慢性精神分裂症男性患者听觉刺激惊跳反射的初步研究

目的 探讨汉族人群精神分裂症患者是否存在听觉惊跳反射缺陷及抗精神病药的影响.方法 第1代药物组:服用第1代抗精神病药的慢性精神分裂症男性患者25例;氯氮平组:服用氯氮平的慢性精神分裂症男性患者25例;对照组:身体健康的男性25名;3组的年龄和受教育年限均匹配.对上述3组进行听觉刺激惊跳反射检测,并使用阳性和阴性症状量表(PANSS)评定精神分裂症患者的临床精神病理症状.结果 (1)第1代药物组惊跳反射的反应波幅(SR)[(553.6±516.9)mV]明显低于对照组[(942.0±447.3)mV,P=0.009],氯氮平组的SR[(755.9±439.4)mV]介于上述2组之间,但与2组间的差异均无统计学意义(P＞0.05);(2)第1代药物组惊跳反射的适应性(HAB)[(17.8±35.8)%]明显低于对照组[(44.9±28.9)%,P=0.027],氯氮平组的HAB[(22.9±34.1)%]介于上述2组之间,但与2组间的差异均无统计学意义(P＞0.05);(3)当时间间隔(LI)为120 ms时,第1代药物组的惊跳反射弱刺激抑制(prepulse inhibition,PPI)显著小于对照组(P=0.024),氯氮平组的PPI值介于上述2组之间,但与2组间的差异均无统计学意义(P＞0.05);LI为30 ms或60 ms时,3组间PPI的差异无统计学意义(P＞0.05);(4)第1代药物组和氯氮平组患者不同LI的PPI与其临床病理症状可能不存在相关(P＞0.05).结论 精神分裂症患者可能存在听觉惊跳反射弱刺激抑制的缺陷;氯氮平可能能部分改善精神分裂症患者对惊跳反射的脱抑制.     

惊跳反射弱刺激抑制及P50在精神分裂症中的应用

目的 探讨精神分裂症患者的惊跳反射弱刺激抑制(PPI)的特点.方法 应用美国Nicolet Bravo脑电生理仪,采用听觉感觉刺激模式对30例精神分裂症患者和28名正常人做听觉PPI及P50检测.结果 病例组PPI低于正常对照组;病例组的S1-P50降低、S2-P50增高、P50抑制明显减弱、S1-S2和100 (1-S2/S1)均下降.结论 精神分裂症患者存在感觉运动门控缺陷,PPI可作为一项实验室指标用于临床.     

精神分裂症感觉运动门控及惊跳反射弱刺激抑制的研究

大脑对信息加工过程的异常是精神分裂症的主要特征，而感觉运动门控(sensorimotor gating SG；又称为感觉门控，sensory gating)的缺损是导致该异常的重要机制之一。SG是大脑一种正常功能，指大脑对感觉刺激反应的调节能力。SG缺损可导致大脑处于感觉淹没状态(即大脑接受了大量的感觉刺激但不能正常地对其进行加工的非正常状态)，使其认知破裂，乃至出现精神症状”。现有2种较为成熟的定量测定感觉滤过量(感觉门控的大小)的方法，     

惊跳反射弱刺激抑制(PPI)实验方法的建立与应用——附78例健康成人分析

目的利用惊跳反射弱刺激抑制(PPI)新技术探讨健康成人感觉门控(SG)的特征。方法应用德国Brain Products公司的脑电生理仪,对78名18~55岁健康成人受试者(男性43名,女性35名),作PPI测定,并于28天后随机抽取21名受试者重复测试PPI。结果 (1)21名受试者首次测试及28天后测试时PPI波幅及潜伏期比较差异不明显(P0.05);(2)本研究中健康成人PPI数值为61±29%;(3)PPI男女性别比较差异未达显著性(P0.05)。结论健康成人PPI可由弱-强刺激结合的被动注意PPI范式诱发,间隔一定时间后仍波形稳定,未发现明显性别差异。     

不同刺激参数rTMS对慢性不可预见应激大鼠行为的作用及大脑BDNF水平的影响

目的 观察不同刺激参数重复经颅磁刺激（rTMS）对慢性不可预见应激（CUS）模型大鼠行为学的作用,并观察其对大鼠脑源性神经营养因子（BDNF）水平的影响.方法 64只SD大鼠随机分为对照组（8只）、模型组（8只）和干预组（共6个亚组,每组8只）.对照组正常饲养21d后连续7d给予rTMS假刺激;模型组在造模后连续7d给予rTMS假刺激;干预组在造模后每天给予不同频率和强度的rTMS刺激,连续7d.实验期间观察大鼠体质量的变化,并采用运动箱和强迫游泳实验评估大鼠抑郁样行为,最后以酶联免疫吸附法测定大脑BDNF的水平.结果 （1）造模结束后,对照组大鼠的体质量、强迫游泳静止时间与其他两组相比均存在显著性差异（P＜0.01,P＜0.05）,而模型组和干预组大鼠比较没有上述差异（P＞ 0.05）.各组大鼠水平运动距离没有显著性差异（P＞0.05）.（2）rTMS干预后,①模型组大鼠的体质量显著低于对照组及干预组（5 Hz,0.84/1.26 T和10 Hz,0.84/1.26 T） （P ＜0.05）.②各组大鼠水平运动距离之间没有显著性差异;模型组强迫游泳静止时间百分比明显高于对照组及干预组（P＜0.05）.③模型组BDNF的水平低于对照组,而一定刺激条件的rTMS可以改善这一现象.④双因素方差分析显示,刺激频率可能是改善大鼠抑郁行为和调节BDNF的关键因素,而且5 Hz的抗抑郁效应更为显著.结论 不同刺激参数的rTMS对CUS动物抑郁行为的改善作用存在差异,大脑BDNF水平的变化可能参与了这一改善过程.     

慢性应激对大鼠海马FAS蛋白表达的影响及帕罗西汀的干预作用

目的探讨慢性轻度不可预见应激对大鼠海马神经元FAS蛋白表达的影响以及抗抑郁剂（帕罗西汀）的拮抗作用。方法将24只SD雄性大鼠随机均分为正常组、慢性应激模型组、氟西汀治疗组。选用慢性轻度不可预见性应激模型,运用OPEN-FILED（旷野试验）观察大鼠的行为学的变化,TUNEL染色和免疫组织化学技术研究大鼠海马各区的细胞凋亡及FAS蛋白的表达。结果慢性应激抑郁大鼠旷野实验中水平穿越格数、竖立次数、修饰次数有减少中央格停留时间有增加。氟西汀可改善大鼠行为学变。TUNEL染色和免疫组织化学技术结果显示模型组大鼠海马细胞内的细胞凋亡数及FAS蛋白的表达量明显高于对照组组（P〈0.05）;氟西汀组大鼠海马细胞内PKA和P-CREB胞凋亡数及FAS蛋白的表达量明显低于模型组（P〈0.05）。结论慢性轻度不可预见性应激可促进大鼠海马神经元内细胞凋亡和FAS蛋白表达水平升高,氟西汀具有一定的拮抗作用。     

慢性应激对海马结构和功能的影响

海马是介导应激反应重重要的脑区之一,也是应激激素作用的主要靶区。慢性应激改变海马结构和功能,引起学习和记忆的缺损。本综述了近几年来慢性应激对海马结构和功能效应的研究进展。     

慢性应激对大鼠行为和体重的影响

目的　观察慢性应激对大鼠行为和体重的影响。方法　采用慢性强迫游泳模型 ,应用行为追踪仪观察大鼠的活动量 ,以电子动物称监测大鼠体重变化。结果　应激组大鼠活动量明显高于对照组 (P <0 0 1) ,排便、排尿增加 ,修饰频繁。应激组大鼠体重增长明显低于对照组 (P <0 0 1)。结论　慢性强迫游泳使大鼠活动量增多 ,抑制体重增长。     

帕罗西汀对抑郁模型大鼠前额叶皮质鞘磷脂和神经酰胺的影响

目的观察帕罗西汀对慢性不可预见应激(CUS)模型大鼠前额叶皮质(PFC)中鞘磷脂(SM)和神经酰胺(Cer)水平的影响。方法按照随机数字表法将21只SD大鼠随机分为对照组(Sham组)、模型组(CUS组)和帕罗西汀组(Par组),每组7只。CUS组和Par组均接受CUS造模,并且在造模后每天腹腔注射生理盐水(1 ml/kg)或帕罗西汀(10 mg/kg),连续7 d;Sham组在同一时间段每天腹腔注射生理盐水。随后处死大鼠,取PFC进行质谱分析,比较各处理组SM和Cer以及其组成小分子相对丰度的差异。结果CUS组的SM相对丰度倍数为(0.73±0.16),显著低于Sham组的(1.02±0.08)和Par组的(0.89±0.05)(均P<0.05);CUS组的Cer相对丰度倍数为(1.35±0.18),显著高于Sham组的(1.05±0.10)和Par组的(1.14±0.11)(均P<0.05);Sham组和Par组的SM和Cer相对丰度比较,差异均无统计学意义(P>0.05)。与Sham组相比,CUS组的5个SM和2个Cer小分子相对丰度降低,1个SM和5个Cer小分子相对丰度升高(均P<0.05);与Par组相比,CUS组的2个SM小分子相对丰度降低,8个Cer小分子相对丰度升高(均P<0.05);Sham组的1个SM和2个Cer小分子相对丰度降低,1个SM和6个Cer小分子相对丰度升高(均P<0.05)。结论CUS模型大鼠前额叶皮质的SM水平降低而Cer水平升高,帕罗西汀干预可以改善这一现象。     

氟西汀对慢性不可预见应激模型大鼠前额叶皮质磷脂酰乙醇胺的影响

目的 探讨氟西汀对慢性不可预见应激（CUS）模型大鼠前额叶皮质磷脂酰乙醇胺（PE）的 影响。方法 按随机数字表法将18 只SD 大鼠随机分为对照组（Sham组）、模型组（CUS 组）和氟西汀组 （Flx组）。CUS组和Flx组均接受CUS造模,并且在造模后接受生理盐水（1 ml/kg）或氟西汀（10 mg/kg）腹腔 注射,连续14 d;Sham组不进行CUS造模,但是每天接受腹腔注射生理盐水。14 d后处死大鼠,取前额 叶皮质进行脂质组学分析,比较各处理组前额叶皮质总的PE和PE小分子相对丰度差异。结果 （1）与 Sham 组［（10.50±7.32）×1011］比较,CUS 组PE 相对丰度［（11.95±8.46）×1011］明显减低（P ＜ 0.01）,而 Flx 组［（10.31±9.16）×1011］差异则无统计学意义（P ＞ 0.05）;（2）与Sham 组比较,CUS 组3 个PE 小分子 相对丰度减低,分别为PE（36：4p）（68.67±14.68）、PE（38：3p）（49.73±19.55）、PE（38：4p）（76.10±7.84）, 差异均有统计学意义（均P ＜ 0.05）;（3）与CUS 组比较,Flx 组6 个PE 小分子相对丰度减低,包括PE （36：4）（72.53±10.22）、PE（36：2）（87.86±8.26）、PE（38：5p）（75.66±9.53）、PE（38：5）（89.93±9.79）、PE （38：4）（86.55±5.40）、PE（40：7p）（81.57±7.55）,差异均有统计学意义（均P＜ 0.05）;（4） 与Sham 组比较, Flx 组6 个PE 小分子相对丰度减低,包括PE（38：4p）（75.85±5.63）、PE（38：3p）（44.22±12.61）、PE（38：4） （82.49±9.41）、PE（40：5p）（78.01±5.31）、PE（36：4）（76.00±6.34）、PE（38：6）（77.45±13.06）,差异均有统计 学意义（均P ＜ 0.05）。结论 CUS 模型大鼠前额叶皮质内PE 水平异常,氟西汀可以调节CUS 模型大鼠 前额叶皮质的PE 水平。     

DOI disrupts prepulse inhibition of startle in rats via 5-HT2A receptors in the ventral pallidum

Serotonin (5-HT)_2A receptors are known to be involved in prepulse inhibition of the startle response (PPI), a measure of sensorimotor inhibition that is deficient in schizophrenia, Huntington's disease, and obsessive compulsive disorder. In the present studies, the localization of the 5-HT_2A receptors responsible for modulating PPI was investigated using central injections of the hallucinogenic 5-HT₂ agonist DOI and the novel 5-HT_2A antagonist MDL 100,907. 5-HT_2A receptors are densely localized in the nucleus accumbens (NAC) and the ventral pallidum (VP), areas known to be important components of neural circuitry that mediates the ventral forebrain modulation of PPI. In the present studies, it was found that the infusion of DOI (0.0–5.0 μg/0.5 μl) into the VP disrupted PPI without having effects on startle reactivity. In contrast, similar infusions into the NAC had no effect on PPI or startle reactivity. The infusion of MDL 100,907 into the VP was found to increase PPI by itself and to attenuate the PPI-disruptive effects of systemically administered DOI. It is concluded that 5-HT_2A receptors within the VP are important for the modulation of PPI, presumably through interactions at intrinsic GABAergic or cholinergic interneurons.     

Sensorimotor gating in rats is regulated by different dopamine-glutamate interactions in the nucleus accumbens core and shell subregions

The amplitude of the acoustic startle reflex is normally reduced when the startling stimulus is preceded by a weak click or ‘prepulse’. Prepulse inhibition (PPI) of acoustic startle has been used as an operational measure of sensorimotor gating or inhibition, and is reduced in schizophrenia patients and in rats with central dopamine (DA) activation. The DA agonist-induced disruption of PPI in rats may thus offer a useful animal model to study impaired sensorimotor gating in schizophrenia. We have previously reported that DA-glutamate interactions in the nucleus accumbens (NAC) regulate PPI. The NAC has at least two major subregions — the core and shell — that have distinct anatomical and neurochemical properties. In this study, we compared changes in PPI after manipulations of DA-glutamate activity in these two NAC subregions. Consistent with previous findings, infusion of the non-NMDA agonist AMPA into the NAC core subregion significantly reduced PPI, and this effect was opposed by systemic administration of the D₂ antagonist haloperidol. Also consistent with previous reports, infusion of the non-NMDA antagonist CNQX into the NAC core subregion did not alter PPI, but its co-infusion with D-amphetamine (AMPH) attenuated the AMPH-disruption of PPI. In contrast, while PPI was reduced after AMPA infusion into the NAC shell subregion, this effect of AMPA could not be blocked by pretreatment with haloperidol. Infusion of either AMPHor CNQX into the NAC shell subregion reduced PPI independently. The PPI-disruptive effects of intra-shell CNQX infusion were not blocked by haloperidol. The present results suggest striking differences between the NAC core and shell subregions in their neurochemical modulation of sensorimotor gating of acoustic startle in the rat.     

Assessment of excitability in brainstem circuits mediating the blink reflex and the startle reaction

Excitability is probably the concept that fits better with the definition of the role of neurophysiology in the study of brainstem functions and circuits. Neurophysiological techniques are likely the best suited of all paraclinical tests for documenting the eventual excitability changes that may occur in certain physiological states and in many neurological disorders. The best known test of brainstem excitability is the blink reflex. While a single stimulus can already indicate the readiness of the interneuronal path and the facial motoneurons to fire, pairs of stimuli (conditioning and test) are suited to analyze the degree of excitability recovery after a single discharge. Another brainstem reflex circuit, which excitability testing can be of interest for physiological and clinical exams is the one involved in the startle reaction. The size of the responses and their habituation are the typical measures of excitability of the startle reflex circuit. Prepulse inhibition is a method to modulate both, the blink reflex and the startle reaction. It is defined as the inhibitory effect caused by a stimulus of an intensity low enough not to induce a response by itself on the response elicited by a subsequent stimulus. The circuits of the blink reflex, startle reaction and prepulse inhibition share some commonalities but they are different enough for the three techniques to provide unique, clinically relevant, information in certain conditions. The role of neurophysiology is not limited to testing those functions. It is important also for the assessment of many other circuits, such as those implicated in eye movements, vestibular reflexes, arousal, sleep, breathing, or autonomic reactions, which are not considered in this review.     

Gestational chronic mild stress: Effects on acoustic startle in male offspring of rats

An increasing number of scientific studies indicate that maternal stress during pregnancy influences fetal development of the nervous system and thereby the behavioural phenotype. We have previously reported attenuated prepulse inhibition (PPI) of the startle reaction in adult female rats derived from dams exposed to chronic mild stress (CMS) during gestation. In humans, decreased PPI has been reported to be associated with anxiety. Because of its potential translational value across species, the modulation of startle reactivity may be a useful tool in examining altered emotional reactivity following prenatal insults. The present study aimed at investigating whether prenatally stressed male offspring would display altered startle phenotype. Stress was induced by maternal gestational exposure to alternating procedures, i.e. CMS. At the age of 3 months, half of the offspring were blood sampled under restraint. At the age of 6 months, i.e. three months later, all animals were tested in the acoustic startle and the light enhanced startle (LES) paradigm. Control and CMS male offspring showed similar basal startle and LES levels. Maternal gestational exposure to the relatively mild, variable paradigm of stressors affected the PPI response pattern in male rats. In prenatally manipulated males, the PPI response differed statistically significantly, depending on prior exposure to an episode of postnatal acute stress (blood sampling under restraint). In contrast, the PPI response in control males was unaffected by this postnatal experience. The present work supports the hypothesis that the maternal environment is a long-term determinant of phenotypic differences in sensitivity to stressors.     

Endogenous neurotensin is involved in estrous cycle related alterations in prepulse inhibition of the acoustic startle reflex in female rats

Ovarian hormones regulate prepulse inhibition (PPI) of the acoustic startle reflex. Results from studies in intact female rodents investigating sex, estrous cycle and ovarian hormone regulation of PPI are inconsistent. In experiment #1, we investigated whether PPI in female rats is influenced by the time of day of testing and the estrous cycle stage of the rat. PPI was examined across the day of proestrus (P) and diestrus 1 (D1) in female rats and compared to males. PPI in males and P females was significantly higher than in D1 females. PPI in males and D1 females was significantly affected by the time of day of testing with PPI being reduced in the afternoon and evening compared to morning. PPI in P females was not significantly affected by the time of day of testing. Previous studies have demonstrated estrous cycle regulation of central nervous system neurotensin (NT) neurons and peripherally administered NT receptor agonists regulate PPI in a manner similar to antipsychotic drugs. Experiment #2 of this study was designed to examine whether endogenous NT is involved in estrous cycle regulation of PPI. The NT receptor antagonist SR 142948A reduced the high levels of PPI during D1 and P. In contrast, when tested at a time of day in which PPI was low in D1 females, administration of both the typical antipsychotic drug haloperidol and the NT receptor antagonist significantly increased PPI. These data support an effect of time of day and estrous cycle stage on PPI in female rats. The estrous cycle variations in PPI are mediated in part by endogenous NT.     

Prepulse inhibition of startle in adults with ADHD

Prepulse inhibition of startle (PPI) is a measure of sensorimotor gating, a pre-conscious regulator of attention. PPI is impaired in adults with schizophrenia and several other neuropsychiatric disorders associated with attentional abnormalities. The core feature of ADHD involves deficits in attention and, like schizophrenia, ADHD is associated with dysregulation of cortical-striatal circuits and dopamine transmission. Therefore, PPI may be disrupted in ADHD. While ADHD persists into adulthood in approximately half the children with ADHD, there has not been any published report of PPI in ADHD adults. In this study, PPI was measured in a sample of ADHD adults and compared to a sample of healthy comparison (HC) subjects. Twenty unmedicated adults with ADHD (11 inattentive subtype, 9 combined subtype) and 17 HC subjects were administered an eyeblink startle PPI paradigm. The PPI of ADHD adults was not significantly different from that of HC subjects in any of the PPI conditions. There was no significant effect of ADHD subtype nor of gender. The lack of PPI deficits in ADHD adults has important implications and suggests that, despite the presence of PPI dysregulation in a large number of disparate neuropsychiatric disorders, it is not a general feature of all neuropsychiatric disorders with attention abnormalities. Furthermore, the attentional deficiency in ADHD may have a neurobiological substrate somewhat distinct from schizophrenia and other neuropsychiatric disorders that are associated with PPI deficits. This distinction may be related to a relative sparing of pre-conscious attentional functions in ADHD compared to other disorders with PPI impairment.     

Prepulse inhibition of the startle reflex in schizophrenia remains stable with short-term quetiapine

Purpose

To study the short-term effect of treatment with quetiapine on prepulse inhibition (PPI) deficits of the startle reflex in schizophrenia patients.

Subjects and methods

Using PPI, we studied a group of 21 schizophrenia patients and 16 controls. Seventeen of the patients were re-tested with PPI after 21 days of treatment with quetiapine.

Results

At baseline, an almost significant decrease in PPI was found in the patients as compared to the controls. PPI measurements did not change in the patients after 21 days of treatment with quetiapine, despite their clinical improvement.

Conclusion

Our results suggest that short-term quetiapine treatment may not modify PPI measures in schizophrenia patients.     

Inhibition of auditory evoked potentials and prepulse inhibition of startle in DBA/2J and DBA/2Hsd inbred mouse substrains

Previous data have shown differences among inbred mouse strains in sensory gating of auditory evoked potentials, prepulse inhibition (PPI) of startle, and startle amplitude. These measures of sensory and sensorimotor gating have both been proposed as models for genetic determinants of sensory processing abnormalities in patients with schizophrenia and their first-degree relatives. Data from our laboratory suggest that auditory evoked potentials of DBA/2J mice differ from those previously described for DBA/2Hsd. Therefore, we compared evoked potentials and PPI in these two closely related substrains based on the hypothesis that any observed endophenotypic differences are more likely to distinguish relevant from incidental genetic heterogeneity than similar approaches using inbred strains that vary across the entire genome. We found that DBA/2Hsd substrain exhibited reduced inhibition of evoked potentials and reduced startle relative to the DBA/2J substrain without alterations in auditory sensitivity, amplitude of evoked potentials or PPI of startle. These results suggest that gating of auditory evoked potentials and PPI of startle measure different aspects of neuronal function. The differences between the substrains might reflect genetic drift. Alternatively, differences could arise from different rearing environments or other non-genetic factors. Future studies will attempt to determine the cause of these differences in sensory and sensorimotor processing between these two closely related inbred mouse strains.