. Amygdala and hippocampus engagement via neurofeedback appears to change limbic-frontotemporal networks during self-face recognition. A placebo group or condition and contrasting amygdala and hippocampus, hippocampi or right amygdala versus frontal loci of neurofeedback, e.g. dorsal anterior cingulate cortex, with longer duration of neurofeedback training will elucidate dosage and loci of neurofeedback in adolescents.     

Lasting effects of stress physiology on the brain: Cortisol reactivity during preschool predicts hippocampal functional connectivity at school age

Prolonged exposure to glucocorticoid stress hormones, such as cortisol in humans, has been associated with structural and functional changes in the hippocampus. The majority of research demonstrating these associations in humans has been conducted in adult, clinical, or severely maltreated populations, with little research investigating these effects in young or more typically developing populations. The present study sought to address this gap by investigating longitudinal associations between preschool (3−5 years) and concurrent (5–9 years) cortisol reactivity to a laboratory stressor and hippocampal functional connectivity during a passive viewing fMRI scan. Results showed that, after controlling for concurrent cortisol reactivity, greater total cortisol release in response to a stressor during preschool predicted increased anterior and posterior hippocampal connectivity with the precuneus and cingulate gyrus at school-age. These findings are consistent with literature from adult and non-human investigations and suggest lasting impacts of early stress physiology on the brain.     

川芎嗪通过激活PKCα/Nrf2信号转导抑制七氟烷诱导的氧化损伤和血脑屏障破坏研究

目的:研究川芎嗪对七氟烷引起的氧化损伤以及血脑屏障(BBB)生理功能损伤的影响及其机制。方法:将新生幼鼠随机分组,设置对照组,并分别使用七氟烷、七氟烷和溶剂、七氟烷和川芎嗪处理小鼠,暴露于七氟烷中不同时长处死并收集小鼠大脑和海马组织,通过免疫酶联吸附检测ROS,SOD,MDA,GSH和S100β蛋白水平,制作小鼠大脑和海马组织切片并通过免疫化学染色和免疫荧光染色检测小鼠大脑和海马组织中MMP-2、MMP-9、TIMP-1、TIMP-2以及HO-1的表达,并检测Nrf2的核易位,HE染色后通过透射电子显微镜检查海马神经元损伤情况,通过蛋白质印迹分析PKC/Nrf2以及MMP-2、MMP-9表达情况,使用原位酶谱检测明胶酶活性并通过PCR检测ZO-1的表达。结果:与对照组相比,七氟烷组海马神经元损伤明显,而川芎嗪处理可以明显改善七氟烷诱导的海马神经元损伤; 与对照组相比,七氟烷处理后MMP-2、MMP-9表达和明胶酶活性明显增加,ZO-1表达明显减少,BBB通透性显著增加,而TIMP-1和TIMP-2表达无显著改变; 与七氟烷组相比,川芎嗪可以抑制明胶酶活性,促进ZO-1表达,改善BBB生理状态; 与溶剂组和七氟烷组相比,对照组和川芎嗪组ROS和BMD水平明显降低,MDA和GSH活性显著增加,PKCα、Nrf2和HO-1 的表达以及Nrf2的核易位显著增加。结论:川芎嗪可以通过PKCα/Nrf2信号通路以及抑制明胶酶活性,改善BBB通透性,保护海马免受氧化应激的伤害,改善海马体组织病理学结构。     

Transcranial focused ultrasound induces sustained synaptic plasticity in rat hippocampus

Transcranial focused ultrasound (tFUS) neuromodulation provides a promising emerging non-invasive therapy for the treatment of neurological disorders. Many studies have demonstrated the ability of tFUS to elicit transient changes in neural responses. However, the ability of tFUS to induce sustained changes need to be carefully examined. In this study, we use the long-term potentiation/long term depression (LTP/LTD) model in the rat hippocampus, the medial perforant path (mPP) to dentate gyrus (DG) pathway, to explore whether tFUS is capable of encoding frequency specific information to induce plasticity. Single-element focused transducers were used for tFUS stimulation with ultrasound fundamental frequency of 0.5 MHz and nominal focal distance of 38 mm tFUS stimulation is directed to mPP. Measurement of synaptic connectivity is achieved through the slope of field excitatory post synaptic potentials (fEPSPs), which are elicited using bipolar electrical stimulation electrodes and recorded at DG using extracellular electrodes to quantify degree of plasticity. We applied pulsed tFUS stimulation with total duration of 5 min, with 5 levels of pulse repetition frequencies each administered at 50 Hz sonication frequency at the mPP. Baseline fEPSP is recorded 10 min prior, and 30+ minutes after tFUS administration. In N = 16 adult wildtype rats, we observed sustained depression of fEPSP slope after 5 min of tFUS focused at the presynaptic field mPP. Across all PRFs, no significant difference in maximum fEPSP slope change was observed, average tFUS induced depression level was observed at 19.6%. When compared to low frequency electrical stimulation (LFS) of 1 Hz delivered to the mPP, the sustained changes induced by tFUS stimulation show no statistical difference to LFS for up to 24 min after tFUS stimulation. When both the maximum depression effects and the duration of sustained effects are both taken into account, PRF 3 kHz can induce significantly larger effects than other PRFs tested. tFUS stimulation is measured with a spatial-peak pressure amplitude of 99 kPa, translating to an estimation of 0.43 °C temperature increase when assuming no loss of heat. The results suggest the ability of tFUS to encode sustained changes in synaptic connectivity through mechanism which are unlikely to involve thermal changes.     

The intracranial correlate of the 14&6/sec positive spikes normal scalp EEG variant

ObjectiveTo investigate the intracranial correlate of the 14&6/sec positive spikes normal variant of scalp EEG.MethodsOut of 35 adult refractory focal epilepsy patients who underwent intracranial electrode implantation with simultaneous scalp EEG electrodes, the 14&6/sec positive spikes variant was found in 4. We used three methods to identify and quantify intracranial correlates to the variant: visual inspection, time-referenced waveform averaging and 3D brain volume spectrum-based statistical parametric mapping (SPM).ResultsWe discovered a novel and robust relationship between the scalp variant and an atypical hippocampal discharge. This intracranial correlate is an ipsilateral hippocampal burst of highly synchronized high-amplitude paroxysmal-like spikes of negative polarity, with a ramping up amplitude profile, which often ramps down and is accompanied by an underlying sequence of low-amplitude negative slow waves. The 14/sec positive spikes of the variant are time-locked to the negative peak of the hippocampal spikes, while the 6/sec positive spikes are time-locked to the negative spikes overlying the low-amplitude slow waves.ConclusionsThe 14&6/sec positive spikes variant correlates with bursts of negative polarity spikes in the ipsilateral hippocampus.SignificanceThe identification of the hippocampal correlate of the 14&6/sec positive spikes variant fills a gap in our knowledge of normal intracranial variants. In clinical practice, this knowledge should reduce the chance that this electrophysiological signature is misinterpreted as epileptiform activity, which could inappropriately influence the interpretation of the intracranial study and subsequent surgical recommendation.     

Task-dependent effects of intracranial hippocampal stimulation on human memory and hippocampal theta power

BackgroundDespite its potential to revolutionize the treatment of memory dysfunction, the efficacy of direct electrical hippocampal stimulation for memory performance has not yet been well characterized. One of the main challenges to cross-study comparison in this area of research is the diversity of the cognitive tasks used to measure memory performance.ObjectiveWe hypothesized that the tasks that differentially engage the hippocampus may be differentially influenced by hippocampal stimulation and the behavioral effects would be related to the underlying hippocampal activity.MethodsTo investigate this issue, we recorded intracranial EEG from and directly applied stimulation to the hippocampus of 10 epilepsy patients while they performed two different verbal memory tasks – a word pair associative memory task and a single item memory task.ResultsHippocampal stimulation modulated memory performance in a task-dependent manner, improving associative memory performance, while impairing item memory performance. In addition, subjects with poorer baseline cognitive function improved much more with stimulation. iEEG recordings from the hippocampus during non-stimulation encoding blocks revealed that the associative memory task elicited stronger theta oscillations than did item memory and that stronger theta power was related to memory performance.ConclusionsWe show here for the first time that stimulation-induced associative memory enhancement was linked to increased theta power during retrieval. These results suggest that hippocampal stimulation enhances associative memory but not item memory because it engages more hippocampal theta activity and that, in general, increasing hippocampal theta may provide a neural mechanism for successful memory enhancement.     

Mineralocorticoid receptor antagonist-mediated cognitive improvement in a mouse model of Alzheimer's type: possible involvement of BDNF-H2S-Nrf2 signaling

The present study explored the role and mechanisms of mineralocorticoid receptor antagonists in β-amyloid (Aβ)-induced cognitive impairment. A single intracerebroventricular injection of Aβ_1-42 was given to mice, and after 14 days of injection, memory was evaluated using the Morris water maze test. Spironolactone (25 and 50 mg/kg) and eplerenone (50 and 100 mg/kg) were administered for two days before and for 14 days after Aβ injection. Mineralocorticoid receptor blockers attenuated Aβ-induced cognitive impairment assessed in terms of decrease in day 4 escape latency time (ELT) in comparison to day 1 ELT (suggesting an increase in learning) along with an increase in time spent in target quadrant on day 5 (suggesting the retrieval of learned things). These drugs also increased the expression of BDNF, H₂S, Nrf2, reduced glutathione, and decreased β-amyloid and TNF-α in the frontal cortex and hippocampus. Co-administration of ANA-12, BDNF receptor antagonist (0.25 and 0.5 mg/kg) abolished cognitive improving functions of mineralocorticoid receptor blockers, attenuated H₂S, Nrf2, reduced glutathione, and decreased β-amyloid and TNF-α. It is concluded that spironolactone and eplerenone attenuate cognitive decline of Alzheimer's type, possibly through upregulation of BDNF levels in the frontal cortex and hippocampus, which may increase H₂S, decrease Aβ, activate Nrf2-dependent antioxidant system, and decrease neuroinflammation.     

磁共振成像阴性颞叶癫痫的临床特点分析

目的探讨磁共振成像(MRI)阴性颞叶癫痫(nonlesional temporal lobe epilepsy,TLE-NL)患者的临床特征、记忆水平和影像学特点。方法纳入2012年9月1日至2017年8月31日在浙江大学医学院附属第二医院确诊的44例单侧TLE-NL患者和53例同期就诊单侧颞叶癫痫伴海马硬化(temporal lobe epilepsy with hippocampal sclerosis,TLE-HS)患者,对TLE-NL和TLE-HS的临床特点进行对比。同时纳入20名健康志愿者作为正常对照组。采用韦氏记忆量表评估患者和对照组记忆功能,并通过高分辨率MRI定量分析海马体积及形态,评估TLE-NL和TLE-HS患者记忆水平和海马体积的改变。结果TLE-NL患者比TLE-HS患者发病年龄更晚[(24.3±12.6)岁与(15.8±10.3)岁;t=3.684,P<0.01],癫痫病程更短[4.00(2.00,8.75)年与14.00(7.50,22.00)年;Z=-4.675,P<0.01],热性惊厥史比例[4.5%(2/44)与62.3%(33/53);χ2=32.270,P<0.01)和药物难治性比例更低[47.7%(21/44)与84.9%(45/53);χ2=15.282,P<0.01)。TLE-NL患者在性别比例、癫痫家族史、致痫灶侧别、先兆发生率、症状学类型及发作频率上与TLE-HS患者类似。TLE-NL患者与正常对照组相比无明显记忆损害(记忆商数:105.2±17.4与103.8±16.2;P=1.000),而TLE-HS患者与正常对照组相比存在明显记忆损害(记忆商数:84.5±20.3与103.8±16.2;P<0.01)。TLE-NL患者海马体积和形态与正常对照组相比无明显改变,而TLE-HS患者存在明显致痫灶同侧海马萎缩[(2953±481)mm3与(4431±505)mm3;P<0.01),形态分析结果提示萎缩以海马头及海马体部明显。结论TLE-NL是一类有别于TLE-HS的颞叶癫痫综合征,具有发病年龄晚、病程短、热性惊厥史少、药物难治性癫痫发生率较低、无明显记忆损害及海马萎缩的临床特点。