Olanzapine effects on auditory sensory gating in schizophrenia

OBJECTIVE: New-generation antipsychotics have been proposed to normalize the P50 sensory gating index in patients with schizophrenia. In the context of a double-blind comparison of olanzapine and haloperidol, the authors examined the effect of olanzapine on P50 suppression. METHOD: P50 measurements were obtained at baseline while patients were being treated with fluphenazine and after 12 weeks of double-blind treatment with either olanzapine (N=12) or haloperidol (N=12). RESULTS: There were no treatment group differences in P50 amplitude, latency, or sensory gating ratio. CONCLUSIONS: These results suggest that there is not a significant differential effect of olanzapine and haloperidol on the P50 sensory gating index in schizophrenia.     

Neurobiological studies of sensory gating in schizophrenia

The sensory disturbance in schizophrenia is often described as an inability to filter out extraneous noise from meaningful sensory inputs. The neurobiological basis of this inability to filter has been examined using auditory evoked potentials, which are computerized averages of the brain's electrical response to sound. The sounds are presented in pairs to test the ability of the brain to inhibit, or gate, its response to a repeated stimulus. Schizophrenic patients lack the ability to gate the neuronal response shown by a particular wave, the P50 wave. The measurement of this deficit in human subjects and the exploration of its neurobiology in animals has produced evidence about several issues in the pathophysiology of schizophrenia: (1) the role of dopamine in improvement of sensory function in schizophrenic patients treated with neuroleptic drugs, (2) the interaction between familial or genetic deficits in sensory functioning in schizophrenic patients and possible abnormalities in dopamine metabolism, and (3) a mechanism by which noradrenergic hyperactivity in mania and other psychiatric illnesses might mimic some pathophysiological deficits in schizophrenia.     

Lateralization of auditory sensory gating and neuropsychological dysfunction in schizophrenia

OBJECTIVE: Sensory gating assessed via EEG in a paired-click paradigm has often served as a neurophysiological metric of attentional function in schizophrenia. However, the standard EEG measure of sensory gating using the P50 component at electrode Cz does not foster differential assessment of left and right hemisphere contributions. Magnetoencephalography (MEG) is complementary to EEG, and its analogous M50 component may be better suited for localization and analysis of such lateralized cortical generators. The authors hypothesized that 1) auditory gating would be evident in M50 sources in superior temporal gyrus, demonstrating ratios similar to P50; 2) M50 would resemble P50 in distinguishing gating in comparison subjects and patients with schizophrenia, but M50 would show lateralization of the gating deficit; and 3) P50 and M50 sensory gating ratios would predict neuropsychological measures in patients and comparison subjects, with the MEG identification of left and right hemisphere sources allowing for the evaluation of lateralization in brain-behavior relationships. METHOD: Event-related EEG and MEG recordings were simultaneously obtained from 20 patients with schizophrenia and 15 comparison subjects. P50 amplitudes, M50 dipole source strengths, and P50 and M50 gating ratios were compared and assessed with respect to scores on neuropsychological performance measures. RESULTS: M50 dipoles localizing to superior temporal gyrus demonstrated gating similar to that of P50. As expected, patients demonstrated less P50 gating than did comparison subjects. Left (but not right) hemisphere M50 gating 1) correlated with EEG gating, 2) differentiated patients and comparison subjects, and 3) correlated with neuropsychological measures of sustained attention and working memory. CONCLUSIONS: Converging evidence from EEG, MEG, and neuropsychological measures points to left hemisphere dysfunction as strongly related to the well-established sensory gating deficit in schizophrenia.     

难治性精神分裂症患者治疗前后感觉门控P50的变化

目的探讨难治性精神分裂症患者治疗前后感觉门控P50的变化特点。方法采用配对听觉条件（s1）、测试（S2）刺激范式,对36例难治性精神分裂症患者进行听觉诱发电位P50检测,测量P50的潜伏期、波幅,并与32例健康被试（对照组）进行比较。结果（1）与对照组比较,患者组S1潜伏期显著延迟,波幅显著降低（P〈0．05）;S2潜伏期和波幅差异无统计学意义（P〉0．05）;s2／s1显著升高（P〈0．05）。（2）与治疗前（8Z．21±8．59）比较,患者组治疗6周后PANSS得分（37．00±6．86）显著降低（t=16．81,P〈0．05）。（3）与治疗前比较,治疗后S1潜伏期显著缩短,波幅显著升高（P〈0．05）,S2潜伏期、波幅差异均无统计学意义（P〉0．05）,S2／S1显著降低（P〈0．05）;与对照组比较,$2／S1仍显著偏高（P〈0．05）。结论难治性精神分裂症患者感觉门控抑制能力有缺陷,提示P50比率可能是难治性精神分裂患者的一个潜在的素质性生物学标记。     

氯氮平与氯丙嗪对精神分裂症患者听觉感觉门控的比较：前瞻性病例对照研究

背景精神分裂症患者听觉感觉门控（以下简称感觉门控）P50受损,各种抗精神病药物对该P50的作用仍有争议。假设第二代抗精神病药物氯氮平治疗的精神分裂症患者比氯丙嗪治疗患者的感觉门控P50的改善明显。方法前瞻性对照研究纳入刚住院的精神分裂症患者,由治疗医师决定氯氮平治疗者26例（研究组）,氯丙嗪治疗者30例（对照组）。氯氮平组有23例完成8周研究纳入分析,氯丙嗪组为20例。检测P50的方法为双短声刺激[听觉条件（S1）-测试刺激（S2）范式],检测时点为基线、治疗第4周和第8周。临床症状用阳性与阴性综合征量表（Positive and Negative Syndrome Scale,PANSS）评定。结果两组年龄、性别、教育程度、病程和基线PANSS总分差异均无统计学意义。氯丙嗪组平均（标准差）治疗剂量为389（96）mg/d,氯氮平组为345（117）mg/d。重复测量的方差分析显示,氯氮平组颅顶中央脑区（central zone,Cz）P50比值（S2/S1）的下降比氯丙嗪组明显[基线为108%比106%,第4周94%比102%,第8周84%比95%,F=4.91,P=0.029],而S1和S2波幅差异无统计学意义。两组间S1和S2的波幅无明显差异。氯氮平组治疗后P50比值较治疗前下降（F=4.39,P=0.014）,氯丙嗪组治疗前后P50比值没有明显变化。结论氯氮平治疗可以减轻精神分裂症患者感觉门控的受损程度;与氯丙嗪治疗相比,氯氮平治疗者的改善程度较明显。     

Cocaine-dependence and cocaine-induced paranoia and mid-latency auditory evoked responses and sensory gating

Cocaine-dependence has been shown to affect the amplitudes of the P50 mid-latency auditory evoked response (MLAER) as well as P50 sensory gating. The effects on subsequent MLAERs (N100 and P200) have not been examined. The objective of the current study was to further assess the effects of chronic cocaine use on the P50, N100, and P200 components. Thirty-four, at least three weeks abstinent, cocaine-dependent individuals and 34 age and gender matched healthy controls were examined. The amplitudes, latencies and gating measures were calculated and compared between the groups. The N100 and P200 were significantly smaller in patients as compared to control subjects. Sensory gating of the P50, the N100, and the P200 were deficient in cocaine-dependent subjects. Latencies of all measured components were prolonged in subjects who reported developing paranoia while intoxicated. Finally, a positive correlation was found between length of abstinence and evoked response amplitudes. We conclude that the effects of cocaine on sensory gating extend beyond the P50 to the N100 and the P200 components. The data also suggest that prolonged latency of the evoked potentials may be a correlate of cocaine-induced psychosis. Finally, the data suggest that some recovery of amplitude and gating occurs with abstinence.     

伴有凶杀行为精神分裂症患者听觉感觉门控P50的随访研究

目的 随访分析伴有凶杀行为的精神分裂症患者听觉感觉门控电位P50的变化.方法 采用条件-测试刺激模式,对25例伴有凶杀行为的精神分裂症患者(患者组)和27名正常对照者(对照组)进行P50检测和比较,经过抗精神病药物治疗3个月后,有11例患者完成了P50随访,同时应用阳性和阴性症状量表(PANSS)评定患者的精神症状.结果 ①与对照组相比,患者组在入组未用药时和随访3个月时的S2-P50波幅均较高(P<0.01),S2/S1比值均较大(P<0.01),S1-S2差值(P<0.05)和100(1-S2/S1)值均较小(P<0.01).患者组P50波幅、潜伏期和P50抑制指标在入组时和3个月时的差异均无统计学意义(P>0.05).②与入组时相比,3个月时患者组PANSS总分、阳性量表分、一般精神病理量表分以及反应缺乏、思维障碍、激活性、偏执、抑郁、攻击等6个症状群得分降低(P<0.05).③患者组在入组时和3个月时S2/S1比值、S1-S2差值和100(1-S2/S1)等P50抑制指标与病程、PANSS各指标均无相关(P>0.05).结论 伴有凶杀行为的精神分裂症患者感觉门控存在异常,且P50抑制指标可能是该人群的素质指标.     

Genetic and environmental influences on sensory gating of mid-latency auditory evoked responses: a twin study

A deficit in sensory gating measured by the suppression of P50 auditory event-related potential (ERP) has been implicated in the biological bases of schizophrenia and some other psychiatric disorders and proposed as a candidate endophenotype for genetic studies. More recently, it has been shown that gating deficits in schizophrenics extend to ERP components reflecting early attentive processing (the N1/P2 complex). However, evidence for heritability of sensory gating in the general population is very limited. Heritability of P50, N1, and P2 amplitudes and gating was estimated in 54 monozygotic and 55 dizygotic twin pairs using a dual-click auditory paradigm. Genetic model-fitting analysis showed high heritability of peak amplitudes of P50, N1, and P2 waves. Genetic influences on P50 gating (S2/S1) were modest, while heritability of N1 and P2 gating was high and significant. The alternative gating measure (S1-S2 difference) showed significant heritability for all three ERP components. Weak genetic influences on P50 gating ratio can be related to its poor test-retest reliability demonstrated in previous studies. These results suggest that gating measures derived from the N1/P2 wave complex may be useful endophenotypes for population-based genetic studies of the sensory gating function and its impairments in psychopathology.     

Comparison of four components of sensory gating in schizophrenia and normal subjects: a preliminary report

Dysfunction of sensory gating has been implicated in the pathophysiology of schizophrenia. The goal of this study was to provide evidence that sensory gating dysfunction in schizophrenia patients is a compounded problem with difficulty in filtering out irrelevant input and filtering in relevant input at both an early-preattentive stage and a later, early-attentive stage of information processing. Four components of sensory gating were examined in 12 medicated, stable schizophrenia patients and 12 age- and sex-matched normal control subjects. Evoked potential paradigms designed to examine the effects of stimulus repetition and stimulus change were utilized. Attenuation of the amplitude of the P50 and the N100 evoked potentials with stimulus repetition was significantly decreased in schizophrenia patients as compared to normal control subjects. The presentation of deviant stimuli caused the degree of attenuation to decrease in normal subjects. This effect was much decreased (and at times reversed) in schizophrenia subjects. These data suggest that schizophrenia patients have difficulty inhibiting incoming, irrelevant stimuli and responding to incoming, significant input as measured by preattentive EPs (P50). The data also suggest that similar abnormalities can be demonstrated at a slightly later phase of information processing (i.e. early-attentive phase) using the N100 EP.     

Investigation of auditory P50 sensory gating with sexual visual stimuli in patients with vaginismus

ObjectivesThe aim of the study was to investigate sensory information processing induced by visual sexual stimuli and to assess its relationship with sexual behaviors and symptoms in patients with vaginismus.MethodsTwenty-one patients with vaginismus and 20 controls were included in the study. The sociodemographic information and sexual life history of the patients with vaginismus and controls were examined and electrophysiological measurements related to auditory P50 sensory gating were obtained using a double click paradigm during by sexual/horror visual stimulation, which was thought to be related to the pathophysiology of the disease.ResultsP50 suppression ratios during visual sexual stimuli were lower in vaginismus group compared to the control group. There was no difference in P50 suppression ratios during visual horror stimuli when the two groups were compared. The P50 suppression of the vaginismus group with visual sexual stimuli was found to be lower than P50 suppression with visual horror stimuli. A positive moderate correlation was found between the duration of foreplay and P50 suppression ratio during visual sexual stimuli in vaginismus group.ConclusionOur study revealed that patients with vaginismus had sensory gating impairment during visual sexual stimuli. Increase in the duration of foreplay in vaginismus patients may improve sensory gating impairment by affecting sensory gating functions.     

The genetics of sensory gating deficits in schizophrenia

Sensory gating abnormalities are an early clinical symptom of schizophrenia, and are characterized by a decrease in the brain’s normal ability to inhibit the response to unimportant stimuli. Patients appear hypervigilant and have difficulty focusing their attention. A neurobiologic mechanism involved in these difficulties is nicotinic cholinergic modulation of inhibitory neuronal activity in the hippocampus. One measure of sensory gating abnormalities, diminished inhibition of the P50 evoked response to repeated auditory stimuli, has been linked to the chromosome 15q14 locus of the alpha-7-nicotinic receptor gene. This site is one of several that have shown evidence for linkage to schizophrenia, as well as to bipolar disorder, across several studies. Polymorphisms in the core promoter of the gene are associated with schizophrenia and also with diminished inhibition of the P50 response. These genetic data may identify a new pathophysiologic target for drug discovery.     

首发精神分裂症听觉感觉门控异常的功能磁共振研究

目的 探讨首发精神分裂症患者听觉门控异常与脑功能异常激活之间的关系.方法 11例首发精神分裂症患者及11名年龄、性别、受教育程度相匹配的正常对照进行脑功能磁共振成像,实验采用多声音刺激和单声音刺激比较的范式,以多声音刺激减单声音刺激的对比探测感觉门控的脑激活效应.以SPM2处理脑影像数据,使用两样本t检验比较两组间听觉感觉门控脑功能激活的差异.结果 患者组的感觉门控脑激活在右侧海马(x ＝ 24,y ＝ -28,z ＝ -8,体素集合数＝ 16)、右侧丘脑(x ＝ 8,y ＝ -4,z ＝ 4,体素集合数＝ 22)低于正常对照组(t ＝ 3.57,P ＝ 0.001;t ＝ 3.38,P ＝ 0.001).结论 首发精神分裂症患者的听觉门控异常可能与海马、丘脑等脑区的功能激活异常有关.     

P50 sensory gating disorders of auditory evoked potentials (AEP) in persons with schizophrenia

The paper presents a review of recent data on research and clinical significance of gating of the P50 component of the auditory evoked potentials (AEP). Information filters are a necessary element for the proper functioning of the brain. It appears as though they have an important role in the information-transfer mechanisms. Neurophysiologically, they appear hypothetically in the sensory gating of the P50 component of the AEP. Schizophrenic patients and their first degree relatives do not have proper sensory gating of the P50 AEP. This suggests that there is a common biological base for these disorders. Some clinical aspects of the schizophrenic psychoses can be linked to this disordered gating. There are also notes which show the contrary. Currently we do not know whether the improper sensory gating of the P50 AEP is a trait endophenotypically linked to schizophrenia, or only something that partially explains the pathophysiology of the illness--especially since the described phenomena may be evoked in healthy persons.     

精神分裂症首次发病患者治疗前后感觉门控功能的动态观察

目的探讨精神分裂症首次发病(以下简称首发)患者治疗前后的听觉诱发电位P50变异的意义。方法应用美国Bravo脑电生理仪,采用条件刺激(S1)-测试刺激(S2)模式,分别于治疗前(66例)、治疗第5周(42例)和第12周(32例)对首发精神分裂症患者(患者组)进行P50检测,同时用阳性和阴性症状量表(PANSS)评定患者的临床症状;并以正常人(对照组,92名)的P50做比较。结果(1)治疗前,患者组的S1-P50波幅[(3±2)μV]低于对照组[(6±3)μV],S2-P50波幅[(4±2)μV]高于对照组[(2±1)μV],均P<0.01;患者组S2/S1比值[(81±40)%]高于对照组[(42±21)%],S1-S2波幅[(2±1)μV]低于对照组[(3±2)μV],100(1-S2/S1)值(19±17)低于对照组(58±21),差异均有统计学意义(P<0.05~0.01)。(2)患者组的S2/S1、S1-S2和100(1-S2/S1)与PANSS评分无相关性(P>0.05)。(3)与治疗前比较,患者组在治疗第5周末及第12周末P50的各项指标均无明显改变(均P>0.05)。结论P50变异可能是精神分裂症患者的早期改变,具有一定的属性标志特性,值得进一步随访研究。     

Attention modulates topology and dynamics of auditory sensory gating

This work challenges the widely accepted model of sensory gating as a preattention inhibitory process by investigating whether attention directed at the second tone (S2) within a paired‐click paradigm could affect gating at the cortical level. We utilized magnetoencephalography, magnetic resonance imaging and spatio‐temporal source localization to compare the cortical dynamics underlying gating responses across two conditions (passive and attention) in 19 healthy subjects. Source localization results reaffirmed the existence of a fast processing pathway between the prefrontal cortex (PFC) and bilateral superior temporal gyri (STG) that underlies the auditory gating process. STG source dynamics comprised two gating sub‐components, Mb1 and Mb2, both of which showed significant gating suppression (>51%). The attention directed to the S2 tone changed the gating network topology by switching the prefrontal generator from a dorsolateral location, which was active in the passive condition (18/19), to a medial location, active in the attention condition (19/19). Enhanced responses to the attended stimulus caused a significant reduction in gating suppression in both STG gating components (>50%). Our results demonstrate that attention not only modulates sensory gating dynamics, but also exerts topological rerouting of information processing within the PFC. The present data, suggesting that the cortical levels of early sensory processing are subject to top‐down influences, change the current view of gating as a purely automatic bottom‐up process.     

Deficits in sensory gating in schizophrenic patients and their relatives. Evidence obtained with auditory evoked responses

A deficit in inhibitory gating of auditory evoked responses was examined in 15 schizophrenic patients, their first-degree relatives, and normal subjects, using a conditioning-testing paradigm with the P50 wave of the auditory evoked response. This paradigm demonstrates inhibition by presenting paired stimuli to the subject; the P50 wave evoked by the second stimulus is reduced because of inhibitory mechanisms activated during the response to the first stimulus. In normal subjects, the mean amplitude of the second P50 response was reduced to less than 20%. In the schizophrenics, the mean amplitude of the second response was more than 85% of the first, a result that replicates our previous finding of a deficit in inhibition in schizophrenia. Approximately half the first-degree relatives, generally including at least one parent, had a similar deficit. Presence of this deficit in the parents was associated with a family history of schizophrenia. Family members with this deficit also had significantly higher scores on several scales of the Minnesota Multiphasic Personality Inventory than did family members without the deficit. Despite the deficit in inhibition, other characteristics of the P50 wave were normal in the relatives, in contrast to unmedicated schizophrenics, who showed additional abnormalities in wave latency and amplitude.     

Memory impairment and auditory evoked potential gating deficit in schizophrenia

Impaired sensory gating and memory function were reported in a study of 10 schizophrenic patients and 10 age- and sex-matched normal subjects. The P50 component of the auditory evoked potential was used as an index of gating. Explicit memory was tested with the Wechsler Memory Scale and implicit memory by artificial grammar learning. The schizophrenic patients showed deficits in both verbal paired associate and visual reproduction tasks. They demonstrated impaired implicit learning in color patterns but not letter strings. They also showed impaired P50 sensory gating. Three-dimensional brain mapping revealed a differential distribution of brain potentials in the processing of S1 and S2 at either P50 or N100 in both groups. However, the group difference was not statistically confirmed. In the controls, both implicit letter-string learning and explicit verbal paired associates were positively correlated with N100 gating, suggesting an association of the early attentive component with lexicons. In the schizophrenic patients, color-pattern implicit learning was positively correlated with P50 gating. The modality-specific impairment of implicit learning in schizophrenia may reflect a failure of adaptive filtering on the flooding input from color patterns.     

Gamma/beta oscillation and sensory gating deficit in schizophrenia

Sensory gating can be measured by the suppression of auditory evoked potentials in a paired-click paradigm. The normal gating of the P50 response to the second stimulus (S2) is impaired in many schizophrenic patients. Various in vitro and in vivo evoked potential paradigms have shown that a stimulus evokes early gamma frequency oscillation, which is followed by beta frequency oscillation. The gamma-to-beta shift in response to the first stimulus (SI) in the paired-click paradigm may contain critical electrophysiological signals that modulate the S2 suppression. The results of the present study showed that post-SI beta frequency response was inversely correlated to the S2 P50 response in patients with schizophrenia.     

M50 sensory gating predicts negative symptoms in schizophrenia

Impaired auditory sensory gating is considered characteristic of schizophrenia and a marker of the information processing deficit inherent to that disorder. Predominance of negative symptoms also reflects the degree of deficit in schizophrenia and is associated with poorer pre-morbid functioning, lower IQ, and poorer outcomes. However, a consistent relationship between auditory sensory gating and negative symptoms in schizophrenia has yet to be demonstrated. The absence of such a finding is surprising, since both impaired auditory gating and negative symptoms have been linked with impaired fronto-temporal cortical function. The present study measured auditory gating using the P50 event related potential (ERP) in a paired-click paradigm and capitalized on the relative localization advantage of magnetoencephalography (MEG) to assess auditory sensory gating in terms of the event related field (ERF) M50 source dipoles on bilateral superior temporal gyrus (STG). The primary hypothesis was that there would be a positive correlation between lateralized M50 auditory sensory gating measures and negative symptoms in patients with schizophrenia. A standard paired-click paradigm was used during simultaneous EEG and MEG data collection to determine S2/S1 sensory gating ratios in a group of 20 patients for both neuroimaging techniques. Participants were administered the Schedule for the Assessment of Negative Symptoms (SANS), the Positive and Negative Symptom Scale (PANSS), and the Calgary Depression Scale for Schizophrenia. Consistent with previous reports, there was no relationship between ERP P50 sensory gating and negative symptoms. However, right (not left) hemisphere ERF M50 sensory gating ratio was significantly and positively correlated with negative symptoms. This finding is compatible with information processing theories of negative symptoms and with more recent findings of fronto-temporal abnormality in patients with predominantly negative symptoms.