Exploration of auditory P50 gating in schizophrenia by way of difference waves
© Arnfred; licensee BioMed Central Ltd. 2006
Received: 20 September 2005
Accepted: 28 January 2006
Published: 28 January 2006
Electroencephalographic measures of information processing encompass both mid-latency evoked potentials like the pre-attentive auditory P50 potential and a host of later more cognitive components like P300 and N400.
Difference waves have mostly been employed in studies of later event related potentials but here this method along with low frequency filtering is applied exploratory on auditory P50 gating data, previously analyzed in the standard format (reported in Am J Psychiatry 2003, 160:2236-8). The exploration was motivated by the observation during visual peak detection that the AEP waveform was different in the patient group, although this was not reflected by the peak measures. The sample included un-medicated schizophrenia spectrum patients (n = 17) and healthy controls (n = 24). The patients had an attenuated difference P50. This attenuation was primarily seen in the sub-sample of patients with severe negative symptoms. The difference attenuation was due to low amplitude at the first stimulus. This suggests an abnormality in readiness more than an abnormality in gating in the patient group.
The deficiency in auditory P50 gating reported in numerous studies of schizophrenic patients has been one of the experimental findings that have supported the theory of defect sensory gating in schizophrenia . P50 gating is the relative amplitude reduction of auditory evoked potential (AEP) P50 from the first stimulus (S1) to the second stimulus (S2). P50 is the second positive component of the mid-latency AEP; a scalp electroencephalographic measure of the brain response to auditory stimulation. The P50 paradigm consists of two identical clicks presented with an interval of 0.5 s followed by a 8–12 s pause before the next paired stimulation.
While P50 gating mostly has been reported as a ratio measure (S2/S1 or 1- S2/S1 × 100), it has been suggested that a difference measure might be more reliable . The latter report suggested the use of the traditional peak amplitudes for the difference measures. Extending this idea to the whole waveform, subtraction waveforms also called difference waves are investigated presently. Difference waves, where the evoked potential of the same individual recorded under one condition is subtracted from a potential recorded in another condition, have been used particularly in the research of the Mis Match Negativity (MMN). The MMN is a negative potential shift evoked when a deviant stimulus is presented in a series of well-known stimuli. It is observed even when attention is focused on something else than the stimulus series, and consequently MMN has been conceived as a manifestation of involuntary attention and as such part of the orienting response . P50 is at a shorter latency than the MMN but it has been demonstrated that attentional modulation of the AEP starts at 15 ms post stimulus . In this sense an abnormal P50 difference wave in schizophrenia might be an indication of faulty involuntary attentional processing at the same time as a small or negative difference wave could imply a gating defect.
The present data were recorded as part of a larger study examining gating in un-medicated schizophrenia spectrum patients and data on subsamples of the present patients have been reported previously [5, 6]. It is noteworthy that auditory P50 gating following the standard processing method  and two other comparisons methods also involving the ratio measure was normal in the schizophrenic patients included in the present sample . However, when performing the visual peak detection on the P50 gating data, it was observed that the AEP waveform was different in the 30–70 ms latency range in the patient group, although this was not reflected by the peak measures. Thus, this is an explorative investigation of using difference waves on the mid-latency auditory evoked potential recorded in a P50 gating paradigm and correlating this to symptom measures.
Amplitudes of mid-latency auditory gating difference wave, P50 gating ratio, sweeps included in the EPs and tobacco consumption in schizophrenia spectrum patients (stratified by their negative symptom score) and healthy controls
Other Group Variables
Illness parameters in the patient group stratified by the negative symptom score
Time since medication
(N = 5)
(N = 8)
Total duration of med.
Duration of illness
Recording and stimulus equipment and settings and the seven electrode montage (Fp1, Fp2, Fz, C3', C4', and Pz + EOG) were identical to earlier reports from our laboratory . Auditory stimuli were clicks of 20–10000 Hz, 1.6 ms duration and 104 dB peSPL delivered binaurally through earphones. During recording the subjects were seated comfortably upright with closed eyes in dim light and with background masking low level (70 dB SPL) white noise. The subject was enrolled in a fixed schedule of several types of EEG experiments and breaks that included two hourly recording sessions before lunch and one hourly session after lunch. In each hourly session one run was recorded of the auditory gating paradigm of 40 paired click stimuli. Sampling rate was 1 kHz pr channel. Subjects were allowed to smoke in the fixed breaks but not the last 15 minutes before resuming recording. Sweeps were rejected if the EOG amplitude exceeded +/- 70 μV, but no baseline correction was performed. As the low frequency activity was examined it was considered important to avoid the de-trending, which would be the consequence of correcting with a baseline mean measured across a slow wave. The possible confounding effect of a difference in baseline was examined by an analysis of variance (ANOVA), as described below, of the maximum value in the latency range -5 to +5 ms. No group differences were observed in baseline or in EOG amplitudes. Following initial exploration and recent results of selective low pass filtering  the digital frequency band-pass was set at 1–15 Hz (24 dB/oct roll-off). The difference waveform was computed by point-to-point subtraction of the S2 waveform from the S1 waveform. P50d onset (minimum amplitude in the latency range 30–50 ms, leading electrode Fz) and P50d peak (max amplitude in the latency range 40–80 ms, leading electrode Fz) were based on computerised detection. The difference amplitudes were analysed using repeated measures analyses of variance (r.m. ANOVA) in an Electrode*Group matrix. Exploratory, the different parameters of illness as listed in table 1 was entered the analysis as covariates. Only negative symptoms covaried with P50d onset (F 1,15 : 5.413, p = .03). Consequently, the patient group was stratified by the median of their negative symptom score. Post-hoc one-way ANOVA was performed for each channel. One-way ANOVAs were also performed for the standard P50 gating measure, previously reported , the number of sweeps included, and the number of cigarettes pr week as listed in table 2. The reported p-values are Bonferroni corrected for multiple comparions.
The AEPs were derived from more epochs in the healthy comparison group than the patient group, but no difference was observed between the patient subgroups, see table 2.
The patients had a negative difference amplitude in the 30–70 ms latency range frontally, while the healthy controls had a positive P50 difference component, a finding that is in agreement with most previous studies of P50 gating in schizophrenia based on 10–50 Hz filtered data and the ratio measure [7, 13]. The major group difference of the P50d onset amplitude was also seen in the S1 amplitude but not in the S2 amplitude. This finding is in agreement with a study by , in which the low frequency P50 S1 amplitude was the group discriminating factor.
The patients having high negative symptom scores had a particular augmentation of negative amplitude at the prefrontal channels, corresponding to a lack of positive deflection in S1 at vertex. The possibility of contamination by reflex eye movements in S1 is contradicted by the lack of correlation to the number of rejected sweeps. Contamination by volume conduction from the frontalis muscle EMG would mostly be filtered out by the frequency band selected, but it cannot be ruled out . Then the findings would have to be interpreted as increased reflex activity with increasing negative symptoms an effect which could be related to an orienting response or a slight startle reflex. The orienting response has been extensively investigated in schizophrenia by way of the skin conductance response reviewed in [15–17]. Increased negative symptoms are associated with decreased orienting response and this is not in accordance with the findings here . Startle habituation is decreased in schizophrenic patients, but it is not correlated to negative symptoms . Recording of P50 gating and simultaneous facial muscle activity in schizophrenic patients would be necessary to solve the issue.
Measuring P50 gating as ratio, one of the earlier reports showed no difference in gating between schizophrenic patients low and high in negative symptoms . Later studies have mostly supported this. Light and colleagues  reported that negative symptoms only accounted for 2% of the variance in gating and a recent meta-analysis showed that symptoms do not predict P50 gating, although this might be due to insuffient statistical power . In opposition to this but in agreement with the present low frequency difference analysis of P50 data, Ringel and colleagues found a positive correlation between the negative symptom subscale of the Positive and Negative Syndrome Scale for Schizophrenia (PANSS) and gating deficits . The negative items on SANS and PANSS have highly significant correlations . Furthermore, Yee and colleagues  found that anergia and attentional impairment correlated with the gating deficiency. In the present data the ratio measure of P50 gating did not show any difference between the two groups nor between patient subgroups . This could imply that the low frequency filtering unveil differences between patient subgroups particularly on S1 in accordance with several studies where the main difference in gating has been explained by variations in the S1 amplitude [25–29].
The P50 paradigm was at first reported to only track so-called "automatic" or pre-attentive processing [1, 26, 30, 31]. Nonetheless, later studies of P50 [32, 33] showed a direct effect of task allocation on the S1 and S2 amplitudes. Amplitude increase was seen when a discrimination task was on either S1 [31, 7] or S2 [31, 32, 34]. When subjects were distracted during recording S1 amplitude was attenuated and S2 amplitude constant [31, 7]. It seems possible that the low frequency S1 P50 amplitude tracks an aspect of involuntary attention, which are delayed and diminished in schizophrenic patients. Several theories concerning the basic deficits in schizophrenia exist. Among them, a hypothesized weakening of the effect of regularity on stimulus processing [, , ] i.e. a decrease in expectancy during repeated stimulation seems to fit the present finding of low S1 amplitude best.
In conclusion, un-medicated male schizophrenia spectrum patients show an attenuation of low frequency amplitude at the first stimulus of the P50-gating paradigm. This is likely to reflect an abnormality in readiness and not an abnormality in gating.
The study was supported by a PhD-grant for the author by the Faculty of Health Sciences, University of Copenhagen as well as unrestricted grants from The Lundbeck Foundation, The Ivan Nielsen Foundation for Rare Psychiatric Disorders, The Schizophrenia Foundation of 1986, and the Danish Hospital Foundation for Medical Research, Region of Copenhagen, The Faroe Islands and Greenland.
- Braff DL: Information processing and attention dysfunctions in schizophrenia. Schizophr Bull. 1993, 19: 233-259.View ArticlePubMedGoogle Scholar
- Smith DA, Boutros NN, Schwarzkopf SB: Reliability of P50 auditory event-related potential indices of sensory gating. Psychophysiology. 1994, 31: 495-502.View ArticlePubMedGoogle Scholar
- Naatanen R, Simpson M, Loveless NE: Stimulus deviance and evoked potentials. Biol Psychol. 1982, 14: 53-98. 10.1016/0301-0511(82)90017-5.View ArticlePubMedGoogle Scholar
- Hackley SA: An evaluation of the automaticity of sensory processing using event- related potentials and brain-stem reflexes. Psychophysiology. 1993, 30: 415-428.View ArticlePubMedGoogle Scholar
- Arnfred SM, Chen AC, Glenthoj BY, Hemmingsen RP: Normal p50 gating in unmedicated schizophrenia outpatients. Am J Psychiatry. 2003, 160: 2236-2238. 10.1176/appi.ajp.160.12.2236.View ArticlePubMedGoogle Scholar
- Arnfred SM, Chen AC: Exploration of somatosensory P50 gating in schizophrenia spectrum patients: reduced P50 amplitude correlates to social anhedonia. Psychiatry Res. 2004, 125: 147-160. 10.1016/j.psychres.2003.12.008.View ArticlePubMedGoogle Scholar
- White PM, Yee CM: Effects of attentional and stressor manipulations on the P50 gating response. Psychophysiology. 1997, 34: 703-711.View ArticlePubMedGoogle Scholar
- Wing JK, Sartorius N, Ûstün TB: Diagnosis and clinical measurement in psychiatry. A reference manual for SCAN. 1998, , Cambridge University PressGoogle Scholar
- Andreasen N: Scale for Assessment of Positive Symptoms (SAPS). 1984, University of Iowa, Iowa City,Google Scholar
- Andreasen N: Scale for Assessment of Negative Symptoms (SANS). 1984, University of Iowa, Iowa City,Google Scholar
- Arnfred SM, Eder DN, Hemmingsen RP, Glenthoj BY, Chen AC: Gating of the vertex somatosensory and auditory evoked potential P50 and the correlation to skin conductance orienting response in healthy men. Psychiatry Res. 2001, 101: 221-235. 10.1016/S0165-1781(01)00226-8.View ArticlePubMedGoogle Scholar
- Clementz BA, Blumenfeld LD: Multichannel electroencephalographic assessment of auditory evoked response suppression in schizophrenia. Exp Brain Res. 2001, 139: 377-390. 10.1007/s002210100744.View ArticlePubMedGoogle Scholar
- Yee CM, Nuechterlein KH, Morris SE, White PM: P50 suppression in recent-onset schizophrenia: clinical correlates and risperidone effects. J Abnorm Psychol. 1998, 107: 691-698. 10.1037/0021-843X.107.4.691.View ArticlePubMedGoogle Scholar
- Perlstein WM, Simons RF, Graham FK: Prepulse effects as a function of cortical projection system. Biol Psychol. 2001, 56: 83-111. 10.1016/S0301-0511(01)00075-8.View ArticlePubMedGoogle Scholar
- Bernstein AS, Schnur DB, Bernstein P, Yeager A, Wrable J, Smith S: Differing patterns of electrodermal and finger pulse responsivity in schizophrenia and depression. Psychol Med. 1995, 25: 51-62.View ArticlePubMedGoogle Scholar
- Bernstein AS, Frith CD, Gruzelier JH, Patterson T, Straube E, Venables PH, Zahn TP: An analysis of the skin conductance orienting response in samples of American, British, and German schizophrenics. Biol Psychol. 1982, 14: 155-211. 10.1016/0301-0511(82)90001-1.View ArticlePubMedGoogle Scholar
- Dawson ME, Nuechterlein KH: Psychophysiological dysfunctions in the developmental course of schizophrenic disorders. Schizophr Bull. 1984, 10: 204-232.View ArticlePubMedGoogle Scholar
- Bernstein AS: Orienting response research in schizophrenia: where we have come and where we might go. Schizophr Bull. 1987, 13: 623-641.View ArticlePubMedGoogle Scholar
- Parwani A, Duncan EJ, Bartlett E, Madonick SH, Efferen TR, Rajan R, Sanfilipo M, Chappell PB, Chakravorty S, Gonzenbach S, Ko GN, Rotrosen JP: Impaired prepulse inhibition of acoustic startle in schizophrenia. Biol Psychiatry. 2000, 47: 662-669. 10.1016/S0006-3223(99)00148-1.View ArticlePubMedGoogle Scholar
- Adler LE, Waldo MC, Tatcher A, Cawthra E, Baker N, Freedman R: Lack of relationship of auditory gating defects to negative symptoms in schizophrenia. Schizophr Res. 1990, 3: 131-138. 10.1016/0920-9964(90)90046-A.View ArticlePubMedGoogle Scholar
- Light GA, Geyer MA, Clementz BA, Cadenhead KS, Braff DL: Normal P50 suppression in schizophrenia patients treated with atypical antipsychotic medications. Am J Psychiatry. 2000, 157: 767-771. 10.1176/appi.ajp.157.5.767.View ArticlePubMedGoogle Scholar
- Bramon E, Rabe-Hesketh S, Sham P, Murray RM, Frangou S: Meta-analysis of the P300 and P50 waveforms in schizophrenia. Schizophr Res. 2004, 70: 315-329. 10.1016/j.schres.2004.01.004.View ArticlePubMedGoogle Scholar
- Ringel TM, Heidrich A, Jacob CP, Pfuhlmann B, Stoeber G, Fallgatter AJ: Sensory gating deficit in a subtype of chronic schizophrenic patients. Psychiatry Res. 2004, 125: 237-245. 10.1016/j.psychres.2004.01.004.View ArticlePubMedGoogle Scholar
- Kay SR, Opler LA: The positive-negative dimension in schizophrenia: its validity and significance. Psychiatr Dev. 1987, 5: 79-103.PubMedGoogle Scholar
- Judd LL, McAdams L, Budnick B, Braff DL: Sensory gating deficits in schizophrenia: new results. Am J Psychiatry. 1992, 149: 488-493.View ArticlePubMedGoogle Scholar
- Freedman R, Adler LE, Gerhardt GA, Waldo M, Baker N, Rose GM, Drebing C, Nagamoto H, Bickford-Wimer P, Franks R: Neurobiological studies of sensory gating in schizophrenia. Schizophr Bull. 1987, 13: 669-678.View ArticlePubMedGoogle Scholar
- Jin Y, Potkin SG, Patterson JV, Sandman CA, Hetrick WP, Bunney WEJ: Effects of P50 temporal variability on sensory gating in schizophrenia. Psychiatry Res. 1997, 70: 71-81. 10.1016/S0165-1781(97)03091-6.View ArticlePubMedGoogle Scholar
- Jin Y, Bunney WEJ, Sandman CA, Patterson JV, Fleming K, Moenter JR, Kalali AH, Hetrick WP, Potkin SG: Is P50 suppression a measure of sensory gating in schizophrenia?. Biol Psychiatry. 1998, 43: 873-878. 10.1016/S0006-3223(98)00115-2.View ArticlePubMedGoogle Scholar
- Patterson JV, Jin Y, Gierczak M, Hetrick WP, Potkin S, Bunney WEJ, Sandman CA: Effects of temporal variability on p50 and the gating ratio in schizophrenia: a frequency domain adaptive filter single-trial analysis. Arch Gen Psychiatry. 2000, 57: 57-64. 10.1001/archpsyc.57.1.57.View ArticlePubMedGoogle Scholar
- Freedman R, Adler LE, Waldo MC, Pachtman E, Franks RD: Neurophysiological evidence for a defect in inhibitory pathways in schizophrenia: comparison of medicated and drug-free patients. Biol Psychiatry. 1983, 18: 537-551.PubMedGoogle Scholar
- Jerger K, Biggins C, Fein G: P50 suppression is not affected by attentional manipulations. Biol Psychiatry. 1992, 31: 365-377. 10.1016/0006-3223(92)90230-W.View ArticlePubMedGoogle Scholar
- Guterman Y, Josiassen RC: Sensory gating deviance in schizophrenia in the context of task related effects. Int J Psychophysiol. 1994, 18: 1-12. 10.1016/0167-8760(84)90010-2.View ArticlePubMedGoogle Scholar
- Jin Y, Potkin SG: P50 changes with visual interference in normal subjects: a sensory distraction model for schizophrenia. Clin Electroencephalogr. 1996, 27: 151-154.View ArticlePubMedGoogle Scholar
- Guterman Y, Josiassen RC, Bashore TRJ: Attentional influence on the P50 component of the auditory event- related brain potential. Int J Psychophysiol. 1992, 12: 197-209. 10.1016/0167-8760(92)90011-Y.View ArticlePubMedGoogle Scholar
- Hemsley DR: Schizophrenia. A cognitive model and its implications for psychological intervention. Behav Modif. 1996, 20: 139-169.View ArticlePubMedGoogle Scholar
- Hemsley DR: A simple (or simplistic?) cognitive model for schizophrenia. Behav Res Ther. 1993, 31: 633-645. 10.1016/0005-7967(93)90116-C.View ArticlePubMedGoogle Scholar
- Shakow D: Some observations on the psychology (and some fewer, on the biology) of schizophrenia. J Nerv Ment Dis. 1971, 153: 300-330.View ArticlePubMedGoogle Scholar
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