Inhibitory gating of an evoked response to repeated auditory stimuli in schizophrenic and normal subjects. Human recordings, computer simulation, and an animal model. Arch Gen Psychiatry

Department of Psychiatry, Denver Veterans Administration Medical Center, Colo, USA.
Archives of General Psychiatry (Impact Factor: 14.48). 01/1997; 53(12):1114-21.
Source: PubMed


Altered sensory response is a prominent feature of schizophrenia. Inhibitory gatting mechanisms, shown by diminished P50 evoked responses to repeated auditory stimuli, seem to be deficient in schizophrenic persons. These inhibitory mechanisms usually are studied by averaging the electroencephalographic responses to many presentations of pairs of stimuli. Although averaging increases signal-to-noise ratio, it may obscure trial-to-trial differences. We compared differences between schizophrenic and normal persons in single trials and averages of P50 response.
Recordings from 10 schizophrenic patients and 10 normal subjects were analyzed using conventional averaging and single-trial measurements. A computer simulation of both methods examined their ability to extract evoked responses from background activity. Related single-neuron activity in the hippocampus in an animal model also was studied, because neuronal action potentials can be reliably identified in single trials.
Averaged evoked potentials showed significant suppression of the P50 response to the second stimulus of the pair in normal patients, but not in schizophrenic patients. Single-trial analysis did not detect a response above background activity. Computer simulations gave similar results, suggesting that failure to detect suppression in single trials comes from inadequate differentiation of signal from noise. Recordings in animals confirmed almost complete suppression of the response of hippocampal pyramidal neurons to the second stimulus.
The normal inhibition of response to repeated auditory stimuli seems to be compromised in schizophrenia. This loss of inhibitory gating could reflect a physiological deficit of hippocampal interneurons that is consonant with other evidence for interneuron pathologic defects in schizophrenia.

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    • "According to the II hypothesis, the ACx neuronal population generating the P50 response also engages inhibitory inputs which, in a feedback loop with these ACx neurons, act to inhibit the responding of ACx to the subsequent arrival of an identical auditory stimulus. These inhibitory inputs were originally thought to originate in the CA3 hippocampal region (Freedman et al., 1996; Hershman et al., 1995) however there is also evidence implicating frontal lobe (Knight et al., 1999) and reticular activating system (Erwin and Buchwald, 1986) involvement in this purported inhibitory process. The II process is thought to be long lasting (N500 ms; (Miller and Freedman, 1995)). "
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    ABSTRACT: P50 suppression refers to the amplitude-reduction of the P50 event related potential to the second (S2) relative to the first (S1) of identical auditory stimuli presented 500 ms apart. Theory suggests that refractory periods (RP) and/or inhibitory inputs (II) underlie P50 suppression. The present study manipulated interval between stimulus pairs (IPI: 2, 8 s) and direction of participants' attention (Attention, Non-Attention) in order to determine which theory best explains P50 suppression. The rationale is that: 1/ RP and II predict opposite effects of manipulating the functionality of the mechanism responsible for S2P50 suppression (e.g. reducing function would increase S2P50 according to the II and decrease S2P50 according to the RP hypothesis); 2/ IPI2 (relative to IPI8) will reduce functionality of the mechanism responsible for S2P50 suppression, as it results in less recovery of (and a greater challenge to) that mechanism - RP would thus predict reduced S2P50, whereas II would predict enhanced S2P50 amplitude; and 3/ Where the mechanism responsible for S2P50 suppression is challenged (i.e. at IPI2, due to insufficient recovery), Attention (relative to Non-Attention) will enhance functionality of this mechanism - RP would thus predict increased S2P50, whereas II would predict reduced S2P50 amplitude. In the Non-Attention paradigm, reducing IPI from 8 to 2 s tended to increase S2P50 amplitude (and consequently impaired P50 suppression), and in the 2 s IPI paradigm, directing attention towards the stimuli reduced S2P50 amplitude (and improved P50 suppression), with both effects supporting the II hypothesis only. Copyright © 2015. Published by Elsevier B.V.
    International journal of psychophysiology: official journal of the International Organization of Psychophysiology 04/2015; 96(3). DOI:10.1016/j.ijpsycho.2015.04.011 · 2.88 Impact Factor
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    • "Therefore, these results should be taken as preliminary. Our findings are in line with previous reports of diminished P50 suppression in the clinical high-risk sample (Myles-Worsley et al., 2004; Brockhaus-Dumke et al., 2008), first episode psychosis (Myles-Worsley et al., 2004; Brockhaus-Dumke et al., 2008) and in schizophrenia and psychotic bipolar disorder (Freedman et al., 1996; Olincy et al., 2000; Olincy and Martin, 2005; Schulze et al., 2007; Shaikh et al., 2010) and support the suggestion that P50 gating deficits are not specific to schizophrenia or bipolar disorder, but might be associated with psychosis in general. A study by Brockhaus-Dumke et al. (2008) included a considerable number of subjects in different stages of schizophrenia and at-risk states including 18 at-risk subjects who did not develop a full psychosis within the follow-up period of two years, 21 truly prodromal subjects who developed frank psychosis within the follow-up period, 46 antipsychoticnaïve subjects with first-episode schizophrenia, 20 antipsychotic-free subjects with chronic schizophrenia, and 46 healthy control subjects to assess P50 suppression. "
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    ABSTRACT: Background: Individuals with an "Attenuated Psychosis Syndrome" (APS) have a 20-40% chance of developing a psychotic disorder within two years; however it is difficult to predict which of them will become ill on the basis of their clinical symptoms alone. We examined whether P50 gating deficits could help to discriminate individuals with APS and also those who are particularly likely to make a transition to psychosis. Method: 36 cases meeting PACE (Personal Assessment and Crisis Evaluation) criteria for the APS, all free of antipsychotics, and 60 controls performed an auditory conditioning-testing experiment while their electroencephalogram was recorded. The P50 ratio and its C-T difference were compared between groups. Subjects received follow-up for up to 2 years to determine their clinical outcome. Results: The P50 ratio was significantly higher and C-T difference lower in the APS group compared to controls. Of the individuals with APS who completed the follow-up (n=36), nine (25%) developed psychosis. P50 ratio and the C-T difference did not significantly differ between those individuals who developed psychosis and those who did not within the APS group. Conclusion: P50 deficits appear to be associated with the pre-clinical phase of psychosis. However, due to the limitations of the study and its sample size, replication in an independent cohort is necessary, to clarify the role of P50 deficits in illness progression and whether this inexpensive and non-invasive EEG marker could be of clinical value in the prediction of psychosis outcomes amongst populations at risk.
    Schizophrenia Research 12/2014; 161(2-3). DOI:10.1016/j.schres.2014.12.021 · 3.92 Impact Factor
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    • "The data presented above strongly suggest that patients with schizophrenia manifest typical disturbances of habituation mechanisms linked to information overload, leading to disruption of information processing.90–94 In this context, many studies have shown that the P50 sensory gating ratio in a paired click task is higher in patients with schizophrenia than in healthy controls, indicating more effective sensory gating processes.37,47,61,88,89,95–113 "
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    ABSTRACT: Sensory gating disturbances in schizophrenia are often described as an inability to filter redundant sensory stimuli that typically manifest as inability to gate neuronal responses related to the P50 wave, characterizing a decreased ability of the brain to inhibit various responses to insignificant stimuli. It implicates various deficits of perceptual and attentional functions, and this inability to inhibit, or "gate", irrelevant sensory inputs leads to sensory and information overload that also may result in neuronal hyperexcitability related to disturbances of habituation mechanisms. These findings seem to be particularly important in the context of modern electrophysiological and neuroimaging data suggesting that the filtering deficits in schizophrenia are likely related to deficits in the integrity of connections between various brain areas. As a consequence, this brain disintegration produces disconnection of information, disrupted binding, and disintegration of consciousness that in terms of modern neuroscience could connect original Bleuler's concept of "split mind" with research of neural information integration.
    Neuropsychiatric Disease and Treatment 07/2014; 10:1309-15. DOI:10.2147/NDT.S64219 · 1.74 Impact Factor
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