Download Sensory gating impairment associated with schizophrenia persists

Psychophysiology, 40 (2003), 29–38. Blackwell Publishing Inc. Printed in the USA.
Copyright r 2003 Society for Psychophysiological Research
Sensory gating impairment associated with
schizophrenia persists into REM sleep
MICHAEL A. KISLEY, ANN OLINCY, EMILY ROBBINS, SHERRIE D. POLK,
LAWRENCE E. ADLER, MERILYNE C. WALDO, AND ROBERT FREEDMAN
Department of Psychiatry, University of Colorado Health Sciences Center and Denver Veteran’s Affairs Medical Center,
Denver, Colorado, USA
Abstract
Physiological measures of sensory gating are increasingly used to study biological factors associated with attentional
dysfunction in psychiatric and neurologic patient populations. The present study was designed to assess sensory gating
during rapid eye movement (REM) sleep in patients with schizophrenia, a population bearing a genetic load for gating
impairment. Auditory event-related potentials (ERPs) were recorded in response to paired clicks during separate
waking and overnight sleep recording sessions in controls and schizophrenia patients. Suppression of ERP component
P50 was significantly impaired in the patient group during both waking and REM sleep, whereas the difference
between groups for N100 gating was dependent on state. These results suggest that REM sleep is an appropriate state
during which to assess P50 gating in order to disentangle the effects of state and trait on sensory gating impairment in
other clinical populations.
Descriptors: Sensory gating, REM sleep, Schizophrenia, Auditory event-related potentials, P50, N100
potential. Whether sensory gating measured physiologically
correlates with behavioral measures of attentional filtering on a
person-by-person basis remains controversial (compare Jin et al.,
1998 to Light & Braff, 2000). Nevertheless, physiological gating
abnormalities associated with schizophrenia have been linked to
a specific chromosomal locus (15q14: Freedman et al., 1997).
This same locus has subsequently been linked to a broader
phenotypeFdiagnosis of schizophrenia (Riley et al., 2000;
Stober et al., 2000)Fconsistent with the notion that sensory
gating impairment, as measured electrophysiologically, is an
inherited trait in families with a history of schizophrenia.
The relative ease of sensory gating assays, and an increasing
understanding of the neural mechanisms responsible for this
phenomenon (reviewed by Adler et al., 1998), make sensory
gating an attractive variable for study in clinical research. For
example, efforts are currently underway to relate sensory gating
impairments to specific genetic polymorphisms in the promoter
region of the human a7 nicotinic receptor gene (Leonard et al.,
2001). Abnormalities in the expression and/or function of these
low-affinity nicotine receptors are believed to underlie sensory
gating deficits associated with schizophrenia (Leonard et al.,
2000). Investigators are also beginning to employ sensory gating
measures in attempts to understand the biological basis of other
clinical syndromes associated with attentional dysfunction
including attention-deficit/hyperactivity disorder (Olincy et al.,
2000), post-traumatic stress disorder (Neylan et al., 1999;
Skinner et al., 1999), drug dependence (Adler et al., 2001;
Boutros et al., 2000; Patrick & Struve, 2000), and various
neurological conditions (Ambrosini, De Pasqua, Afra, Sandor,
& Schoenen, 2001; Arciniegas et al., 2000; Jessen et al., 2001;
Persons afflicted with schizophrenia suffer from, among other
symptoms, dysfunction in the allocation of attention (McGhie &
Chapman, 1961). For these individuals a perceptual impairmentFan inability to ignore, or filter out, irrelevant sensory
informationFis paralleled by a neurophysiological abnormality
in ‘‘sensory gating’’ (Cullum et al., 1993; Erwin, Turetsky,
Moberg, Gur, & Gur, 1998). Typically, sensory gating is assessed
by comparing the magnitude of evoked brain activity in response
to repetitive auditory stimuli. After the first stimulus, electroencephalographic activity evoked by subsequent stimuli is
attenuated (i.e., ‘‘gated’’) in a majority of healthy persons.
However, individuals with schizophrenia (Adler et al., 1982;
Boutros, Zouridakis, & Overall, 1991; Erwin, Mawhinney-Hee,
Gur, & Gur, 1991; Jerger, Biggins, & Fein, 1992; Judd,
McAdams, Budnick, & Braff, 1992) and many of their
unaffected first degree relatives (Clementz, Geyer, & Braff,
1997; Siegel, Waldo, Mizner, Adler, & Freedman, 1984; Waldo
et al., 1994) do not exhibit this type of response inhibition,
particularly for component P50 of the auditory event-related
For helpful discussion and suggestions, the authors gratefully
acknowledge David Dinges, Adrian Morrison, Randal Ross, Kimberly
Indermaur, and Herb Nagamoto. Technical assistance was provided by
Ryan Paterson, Michael All, Bernadette Sullivan, and Katie Lockley.
This work was supported by the Veteran’s Affairs Medical Research
Service and the U.S. National Institute of Mental Health (MH64466,
MH38321).
Address reprint requests to: Michael Kisley, Department of
Psychology, University of Colorado at Colorado Springs, 1420 Austin
Bluffs Parkway, Colorado Springs, CO 80933-7150, USA. E-mail:
[email protected].
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Teo et al., 1997). Because sensory gating measures are sensitive to
state, particularly acute stress (Johnson & Adler, 1993; White &
Yee, 1997), it is important in future studies to distinguish between
transient gating impairments and gating abnormalities due to
persistent brain modification caused by genetic program and/or
environmental insult. This is especially true for reactive populations, such as children and traumatized individuals.
To overcome the potential confound of brain state, we
propose to assess sensory gating during rapid eye movement
(REM), or ‘‘paradoxical’’ sleep. REM sleep is characterized by a
cessation of activity in the locus coeruleus (Hobson, McCarley,
& Wyzinski, 1975), a brainstem nucleus providing the norepinephrine innervation for the entire brain. This is important
because increased central noradrenergic activity is believed to
underlie transient gating impairments associated with control
subjects’ state (Adler, Pang, Gerhardt, & Rose, 1988; Adler
et al., 1994; Stevens, Meltzer, & Rose, 1993). It has recently
been shown that sensory gating can be assessed during sleep in
healthy adults, and that gating measures taken during REM
sleep are within the previously established ‘‘normal’’ range for
control subjects (Kisley, Olincy, & Freedman, 2001). However, it
has not been shown that populations known to exhibit high rates
of gating impairment during wakingFsuch as persons with
schizophreniaFalso exhibit high rates of gating impairment
during REM sleep. Such a demonstration would establish that
(a) sensory gating abnormalities associated with schizophrenia
are not state dependent, and (b) REM sleep is an appropriate
brain state under which to measure sensory gating in future
clinical studies.
The present study was designed to test three novel hypotheses:
(a) patients with schizophrenia differ from control subjects in
their ability to filter auditory stimuli, as measured by a pairedclick paradigm, during REM sleep; (b) this difference between
groups is similar across waking and REM sleep states, consistent
with a state-independent impairment; (c) sensory gating varies
over the course of a REM sleep period for schizophrenia patients.
The third hypothesis was tested because previous studies have
shown that P50 gating can be transiently normalized in schizophrenia patients immediately after awakening from a bout of
non-REM sleep (Griffith & Freedman, 1995; Griffith, Waldo,
Adler, & Freedman, 1993). Therefore, because REM sleep
follows non-REM sleep in adults, we expected schizophrenia
patients to exhibit ‘‘normal’’ P50 gating during the first few
minutes of a REM sleep period. In addition to, and for
comparison with, event-related potential component P50 (i.e.,
P1 or Pb) we assessed the state-dependence of wave N100 (i.e., N1
or Nb), as this wave is also commonly employed to study sensory
gating.
Methods
Participants
Procedures were approved by the Colorado Multiple Institute
Review Board. Participants gave written informed consent, and
received monetary compensation upon completion of the study.
Exclusion criteria for all participants were current illicit
substance use and past traumatic brain injury (requiring loss of
consciousness lasting at least 5 min after head injury), both of
which have been shown to affect sensory gating measures (e.g.,
Arciniegas et al., 2000; Boutros et al., 2000). Also, patients
taking clozapine were excluded because this atypical antipsycho-
M.A. Kisley et al.
tic has been shown to modify sensory gating measures
(Nagamoto et al., 1999). Diagnosis of schizophrenia was
confirmed for all patients by the Structured Clinical Interview
for DSM-IV Axis I Disorders (SCID-I: First, Gibbon, Spitzer, &
Williams, 1996) except for one man, who did not complete a
diagnostic interview, but met diagnostic criteria based on
informal interview and review of medical records. Eleven patients
with schizophrenia completed the study; 1 was excluded from
analysis as he exhibited less than 5 min of REM sleep, leaving 5
men and 5 women (mean age 41.6, range 20–50 years). The
control group, consisting of volunteers from the local community, also consisted of 5 men and 5 women, and mean age of 34.4
years (range 21–47) was not significantly different from the
patients. Three patients and 1 control were smokers. All patients
were taking antipsychotic medications (2 olanzapine, 2 quetiapine, 2 risperidone, 1 olanzapine and risperidone, 1 quetiapine
and thiothixene, and 2 loxapine). One patient on loxapine was
taking an anticholinergic medication.
Electrophysiology
Ongoing electroencephalographic (EEG) and stimulus-evoked
brain activity were recorded (Neuroscan Acquisition System:
SynAmps amplifiers, Scan 4.1 acquisition software; Sterling,
VA) from each participant during two separate sessions: one
during daytime waking, and one during overnight sleep. Two
patients and 3 controls preferred to undergo the overnight sleep
recording before the daytime waking recording. Sleep staging
and event-related potentials measurements were taken from
vertex (Cz) referenced to right ear. Electrooculogram (EOG) was
recorded in a bipolar configuration between electrodes directly
superior and lateral to the left eye. During overnight recordings,
the electromyogram (EMG) was also recorded with a bipolar
submental configuration (Rechtschaffen & Kales, 1968). A
ground electrode was attached to the left ear. All electrodes were
gold-plated 10-mm disc (Grass; West Warwick, RI), affixed with
Ten20 conductive paste (D.O. Weaver and Co.; Aurora, CO) and
surgical tape (no tape was used for ear-clip electrodes). All
impedances were maintained below 10 kO.
Average auditory event-related potentials were computed
from the EEG activity immediately following acoustic clicks
(1-ms duration), which were delivered to the participants through
insert earphones. The click intensity was 40 dB above hearing
level. Before recording, both ears were tested independently for
all participants (method of limits) to ensure normal hearing.
Clicks occurred in pairs (0.5-s interclick interval) and pairs
occurred every 10 s.
During the waking recording, supine participants were
instructed to keep their eyes open and still during the click pairs.
After 5 min acclimatization, recording began and lasted until 20
min of data had been acquired. Typically participants took one
break during the recording. For 2 control participants, recording
was paused because of the presence of slow waves and vertex
sharp waves in the EEG, and the participants were roused. Overnight sleep recordings were performed in the same laboratory
using identical equipment. The acoustic clicks occurred continuously throughout the night.
For acquisition, EEG signals were amplified 5,000 times and
filtered between 0.1 and 200 Hz, EOG amplified 1,000 times and
filtered between 0.1 and 100 Hz, EMG amplified 12,500 times
and filtered between 5.0 and 200 Hz. All channels were sampled
at 1000 Hz. Continuously recorded data were converted from
Neuroscan’s Scan 4.1 software format to ASCII format, then
Sensory gating impairment during REM sleep
imported into the Matlab software package (Mathworks;
Natick, MA) for further analysis with custom programs.
Isolation of REM Sleep Episodes for Event-Related Potential
Measurement
Continuous overnight recordings were divided into 20-s epochs
for scoring of sleep stages, and initially screened for REM sleep
periods by analyzing EEG power in the spindle (12–14 Hz) band,
total EOG power, and total EMG power. Putative REM
episodes were then identified as periods of greatly reduced spindle
power, increased EOG power, and reduced submental EMG
power (for more detail and an example, see Kisley et al., 2001).
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 traditional criteria as described in
Rechtschaffen and Kales (1968) by a blind rater. Stage I sleep
was discriminated from REM sleep by the absence of rapid eye
movements and elevated EMG activity. Stage II was identified
by the presence of spindle activity and K-complexes in the EEG.
Stages III and IV were characterized by the presence of delta
waves (up to 2 Hz) in the EEG.
Average auditory event-related potentials were computed
from EEG signals recorded during the initial 20 min of the first
REM episode of the night that lasted 20 min or longer. The
duration was set at 20 min because all participants exhibited
REM periods at least this long. A distinct ‘‘REM episode’’ was
considered to begin when two consecutive 20-s epochs were
scored as REM sleep, and end when three or more consecutive
epochs were scored as non-REM sleep or waking. Defined in this
manner, a REM episode could include epochs containing
movement artifact, arousals, K-complexes, and spindles as long
as the participant returned to REM sleep within two epochs.
Sensory Gating Paradigm and the T/C Ratio
Pairs of clicks (0.5-s interclick interval) were presented every 10 s
throughout the recording session, and average event-related
potentials computed separately for each click of the pair. The
amplitude of wave P50 to the second (test) click of a pair was then
compared with P50 magnitude evoked by the first (conditioning)
click. Specifically, 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 from 0 to 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 with schizophrenia usually have T/C ratios
above 0.5 (e.g., Adler et al., 1982). For the present study, to
prevent bias from outliers, T/C ratios above 2.0 were assigned a
value of 2.0. This affected the P50 T/C ratio for 2 patients during
the waking recording and 2 patients during the REM sleep
recording.
Computation of Average Event-Related Potentials and
Component Definition
For both states of vigilance, average event-related potentials
were computed from single-trial responses evoked during carefully defined 20 min intervals. During waking, the average was
computed from the first 20 contiguous minutes of recording time
following the initial 5-min acclimatization. The 20-min periods
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utilized for REM sleep are detailed above in the description of
sleep stage scoring. Single-trial event-related potentials, epoched
from 100 ms before to 200 ms after each click, were detrended
(linear) and subject to artifact rejection. In particular, if the signal
on any channel (EEG, EOG, EMG) exceeded 775 mV during an
event-related potential epoch, that trial was excluded from
further analysis. After this step, the number of single trials
remaining for averaging ranged from 72 to 116 for controls and
77 to 111 for patients during the waking recording, and from 97
to 113 for controls and 99 to 113 for patients during the analyzed
REM episode. Average waveforms computed from the remaining single trials were band-pass filtered between 5 and 100 Hz to
accentuate component P50 (Suzuki, Kobayashi, & Hirabayashi,
1983). This filter was applied both forward and reverse to
eliminate phase distortion (Matlab’s ‘‘filtfilt’’ function).
Component P50 in response to the conditioning click was
defined as the first positive waveform peak between 50 and 75 ms.
When no such peak was evident (N 5 1 control subject), the most
positive peak between 40 and 50 ms was used. Component P50
for the test click was determined the same way, with the
restriction that the peak latency must be within 710 ms of the
conditioning latency. If no peak satisfied these criteria, the P50
test amplitude was taken as zero. To maintain consistency with
previous sensory gating literature, P50 magnitude was measured
from the preceding negative trough, the N40 (Nagamoto, Adler,
Waldo, & Freedman, 1989). When an expected peak or trough
was absent, the value at the nearest ‘‘shoulder’’ (i.e., point of
minimal slope) was used. All subjects exhibited conditioning P50
waves larger than 0.5 mV during the waking state.
To make selection of component N100 easier, average
waveforms were filtered again with a low-pass at 50 Hz to
remove small and fast fluctuations. N100 was then defined for
the conditioning click as the first negative trough later than 75
ms. The test N100 was similarly identified, with the added
restriction that the trough must be within 720 ms of the
conditioning latency. N100 amplitude was measured from the
preceding positive peak, which was usually the P50, but
occasionally a distinct positive component occurring after P50
(Kisley et al., 2001). Although N100 amplitude is often measured
relative to prestimulus baseline activity, we employed a peak-totrough measurement to maintain consistency with the method of
analysis for component P50. To ensure that this approach did not
bias the present results, we repeated all analyses of N100
variables based on amplitude measures from baseline (mean over
50 ms preceding clicks). Although the mean N100 amplitudes
were smaller with this method, the results of statistical
comparison between groups and across states were essentially
unchanged (not shown).
Statistics
Event-related potential and sensory gating measures were
compared across groups by one-way ANOVA, computed
separately for the waking and REM-sleep states. The effect of
state on sensory gating, particularly the expected difference
between groups, was assessed by repeated measure ANOVA:
waking versus REM as within-group factors and control versus
patient as between-group factors. To investigate whether eventrelated potential and sensory gating measures changed over time
during a REM episode, repeated measures ANOVA was also
applied to serial measurements taken at 5-min intervals. To
protect against Type I errors, the degrees of freedom for all
32
M.A. Kisley et al.
Figure 1. Example of strong response suppression during waking in a control subject. Top: Average event-related brain potential
evoked by the first (conditioning) and second (test) click. Clicks occur at time 5 0 ms. Wave amplitude was measured from N40
trough (tick mark) to P50 peak. Dividing amplitude of test P50 by amplitude of conditioning P50 leads to a T/C ratio of 0.25.
Bottom: The identical waveforms after further low-pass filtering to accentuate component N100. For this and all other figures,
positivity is plotted upwards.
repeated measures ANOVAs were adjusted by the method of
Greenhouse and Geisser (1959).
Results
Comparison of Groups during the Waking State
Sensory gating measures taken during the waking state differed
between control and schizophrenia groups. In general, control
subjects exhibited strong suppression of event-related potential
components P50, mean T/C 5 0.39, range 0.01–1.22, and N100,
mean 0.24, range 0.00–0.68, whereas schizophrenia patients did
not, P50: mean 0.93, range 0.04–2.00; N100: mean 0.85, range
0.24–1.83. Figures 1 and 2 exemplify event-related potentials
recorded from a control and patient, respectively. T/C ratios
were significantly different between groups for both P50,
F(1,18) 5 5.20, p 5 .035, and N100, F(1,18) 5 12.24, p 5 .003.
No other event-related potential variables were significantly
different for wave P50, but N100 test amplitude was significantly
larger in patients, F(1,18) 5 7.91, p 5 .012. Results are summarized in Tables 1 and 2.
Comparison of Groups during the REM-Sleep State
Sensory gating measures taken during REM sleep also differed
between control and schizophrenia groups. Control subjects, in
general, exhibited strong suppression of event-related potential
components P50, mean T/C 5 0.20, range 0.00–0.57, but not
N100, mean T/C 5 0.89, range 0.36–1.93; schizophrenia patients
did not suppress either component during REM sleep, P50: mean
T/C 5 0.93, range 0.00–2.00; N100: mean 0.74, range 0.17–1.81.
Event-related potentials recorded from 2 schizophrenia patients
during REM sleep are shown in Figure 3. T/C ratios were
significantly different between groups for component P50,
F(1,18) 5 9.25, p 5 .007, but not N100. Unlike waking, P50 test
amplitude differed between groups, F(1,18) 5 6.75, p 5 .018.
Results are summarized in Tables 3 and 4.
REM sleep variables were assessed to ensure that the
observed difference in P50 sensory gating between groups was
not simply due to differences in sleep architecture. Although
there was a trend suggesting that controls had more distinct
REM episodes during the entire night than patients, mean 5 3.0
versus 1.9, p 5 .051, there was no significant difference between
groups in the total number of minutes constituting ‘‘REM
episodes’’ or in the total percentage of epochs during those
episodes considered to be classical ‘‘REM epochs’’ (Table 5).
Considering only those REM episodes used for computing
average event-related potentials, there was no significant
difference between groups in the rank of REM episode used
(i.e., first of the night, second, etc.), the overall length of those
episodes, or the percentage of epochs within those episodes that
were scored as REM sleep (Table 6).
33
Sensory gating impairment during REM sleep
Figure 2. Example of impaired response suppression during waking in a patient with schizophrenia. Top: Analysis of conditioning
and test P50 responses yields a T/C ratio in the elevated range. Bottom: Analysis of N100 gating is achieved by further filtering.
Table 1. P50 Variables Compared between Controls and Patients
during Waking
Conditioning
amplitude (mV)
Test amplitude (mV)
Conditioning
latency (ms)
Test latency (ms)
T/C ratio
Controls:
Mean (SD)
Patients:
Mean (SD)
p-value
1.51 (0.62)
0.67 (0.81)
1.63 (1.27)
1.85 (2.58)
.789
.183
56.8 (7.9)
58.5 (8.0)
0.39 (0.35)
55.6 (3.4)
56.6 (4.7)
0.93 (0.66)
.665
.524
.035
Table 2. N100 Variables Compared between Controls and Patients
during Waking
Conditioning
amplitude (mV)
Test amplitude (mV)
Conditioning
latency (ms)
Test latency (ms)
T/C ratio
Controls:
Mean (SD)
Patients:
Mean (SD)
p-value
5.66 (2.02)
1.05 (1.03)
4.37 (1.62)
3.74 (2.84)
.133
.012
96.1 (9.8)
92.8 (14.3)
0.24 (0.26)
92.2 (8.1)
87.3 (9.8)
0.85 (0.49)
.344
.340
.003
Notes: One-way ANOVA 1,18 df. Bold entries highlight significant
differences between groups.
Notes: One-way ANOVA 1,18 df; test latency 1,17 df. Bold entries
highlight significant differences between groups.
Effect of State on Sensory Gating Measures
To assess the effect of state on sensory gating, repeated measures
ANOVAs were applied across state (waking vs. REM sleep),
with diagnosis (control vs. schizophrenia) as a between-groups
factor. For component P50, no significant state or State Diagnosis effects were found for T/C ratio, conditioning, or test
amplitudes or latencies. For component N100, significant effects
of state on T/C ratio, F(1,18) 5 5.19, p 5 .035, and conditioning
amplitude, F(1,18) 5 15.78, p 5 .001, were found. Significant
State Diagnosis effects were also found for N100 T/C ratio,
F(1,18) 5 10.03, p 5 .005, and test amplitude, F(1,18) 5 18.42,
po.001. This was expected, as N100 sensory gating differed
between groups during waking, but not during REM sleep (see
above). A graphical representation of the effect of state on P50
and N100 sensory gating differences between control and
schizophrenia groups is shown in Figure 4.
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M.A. Kisley et al.
Table 3. P50 Variables Compared between Controls and Patients
during REM Sleep
Conditioning
amplitude (mV)
Test amplitude (mV)
Conditioning
latency (ms)
Test latency (ms)
T/C ratio
Controls:
Mean (SD)
Patients:
Mean (SD)
p-value
0.79 (0.29)
0.18 (0.18)
1.40 (1.02)
1.31 (1.36)
.085
.018
57.2 (2.4)
56.4 (4.9)
0.20 (0.22)
58.3 (5.7)
57.4 (9.6)
0.93 (0.73)
.579
.780
.007
Notes: One-way ANOVA 1,18 df; test latency 1,15 df. Bold entries
highlight significant differences between groups.
Table 4. N100 Variables Compared between Controls and Patients
during REM Sleep
Conditioning
amplitude (mV)
Test amplitude (mV)
Conditioning
latency (ms)
Test latency (ms)
T/C ratio
Controls:
Mean (SD)
Patients:
Mean (SD)
p-value
3.72 (0.86)
3.23 (1.85)
2.76 (1.13)
2.05 (1.52)
.046
.138
98.1 (4.8)
94.0 (12.4)
0.89 (0.48)
99.0 (17.2)
104.3 (20.6)
0.74 (0.51)
.875
.193
.507
Notes: One-way ANOVA 1,18 df. Bold entries highlight significant
differences between groups.
Table 6. REM Sleep Variables for Periods Used for Event-Related
Brain Potential Analysis
REM period used
for analysis
Length of REM
period (min)
% of epochs
within REM
period scored
as ‘‘REM’’
Controls:
Mean (SD)
Patients:
Mean (SD)
p-value
1.80 (1.03)
1.40 (0.52)
.288
28.0 (9.9)
32.8 (16.8)
.452
92.5 (6.9)
94.7 (4.8)
.426
Note: One-way ANOVA 1,18 df.
gating improvement than does sleep stage I and waking. Thus,
for the present study, one subgroup consisted of patients
exhibiting only stages II, III, and IV during the 10 min preceding
the relevant REM-sleep period (N 5 7), whereas members of the
other subgroup exhibited more than 1 min of stage I and/or
‘‘movement time’’ (Rechtschaffen & Kales, 1968) during the
preceding period (N 5 3). A summary of the changes in P50
gating during the course of a REM period for these two patient
subgroups is shown in Figure 5. The patients that expressed
deeper sleep in the period immediately preceding the REM
period initially displayed intact P50 gating, but rapidly shifted to
the impaired pattern over several minutes. This main effect
change in T/C ratio was significant by repeated measures
ANOVA, F(3,18) 5 4.00, p 5 .047, where e 5 .667. In contrast,
the other patients exhibited poor P50 gating throughout the 20
min of REM sleep.
Table 5. REM Sleep Variables for Entire Night
Number of REM
periods 5 min
Total amount of
REM sleep (min)
% of epochs within
REM periods
scored as
‘‘REM’’
Controls:
Mean (SD)
Patients:
Mean (SD)
p-value
3.00 (1.33)
1.90 (0.99)
.051
65.2 (17.3)
51.1 (26.2)
.173
92.7 (4.9)
95.5 (4.3)
.185
Note: One-way ANOVA 1,18 df.
Repeated measures were also employed to determine if eventrelated potential measures including sensory gating changed
during the course of a REM period. When the first 20 min of the
REM episodes were divided into four 5-min segments, no
significant effect of time or Time Diagnosis was found on T/C
ratio, conditioning, or test amplitude or latency for either wave
P50 or N100.
Based on previous reports (Griffith et al., 1993; Griffith &
Freedman, 1995), we had expected to find a transient improvement of P50 gating in the patient group during the first 5 min of a
REM sleep period. To examine why such an effect was not found
in the repeated measures analysis above, the patients were
divided into two groups. Group division was based on the finding
of Griffith et al. (1993) that ‘‘deeper’’ non-REM sleep (i.e. stages
II, III, and IV) preceding a waking period leads to larger P50
Discussion
Sensory gating measures differed significantly between control
and schizophrenia groups during waking and during REM sleep.
In particular, patients with schizophrenia exhibited impaired
gating of auditory event-related potential component P50 across
both states. In contrast, the difference between groups in gating
of component N100 was only found during the waking state. For
this wave, control subjects exhibited a relative lack of response
suppression during REM sleep, and corresponding T/C ratios
comparable to that of the schizophrenia group. However, given
the relatively small sample size used in this study, only a relatively
large difference in N100 gating between groups would be
detectable.
The central goal of this research was to demonstrate that
impairments in P50 sensory gating associated with schizophrenia
are present not only during the waking state, but also during
REM sleep. Such a demonstration is useful because it (a)
confirms the state independence of the P50 gating deficit in
schizophrenia, and (b) validates the use of REM sleep-based
gating paradigms for future studies designed to discriminate
between sensory gating deficits due to state-related effects such
as stress and lasting brain lesions caused by developmental
program, personal experience, or some combination thereof.
Stronger justification for measuring sensory gating during REM
sleep could be generated in future studies by demonstrating that
the stability of sensory gating, across multiple recording sessions,
is higher in this state than during waking.
35
Sensory gating impairment during REM sleep
Figure 3. Examples of P50 gating during REM sleep in two patients with schizophrenia. Top: This patient exhibits a rather large P50
conditioning response, but very little suppression of component P50 to the paired clicks. Bottom: This rather unusual patient shows
strong P50 suppression to the paired clicks during REM sleep. P50 amplitude in response to test click is zero; thus no waveform
components are marked. This patient also had intact P50 gating during the waking state (T/C 5 0.04).
It should be noted that the manifestation of acute stress may
not be totally neutralized during REM sleep. Studies of so-called
oneiric behavior and functional brain activation support the
notion that paradoxical sleep is often associated with neural
activity linked to the emotional experience (Jouvet, 1965; Henley
& Morrison, 1974; Maquet et al., 1996). Further, it has been
shown that both acute and chronic stress can affect the
expression of REM sleep (e.g., Hefez, Metz, & Lavie, 1987;
Rampin, Cespuglio, Chastrette, & Jouvet, 1991). Nevertheless,
once an organism enters REM sleep, the brainstem noradrenergic neuronsFwhich are a central component of the CNSmediated acute stress response (Johnson, Kamilaris, Chrousos,
& Gold, 1992; Valentino, & Aston-Jones, 1995)Fand autonomic arousal systems are quiescent, leading to a state described
by Horne (2000) as ‘‘putative emotional inhibition.’’ Serotonin
activityFwhich has also been shown to modulate sensory gating
(Johnson, Stevens, & Rose, 1998)Fis similarly dampened
during REM sleep (Lydic, McCarley, & Hobson, 1983). At the
least, then, REM sleep represents a state of reduced pharmacological confound compared to waking in the context of sensory
gating assessment.
Another potential criticism of this study involves the
observation that patients with schizophrenia often experience
disrupted sleep patterns, including abnormal REM sleep
architecture (Zarcone, 1988). However, whether these disturbances are inherent to the illness itself or due to chronic
neuroleptic treatment remains controversial (Lauer, Schreiber,
Pollmacher, Holsboer, & Krieg, 1997; Thaker, Wagman, &
Tamminga, 1990). There is also indirect evidence that REM sleep
itself is somehow qualitatively abnormal in schizophrenia
(Roschke, Wagner, Mann, Prentice-Cuntz, & Frank, 1998).
Regardless, we detected no differences in basic REM sleep
variables between control and patient groups that could explain
the observed difference in P50 sensory gating.
Finally, it should be noted that the present data do not
necessarily confirm that the observed sensory gating impairment
associated with schizophrenia is of identical neural origin in
waking and REM-sleep states. It has been hypothesized that
sensory gating deficits due to increases in P50 test amplitude
might be fundamentally different than deficits caused by
decreases in conditioning amplitude (e.g., Stevens, Kem, &
Freedman, 1999). Although the T/C ratio significantly differed
between control and patient groups during both states in the
present study, P50 test amplitudes were significantly elevated in
the patient group only during REM sleep (compare Tables 1 and
3). However, we suggest that this discrepancy between states is
due to increased variability in test response amplitude during
waking for both groups (note higher standard deviations
during waking). In support of this, repeated measures analysis
uncovered no significant changes in either conditioning
or test P50 amplitudes from waking to REM sleep (see
Results).
36
M.A. Kisley et al.
Figure 5. The effect of time on P50 sensory gating in schizophrenia
patients during a 20-min REM sleep period. For this analysis, patients
were divided into those exhibiting relatively deep non-REM sleep (only
stages II, III, and IV) during the 10 min preceding the relevant REM
period (downward pointing symbols, N 5 7), and those exhibiting at
least 1 min of stage I sleep and/or movement time (upward pointing
symbols, N 5 3). Symbols represent the mean P50 T/C ratio for each
subgroup at each time point during the 20-min REM sleep period, and
vertical bars represent standard error of the mean (SE 5 0 at the first
time point for the second group because all 3 subjects had T/C ratios that
were truncated to 2.0). Note that the first subgroup experienced a
transient improvement in P50 gating, beginning at the onset of REM
sleep. However, by the end of 20 min, the two subgroups were exhibiting
similar, and elevated, P50 gating measures.
Figure 4. The effect of brain state on sensory gating. P50 gating is
significantly different between control and patient groups regardless of
brain state (top). However, the difference in N100 gating observed during
the waking state does not persist into REM sleep (bottom). For both
plots, circles represents mean for controls, squares represent mean for
patients, and vertical bars represent standard error of the mean.
Comparison with Previous Studies
Sensory gating measures obtained during waking in the present
study are consistent with previous reports from the past two
decades (Adler et al., 1982; Boutros, Belger, Campbell, D’Souza,
& Krystal, 1999; Erwin et al., 1991; Jerger et al., 1992; Judd et al.,
1992). In particular, we found that response suppression of both
auditory event-related potential components P50 and N100 was
significantly impaired in patients with schizophrenia compared
to healthy controls. Because abnormalities of P50 sensory gating
associated with schizophrenia have been linked to a specific
chromosomal locus (Freedman et al., 1997), we expected that
this impairment would be expressed during REM sleep. The
pattern observed for N100 gating was also anticipated. Kisley
et al. (2001) showed that, in contrast to the waking state, N100
does not show response suppression in a different group of
control subjects during REM sleep. Furthermore, more subtle
manipulations of brain state (e.g., selective attention) can
modulate N100 gating (Jerger et al., 1992; White et al., 1997).
Although the biological basis for this differential expression of
N100 gating across states in control subjects is unclear, these
findings further support the notion that measurements of P50
and N100 sensory gating are assaying distinct neural processes
(Boutros et al., 1999).
Patients taking clozapine were excluded from this study
because Nagamoto et al. (1999) demonstrated that this medication, when taken over months, actually improves P50 sensory
gating. Although evidence now exists that other atypical
antipsychotic medications may improve sensory gating (Light,
Geyer, Clementz, Cadenhead, & Braff, 2000; Yee, Nuechterlein,
Morris, & White, 1998), patients taking these drugs (N 5 8) were
included in the present study due to difficulties in recruiting
patients taking only traditional neuroleptics (N 5 2). Although
P50 gating in our schizophrenia group was significantly impaired
compared to healthy controls, 3 of 10 patients did exhibit sensory
gating measures within the normal range (T/Co0.4: Siegel et al.,
1984; Waldo et al., 1994) during REM sleep. Each of these 3
patients was taking a different atypical medicationFolanzapine,
quetiapine, and risperidone. A recent study suggests that all three
of these medications can produce sensory gating improvements,
but only in a relatively small number of schizophrenia patients
(L. E. Adler, unpublished observations).
Previous studies have shown that sensory gating is transiently
improved in schizophrenia patients when measurements are
taken within a few minutes of awakening from a bout of nonREM sleep (Griffith et al., 1993; Griffith & Freedman, 1995).
The mechanism for this phenomenon is believed to involve
resensitization of low-affinity nicotine receptors during the
progressively suppressed acetylcholinergic synaptic transmission
that is associated with stages II, III, and IV sleep (Griffith et al.,
1998). Because paradoxical sleep typically follows non-REM
sleep, we expected to find that P50 gating was temporarily
improved in schizophrenia patients during the first 5 min of
REM sleep. This was observed in a subgroup of patients that
exhibited only relatively deep non-REM sleep (i.e., stages II, III,
and IV) immediately before the REM period, consistent
with Griffith et al. (1993), who demonstrated that deeper
non-REM sleep preceding a waking period leads to more
detectable P50 gating improvement than does stage I and
waking.
37
Sensory gating impairment during REM sleep
Conclusion
Previous research has shown that relatively complex differential
processing of acoustic information continues during paradoxical
sleep, as evidenced by the presence of event-related potential
components P300 (Cote & Campbell 1999a, 1999b; Perrin,
Garcia-Larrea, Mauguiere, & Bastuji, 1999; Sallinen, Kaartinen,
& Lyytinen, 1996) and mismatch negativity (Atienza, Cantero, &
Gomez, 2000; Loewy, Campbell, & Bastien, 1996; Loewy,
Campbell, de Lugt, Elton, & Kok, 2000; Nashida et al., 2000).
The present study demonstrates that impairment of differential
acoustic processing, as measured by P50 sensory gating, can also
be expressed during this particular state. This finding validates
potential future applications of REM-sleep-based sensory gating
assays in clinical research, especially when variables associated
with the waking state might confound measurement. Such
applications are anticipated to include studies of sensory gating
in infants and children at elevated risk for schizophrenia, family
and genetic studies requiring very accurate phenotypic characterization, and studies of other clinical populations known to
be reactive to stressful situations.
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(Received December 17, 2001; Accepted June 8, 2002)