重复经颅磁刺激治疗精神分裂症阴性症状的随机双盲研究

目的探讨重复经颅磁刺激（rTMS）治疗精神分裂症阴性症状的疗效。方法 30例精神分裂症患者被随机分为rTMS真刺激组（治疗组,15例）和rTMS伪刺激组（对照组,15例）,采用θ短阵快速脉冲刺激（TBS）模式刺激左侧前额叶背外侧皮质（DLPFC）,每周5次,共干预20次。于基线、治疗2周及治疗4周时应用阳性与阴性症状量表（PANSS）的阴性因子分和阴性症状量表（SANS）进行疗效评定。结果共有27例患者完成研究,对照组有3例脱落。经rTMS干预4周后,治疗组与对照组的PANSS阴性因子分减分值分别为（4.67±2.47）分和（2.33±1.87）分,两组比较有统计学差异（z=-2.41,P=0.016）;SANS总分减分值分别为（11.87±8.04）分和（5.92±6.47）分,两组比较有统计学差异（z=2.08,P=0.038）。根据PANSS阴性因子分评定,治疗组的有效率达到46.7%,对照组的有效率为16.7%;根据SANS总分评定治疗组的有效率达到46.7%,而对照组的有效率为8.3%;阴性症状的组间疗效差异有统计学意义（P〈0.05）。除了轻微的一过性头痛和入睡困难,未见有其他严重不良反应。结论 TBS模式可改善精神分裂症患者的阴性症状。     

抗精神病药对精神分裂症患者探索性眼球活动的影响

目的：探讨抗精神病药对精神分裂症患者探索性眼球活动障碍的疗效及与精神症状变化的关系。方法：对62例精神分裂症患者分别于治疗前和治疗8周做探索性眼球活动检测和阳性与阴性症状量表（PANSS）评分，主要观察指标为凝视点数（number of eye fixation，NEF）、反应性探索评分（responsive search score，RSS）及PANSS总分。结果：精神分裂症患者治疗前NEF和RSS评分均显著低于对照组（P〈0．001），治疗8周后的NEF和RSS与治疗前相比差异均无显著性（P均〉0.05）；PANSS总分显著下降，与NEF和RSS变化无显著相关性（P〉0．05）。结论：抗精神病药对精神分裂症患者探索性眼球活动障碍无明显改善作用。     

高频重复经颅磁刺激对精神分裂症阴性症状及认知 功能疗效的性别差异

目的 观察高频重复经颅磁刺激（rTMS）对精神分裂症患者阴性症状及认知功能疗效的 性别差异。方法 选取62例精神分裂症患者按照随机数字表法分为真刺激组和伪刺激组，刺激部位为 左前额叶背外侧皮质区（DLPFC），刺激参数为高频10 Hz，治疗4周，伪刺激组使用无实际刺激作用的专用 线圈。应用阳性与阴性症状评估量表（PANSS）评价患者的精神症状，精神分裂症简明认知功能成套测评 量表（BACS）评价患者的认知功能。结果 经过4周干预，真刺激组治疗后患者的阴性症状改善更明显， 且具有性别差异，女性经治疗后阴性症状改善更明显（P＜ 0.05）。认知量表评估结果显示，真刺激组治疗 后在言语流畅性、符号编码、数字序列、代币运动、语言记忆、伦敦塔及字词流畅性中得分较伪刺激组高， 且差异有统计学意义（P＜ 0.05），但无性别差异（P＞ 0.05）。结论 经rTMS治疗能改善患者的阴性症状及 认知功能，在改善阴性症状方面具有性别差异，女性效果更好。     

重复经颅磁刺激对首发精神分裂症患者血清脑源性神经营养因子的影响

目的：初步探讨高频重复经颅磁刺激（rTMS）对以阴性症状为主的首发精神分裂症患者血清脑源性神经营养因子（BDN F ）水平的影响。方法采用随机、双盲、对照研究,选取符合国际疾病分类第十版（ICD－10）中精神分裂症诊断标准的门诊患者70例。在常规抗精神病药物治疗的基础上,按照随机数字表法分为真刺激组（n ＝35）和伪刺激组（n ＝35）,并在基线时和治疗4周末时进行BDNF浓度测定和PANSS评估。结果治疗4周后,真刺激组的PANSS总分、阴性症状分和一般精神病理分均低于伪刺激组,BDNF浓度高于伪刺激组,差异均有统计学意义（P ＜0．05）。真刺激组BDNF浓度变化值与PANSS总分及各因子分变化值均无相关性（P ＞0．05）。两组不良反应差异无统计学意义（P ＞0．05）。结论 rTMS治疗可显著增加首发精神分裂症患者的血清BDNF浓度,但其浓度变化与临床症状（尤其是阴性症状）的改善无相关性。     

重复经颅磁刺激对精神分裂症患者事件相关电位N400及血清脑源性神经营养因子水平的影响

目的:探讨重复经颅磁刺激(rTMS)对精神分裂症患者(患者组)事件相关脑电位(ERP)N400及血清脑源性神经营养因子(BDNF)的影响。方法:70例接受利培酮治疗的精神分裂症患者以随机数字表法分组,给予真刺激组(n=35)左侧背外侧前额叶rTMS治疗,伪刺激组(n=35)相应部位伪刺激治疗。采用酶联夹心免疫吸附法测定基线时及治疗5周的血清BDNF浓度,进行事件相关电位检测N400的潜伏期及波幅;并给予阳性与阴性症状量表(PANSS)及阴性症状量表(SANS)评估。结果:与治疗前相比,患者PANSS的阴性症状分、一般精神病理症状分及SANS分均明显下降(P均0.01)。与治疗前相比,治疗5周末2组(真刺激组和伪刺激组)血清BDNF水平显著升高(P0.05)。BDNF水平变化值与PANSS总分及各因子分变化值均无统计学相关性(P0.05)。治疗后真刺激组在额区N400中同音异形异义波幅和异音异形异义波幅,较治疗前显著提高(P均0.05)。结论:rTMS治疗可提高精神分裂症患者血清BDNF浓度,并有可能改善患者的认知功能。     

探索性眼球活动与精神分裂症病情严重度的关系

目的通过与正常人群对照,研究探索性眼球活动（EEM）与精神分裂症病情的关系,并探索EEM是精神分裂症的特征性标志还是状态性标志。方法48名精神分裂症患者在入院初、治疗第4周末和第8周末,分别用三套EEM进行检查,并评定阳性与阴性症状量表（PANSS）。对42名正常对照者进行类似的三次EEM检查。比较两组PANSS得分以及EEM的凝视点数（NEF）、反应性探索（RSS）、判别值（D）。NEF、RSS、D越高,越正常。结果精神分裂症患者基线的NEF（27.2±7.0）低于正常对照组（30.9±4.9）,差异有统计学意义（t=-2.9,P=0.05）,基线RSS（4.7±1.9）也低于正常对照组（12.1±3.9）,差异有统计学意义（t=-11.7,P〈0.01）。患者组治疗第8周NEF（29.9±5.0）较基线增加（t=-2.2,P=0.03）,与对照组差异无统计学意义（t=-0.4,P=0.7）,而RSS（4.7±1.4）与基线相似（t=-0.2,P=0.9）,仍低于对照组（12.0±2.9）,差异有统计学意义意义（t=-8.3,P〈0.01）。结论EEM可作为精神分裂症的一种生物学标志,其NEF可能为状态性标志,而RSS则可能是特征性标志。     

精神分裂症患者探索性眼球运动的研究

目的:探讨精神分裂症患者探索性眼球运动(EEM)特点及与精神病性症状关系。方法:根据阳性与阴性症状量表(PANSS)评分将精神分裂症患者分为Ⅰ型组(33例)、Ⅱ型组(36例)和混合组(30例),分别进行EEM检查,比较各组眼球运动注视点(NEF)、眼球注视总距离(TESL)、眼球注视平均距离(MESL)、反应性探索分(RSS)、判别分析(D)值等;分析各指标与PANSS的关系。结果:3组间PANSS总分差异有统计学意义(F=3.429,P0.05),I型组PANSS总分明显低于Ⅱ型组及混合组(t=2.023,P0.05;t=5.962,P0.01);3组间EEM的D值差异有统计学意义(F=18.376,P0.01);I型组NEF明显高于混合组(t=2.026,P0.05),RSS明显高于Ⅱ型组(t=2.438,P0.05),D值明显低于Ⅱ型组(t=2.615,P0.01)。RSS与PANSS阴性症状分和阴性因子分呈负相关(r=-0.219,P0.05;r=-0.262,P0.01);D值与PANSS阳性因子分呈负相关(r=-0.203,P0.05),与PANSS阴性因子、认知因子以及阴性症状分呈正相关(r=0.223,P0.05;r=0.198,P0.05;r=0.265,P0.01)。结论:Ⅰ型及Ⅱ型精神分裂症患者有不同的EEM特征,其中RSS与精神分裂症阴性症状相关。     

重复经颅磁刺激对精神分裂症患者阴性症状和认知功能的疗效及安全性研究

目的:探讨重复经颅磁刺激(rTMS)改善精神分裂症患者阴性症状及认知功能的疗效及安全性。方法:入组2018年1月至2019年6月上海市民政第三精神卫生中心就诊的90例病程5年以下精神分裂症患者,给予利培酮药物维持治疗,后随机分为rTMS组(n=47)和伪刺激组(n=43),分别于治疗前、治疗4周末、治疗8周末对研究对象行阳性和阴性综合量表(PANSS)、神经心理状态评定量表(RBANS)测试,比较两组间各变量治疗前后的差异。结果:治疗4周后,rTMS组PANSS量表总分和阴性症状分均低于治疗前,且均低于伪刺激组,差异有统计学意义(P均<0.01)。对分组主效应方差分析发现rTMS组和伪刺激组在PANSS量表阴性分、总分2项和RBANS量表即刻记忆、视空间结构、语言功能、注意力、延迟记忆及RBANS总分6项有统计学差异(P均<0.01)。结论:rTMS治疗对精神分裂症患者阴性症状及认知功能具有改善作用,且疗效有持续效应,安全性好。     

精神分裂症患者认知功能与临床特征关系分析

目的探讨精神分裂症患者认知功能与临床特征的关系。方法采用事件相关电位(Event-related Potentials,ERP)P300和探究性眼动分析(exploratory eye movement,EEM)评估患者组及对照组的认知功能,同时采用阳性和阴性症状量表(PANSS)评定患者的精神症状。结果患者组P300潜伏期较对照组延长,波幅降低,EEM中NEF及RSS减少,D值增加,差异均具有统计学意义(P0.01)。患者组P300潜伏期与PANSS量表一般状况分、思维障碍评分及激活性评分均呈负相关(P0.05),波幅与PANSS量表阴性症状分及一般状况分均呈负相关(P0.01,P0.05);EEM中凝视点数(NEF)与阴性症状分呈负相关(P0.05),PANSS总分与反应性探索评分(RSS)呈负相关(P0.05),与D值呈正相关(P0.01)。结论 P300和EEM测定可作为精神分裂症认知功能诊断的参考指标之一;阴性症状的严重程度是影响精神分裂症患者认知功能的主要因素。     

TBS模式磁刺激对精神分裂症患者症状、认知和社会功能的影响

目的 探讨θ短阵快速脉冲（TBS）式重复经颅磁刺激（rTMS）治疗精神分裂症的疗效及其对患者认知功能和社会功能的影响。方法 精神分裂症患者120例随机分组为rTMS组与对照组,每组60例。rTMS组予以TBS式rTMS治疗,对照组予以伪刺激,连续进行4周,两组干预期间继续使用原抗精神病药物治疗。于治疗前和治疗4周末,进行总体精神症状[阳性与阴性症状量表（PANSS）]、阴性症状[阴性症状量表（SANS）]、认知功能[可重复成套神经心理状态测量（RBANS）]和社会功能[个人和社会功能量表（PSP）量表]的评估。结果 治疗4周末,r TMS组PANSS阴性因子及SANS评分显著低于对照组（P<0.05）,两组PANSS量表阳性因子、一般精神病理评分无统计学差异（P>0.05）。治疗4周末,r TMS组RBANS评分、PSP评分显著高于对照组（P<0.05）。两组不良反应有头痛、头晕等,均为一过性,两组不良反应发生率无统计学差异（P>0.05）。结论 TBS模式的r TMS治疗精神分裂症对患者阴性症状、认知功能和社会功能均有显著改善作用,且安全性良好。     

Impairment of exploratory eye movement in schizophrenia patients and their siblings

Aims: Previous family, adoption and twin studies of schizophrenia have shown that genetic factors contribute significantly to the risk of schizophrenia. The aim of the present study was therefore to investigate whether exploratory eye movement (EEM) abnormalities are related to the genetic markers linked to schizophrenia. Methods: Twenty‐three probands with schizophrenia, 23 of their healthy siblings (23 proband–sibling pairs), and 43 unrelated normal controls performed EEM tasks. Two parameters were measured: (i) number of eye fixations in responsive search (NEFRS) and (ii) responsive search score (RSS). Results: Abnormalities in NEFRS and RSS were more frequent in schizophrenia probands than in their unaffected siblings and in normal controls, and were also more frequent in the healthy siblings than in normal controls. Thus, the EEM test performances of the healthy siblings were intermediate between those of the probands with schizophrenia and those of normal controls. Conclusion: Abnormalities of the EEM test parameters may be related to the genetic etiology of schizophrenia. The use of EEM parameters as an endophenotype for schizophrenia may facilitate linkage and association studies in schizophrenia.     

Relationships between exploratory eye movement dysfunction and clinical symptoms in schizophrenia

Aim: Many psychophysiological tests have been widely researched in the search for a biological marker of schizophrenia. The exploratory eye movement (EEM) test involves the monitoring of eye movements while subjects freely view geometric figures. Suzuki et al. (2009) performed discriminant analysis between schizophrenia and non‐schizophrenia subjects using EEM test data; consequently, clinically diagnosed schizophrenia patients were identified as having schizophrenia with high probability (73.3%). The aim of the present study was to investigate the characteristics of schizophrenia patients who were identified as having schizophrenia on EEM discriminant analysis (SPDSE) or schizophrenia patients who were identified as not having schizophrenia on EEM discriminant analysis (SPDNSE). Methods: The data for the 251 schizophrenia subjects used in the previous discriminant‐analytic study were analyzed, and the demographic or symptomatic characteristics of SPDSE and SPDNSE were investigated. As for the symptomatic features, a factor analysis of the Brief Psychiatric Rating Scale (BPRS) rating from the schizophrenia subjects was carried out. Results: Five factors were found for schizophrenia symptoms: excitement/hostility; negative symptoms; depression/anxiety; positive symptoms; and disorganization. SPDSE had significantly higher factor scores for excitement/hostility, negative symptoms and disorganization than SPDNSE. Furthermore, the BPRS total score for the SPDSE was significantly higher than that for the SPDNSE. Conclusion: SPDSE may be a disease subtype of schizophrenia with severe symptoms related to excitement/hostility, negative symptoms and disorganization, and EEM parameters may detect this subtype. Therefore, the EEM test may be one of the contributors to the simplification of the heterogeneity of schizophrenia.     

Relationship between exploratory eye movement, P300, and reaction time in schizophrenia

Aims:  Exploratory eye movement (EEM), P300 and reaction time (RT) tests may relate to the important parts of information processing in the human brain. Therefore the aim of the present study was to compare EEM, P300 and RT test data in schizophrenic and normal control groups to investigate whether schizophrenic patients have information processing abnormalities. In addition, the potential correspondence between the three tests was examined in order to investigate the information processing dysfunctions seen in schizophrenic patients.
Methods:  The EEM, P300 and RT performances were recorded in 34 schizophrenic and 36 normal control subjects. Ten parameters were measured: four from the EEM test (number of eye fixations, total eye scanning length, cognitive search score and responsive search score [RSS]); two from the P300 test (amplitude and latency); and four from the RT test (simple reaction time, index of reaction time crossover [IRT-crossover], set index and coefficient of variation).
Results:  These parameters in the schizophrenic patients differed significantly from those in the control group. Additionally, there was a significant correlation between the RSS and the IRT-crossover in the schizophrenic patients.
Conclusion:  The present group comparisons (schizophrenia vs normal controls) are consistent with previous studies in that the abnormalities in EEM, P300 and RT tests in schizophrenic patients were able to be replicated. Moreover, based on the former psychological theory, it is reasonable to propose that the RSS is associated with the IRT-crossover. The present results may contribute to elucidation of the pathophysiological signature of schizophrenia.     

Transcranial magnetic stimulation for auditory hallucination in severe schizophrenia: Partial efficacy and acute elevation of sympathetic modulation

Repetitive transcranial magnetic stimulation (rTMS) has been reported to be an effective treatment for auditory hallucination (AH) in schizophrenia patients. The efficacy of rTMS and immediate changes in cardiac autonomic function (CAF) after rTMS in severe schizophrenia patients with AH (n = 8) were investigated. Three patients reported a ≥50% reduction of AH after rTMS. The ratio of low‐frequency power to high‐frequency power, an index of sympathetic modulation, increased significantly after rTMS. Further replication studies with larger sample sizes are indicated.     

Treatment of negative symptoms of schizophrenia using repetitive transcranial magnetic stimulation in a double-blind, randomized controlled study

OBJECTIVE: To verify whether high-frequency rTMS applied above the area of the left prefrontal cortex in 15 stimulation sessions with maximum stimulation intensity is able to modify negative symptoms of schizophrenia in a double-blind, randomized controlled study. METHODS: Twenty-two patients with schizophrenia stabilized on antipsychotic medication with prominent negative symptoms were included in the trial. They were divided into two groups: eleven were treated with effective rTMS and eleven with ineffective "sham" rTMS. The ineffectiveness of the sham rTMS was achieved through the stimulation coil position. Stimulation was applied to the left dorsolateral prefrontal cortex. The stimulation frequency was 10 Hz. Stimulation intensity was 110% of the motor threshold intensity. Each patient received 15 rTMS sessions on 15 consecutive working days. Each daily session consisted of 15 applications of 10-second duration and 30-second intervals between sequences. There were 1500 stimuli per session. RESULTS: During real rTMS treatment a statistically significant decrease of negative symptoms was found (approximately 29% reduction in the PANSS negative symptom subscale and 50% reduction in the SANS). No adverse events occurred during therapy except for a mild headaches. In sham rTMS treatment a decrease of negative symptoms was also identified, but to a lesser extent than in real rTMS (about 7% in negative subscale PANSS and 13% in SANS). The change in SANS achieved statistical significance. Mutual comparison revealed a greater decrease of negative symptoms in favor of real rTMS in contrast to sham rTMS. CONCLUSION: The augmentation of rTMS enabled patients to experience a significant decrease in the severity of the negative symptoms. Our results support the therapeutic potential of rTMS at higher frequency for negative symptoms of schizophrenia.     

重复经颅磁刺激治疗对精神分裂症认知功能影响的对照研究

目的观察和评价重复经颅磁刺激（rTMS）治疗对精神分裂症患者认知功能的影响。方法收集精神分裂症患者，并随机分为rTMS真刺激组和rTMS伪刺激组，进行4周治疗。应用注意网络测验（ANT）和威斯康星卡片分类测验（WCST），在rTMS治疗前后评估患者的注意和执行功能。共23例患者完成治疗，rTMS真刺激组12例，rTMS伪刺激组11例。结果rTMS干预前后，两组的注意网络测验各项指标没有显示明显差异（P〉0．05）。与rTMS干预前相比，rTMS干预结束时，rTMS真刺激组的WCST测试总时间缩短（干预前536S±217S，干预后405S±174S；t=2．69，P〈0．05），错误思考时间缩短（干预前335S±148S，干预后233S±128S；t=3．19，P〈0．01）和选择错误率降低（干预前58．1％±14．8％，干预后51．6％4-15．3％；t=2．16，P：0．05）；rTMS伪刺激组WCST测试的正确思考时间也有缩短（P〈0．01）。结论重复经颅磁刺激rTMS治疗没有引起精神分裂症患者的认知功能损害。同时，有改善患者部分认知功能损害倾向，值得进一步研究。     

Right prefrontal slow repetitive transcranial magnetic stimulation in schizophrenia: a double-blind sham-controlled pilot study.

BACKGROUND: The aim of this study was to extend our previous work on the therapeutic efficacy of repetitive transcranial magnetic stimulation (rTMS) in major depression to patients with schizophrenia. METHODS: Thirty-five inpatients with schizophrenia were randomly assigned to either right prefrontal rTMS or sham treatment and were rated before and after treatment for positive, negative, and depressive symptoms. RESULTS: Thirty-one subjects (rTMS = 16, sham = 15) completed a 2-week treatment protocol. No serious adverse effects were reported; however, rTMS was not superior to sham treatment on any of the clinical ratings. CONCLUSIONS: In contrast to our previous positive findings in major depression, right prefrontal slow rTMS does not appear to have a beneficial effect for actively psychotic patients with schizophrenia.     

Exploratory eye movement dysfunction as a discriminator for schizophrenia

In our previous studies, we identified that exploratory eye movement (EEM) dysfunction appears to be specific to schizophrenia. The availability of a biological marker specific to schizophrenia would be useful for clinical diagnosis of schizophrenia. Consequently, we performed the discriminant analysis between schizophrenics and non-schizophrenics on a large sample using the EEM test data and examined an application of the EEM for clinical diagnosis of schizophrenia. EEM performances were recorded in 251 schizophrenics and 389 non-schizophrenics (111 patients with mood disorders, 28 patients with neurotic disorders and 250 normal controls). The patients were recruited from eight university hospitals and three affiliated hospitals. For this study with a large sample, we developed a new digital computerized version of the EEM test, which automatically handled large amounts of data. We measured four parameters: number of eye fixations (NEF), total eye scanning length (TESL), mean eye scanning length (MESL) and responsive search score (RSS). These parameters of schizophrenics differed significantly from those of the other three groups. The stepwise regression analysis selected the TESL and the RSS as the valid parameters for discriminating between schizophrenics and non-schizophrenics. In the discriminant analysis using the RSS and TESL as prediction parameters, 184 of the 251 clinically diagnosed schizophrenics were discriminated as having schizophrenia (sensitivity 73.3%); and 308 of the 389 clinically diagnosed non-schizophrenic subjects were discriminated as non-schizophrenics (specificity 79.2%). Based on our findings we believe that the EEM measures may be useful for the clinical diagnosis of schizophrenia.     

女性精神分裂症患者探究性眼运动对照研究

目的：探讨女性精神分裂症患者探究性眼运动(EEM)异常的特点以及其与认知功能障碍之间的关系。方法：采用病例对照研究设计。测查26例首发女性精神分裂症患者和22例女性心境障碍患者以及25名正常女性对照的EEM，记录眼凝视点(NEF)和探索性反应分(RSS)。同时测查精神分裂症组的威斯康星卡片分类测验(WCST)，记录持续性错误数(Rpe)和完成第一个分类所需应答数(R1st)。结果：3组间NEF和RSS均存在非常显著差异。精神分裂症组分别与心境障碍组和正常对照组比较，NEF和RSS差异均有非常显著性。心境障碍组与正常对照组比较，RSS差异显著，而NEF则无显著差异。EEM与WCST之间无显著相关。结论：女性精神分裂症患者的眼运动异常与女性心境障碍和正常对照组比较均有显著性差异，RSS能更好地反映精神分裂症的病理特质。EEM与WCST反映了精神分裂症不同的病理维度。     

Repetitive transcranial magnetic stimulation for the treatment of negative symptoms in residual schizophrenia: rationale and design of a sham-controlled,randomized multicenter study

Current meta-analysis revealed small, but significant effects of repetitive transcranial magnetic stimulation (rTMS) on negative symptoms in patients with schizophrenia. There is a need for further controlled, multicenter trials to assess the clinical efficacy of rTMS on negative symptoms in schizophrenia in a larger sample of patients. The objective of this multicenter, randomized, sham-controlled, rater- and patient-blind clinical trial is to investigate the efficacy of 3-week 10-Hz high frequency rTMS add on to antipsychotic therapy, 15 sessions per 3 weeks, 1,000 stimuli per session, stimulation intensity 110% of the individual motor threshold) of the left dorsolateral prefrontal cortex for treating negative symptoms in schizophrenia, and to evaluate the effect during a 12 weeks of follow-up. The primary efficacy endpoint is a reduction of negative symptoms as assessed by the negative sum score of the positive and negative symptom score (PANSS). A sample size of 63 in each group will have 80% power to detect an effect size of 0.50. Data analysis will be based on the intention to treat population. The study will be conducted at three university hospitals in Germany. This study will provide information about the efficacy of rTMS in the treatment of negative symptoms. In addition to psychopathology, other outcome measures such as neurocognition, social functioning, quality of life and neurobiological parameters will be assessed to investigate basic mechanisms of rTMS in schizophrenia. Main limitations of the trial are the potential influence of antipsychotic dosage changes and the difficulty to ensure adequate blinding.