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Published in final edited form as: Schizophr Res. 2020 Feb 13;218:93–98. doi: 10.1016/j.schres.2020.02.003

P50 inhibitory sensory gating in schizophrenia: analysis of recent studies

Robert Freedman a, Amanda M Olsen-Dufour a, Ann Olincy a; Consortium on the Genetics of Schizophreniab
PMCID: PMC7299819  NIHMSID: NIHMS1563462  PMID: 32061454

Abstract

Introduction:

Inhibitory sensory gating of the P50 cerebral evoked potential to paired auditory stimuli (S1, S2) is a widely used paradigm for the study of schizophrenia and related conditions. Its use to measure genetic, treatment, and developmental effects requires a metric with more stable properties than the simple ratio of the paired responses.

Methods:

This study assessed the ratio P50S2μV/P50S1μV and P50S2μV co-varied for P50S1μV in all 27 independent published studies that compared schizophrenia patients with healthy controls from 2000–2019. The largest study from each research group was selected. The Colorado research group’s studies were excluded to eliminate bias from the first report of the phenomenon.

Results:

Across the 27 studies encompassing 1179 schizophrenia patients and 1091 health controls, both P50S2μV co-varied for P50S1μV and P50S2μV/P50S1μV significantly separated the patients from the controls (both P < 0.0001). Effect size for P50S2μV co-varied for P50S1μV is d’ = 1.23. The normal distribution of P50S2μV co-varied for P50S1μV detected influences of maternal inflammation and effects on behavior in a recent developmental study, an emerging use for the P50 inhibitory gating measure. P50S2μV/P50S1μV was not normally distributed. Results from two multi-site NIMH genetics collaborations also support the use of P50S2μV as a biomarker.

Conclusion:

Both methods detect an abnormality of cerebral inhibition in schizophrenia with high significance across multiple independent laboratories. The normal distribution of P50S2μV co-varied for P50S1μV makes it more suitable for studies of genetic, treatment, and other influences on the development and expression of inhibitory deficits in schizophrenia.

Keywords: Sensory gating, schizophrenia, hippocampus, interneuron, evoked potential auditory, inhibition

1. Introduction

A function of the hippocampus is to regulate the flow of information from the neocortex association areas to areas of learning and memory that have more limited capacity to process that information. The hippocampus uses both it own intrinsic inhibitory interneurons and subcortical inputs from the brainstem and midbrain that help assess the novelty and urgency of incoming stimuli (Vinogradova, 2001). Information that is unexpected or elicits a fight or flight reaction can then be prioritized, while response to repeated, less meaningful stimuli is inhibited. A deficit in cerebral inhibition, particularly in the hippocampus, has become a well-characterized pathophysiological feature of schizophrenia.

Deficient inhibition has been proposed to result in the flooding of the schizophrenia patient’s input capacity by sensory information (Venables, 1964). The resultant hippocampal hyperactivity occludes the response of the hippocampus to meaningful stimuli and is associated with lower levels of cognitive performance (Heckers et al., 1998; Tregellas et al., 2014; Heckers and Konradi, 2015). More recently, developmental studies have shown early inhibitory deficits in individuals with emerging psychoses and in offspring of psychotic parents as young as 1 month of age (Yee et al., 1998; Hamilton et al., 2018; McHugo et al., 2019, Hunter et al., 2011; Smith, Crawford, Thomas, Reid, 2018). Several genetic influences in schizophrenia have been related to inhibitory deficits as well (Freedman et al., 1997; Houy et al., 2004; Hall et al., 2006; Lu et al., 2007; Greenwood et al., 2013).

Sir Charles Sherrington’s work with spinal reflexes first identified inhibition and excitation as competing nervous system mechanisms (Sherrington, 1906). Sherrington found that a second stimulus elicited a smaller response that the first, which he identified as the effects of inhibitory neurons activated as part of the response to the preceding stimulus. The P50 averaged cerebral response to repeated auditory stimuli (S1, S2) has been used in a similar strategy to characterize inhibitory deficits in schizophrenia (Adler et al., 1982). The P50 response to the second stimulus S2 is normally decreased compared to the response to the first stimulus S1. In schizophrenia this normal decrease is less vigorous, which provides electrophysiological evidence for a defect in cerebral inhibition (Fig.1).

Fig 1.

Fig 1.

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Simplified inhibitory circuit for P50 inhibitory sensory gating. The first sound S1 activates excites the pyramidal neuron to produce P50S1μV (dotted line). The black inhibitory neuron is also activated, but it does not inhibit the pyramidal neuron until after S1 had evoked the P50S1μV response. The inhibition of the pyramidal neuron is demonstrated when the second sound S2 excites the pyramidal neuron. P50S2μV is less than P50S1μV because of the inhibition activated by S1. The waveforms below are idealized diagrams, based on the values from the 27 studies. The sounds S1 and S2 occur at the vertical bars at time 0 for each evoked response. S1 and S2 were separated by 500 ms. The tic mark above the largest positive wave identifies the P50 response.

P50 sensory gating is a physiological measure in the NIMH RDoC Cognition Domain, Perception Construct, Auditory Sub-Construct (National Institute of Mental Health, 2019). The ratio of P50S2μV to P50S1μV has been the most commonly used metric and best separates patients from controls (Smith, Boutros, Schwarzkopf, 1994). However, its non-normal distribution and susceptibility to skewing often results in its being converted to a dichotomous variable, e.g., P50S2μV/P50S1μV less than or greater than 0.5. Alternatives have been proposed, of which the most satisfactory from a parametric perspective is P50S2μV covaried for P50S1μV (Smith, Boutros, Schwarzkopf, 1994).

This report compares these two techniques in studies from 27 independent laboratories. Studies of the past two decades were chosen to permit evaluation of the current use of P50 auditory sensory gating. Earlier studies were often working through technical issues in stimulation and recording paradigms (Light and Braff, 1998; Nagamoto et al., 1991, Griffith et al., 1995).

2. Methods

A Medline search “P50 AND evoked potentials auditory AND schizophrenia, limit 2000–2019” yielded 142 articles, of which 115 were excluded for reasons detailed in Table 1. The 27 articles represent unique reports from independent laboratories, none of which were affiliated with our Colorado group. Both authors independently reviewed the 27 articles and extracted P50S1μV, P50S12μV, and P50S2μV/P50S1μV (Appendix A). The Colorado group was not included because it had originally reported P50 inhibitory sensory gating. Inclusion of reports from the group that makes an initial observation can bias the assessment of its replicability by other groups. The Colorado group is a member the NIMH Consortium on the Genetics of Schizophrenia (COGS), whose data were analyzed separately.

Table 1,

Medline search “P50 AND evoked potentials auditory AND schizophrenia, limit 2000–2019.”

Reason for exclusion Number of articles = 142
Not human 4
Protocol deviation—failure to use paired pulse paradigm, introduction of distractor stimuli, or inclusion in a battery with target or startling stimuli 7
Review article 81
Magneto-encephalography 3
No reporting of vertex P50S1 and P50S2 amplitudes1 1
Publications from the same laboratory with larger N 6
Origination from University of Colorado site2 2
Missing control or schizophrenia group 11
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Two major data sets that were excluded are reported separately below:

1

The 5-site NIMH B-SNIP collaboration because it reported only P50S2 d’ for schizophrenia patients versus controls.

2

The 7-site NIMH COGS collaboration because it included the University of Colorado.

Quality considerations raised in the past include digital filtering adequate to isolate P50 from N100 with which it often overlaps, use of sounds of moderate intensity that do not engage startle or selective attention, EEG monitoring to assure that subjects do not sleep, which alters P50 suppression, and an averaging algorithm that distinguishes signal from noise (Light and Braff, 1998; Freedman et al., 1995; Griffith et al., 1995). Electro-oculographic (EOG) monitoring is a critical step to detect that the subject is not orienting to the sounds, which would indicate selective attention to them; covariance for the EOG electrical contribution to the EEG signal is not sufficient to exclude this phenomenon (Griffith et al., 1995). Lateral electrodes record neocortical responses rather than the limbic response recorded by central electrodes; these neocortical sources process information quickly and do not have the prolonged inhibition used for sensory gating by limbic sources including the hippocampus (Nagamoto et al., 1991).

For the analysis of studies in this report, no attempt was made to judge the quality of studies, as long as they reported P50S1 and P50S2 amplitudes in schizophrenia subjects and unaffected controls of any number. Among studies that reported original data, the most common reason that they were not included was the absence of an unaffected control group (Huang et al., 2019). Typically these were Phase 1 pharmaceutical studies (Aidelbaum et al., 2018). A second reason was the absence of reporting of P50S1 and P50S2 amplitudes (Quednow et al., 2012). One study was rejected because its protocol required that P50 recording always be preceded by Prepulse Inhibition of Startle (Light et al., 2012). The S1 stimulus in the Prepulse Inhibition of Startle is a warning that the S2 will be startling, which engages additional neuronal mechanisms that interfere with the inhibition of the P50 response (Javitt and Freedman, 2015). A limitation of the P50 sensory gating paradigm is that the usual inhibition is diminished in experimental environments in which the subject engages selective attention to the stimuli, to count them or respond to them, or is otherwise excessively stressed because of additional demands of the experimental day.

Two studies reported only subgroups of patients; these subgroups were combined. Two studies reported repeated trials. The first trial was tabulated for comparison with the other studies. P50S2μV is reported unadjusted and adjusted for the regression of P50S2 on P50S1 in the controls across the 27 studies. The means for each study were weighted by the N’s in each group to calculate the grand means for schizophrenia patients and controls. The squared deviation for each study from this mean was weighted by its N. The reported standard deviation is the square root of the summed squares across all studies divided by the total number of subjects, patients or controls, minus one. The degrees of freedom for t tests for each parameter (52) are based on independent schizophrenia and control groups, 27 each.

3. Results

Across the 27 studies, encompassing 1179 schizophrenia patients and 1091 healthy controls both P50S2μV co-varied for P50S1μV and P50S2μV/P50S1μV significantly separate the patients from the controls (both P < 0.0001; Fig. 1, Table 2). Amplitude of neither P50S1μV or P50S2μV by itself was significantly different between the two groups. The effect size for P50S2μV co-varied for P50S1μV is d’ = 1.23. A plot of difference between control and schizophrenia subjects for P50S2μV co-varied for P50S1μV versus number of subjects in each study is shown in Fig 2.

Table 2.

Results of the analysis of the P50 auditory sensory gating task in 27 independent studies.

Schizophrenia Control t (df52) P
Studies N 27 27
Subjects N 1179 1091
P50S1μV mean (SD) 2.82 (0.93) 3.18 (1.15) 1.26 0.21
P50S2μV mean (SD) 1.88 (1.37) 1.37 (0.53) 1.80 0.08
P50S2μV covaried for P50S1μV mean (SD) 1.42 (0.30) 0.94 (0.46) 4.54 <0.0001
P50s2μV/P50s1μV (SD) 0.73 (0.15) 0.41 (0.06) 10.29 <0.0001
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Fig. 2.

Fig. 2.

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Histogram of 27 studies, weighted by subject number, P50S2 co-varied for P50S1 (μV).

Two large NIMH genetics collaborations that included P50 sensory gating in their phenotypes: the 7-site Consortium on the Genetics of Schizophrenia (COGS; Olincy et el., 2010) and the 5-site Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP; Clementz et al., 2016). COGS included a University of Colorado site. An additional analysis of the published COGS P50 findings found that P50S2μV adjusted for P50S1μV had a larger effect size d’ = 0.60 for the comparison of schizophrenia probands with community controls, compared to d’ = 0.52 for P50S2μV/ P50S1μV and d’ = 0.51 for P50S1μV-P50S2μV (Table 3). The Odds Ratio for a COGS schizophrenia proband having P50S2μV adjusted for P50S1μV greater than the upper confidence limit for community controls is 4.09, CI 2.05–8.17, P < 0.0001. The B-SNIP study did not report P50S1 amplitudes and analyzed only P50S2 amplitude (not co-varied for P50S1μV) in schizophrenia and bipolar patients, compared to controls (Clementz et al., 2016). The B-SNIP biotype associated with chronic psychosis had d’ = 0.22 for P50S2μV compared to controls.

Table 3.

P50 inhibition in the NIMH Consortium on the Genetics of Schizophrenia (COGS)

A. Means and standard deviations (SD) for P50 parameters
COGS P50S1ms P50s1μV P50s2μV P50s2μV/ P50s1μV P50s1μV -P50s2μV P50s2μV co-varied for P50s1μV Number of subjects
Community Control
Mean 57.1 3.17 1.16 0.38 −2.01 1.14 336
SD 4.3 1.78 0.99 0.32 1.48 0.83
Schizophrenia Proband
Mean 58.7 2.74 1.48 0.59 −1.26 1.71 184
SD 6.0 1.56 1.18 0.47 1.48 1.06
t test P 0.0005 0.006 0.001 2.7E-09 5.3E-08 1.6E-11
d’ 0.30 0.26 0.29 0.52 0.51 0.60
B. Odds ratio for number of schizophrenia probands above the community controls’ upper confidence limit.
P50s2μV adjusted for P50s1μV N Control upper Confidence Interval (CI) N>Control upper CI Odds Ratio for N> upper CI, Proband versus Control Confidence Interval of Odds Ratio Fishers Exact P
Control 336 2.76 N=13 (3.9%)
Proband 184 N=26 (14.1%) 4.09 2.05–8.17 <0.0001
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4. Discussion

The preference of covariance for P50S2 amplitude adjusted for P50S1 amplitude was first raised on statistical grounds because of the often-skewed distribution of ratios, which hampered the determination of test-retest reliability in normal subjects (Smith, Boutros, Schwarzkopf, 1994). However, that early paper also reported that P50S2μV/P50S1μV distinguished patients from control with slightly higher significance, which prompted our research group to continue its use despite its limited properties as a parameter. We continue to find that P50S2μV/P50S1μV detects differences between patients and controls with high significance.

However, because P50S2μV/P50S1μV has a skewed distribution, for genetic studies we and others either dichotomized P50S2μV/P50S1μV into normal <0.5 and abnormal ≥ 0.5 (affected for genetic analysis) or substituted P50S1μV-P50S2μV for linkage and heritability analyses (Freedman et al., 1997, Houy et al., 2004, Greenwood et al., 2018). Dichotomization sacrifices statistical power, and P50S1μV-P50S2μV has the disadvantage that P50 amplitudes are dependent upon the medication status of the patient (Straumanis et al., 1982). Anti-dopaminergic neuroleptics increase P50 amplitudes significantly (Adler et al., 1989). It was therefore desirable to re-evaluate P50S2 amplitude covaried for P50S1 amplitude as a metric. To assess its usefulness, we compared its performance in studies by 27 others laboratories. The comparison shows the parameter has sufficient reproducibility between studies and mean effect size for use in studies of developmental, genetic, and treatment effects.

Comparison of mean values has the advantage of assessing the usefulness of a parameter across multiple independent groups. However, a limitation of this analysis is that none of the 27 studies calculated P50S2μV co-varied for P50S1μV. Therefore standard errors are not available for formal meta-analytic testing of bias. A more stringent test for a parameter’s utility is whether it can distinguish effects in individual subjects. P50S2μV co-varied for P50S1μV was calculated for two studies, not included among the 27 studies because they did not compare patients with schizophrenia and healthy controls. These two studies, both from Colorado, found that P50S2μV co-varied for P50S1μV performed as well or better than P50S2μV/P50S1μV.

Both P50S2μV/P50S1μV and P50S2μV co-varied for P50S1μV were used in an initial Phase 1 study of a nicotinic agonist in schizophrenia and gave comparable results (Olincy et al., 2006). A more recent use for P50 sensory gating is in early developmental studies, to capture genetic and intrauterine environmental effects at birth. We and another group have shown that P50 sensory gating is present at nearly normal adult levels in 1-month-old newborns. However, newborns with a psychotic mother or father have deficits in P50 sensory gating similar to those in adults with schizophrenia (Hunter et al., 2011; Smith, Crawford, Thomas, Reid, 2018). As first-degree relatives of a person with schizophrenia, these newborns are thus comparable to siblings, parents, and adult children of persons with schizophrenia, many of whom have sensory gating deficits (Freedman et al., 1997; Houy et al., 2004). As in adult patients, the predominant abnormality is elevation of P50S2μV in these children of psychotic parents. P50S2μV/P50S1μsV and P50S2μV co-varied for P50S1μV were compared in newborns in a recent study of the effects of maternal infection, a common prenatal factor that predisposes offspring to later mental illness (Freedman et al., 2019). There was significant elevation in both P50S2μV co-varied for P50S2μV (uninfected 0.75 μV (SE 0.05) versus infected 0.94μV (SE 0.06) P < 0.001) and the P50S2μV/ P50S1μV (uninfected 0.44 (SE 0.03) versus infected 0.55 (SE 0.04) P = 0.003). However, tests for normality rejected the assumption of normal distribution for P50S2μV/P50S1μV (Shapiro-Wilks 0.977, df 163, P = 0.009), but not for P50S2μV covaried for P50S1μV (Shapiro-Wilks 0.987, df 163, P = 0.124). Higher P50S2μV co-varied for P50S1μV, because of its normal distribution, better detected the effects of maternal inflammation measured as C-Reactive protein on the baby in these infected mothers, and higher P50S2S2μV co-varied for P50S1μV was associated with decreased behavioral regulation in the children at 3 months of age (Freedman et al., 2019). Thus, the improved P50S2μV parameter allowed observation of how fetal development of cerebral inhibition is interposed as a pathophysiological mechanism between prenatal maternal inflammation and the child’s later behavioral problems.

The pathophysiological importance of P50 inhibitory sensory gating is linked to the role of the hippocampus and its inhibition in schizophrenia. The P50 evoked potential response to auditory stimuli was first recorded by Davis, who noted that repetition of the stimulus resulted in decrement of the response (Davis, 1939). This phenomenon was interpreted as neuronal fatigue, but later re-interpreted as an example of inhibition (Miller and Freedman, 1995). A source for the P50 response is found in the human hippocampus by depth recording during neurosurgery, and the inhibition of afferent response in the hippocampus has been shown to be the activity of hippocampal interneurons (Goff et al., 1980, Spencer and Kandel, 1961).

The restriction of the present analysis to vertex EEG recordings favors a deep source in the hippocampus, as opposed to the lateral surface sources in the auditory neocortex. Neocortical sources, recorded by either EEG or MEG, do not show inhibition at the long interstimulus interval (500 msec) in the P50 inhibitory sensory gating paradigm (Nagamoto et al., 1991; Bachmann et al., 2010). A recent MEG study used source reconstruction to mimic the midline EEG sources and found differences in inhibitory gating between patients with schizophrenia and healthy controls that were robust to the parameter used to quantify the inhibition (Schubring et al., 2018).

The hippocampus integrates neocortical activity with the alerting reticulo-septal input, which reaches hippocampal interneurons through subcortical cholinergic afferents from the medial septal nucleus (Vinogradova, 2001). Cholinergic activation of hippocampal interneurons permits the hippocampus to use pontine reticular system input to regulate or gate the cortical activity reaching the hippocampus, which has limited capacity to process all the sensory information reaching it through its neocortical inputs (Miller and Freedman, 1993). fMRI studies of the P50 gating paradigm have shown increased BOLD signal in the hippocampus in schizophrenia, as well as the thalamus and frontal cortex (Tregellas et al., 2007). Thalamic reticular neurons gate the input of sensory information to cerebral neocortical neurons by a similar cholinergic mechanism from the midbrain nucleus basilis of Meynert (Breese et al., 1997).

In mouse models of P50 auditory gating, prolonged firing of interneurons occurs between the first and second stimuli in both the CA3 and CA1 subfields (Miller and Freedman, 1995). CA3 is responsible for shaping recognition of familiar objects and persons by partial clues, and CA1 is responsible for learning specific places and events (Schapiro et al., 2017). Both these types of learning are deficient in schizophrenia, related to hippocampal activity (Nestor et al., 2007, Bilder et al., 2000). In animal models, optogenetic inactivation of inhibitory interneurons decreases both attention and social interaction, characteristic behavioral problems of schizophrenia (Yizhar et al., 2011). Hippocampal interneurons have been transplanted in mouse models and found to overcome the effects of on behavior of dopaminergic hyperactivity, another pathophysiological feature related to schizophrenia (Perez and Lodge, 2013). In patients with schizophrenia, P50 inhibition deficits are specifically related to greater difficulties in attention, poorer working memory, and reduced processing speed in the NIMH MATRICS Cognitive Consensus Battery (Hamilton et al., 2018).

Hippocampal interneurons have also been the subject of neuropathological inquiry, both in postmortem studies of schizophrenia and in animal models. The hippocampus is one of the most severely compromised brain regions in schizophrenia (Falkai and Bogerts, 1986). Interneurons from brains of patients with schizophrenia specifically express less GAD1, the gene for the GABA synthesizing enzyme, proportionally less KCC2, the gene for the chloride transporter that allows GABA-sensitive chloride channels to inhibit neuronal response, and less CHRNA7, the gene for the cholinergic receptor subunit that receives the septal cholinergic input (Hyde et al., 2011; Freedman et al., 1995).

5. Conclusion

The P50 sensory gating paradigm provides an electrophysiological biomarker to characterize the activity of hippocampal interneurons in responding to sensory stimuli, a fundamental functional mechanism of the human brain that is also a basic pathophysiological feature of schizophrenia. Reproducible paradigms and parameters are essential, which this analysis of results from 27 independent laboratories and the NIMH COGS over the past two decades helps substantiate.

Supplementary Material

1

Fig 3.

Fig 3.

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Difference between control and schizophrenia subjects for P50S2μV co-varied for P50S1μV versus number of schizophrenia subjects in each study. The apex of the triangle is the mean of the 27 studies and the 95% confidence interval is the base. The COGS study is also plotted onto the diagram.

Acknowledgement:

The Consortium on Genetics of Schizophrenia (COGS): David L. Braff, Kristin S. Cadenhead, Monica E. Calkins, Dorcas J. Dobie, Robert Freedman, Michael F. Green, Tiffany A. Greenwood, Raquel E. Gur, Reuben C. Gur, Gregory A. Light, James Mintz, Keith H. Nuechterlein, Ann Olincy, Allen D. Radant, Nicholas J. Schork, Larry J. Seidman, Larry J. Siever, Jeremy M. Silverman, William S. Stone, Neal R. Swerdlow, Debby W. Tsuang, Ming T. Tsuang, Bruce I. Turetsky.

Funding: The study was funded by NIH/NCATS ULT1TR001082, and NIMH grants R01-MH-065571 , R01-MH-065588 , R01-MH-065562 , R01-MH-065707 , R01-MH-065554, R01-MH-0 65578, R01-MH-6 5558 , R01-MH-86135.

Footnotes

Data Sharing: All data are contained within the Tables of the article and its Supplement.

Conflict of Interest: Dr. Freedman is a consultant to Minerva Pharmaceuticals. The others authors report no conflict of interest.

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