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.     

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.     

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。     

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。     

Neurophysiologic studies of sensory gating in schizophrenia: Comparison of auditory and visual responses

Gating of visual and auditory evoked responses was assessed in chronic schizophrenic patients treated with neuroleptic drugs. Middle latency components of the visual evoked response (N90-P130) were recorded at the occiput after flash stimulus. Possible inhibitory mechanisms of sensory gating were assessed in a conditioning-testing paradigm by measuring the change in amplitude of response to a second stimulus, relative to the response to the first stimulus. Simultaneous electrooculograms were recorded to detect contamination of recordings by eye movement. Neither schizophrenic patients nor normal control subjects demonstrated significant suppression of visual evoked responses in the conditioning-testing paradigm. These results differed markedly from similar measurements of a middle latency component of the auditory evoked response (P50) recorded using the same conditioning-testing paradigm in these subjects. Normal controls showed significant decrements of the P50 response to the second auditory stimulus (mean decrement over 80%), whereas schizophrenic patients failed to show a significant decrement (mean less than 40%). This finding for auditory evoked responses replicated previous studies of normal and schizophrenic subjects. Multiple conditioning stimuli were substituted for the single conditioning stimulus used previously in an attempt to enhance gating of auditory responses, but suppression of the P50 test response did not increase in either normal or schizophrenics.     

Varied effects of atypical neuroleptics on P50 auditory gating in schizophrenia patients

OBJECTIVE: Sensory gating deficits found in schizophrenia can be assessed by using a paired auditory stimulus paradigm to measure auditory evoked response. The ratio of the P50 response amplitude of the second or test stimulus to that of the first or conditioning stimulus is expressed as a percentage. Normal subjects generally suppress the second response and typically have ratios of less than 40%. Subjects with schizophrenia and half their first-degree relatives have deficits in sensory gating, with P50 ratios that are generally greater than 50%. Treatment with typical neuroleptics does not reverse this deficit. However, previous studies have shown that treatment with clozapine, an atypical neuroleptic, ameliorates this deficit in clinically responsive patients. This study sought to determine whether other atypical neuroleptics improve P50 ratios. METHOD: P50 evoked potential recordings were obtained from 132 patients with schizophrenia and 177 healthy comparison subjects. Eighty-eight patients were being treated with atypical neuroleptics (clozapine [N=26], olanzapine [N=31], risperidone [N=22], and quetiapine [N=9]). Thirty-four patients were taking typical neuroleptics, and 10 were unmedicated. RESULTS: Healthy subjects exhibited P50 suppression that was significantly better than the schizophrenia patients receiving typical neuroleptics (mean=19.8% [SD=21.0%] versus 110.1% [SD=87.9%]). Patients receiving atypical neuroleptics had a mean P50 ratio that fell between these two means (mean=70.4%, SD=53.7%). When patients treated with different atypical neuroleptics were compared, only the clozapine group had mean P50 ratios that were in the normal range. All other groups exhibited auditory P50 response inhibition that was significantly poorer than that of the healthy subjects. CONCLUSIONS: Improvement in P50 gating appears to be greatest in patients treated with clozapine.     

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.     

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。     

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.     

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.     

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.     

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.     

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.     

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.     

Functional imaging of the hemodynamic sensory gating response in schizophrenia

The cortical (auditory and prefrontal) and/or subcortical (thalamic and hippocampal) generators of abnormal electrophysiological responses during sensory gating remain actively debated in the schizophrenia literature. Functional magnetic resonance imaging has the spatial resolution for disambiguating deep or simultaneous sources but has been relatively under‐utilized to investigate generators of the gating response. Thirty patients with chronic schizophrenia (SP) and 30 matched controls participated in the current experiment. Hemodynamic response functions (HRFs) for single (S1) and pairs (S1 + S2) of identical (“gating‐out” redundant information) or nonidentical (“gating‐in” novel information) tones were generated through deconvolution. Increased or prolonged activation for patients in conjunction with deactivation for controls was observed within auditory cortex, prefrontal cortex, and thalamus in response to single tones during the late hemodynamic response, and these group differences were not associated with clinical or cognitive symptomatology. Although patient hyperactivation to paired‐tones conditions was present in several regions of interest, the effects were not statistically significant for either the gating‐out or gating‐in conditions. Finally, abnormalities in the postundershoot of the auditory HRF were also observed for both single and paired‐tones conditions in patients. In conclusion, the amalgamation of the entire electrophysiological response to both S1 and S2 stimuli may limit hemodynamic sensitivity to paired tones during sensory gating, which may be more readily overcome by paradigms that use multiple stimuli rather than pairs. Patient hyperactivation following single tones is suggestive of deficits in basic inhibition, neurovascular abnormalities, or a combination of both factors. Hum Brain Mapp 34:2302–2312, 2013. © 2012 Wiley Periodicals, Inc.     

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.     

感觉门控P50对精神分裂症诊断价值的初步探讨

目的探讨听觉感觉门控电位P50对精神分裂症的诊断价值。方法共入组56例患者（患者组）和22名正常对照（对照组）。患者符合美国精神障碍诊断与统计手册第4版（DSM-IV）的精神分裂症诊断标准。采用听觉条件（S1）-测试刺激（S2）范式检测P50电位,计算S2与S1波幅的比值即P50比值。使用阳性与阴性综合征量表（PANSS）评定患者的精神症状。结果患者组P50比值（89.7±57.1）高于对照组（47.2±26.4）,差异有统计学意义（t=2.97,P〈0.01）。患者组P50比值与PANSS总分和病程之间无相关性（r值分别为0.123、0.119）。P50比值的ROC曲线下面积（AUC）=0.743。以34为临界值,灵敏度和特异度分别为96.4%和45.5%;以50为临界值,灵敏度和特异度分别为80.4%和50.0%。结论精神分裂症患者存在感觉门控障碍,P50比值与其病情和病程无关,P50比值在精神分裂症有中等诊断价值。     

Improved p50 auditory gating with ondansetron in medicated schizophrenia patients

OBJECTIVE: Most schizophrenia patients have a deficit in auditory sensory gating, which appears to be mediated by the alpha-7 nicotinic receptor, that is not improved with conventional antipsychotic treatment. This study examined the effects of ondansetron, a highly selective 5-HT3 antagonist, on the P50 auditory evoked potential. METHOD: Eight medicated outpatients with schizophrenia were given either ondansetron (16 mg) or placebo in a double-blind, placebo-controlled design. Evoked potentials were recorded at baseline and 1 hour, 2 hours, and 3 hours after receipt of drug. RESULTS: There was a highly significant improvement in P50 gating after ondansetron treatment. The maximal treatment difference was at 2 hours posttreatment (ondansetron: mean=41.4%, SD=39.7%; placebo: mean=80.2%, SD=21.3%). CONCLUSIONS: Ondansetron significantly enhanced P50 auditory gating in schizophrenia patients treated with typical antipsychotics.