The effect of state on sensory gating: comparison of waking, REM and non-REM sleep

The effect of state on sensory gating:comparison of waking, REM and non-REM sleep

M.A. Kisley*, A. Olincy, R. Freedman

Department of Psychiatry, University of Colorado Health Sciences Center, 4200 E. 9th Avenue, Box C268-71, Denver, CO 80262, USA

Accepted 6 April 2001

Abstract

Objectives: Auditory sensory gating is an electrophysiological assay that has been employed in clinical and basic research to clarify the

neurobiological basis of perceptual and attentional impairments associated with schizophrenia and other diseases. In addition to genetically-

linked characteristics, this measure also exhibits potentially confounding sensitivity to behavioral state, most notably acute stress. The goal of

the present study is to determine if auditory sensory gating of evoked potential component P50 (`P1') could be measured during rapid eye

movement (REM) sleep, as an alternative to the waking state.

Methods: The suppression of vertex-recorded auditory evoked potential components, P30, P50 and N100, was measured as a function of

stimulus redundancy using the paired-click paradigm during all-night sleep in 10 control subjects. Average evoked responses were computed

separately for 30 min periods of waking, REM sleep, and non-REM (stage 2) sleep.

Results: Evoked response component P50 exhibited suppression to the paired-click stimulus during REM sleep, not signi®cantly different

than waking. Suppression of wave N100 was signi®cantly poorer during both sleep stages than waking. Component P30 was not suppressed

in response to repetitive stimuli under any state of vigilance.

Conclusions: In addition to waking, response suppression of evoked potential component P50 can be measured during REM sleep, thus

allowing the separation of trait- and state-dependent effects in future investigations of auditory sensory gating. Published by Elsevier Science

Ireland Ltd.

Keywords: Auditory evoked potentials; Sensory gating; P50; P1; Sleep; Rapid eye movement

1. Introduction

Auditory sensory gating is a rudimentary physiological

assay of the brain's ability to ®lter out or `gate' extraneous

acoustic information. This phenomenon is generally

measured by observing the reduction in magnitude of parti-

cular auditory evoked potentials as a function of stimulus

repetition (i.e. stimulus redundancy). Evoked potential

attenuation of this type has been alternatively interpreted

as a re¯ection of the brain's ®nite `recovery function'

(e.g. Davis et al., 1966).

Regardless of terminology, the electrophysiological

response-reduction paradigm has proven extremely useful

in clinical and basic research directed towards understanding

the neurobiological basis of perceptual ®ltering impairments

commonly associated with schizophrenia (neurobiology

reviewed by Adler et al., 1998; perceptual impairments

reviewed by Light and Braff, 2000). Adler et al. (1982) ®rst

demonstrated that component P50 (i.e. `P1' or `Pb') of the

vertex auditory evoked potential is generally not suppressed

in response to redundant stimuli for patients with schizophre-

nia, whereas it is attenuated in healthy subjects. Intact and

impaired sensory gating of wave P50, in control and schizo-

phrenia patient populations, respectively, has since been

replicated by several independent research groups (e.g.

Boutros et al., 1991; Erwin et al., 1991; Judd et al., 1992;

Jerger et al., 1992). More recently, an animal model of

sensory gating (Adler et al., 1986; Luntz-Leybman et al.,

1992; Stevens et al., 1996) and a human genetic linkage

study (Freedman et al., 1997) have both implicated abnorm-

alities of a very speci®c neuronal element ± the a7 nicotinic

receptor ± in auditory gating de®cits associated with schizo-

phrenia.

In addition to trait-dependence, auditory sensory gating is

sensitive to a subject's behavioral state. In particular, acute

stress has been shown to impair sensory gating in control

individuals (Johnson and Adler, 1993; White and Yee,

1997), most likely through a noradrenergic mechanism

(humans: Adler et al., 1994; animal model: Adler et al.,

Clinical Neurophysiology 112 (2001) 1154±1165

1388-2457/01/$ - see front matter. Published by Elsevier Science Ireland Ltd.

PII: S1388-2457(01)00578-8

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CLINPH 2000184

* Corresponding author. Tel.: 11-303-315-1044; fax: 11-303-315-5347.

E-mail address: [email protected] (M.A. Kisley).

1988; Stevens et al., 1993). Whether attention modulates

sensory gating is still under debate (compare Guterman et

al., 1992 with Jerger et al., 1992; White and Yee, 1997).

Sensitivity to these and other experimental parameters

might explain one group's failure to ®nd intact sensory

gating of wave P50 in a sample of healthy individuals (Kath-

mann and Engel, 1990).

To maximize the utility of sensory gating assays in clin-

ical research, it is desirable to distinguish long-lasting

neurobiological modi®cations due to genetic inheritance

and damage caused by environmental insult from relatively

transient, state-dependent effects. Enhanced reliability

becomes especially important as more psychiatric and

neurological patient populations are tested for sensory

gating abnormalities (e.g. posttraumatic stress disorder:

Neylan et al., 1999; Skinner et al., 1999; Parkinson's

disease: Teo et al., 1997; attention-de®cit/hyperactivity

disorder: Olincy et al., 2000; drug abuse: Boutros et al.,

2000; Patrick and Struve, 2000; traumatic brain injury:

Arciniegas et al., 2000; Alzheimer's disease: Tanila et al.,

2000). Whereas past attempts to increase reliability have

focused on methodological (Nagamoto et al., 1991; Clem-

entz et al., 1997; McCallin et al., 1997) and analytical

(Cardenas et al., 1993; Smith et al., 1994; Patterson et al.,

2000) aspects of gating measures, the present study is moti-

vated by the search for a stable, easily-de®ned brain/beha-

vioral state during which to measure auditory sensory

gating.

Rapid eye movement (REM) sleep is a particularly appro-

priate candidate `state' for the measurement of component

P50 sensory gating. During REM sleep, the activity of nora-

drenergic neurons in the locus coeruleus are greatly reduced

(Hobson et al., 1975), potentially removing the confounding

effect of norepinephrine. Furthermore, the possible in¯u-

ence of selective attention on sensory gating becomes irre-

levant if subjects are asleep. Waveform measurements

necessary to assess gating can be achieved because all

components of the auditory evoked potential, including

P50, are present during REM sleep (Williams et al., 1962;

Weitzman and Kremen, 1965). Further, differential proces-

sing of sequential acoustic stimuli occurs during REM sleep

as re¯ected in later evoked potential components, such as

the mismatch negativity (Loewy et al., 1996, 2000; Nashida

et al., 2000) and P300 (Sallinen et al., 1996; Cote and Camp-

bell, 1999a,b). Nevertheless, only one previous study has

examined auditory evoked potential attenuation as a func-

tion of stimulus repetition during REM sleep: Ornitz et al.

(1972, 1974) found that component N2 ± a negative wave

occurring about 250 ms after stimulus onset ± exhibits better

recovery (i.e. poorer gating) during REM sleep than during

waking in healthy children. Our understanding of sleep's

effect on gating of wave P50 is limited to the observation

that preceding episodes of non-REM sleep, but not episodes

of REM sleep, can actually improve sensory gating

measured in waking schizophrenia patients (Grif®th and

Freedman, 1995).

The primary goal of the present study is to show that

auditory sensory gating of wave P50 can be measured

during REM sleep in control subjects, thus demonstrating

the validity of this experimental procedure for clinical

research. A secondary goal is to compare quantitative esti-

mates of sensory gating obtained across different states of

vigilance ± speci®cally to test whether gating of P50 is

improved in REM sleep compared with waking for this

population. Additionally, amplitude suppression of evoked

potential components P30 (i.e. `Pa') and N100 (i.e. `N1') are

also described for waking and REM sleep, and gating of all

3 waves is examined during non-REM sleep.

2. Methods

Ten adult subjects (aged 21±44 years; mean, 31.2 years; 5

male) participated in this study. None had a positive perso-

nal or family history of schizophrenia. All subjects gave

informed consent. Experimental procedures were approved

by the Colorado Multiple Institutional Review Board.

2.1. General procedures

Electroencephalographic signals were recorded (Neuros-

can Acquisition System; Sterling, VA) from each subject

during two separate sessions: one during waking, and one

during sleep. Half of the subjects underwent the waking

recording ®rst. For both sessions, the continuous electroen-

cephalogram (EEG) was recorded from a vertex electrode

(Cz) referenced to the right ear, and the electrooculogram

(EOG) from a bipolar con®guration between electrodes

directly above and lateral to the left eye. During sleep

recordings, the electromyogram (EMG) was also recorded

with a bipolar submental con®guration. A ground electrode

was attached to the left ear. All electrode impedances were

maintained below 10 kV.

Average auditory evoked potentials were computed from

the EEG activity immediately following acoustic clicks

(0.04 ms pulse, ®ltered between 20 and 12 000 Hz),

which were delivered through insert earphones. The click

intensity was adjusted to 40 dB above each subject's hearing

threshold (determined by method of limits; thresholds for all

subjects were within a 10 dB range), separately for each ear.

Clicks occurred in pairs (0.5 s inter-click interval), and pairs

occurred every 10 s.

For the awake recording, supine subjects were instructed

to keep their eyes open and still during auditory stimuli

(which occurred every 10 s), and to apprise the experimenter

of any dif®culty in staying awake or keeping their eyes

open. After a 5 min acclimatization, recording began and

lasted until 30 min of data had been acquired. Each subject

decided during the experiment whether acquisition contin-

ued unabated for 30 min (N � 4), or whether this time was

broken up into two 15 min blocks (N � 4), or 3 blocks of 10

min each (N � 2). Drowsiness (i.e. dif®culty staying awake)

was generally the determining variable. None of the subjects

M.A. Kisley et al. / Clinical Neurophysiology 112 (2001) 1154±1165 1155

fell asleep during data acquisition (veri®ed by observation

of the EEG and subject report).

Sleep recordings occurred in the same laboratory, and in

one of two general paradigms. For 8 subjects, evoked poten-

tials were measured continuously during all-night sleep. The

other two subjects came to the laboratory at 03:00 h, after a

partial night's sleep.

2.2. Signal processing

For acquisition, EEG signals were ampli®ed 5000 times

and ®ltered between 0.1 and 200 Hz, EOG ampli®ed 1000

times and ®ltered between 0.1 and 100 Hz, EMG ampli®ed

12 500 times and ®ltered between 5.0 and 200 Hz. Occa-

sionally, a 60 Hz bandstop ®lter was used to attenuate

power line artifact. All channels were sampled at 1000

Hz. Continuously recorded data were converted from

Neuroscan's Scan 4.1 software format to ASCII format,

then imported into the Matlab software package (Math-

works; Natick, MA) for further analysis with custom

programs.

Single trial evoked potentials were isolated from the

continuous EEG by aligning the signal with stimulus

markers to the nearest millisecond. These trials were ®ltered

with a bandpass (5±100 Hz) that includes those frequencies

which contribute the most power to auditory middle latency

components (Suzuki et al., 1983), and a bandstop ®ltered at

60 Hz. All ®lters were applied both forward and reverse to

eliminate phase distortion (Matlab's `®lt®lt' function).

2.3. Isolation of sleep stages for evoked potential

measurement

Continuous recordings were divided into 20 s epochs for

scoring of sleep stages, and initially screened for REM sleep

periods by simple power analysis: the average power in the

EEG channel between 12 and 14 Hz (`spindle' band), the

total power in the EOG channel, and the total power in the

EMG channel were plotted as a function of time for the

entire recording session (e.g. Fig. 1). Putative REM sleep

episodes were then easily detected as periods of greatly

reduced spindle power, increased EOG power (due to

REMs), and reduced submental EMG power (due to reduced

muscle tone). Final determination of sleep stage was

achieved by visual inspection of the EEG, EOG, and

EMG signals in 20 s epochs, and the application of tradi-

tional criteria as described in Rechtschaffen and Kales

(1968).

Average auditory evoked potentials were computed from

EEG signals recorded during the initial 30 min of the ®rst

REM episode of the night that lasted 30 min or longer. A

`REM episode' was considered to begin when two conse-

cutive 20 s epochs were scored as REM sleep, and end when

3 or more consecutive epochs were scored as non-REM

sleep or waking. A REM episode de®ned in this manner

could include epochs with movement artifact and arousals

as long as the subject returned to REM sleep within two

epochs. For all subjects, the average percentage of 20 s

epochs within a `REM episode' that were actually scored

as `REM epochs' by the criteria of Rechtschaffen and Kales

(1968) was 95.4% (SD � 3:1%). The majority of other

epochs contained within REM episodes were either `move-

ment time' or occasionally stage II sleep because of multiple

K-complexes. One subject never exhibited a REM episode

lasting 30 min. For this subject, the average evoked poten-

tial was computed from the EEG recorded during the initial

15 min of the two longest REM periods of the night.

For comparison, average evoked potentials were also

computed from signals recorded during non-REM sleep.

Efforts were made to compute these evoked potentials

from 30 min periods characterized by relatively stable

stage II sleep. In particular, the EEG signal recorded during

the 30 min directly preceding the last REM episode of the

night was utilized. This approach was motivated by the fact

that most slow-wave sleep (i.e. stage III and IV sleep)

occurs during the ®rst few hours of the night (Feinberg,

1974; BorbeÂly, 1982). If the subject awakened during this

period, the 30 min directly preceding the awakening were

used to compute the non-REM average auditory evoked

potential (N � 1). For the 30 min non-REM periods of all

10 subjects, the average number of 20 s epochs scored as

stage II sleep by the criteria of Rechtschaffen and Kales

(1968) was 86.5% (SD � 13:3%), which roughly agrees

with the percentage of non-slow-wave sleep occurring

during the later non-REM periods of the night for adults

(Bes et al., 1991). The majority of the other 13.5% of epochs

were scored either as `movement time' or stage III sleep.

2.4. Auditory sensory gating paradigm: T/C ratio

Pairs of clicks (0.5 s inter-click interval) were presented

every 10 s throughout the recording session, and average

evoked potentials computed separately for each click of the

pair. For each of the individual evoked potential compo-

nents, the magnitude of evoked response to the second

(`test') click of a pair was then compared with the magni-

tude of evoked response to the ®rst (`conditioning') click.

Speci®cally, a ratio of the magnitudes, the test/conditioning

or `T/C' ratio, was computed to quantify sensory gating. A

T/C ratio close to 0 indicates robust suppression (very small

test response compared with conditioning response) and a T/

C ratio of 1 indicates essentially no sensory gating (test and

conditioning responses were comparable in magnitude). In

the general population, T/C ratios for component P50 range

between 0 and well over 1, but are generally below 0.4 for

subjects without a personal or family history of psychosis

(Siegel et al., 1984; Waldo et al., 1994). Individuals af̄ icted

with schizophrenia usually have T/C ratios above 0.4 (e.g.

Adler et al., 1982). Thus, for the present study, T/C ratios for

component P50 below 0.4 are considered to represent

`intact' sensory gating. No equivalent de®nition has been

established for the other evoked potential components.

M.A. Kisley et al. / Clinical Neurophysiology 112 (2001) 1154±11651156


Fig. 1. Example of sleep staging techniques. (Top) Mean relative signal power for EEG (spindle frequency band only), EOG, and EMG channels; 3 consecutive

h, beginning in the middle of the night, divided into 20 s epochs. Note two separate periods with reduced spindle power and increased EOG power. The latter

episode, accompanied by suppressed EMG power, was REM sleep (broken lines indicate start and stop times for this period, determined by classical sleep

staging techniques applied to each 20 s epoch). The former was a period of waking. (Bottom) Twenty second epochs exemplifying waking, REM, and non-

REM periods. Note large, fast eye movements during REM sleep. Large, widespread K-complexes were detectable even on the EOG channel during the

illustrated non-REM epoch ± in this case stage II sleep. Positivity is plotted upwards.

2.5. Computation of average evoked potentials and

component de®nition

For all states of vigilance, average evoked potentials were

computed from single trial responses evoked during care-

fully de®ned 30 min intervals. During waking, the average

was computed from the ®rst 30 contiguous min of recording

time following the initial 5 minute acclimatization. The 30

min periods utilized for REM and non-REM sleep are

detailed above in the discussion of sleep stage scoring. Arti-

fact rejection was achieved by treating the value of each

signal channel (EEG, EOG, EMG) at each millisecond as

a normal random variable, and eliminating those single

trials that occurred when any of these channels contained

an extreme value. More speci®cally, for each channel, the

standard deviation (SD) of all signal values recorded during

the entire session was computed. If, during a single trial

evoked potential (from post-stimulus time 0 to 200 ms),

any of the signal channels exceeded 4 of its standard devia-

tions, that trial was excluded from further analysis. For each

30 min period, regardless of vigilance state, an average of

177 single trial conditioning and 177 single trial test evoked

responses were recorded. This represents a large number of

trials compared with other studies of auditory sensory gating

(typically 32 trials for each click of the pair). After artifact

rejection, the mean number of single trial conditioning/test

evoked responses available to compute average evoked

potentials was 164.9/163.2 (waking), 162.6/164 (REM)

and 161/158.8 (non-REM). As expected, the majority of

single trials rejected during REM sleep were due to extreme

values on the EOG channel (due to large eye movements),

and the majority rejected during non-REM sleep were due to

extreme values on the EEG channel (because of large,

synchronous events such as K-complexes). Single trials

evoked during arousals and movements were robustly

rejected by this method because of increased signal size

on the EMG channel and movement artifact on all 3 chan-

nels. The majority of trials rejected during the waking

condition were due to eye-blinks, clearly evident on the

EOG channel.

Auditory evoked potential components were de®ned as

follows: P30, positive wave, peaking between 25 and 45 ms;

P50, positive, peak 45±65 ms; and N100, negative, ®rst

trough .75 ms. Examples are shown in Fig. 2. To maintain

consistency with previous sensory gating literature, magni-

tudes of these components were measured from preceding

trough to peak (P30 and P50: Nagamoto et al., 1989) and

from preceding peak to trough (N100). When an expected

peak or trough was absent, the value at the nearest

`shoulder' (i.e. point of minimal slope) was used (P50 of

REM sleep conditioning response in Fig. 2B). Measurement

of the N100 amplitude was often confounded by the

presence of another positive wave after P50 but before

N100. Based on this wave's latency and polarity, it might

correspond to `TP78' of Wood and Wolpaw (1982), a

component usually more prominent over temporal regions.

The N100 magnitude was measured from this unde®ned

positive component when present (Fig. 2A,B), but otherwise

from the peak of wave P50 (conditioning response of Fig.

2C). Further complications arise because N100 is a multi-

component waveform (Fig. 2C; reviewed by Woods, 1995).

In this study, N100 was de®ned as the ®rst negative trough

(not shoulder) after 75 ms.

2.6. Statistics

All statistical hypothesis tests were planned in advance.

Two-sided, paired Student's t tests were used to compare the

mean evoked potential amplitude, latency, and T/C ratios

between waking and REM sleep, and between waking and

non-REM sleep. A repeated-measures analysis of variance

was utilized to determine if any of these variables, for any of

the individual evoked potential components, exhibited

signi®cant variation over the course of a 30 min REM

period. For all tests, the criterion for signi®cance was

a � 0:05. Statistical analysis was carried out with version

8 of SAS Analysis Software (SAS Institute, Inc.; Cary, NC).

3. Results

Average auditory evoked potentials in response to paired-

click stimuli were recorded from 10 control subjects during

two separate sessions: waking and sleeping. The upper

portion of Fig. 2A exempli®es conditioning and test evoked

responses for an individual while awake. Note that compo-

nent P30 was robustly present in response to both clicks of

the pair, indicating that this wave was not `gated'. This was

true of the sample in general, as the mean T/C ratio for P30

was 0.77 (SD � 0:44), not signi®cantly different from 1

(two-tailed, one-sample t test, d:f: � 9, P � 0:14). Compo-

nent N100, on the other hand, was strongly attenuated in

response to the test click for this particular individual and

for the sample (d:f: � 9, P , 0:001). Although the subject

in Fig. 2A did not exhibit sensory gating of component P50,

the sample as a whole did (d:f: � 9, P , 0:001). Average T/

C ratios and corresponding standard deviations are summar-

ized in Table 1.

3.1. Auditory sensory gating during REM sleep

Average evoked potentials and sensory gating were

measurable during REM sleep as well. The lower portion

of Fig. 2A shows the average conditioning and test evoked

responses for the same subject, now during REM sleep.

Compared with waking, component P50 was strongly

gated. For this subject and two others, the P50 T/C ratio

was elevated (.0.4) during waking and intact (,0.4) during

REM sleep. No subjects exhibited the opposite pattern.

However, one subject had elevated T/C ratios under both

conditions. Fig. 2B demonstrates perfect sensory gating (i.e.

T=C � 0) in another subject during REM sleep. Generally,

the mean T/C ratio for component P50 was lower in REM



Fig. 2. Average auditory evoked potentials across different states of vigilance. (A; top) Example of averaged condition and test responses evoked during

waking. This subject showed poor gating of component P50 (T=C � 1:23). Wave N100, which was strongly suppressed in response to the test click

(T=C � 0:20), was measured from the preceding, unidenti®ed shoulder near 70 ms for this subject. (A; bottom) Condition and test responses for the same

subject during REM sleep. The sensory gating of component P50 was greatly improved (T=C � 0:11), whereas N100 suppression was poorer compared with

the awake state (T=C � 0:74). Wave P30 did not exhibit suppression during either waking or REM sleep (T=C � 1:18 and 1.24, respectively). (B) Condition and

test responses evoked during waking (top) and REM sleep (bottom) for another subject. Note complete suppression of component P50 in response to the second

click of the pair (T=C � 0) during REM sleep. For all evoked potentials, positivity is plotted upwards.

sleep than during waking for the sample (mean reduction,

0.19), but not signi®cantly so (d:f: � 9, P � 0:21). This

reduction in T/C ratio was anticipated, but the power to

declare this difference signi®cant based on this particular

sample is only 23%. A power of 80% would require a

sample of approximately 45 subjects.

A summary of change in T/C ratios for all subjects and all

evoked potential components is shown in Fig. 3. Sensory

gating of component P30 did not change between waking

and REM, but gating of wave N100 did. In particular,

response suppression due to redundant acoustic stimulation

for N100 was signi®cantly poorer during REM sleep

compared with waking (Table 1).

In response to the conditioning click, the latency and

amplitude of the 3 evoked potential components were differ-

entially affected by REM sleep. In particular, the peak of

P30 and the trough of N100 were both signi®cantly delayed

in time during REM sleep compared with waking (Table 2).

Regarding the evoked potential magnitude, P30 remained

unchanged, P50 exhibited a trend towards reduction

(d:f: � 9, P � 0:0575), and N100 was signi®cantly reduced

(Table 3).

In order to determine if any evoked potential variables

changed over the course of a 30 min REM period, separate

repeated-measures ANOVAs were applied to the T/C ratio,

the conditioning response latency, and the conditioning

response amplitude for each of the 3 evoked potential

components. Speci®cally, average evoked potentials were

computed individually from 3 adjacent 10 min periods, and

appropriate measures were taken (N � 9, because one

subject never exhibited a REM episode lasting 30 min).

Assessed in this manner, none of the variables exhibited

signi®cant time-effects (d:f: � 2,16; a � 0:05). This

implies that any ¯uctuation of auditory sensory gating

measures exhibited over the course of a given REM sleep

period was random across subjects.

3.2. Auditory sensory gating during non-REM sleep

Auditory sensory gating was also assessed during non-

REM sleep in 8 subjects. The remaining two individuals

were without observable P30 and P50 components during

this sleep stage. Like REM sleep, the N100 component

exhibited signi®cantly poorer gating during non-REM

sleep compared with waking (Table 1). Average T/C ratios

for both P30 and P50 were not signi®cantly different from

the awake condition. For 3 of 8 subjects, component P50

exhibited elevated T/C ratios during non-REM sleep,

including one subject that had a T/C ratio of 0 during

waking. The only signi®cant change in latency from waking

to non-REM sleep was a delay of more than 5 ms for wave

P30's peak (Table 2). P50 and N100 amplitudes in response

to the conditioning click were both attenuated compared

with waking, but neither were signi®cantly so (Table 3;

trend for N100: d:f: � 7, P � 0:08). As during REM

sleep, no systematic variation in evoked potential and

sensory gating measures was detected over the course of a


Fig. 3. Change in sensory gating from waking to REM sleep for each

subject, for each evoked potential component. The plus sign indicates the

corresponding average T/C ratio for all 10 subjects. P50 T/C ratios above

dotted line (at 0.4) are considered to be above the normal range by tradi-

tional criteria. For wave P50, gating appears to have generally improved

(i.e. T/C ratios tended to decrease) in REM sleep. In contrast, suppression

was clearly stronger during waking for wave N100. No systematic pattern

of change is obvious for P30.

Table 2

Mean latencya for each wave as a function of state

P30 P50 N100

Awake 32.6 (3.0) 57.5 (2.7) 92.8 (6.9)

REM 37.9 (4.1)b 59.2 (2.4) 101.6 (9.4)b

Non-REMc 37.9 (2.3)d 57.1 (6.4) 95.3 (14.2)

a Mean latency (ms); SD in parentheses.b Signi®cantly different than awake, two-sided paired t test, P , 0:05.c N � 8 for computation of means and for t tests.d P , 0:01.

Table 1

Mean T/C ratioa for each wave as a function of brain state

P30 P50 N100

Awake 0.77 (0.44) 0.34 (0.42) 0.24 (0.16)

REM 0.94 (0.43) 0.15 (0.27) 0.69 (0.15)b

Non-REMc 1.17 (0.58) 0.33 (0.43) 0.75 (0.36)d

a SD in parentheses.b P , 0:0001.c N � 8 for computation of means and for t tests.d Signi®cantly different than awake, two-sided paired t test, P , 0:05.

given 30 min non-REM sleep episode when that period was

divided into 3 periods of 10 min each (repeated-measure

ANOVA, d:f: � 2,14; a � 0:05).

4. Discussion

This study demonstrates that sensory gating of auditory

evoked potential component P50 can be measured during

REM sleep. Theoretically, gating measures involving this

particular wave should be more reliable during REM sleep

because of reduced noradrenergic activity (Hobson et al.,

1975) and inattentiveness to the external sensory environ-

ment. Accordingly, we expected P50 T/C ratios to be lower

during REM sleep than during waking. Our results are

consistent with this notion, but not statistically signi®cant

due to sample size. To maximize the signal-to-noise ratio of

the average evoked potential, analysis was restricted to

REM sleep lasting for 30 continuous min. Nevertheless,

we believe that auditory sensory gating could be measured

during shorter REM episodes because all such periods

during the night, except the ®rst, exhibit similar acoustic

transfer properties as measured by evoked potentials

(RoÈschke et al., 1995).

Although paired-click evoked potential measures were

generally obtainable during non-REM sleep, several

features of this brain state make it less desirable for clinical

research involving auditory gating, especially for compo-

nent P50. First, the correlation between intact and elevated

T/C ratios between states was poor: for some subjects,

gating improved from waking to non-REM, while for

others, it worsened. Also, two of 10 subjects could not be

studied during non-REM sleep because P30 and P50

components could not be detected in the average evoked

potential.

The sensory gating of waves P30 and N100 was also

assessed in this study. Component P30 did not exhibit

response suppression during any state: waking, REM

sleep, or non-REM sleep. Surprisingly, gating of N100

was signi®cantly poorer (i.e. better `recovery') during

REM sleep than during waking. This effect cannot be

explained by differences in attention between waking and

sleeping, because previous studies have shown that reduced

attention to the paired-click stimulus leads to better auditory

sensory gating of wave N100 (Jerger et al., 1992; White and

Yee, 1997). Further, this ®nding is not likely to be explained

by changes in the activity of a single neurotransmitter

system ± e.g. noradrenergic or cholinergic ± because gating

of component N100 was also disrupted during non-REM

sleep. An intriguing hypothesis is that different sub-compo-

nents of vertex wave N100 have different gating ± or recov-

ery ± functions (LuÈ et al., 1992), and further that these sub-

components are differentially detectable during waking and

sleeping states (i.e. one is larger during waking, the other

during sleep). Consistent with this idea, we found N100

latency to be longer during sleep than during waking, parti-

cularly for REM sleep. Since sub-components of wave

N100 exhibit differential scalp distributions (reviewed by

Woods, 1995), the validity of this explanation for the

observed state-dependent modulation of N100 sensory

gating could be pursued with multiple electrodes distributed

over the head.

4.1. Comparison with previous studies

Although several investigators have examined the effect

of sleep on evoked potential components P30, P50 and

N100, there are no reports describing sensory gating of

these waves during sleep. Our ®ndings for the waking

condition are consistent with previous studies demonstrat-

ing essentially no response suppression as a function of

stimulus repetition for wave P30 (Goldstein et al., 1972;

Erwin and Buchwald, 1986a) compared with strong sensory

gating for components P50 (Adler et al., 1982) and N100

(Nelson and Lassman, 1968) in control subjects. Investiga-

tions of P50 gating during waking have estimated that one in

10 healthy individuals actually exhibit T/C ratios in the

elevated range (.0.4, Siegel et al., 1984; Waldo et al.,

1994). We found a similar proportion in our sample for

the REM sleep condition. This suggests that 10% of indivi-

duals without a positive personal or family history of schi-

zophrenia might still have a state-independent impairment

in auditory sensory gating. Although genetic linkage has

implicated a speci®c locus on chromosome 15 in the proper

and improper expression of P50 sensory gating in families

of individuals with schizophrenia (Freedman et al., 1997),

no evidence yet exists that elevated T/C ratios in control

subjects can be attributed to modi®cations at the same

region of the genome. Further, environmental ± rather

than genetic ± factors could be responsible for `abnormal'

sensory gating in these healthy individuals.

It is unclear why 4 of 10 control subjects exhibited T/C

ratios above 0.4 during waking in the present study,

compared with one of 10 in previous studies. Screening

procedures might account for the differences, as subjects

in the present study were not formally assessed for drug

use, a behavior that can impair sensory gating (Boutros et

al., 2000; Patrick and Struve, 2000; Adler et al., 2001).

Variations in brain state, particularly wakeful alertness

(Grif®th et al., 1993; but see Cardenas et al., 1997) and


Table 3

Mean amplitudea for each wave, evoked by the conditioning click, as a

function of state

P30 P50 N100

Awake 1.65 (1.11) 1.93 (1.57) 6.38 (2.69)

REM 1.67 (0.62) 0.96 (0.57) 4.10 (1.43)b

Non-REMc 1.99 (1.01) 1.06 (0.84) 3.65 (1.41)

a Mean amplitude (mV); SD in parentheses.b Signi®cantly different than awake, two-sided paired t test, P , 0:05.c N � 8 for computation of means and for t tests.

acute stress (Adler et al., 1994), could also have caused

elevated T/C ratios in some of these control subjects.

Regarding modulation of amplitude and latency for indi-

vidual evoked potential components by REM and non-REM

sleep, the present results generally support previous inves-

tigations with one notable exception: the amplitude of wave

P50 during non-REM sleep. In contrast to Erwin and Buch-

wald (1986b) who reported a virtual absence of component

P50 during stage II sleep for all 14 of their subjects, we

found clear evoked potential components corresponding to

P50 in 8 of our 10 subjects during non-REM (mostly stage

II) sleep. Further, we found the mean amplitude of P50

during non-REM sleep to be approximately equal to that

for REM sleep. Methodological elements which differed

between our studies might be responsible for the discre-

pancy. Erwin and Buchwald (1986b) ®ltered auditory

evoked potentials between 10 and 300 Hz, whereas we

®ltered between 5 and 100 Hz. Since evoked potentials

were recorded with a wide bandpass (0.1±200 Hz) for the

present study, and subsequently ®ltered digitally, we are

able to compare the effect of different cut-off frequencies

on the magnitude of wave P50. The example shown in Fig.

4A demonstrates that a ®lter very similar to that used by

Erwin and Buchwald (10±200 Hz) does not reduce the

amplitude of P50 evoked during non-REM sleep. Thus,

the difference in ®lter parameters probably cannot explain

the discrepancy in results between the present study and that

of Erwin and Buchwald (1986b).

We feel the difference between acoustic stimulation para-

digms utilized in the two studies is more likely to be respon-

sible for the disparate ®ndings regarding the magnitude of

wave P50 during non-REM sleep. The critical variable is

probably the inter-click interval. Erwin and Buchwald

(1986b) presented auditory clicks in trains at 1 Hz, whereas

we employed the paired-click paradigm. Average evoked

potentials were computed from all evoked responses in a

click-train for the former (inter-click interval, 1 s), and only

from the conditioning evoked responses for the latter (inter-

click interval, 10 s). Like Erwin and Buchwald, Jones and

Baxter (1988) reported the disappearance of component P50


Fig. 4. Example of ®ltering effects on average evoked responses recorded during non-REM sleep. (A) Response to conditioning click. (Top) Evoked potential

comprised of single trials ®ltered between 5 and 100 Hz. (Bottom) Evoked potential computed from the same single trials, now ®ltered between 10 and 200 Hz

(similar to Erwin and Buchwald, 1986b). Note the overall similarity between evoked responses, most notably the clear detectability of component P50. (B)

Example test response recorded during non-REM sleep (does not correspond to conditioning response in (A)). (Top) Note that component P50 is virtually

absent (i.e. it is gated) when single trials are ®ltered between 5 and 100 Hz. (Bottom) Filtering the single trials between 0.3 and 15 Hz distorts the average

evoked waveform, making it appear to contain a clear `P50' wave (latency� 58 ms).

during non-REM sleep when clicks were presented in rapid

trains (5 Hz), even though very wide-band ®lters (0.3±3000

Hz) were applied to the evoked potential signal. In compar-

ison, studies using click-trains at slower rates of presenta-

tion (#0.5 Hz) have consistently reported the robust

presence of component P50 across all sleep stages, includ-

ing II, III, and IV in adults (Williams et al., 1962; Weitzman

and Kremen, 1965; Kevanishvili and von Specht, 1979) and

children (Barnet et al., 1975).

To summarize, vertex component P50 appears to be

measurable under non-REM sleep for most subjects in

response to the conditioning click for the paired-click para-

digm, and also in response to clicks during the click-train

paradigm for rates of 0.5 Hz or less, but not for rates of 1 Hz

or more. Two studies in the literature at ®rst seem to contra-

dict this conclusion. de Lugt et al. (1996) described a clear

P50 component during all sleep stages in response to clicks

presented at 1.67 Hz. However, their signal was low-pass

®ltered at 15 Hz. Utilizing such an extreme cut-off

frequency could have distorted the evoked potential wave-

forms suf®ciently to lead these investigators to mistake

component P30 for P50 (e.g. see Fig. 4B). Paavilainen et

al. (1987) also reported the presence of P50 during stage II

sleep when click-trains of 1.96 Hz were used. However,

their de®nition of component P50 was unusual: the largest

positivity between 0 and 100 ms post-stimulus. This overly

general de®nition could have allowed other waveform

components ± such as P30, TP78 (Wood and Wolpaw,

1982), or evoked slow-wave activity that would not have

been attenuated by their high-pass ®lter at 1 Hz ± to be

mistakenly identi®ed as P50.

5. Conclusion

Motivation for this study came from the growing realiza-

tion that functional assessment of the nervous system orga-

nization depends crucially on the brain and behavioral state

under which measurements are taken (e.g. Kisley and

Gerstein, 1999; WoÈrgoÈtter and Eysel, 2000). The present

results demonstrate two relevant, and related points: (1),

measurement of component P50 auditory gating can be

achieved during REM sleep; and (2), intact sensory gating

of this wave does not depend on a particular brain state, and

is thus likely to be determined by trait. It remains to be

demonstrated that the genetically-determined difference in

sensory gating, previously observed between waking

control and schizophrenia populations, also exists during

REM sleep. This demonstration would con®rm the appro-

priateness of REM sleep for future auditory gating studies

involving clinical populations.

Acknowledgements

For helpful discussion and suggestions, the authors grate-

fully acknowledge Drs Lawrence Adler, Randal Ross, and

Merilyne Waldo. Technical assistance was provided by

Kara McRae and Ellen Cawthra. This work was supported

by the Veteran's Administration Medical Research Service

and the US National Institute of Mental Health (MH4212,

MH38321).

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