Neural synchrony indexes disordered perception and
cognition in schizophrenia
Kevin M. Spencer, Paul G. Nestor, Ruth Perlmutter, Margaret A. Niznikiewicz, Meredith C. Klump, Melissa Frumin,
Martha E. Shenton, and Robert W. McCarley*
Department of Psychiatry, Veterans Affairs Boston Healthcare System, Harvard Medical School, Psychiatry 116A, 940 Belmont Street, Brockton, MA 02301
Edited by Rodolfo R. Llinas, New York University Medical Center, New York, NY, and approved October 8, 2004 (received for review August 17, 2004)
Current views of schizophrenia suggest that it results from abnor-
malities in neural circuitry, but empirical evidence in the millisec-
ond range of neural activity has been difficult to obtain. In pursuit
locking of the electroencephalogram in the ? band (30–100 Hz).
These patterns may reflect impairments in neural assemblies,
which have been proposed to use ?-band oscillations as a mech-
in both healthy controls and schizophrenia patients, visual Gestalt
stimuli elicit a ?-band oscillation that is phase-locked to reaction
time and hence may reflect processes leading to conscious percep-
tion of the stimuli. However, the frequency of this oscillation is
lower in schizophrenics than in healthy individuals. This finding
suggests that, although synchronization must occur for perception
of the Gestalt, it occurs at a lower frequency because of a reduced
capability of neural networks to support high-frequency synchro-
nization in the brain of schizophrenics. Furthermore, the degree of
phase locking of this oscillation is correlated with visual halluci-
nations, thought disorder, and disorganization in the schizophre-
nia patients. These data provide support for linking dysfunctional
neural circuitry and the core symptoms of schizophrenia.
electroencephalogram ? ? band
cuits, rather than specific brain areas or neurotransmitter sys-
tems. These views are based on postmortem studies of the brains
of schizophrenia patients (SZ), which have reported abnormal-
ities at the cellular level, including inhibitory interneurons (1–3).
Moreover, animal studies suggest that such disturbances may
involve the hypofunctioning of N-methyl-D-aspartate receptors
on inhibitory interneurons because psychotomimetics selectively
block this receptor (4, 5). Inhibitory interneurons appear to be
crucial elements in the generation of synchronous neural activity
in the ? (13–30 Hz) and ? (30–100 Hz) bands of the electroen-
cephalogram (EEG) (6, 7). Evidence is accumulating that such
synchronous oscillations may underlie cognitive functions such
as object perception, selective attention, and working memory
(8, 9), as well as consciousness (10). Thus, the analysis of
high-frequency EEG oscillatory activity may provide functional
evidence for neural circuitry abnormalities in schizophrenia.
In earlier studies we have found that SZ exhibit deficits in
?-band neural synchrony as measured by EEG phase locking
during auditory steady-state stimulation (11) and during the
perception of visual Gestalt patterns (12). In the latter study, SZ
displayed several abnormalities in the early visual ?-band oscil-
lation in comparison with matched healthy control subjects. The
most striking finding was that Gestalt stimuli failed to elicit the
occipital component of the early ?-band oscillation in schizo-
phrenics, suggesting that their visual feature-binding processes
were abnormal. However, there was no relationship between this
effect and symptomatology.
We hypothesized that a clearer relationship between neural
synchrony and schizophrenic symptoms might be found if we
ontemporary views of schizophrenia propose that the basis
of this disorder lies in the dysfunction of neural microcir-
examined oscillations that were phase-locked to reaction time
(RT), rather than stimulus onset. Because single-unit recording
studies have found that the processes associated with making a
perceptual decision are more correlated with RT than stimulus
onset time (13), response-locked oscillations might be more
closely related to the feature-binding processes that support
conscious perception than stimulus-locked oscillations. Further-
more, a series of psychophysical studies by Silverstein and
coworkers (14, 15) has found that deficits in visual Gestalt
perception are associated with disorganization and thought
disorder in chronic schizophrenics and schizotypal individuals.
Therefore, schizophrenic abnormalities in a putative response-
locked signature of Gestalt perception might be closely related
to these core symptoms of schizophrenia.
In the present study, 20 chronic SZ and 20 normal control
subjects (NC) performed the same Gestalt perception task as in
our previous report (12). Phase locking (9, 16) was used as a
measure of neural synchrony at the macroscopic level of the
scalp-recorded EEG and was computed separately on stimulus-
and response-locked single trials.
Subjects. Inclusion criteria for all subjects were: (i) 18–55 years
of age; (ii) right-handedness; (iii) no history of electroconvulsive
treatment; (iv) no history of neurological illness; (v) no history
of alcohol or drug dependence or abuse within the last year, or
long duration (?1 year) of past abuse; (vi) no present medication
for medical disorders that would have deleterious EEG, neuro-
logical, and?or cognitive consequences; (vii) verbal IQ of ?75;
(viii) no alcohol use ?24 h before testing; and (ix) an ability and
desire to cooperate with our experimental procedures as evinced
by giving informed consent (following Veterans Affairs Boston
Healthcare System and Harvard Medical School guidelines).
Participants in this study were 23 SZ, diagnosed according to
the DSM-IV Diagnostic Criteria (17), and 21 NC (all male).
Three of the patients’ data were unusable, one because of
artifacts, the others because of excessive error rates (? 20% in
at least one condition). The final SZ sample consisted of 20 [age,
41.8 ? 9.2 years; age at onset, 22.5 ? 4.9; total positive symptom
score on the Positive and Negative Syndrome Scale (18), 18.1 ?
8.8; total negative symptom score, 21.2 ? 7.3]. Two SZ were
receiving conventional neuroleptics, 16 SZ were receiving atyp-
ical antipsychotics, and 2 SZ received both types. Mean equiv-
alent chlorpromazine dosage was 412 ? 312 mg per day (range
Of the NC, one subject’s data were unusable because of
artifacts, leaving a final sample of 20 (age, 43.1 ? 6.4 years). The
SZ and NC groups did not differ on the basis of age (P ? 0.59)
This paper was submitted directly (Track II) to the PNAS office.
NC, normal control subject(s); VEP, visual evoked potential; VH, visual hallucinators; NVH,
whomcorrespondence shouldbe addressed. E-mail:robert?mccarley@hms.
© 2004 by The National Academy of Sciences of the USA
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no. 49 www.pnas.org?cgi?doi?10.1073?pnas.0406074101
or parental socioeconomic status (P ? 0.99). The stimulus-
evoked data from 12 SZ and 12 NC have been reported (12).
Stimuli and Experimental Procedures. Subjects fixated on a central
cross and responded with a button press according to whether an
illusory square (Fig. 1A) was present or absent. Stimuli remained
visible until 300 ms after a response had been made. If no
response had been made by 2,000 ms after stimulus onset, the
trial was ended and the next trial began (1,000-ms intertrial
interval). Subjects performed one practice block and two ex-
perimental blocks, each consisting of 45 trials per condition.
Response hands were counterbalanced across subjects.
Electrophysiological Recording and Processing. The EEG was re-
corded (0.01–100 Hz, 500-Hz digitization rate) with tin elec-
trodes at 16 scalp sites (F3?Fz?F4, C3?Cz?C4, P3?Pz?P4, O1?
Oz?O2, T5?T6, and PO5?PO6) and the right mastoid,
referenced to the left mastoid. The vertical and horizontal
electrooculograms were recorded, respectively, at Fp1 and the
outer canthi of the eyes. Electrode impedances were ?5 k?.
Error and no-response trials were excluded from analyses.
Independent component analysis (19) was used to correct for
eyeblink artifacts. Corrected single-trial epochs were re-
referenced to averaged mastoids. The SZ and NC groups had
averages of 84.9 and 86.6 trials per condition, respectively.
Time-Frequency Analysis. For the response-locked analyses, each
single-trial epoch was shifted according to the RT on that trial.
The Morlet wavelet transform (9) was applied to the 20- to
100-Hz frequency range of the EEG on correct-response trials
for stimulus- and response-locked epochs. Wavelet center fre-
quencies were 20.3, 22.1, 24.1, 26.3, 28.7, 31.3, 34.1, 37.2, 40.5,
44.2, 48.2, 52.6, 57.3, 62.5, 68.2, 74.3, 81.1, 88.4, and 96.4 Hz.
Phase locking was computed as 1 minus the circular variance of
phases at each time point, wavelet frequency, and electrode (9,
16). Baseline levels were subtracted from each time-frequency
map (stimulus-locked, ?200 to ?50 ms relative to stimulus
onset; response-locked, ?50 to ?50 ms relative to RT).
Dependent variables were analyzed by using ANOVA with the
factors group (NC?SZ), stimulus (Square?No-Square), and the
appropriate factors for electrode site. For within-subjects factors
with more than two levels, the Greenhouse–Geisser correction
for inhomogeneity of covariance (20) was used and is reflected
in the reported P values. Pearson’s r was used for correlation
analyses (two-tailed; n ? 20 unless noted).
and had longer median RTs [F(1,38) ? 16.9, P ? 0.0001] than
NC (Fig. 1B). SZ also made more errors in response to Square
than No-Square stimuli [F(1,19) ? 5.56, P ? 0.05]. Both groups
had shorter RTs in response to Square than No-Square stimuli
[NC, F(1,19) ? 6.46, P ? 0.05; SZ, F(1,19) ? 18.3, P ? 0.001],
with this effect being larger for SZ [group ? stimulus, F(1,38) ?
4.84, P ? 0.05].
N1 (Fig. 1C) was measured at occipital (O1?O2), temporal (T5?
T6), and parietooccipital (PO5?PO6) electrodes (P1, 90–130 ms
NC, 110–140 ms SZ; N1, 130–206 ms NC, 140–212 ms SZ). The P1
was smaller for SZ than NC at right hemisphere sites in the Square
condition [F(1,38) ? 6.94, P ? 0.05; group ? stimulus ? hemi-
sphere, F(1,38) ? 9.12, P ? 0.01]. The N1 was smaller overall in SZ
than NC [F(1,38) ? 5.37, P ? 0.05] and tended to be larger for
P ? 0.01; SZ, F(1,19) ? 4.29, P ? 0.052].
elicited the early visual ?-band oscillation at occipital electrodes
(O1?Oz?O2, 72–98 ms, 34.1–40.5 Hz). This oscillation was
absent in the No-Square condition [F(1,19) ? 8.96, P ? 0.01].
The Square minus No-Square effect was largest at the left
occipital site O1 [t(19) ? 3.38, P ? 0.01]. A similar effect of
Gestalt perception on early ?-band phase locking has been
reported by Rodriguez et al. (16), although at a longer latency.
For SZ (Fig. 2 Lower), neither stimulus elicited this oscillation
0.05]. These data confirm the findings of our previous study (12)
with a larger sample.
A second effect was present at parietal sites (P3?Pz?P4) for
NC: phase locking was enhanced for Square compared to
No-Square stimuli in the 136- to 188-ms, 28.7- to 34.1-Hz range
[F(1,19) ? 9.95, P ? 0.01]. This effect was most significant at the
left parietal electrode P3 [t(19) ? 4.53, P ? 0.001; stimulus ?
site, F(2,38) ? 11.8, P ? 0.001]. [There was some overlap in time
and frequency between the parietal effect and the N1 VEP, but
as the parietal effect was not correlated with N1 amplitude (r ?
?0.18, P ? 0.44), we conclude that it is another oscillatory
response to Square stimuli rather than an artifact of changes in
the N1.] For SZ the parietal effect was not present [F(1,19) ?
1.72, P ? 0.21; group ? stimulus, F(1,19) ? 9.53, P ? 0.01].
Response-Locked Oscillations. Oscillations that preceded and were
phase-locked to RT were found in the data of both groups (Fig.
3). For NC, Square stimuli elicited an oscillation in the ?270- to
?216-ms, 31.3- to 44.2-Hz range at occipital sites. This oscilla-
VEPs (Upper) and stimulus-locked phase-locking values (Lower; 34.1–40.5 Hz)
in the square condition relative to stimulus onset for each group.
Gestalt perception task. (A) Stimuli. The ratio of inducer radius to
Spencer et al.
December 7, 2004 ?
vol. 101 ?
no. 49 ?
tion was absent in the No-Square condition [F(1,19) ? 12.6, P ?
0.01]. As with the early occipital stimulus-locked oscillation, this
effect was largest at the left occipital site [t(19) ? 3.69, P ? 0.01].
macroscopic EEG level and, to our knowledge, has not been
monkey was recently reported (21).] The fact that this oscillation is
elicited by Gestalt patterns and is phase-locked to RT suggests that
it could reflect the neural mechanisms involved in linking the
elements of the illusory square into a coherent percept. Further-
more, its scalp topography is consistent with generators in visual
cortex. The similarity between the frequency ranges and topogra-
phies of the stimulus- and response-locked occipital oscillations
suggests the possibility that the response-locked oscillation reflects
a significant difference between the topographies of the two
oscillations [measured across occipital, temporal, and parieto-
occipital electrodes; oscillation ? electrode, F(6,114) ? 1.75,
P ? 0.18].
For SZ, no oscillations were observed in the same latency and
frequency range as for the NC group [F(1,19) ? 0.132, P ? 0.72;
group ? stimulus, F(1,38) ? 4.54, P ? 0.05]. However, a
response-locked oscillation was elicited by Square stimuli at
occipital sites in a lower frequency range (from 22.1 to 24.1 Hz)
and at a longer latency before RT (?300 to ?266 ms). The
topography of this oscillation was very similar to that in the NC
group comparisons of the topographies of the occipital oscilla-
tions did not find any significant differences (P ? 0.13), com-
patible with the same mechanism operating in both groups.
A second response-locked oscillation was found in the SZ
data. At parietal electrodes, Square stimuli evoked a prominent
oscillation in the ?280- to ?216-ms, 22- to 26-Hz range. This
oscillation was not present in the No-Square condition
[F(1,19) ? 17.6, P ? 0.001], nor was it elicited by either stimulus
for NC [group ? stimulus, F(1,38) ? 4.28, P ? 0.05]. The group
effect was maximal at the left parietal site P3 [group ? stimu-
lus ? electrode, F(2,76) ? 4.54, P ? 0.05; group ? stimulus at
P3, F(1,38) ? 12.8, P ? 0.001], similar to the stimulus-locked
parietal oscillation in NC. The parietal oscillation was distin-
guished from the occipital oscillation by its shorter latency to RT
and wider frequency range. The magnitudes of the parietal and
occipital oscillations were not correlated (r ? 0.20, P ? 0.39),
confirming that they constituted separate effects.
Clinical Symptom Correlations. We examined correlations between
the above phase-locking effects (Square ? No-Square) and
schizophrenic symptoms on the Positive and Negative Syndrome
Scale (18) and Scale for the Assessment of Negative Symptoms
(22)?Scale for the Assessment of Positive Symptoms (23). Our
focus was on perceptual and cognitive symptoms, particularly
hallucinations, attention, delusions, disorganization, and
scales indicate phase-locking values. The frequency and stimulus-locked latency of the response-locked oscillations are indicated by the arrows.
www.pnas.org?cgi?doi?10.1073?pnas.0406074101Spencer et al.
thought disorder. Here, we report only correlations with abso-
lute values ?0.5 and P values of ?0.01 (see Fig. 4A). These
correlations were also significant according to the nonparamet-
ric Spearman’s ?.
The occipital response-locked effect was significantly corre-
(r ? 0.58) on the Positive and Negative Syndrome Scale (18), and
visual hallucinations (r ? 0.56), thought withdrawal (a delusion
subscale) (r ? 0.65), and the global thought disorder rating (r ?
0.61) on the Scale for the Assessment of Positive Symptoms (23).
In contrast, the parietal response-locked effect was correlated
with negative symptoms: the total negative symptom scale on the
Positive and Negative Syndrome Scale (18) (r ? 0.57), and social
inattentiveness on the Scale for the Assessment of Negative
Symptoms (22) (r ? 0.66). There was no correlation between
medication dosage and these symptoms.
None of the other phase-locking effects correlated signifi-
cantly with symptoms. Nor was the peak frequency of the
occipital response-locked effect, which differed between groups,
correlated with any symptom scales. None of the phase-locking
effects were correlated with age, age of onset, or medication
dosage (all P ? 0.09).
The pattern of the correlation between the occipital response-
locked effect and visual hallucinations suggests that it reflects an
overall difference between patients who experienced visual
hallucinations [visual hallucinators (VH) (n ? 7)] and those who
did not [nonvisual hallucinators (NVH) (n ? 13)]. The occipital
response-locked effect was significantly greater for VH than
NVH [t(18) ? 2.80, P ? 0.05], but when VH were considered
alone, the correlation was no longer significant (r ? 0.35, P ?
of the group difference was assessed further by using a permu-
tation test in which the VH and NVH patients were assigned at
random to groups of 7 and 13, and the t test was computed 1,000
times. Using this method, the significance of the observed group
difference was found to be P ? 0.01.
The VEPs for the VH and NVH were also examined. In the
grand averages, with the N1 appears reduced in VH compared
with NVH patients (Fig. 4B). This difference was significant in
the Square condition at the temporal electrodes [T5?T6, t(18) ?
?2.20, P ? 0.05; permutation test, P ? 0.05].
The main findings of this study are as follows. (i) A ?-band
oscillation is elicited by perceived Gestalt stimuli at occipital
electrodes that is phase-locked to RT, making it a potential
signature of feature-binding processes in visual cortex. (ii) In
individuals with schizophrenia, an oscillation with a similar topog-
core symptoms of schizophrenia. We have demonstrated a link
between perceptual and cognitive disturbances, feature-binding
processes, and abnormal neural synchrony.
These data suggest that the occipital response-locked oscilla-
tion reflects feature-binding processes in both the NC and SZ
groups, although further experiments will be necessary for
Fig. 3. Grand average response-locked phase-locking maps, as in Fig. 2. The RT on each trial is shifted to 0 ms.
Spencer et al.
December 7, 2004 ?
vol. 101 ?
no. 49 ?
definitive confirmation. Within the SZ group, the correlations
between this oscillation and the conceptual disorganization and
thought disorder scales in the patients are consistent with similar
correlations reported by Silverstein and coworkers (14, 15) by
using psychophysical measures of Gestalt perception. The high
degree of convergence between their psychophysical data and
the present results supports the proposal of Phillips and Silver-
stein (24) that thought disorder and disorganization are caused
by dysfunctional coordinating interactions in the brains of
schizophrenics. A role for the occipital response-locked oscilla-
tion in feature-binding processes is further suggested by the
relationship between this oscillation and visual hallucinations.
The occipital response-locked oscillation had two abnormal-
ities in the SZ group. First, the frequency of this oscillation was
lower than in NC. This finding suggests that a dysfunction
rendered the underlying neural circuitry unable to synchronize
at a high frequency. One possible cause of this effect could be
decreased connectivity, as Kopell et al. (25) have demonstrated
that synchronization frequency depends on conduction velocity
in simulations of neural circuits, and there is abundant evidence
for white matter deficits in schizophrenia (26). There is also
evidence for reduced excitatory input to pyramidal cells in
schizophrenia (2, 27–30), which might also explain the synchro-
nization at a lower frequency. As Steriade et al. (31) have shown
that more negative values of pyramidal cell membrane potential
favor lower frequency oscillations, the reduced synchronization
frequency in SZ could be caused by disfacilitation from reduced
thalamic inputs (30) and?or a reduction in inhibitory neuro-
transmission (4, 30).
The second abnormality of the occipital response-locked
oscillation (and for the parietal response-locked oscillation)
was that increases in symptom ratings were associated with
increased, rather than decreased, phase-locking effects. One
possibility is that increased phase locking could be related to
the phenomenon of cortical hyperexcitability that has been
reported in studies of schizophrenia by using transcranial
magnetic stimulation (32, 33). It is notable that auditory
hallucinations are reduced by the application of slow repetitive
transcranial magnetic stimulation, which reduces the excitabil-
ity of the underlying cortex (34). Furthermore, a neuroimaging
study by ffytche et al. (35) reported that visual hallucinations
were associated with increased baseline activation of visual
cortex, which is consistent with increased cortical excitability.
This study also reported that the visual cortex of hallucinators
was less responsive to external stimulation, which we also
found in the lower N1 VEP of the VH subgroup. Still another
possibility is that the correlations between increased phase
locking and symptoms reflects the presence of abnormally
increased connectivity in particular neural circuits, as was
recently reported for SZ with auditory hallucinations (36).
In the present study, we confirmed our previous finding that
perceived Gestalt stimuli do not elicit the early occipital stimulus-
locked oscillation in SZ. Herrmann and Mecklinger (37) have
similarity of the current stimulus to the target stimulus and have
proposed that this oscillation reflects a template-matching process.
Thus, for the NC in this study, the elicitation of the early occipital
oscillation by Square stimuli may reflect the status of these stimuli
as targets. The task instructions to ‘‘press one button if you see a
square, otherwise press the other button’’ gave priority to respond-
The absence of the early occipital oscillation for SZ may indicate a
failure to engage this process.
We have proposed that measures of neural synchrony are sen-
sitive to the integrity of neural circuitry in schizophrenia (11, 12).
Impaired cortical circuitry would be unable to synchronize prop-
erly, leading to the perceptual distortions and failures of cognitive
esis, postmortem brain studies have revealed abnormalities in
decreased density of inhibitory interneurons (1), and decreased
somal size (38) and spine density (27–29) of pyramidal cells.
Because local interneuron networks appear to be crucial for the
generation of neural synchrony (6, 7), it is plausible that abnor-
malities in interneurons, and?or the excitatory glutamatergic input
that drives them (4, 5, 39), could result in dysfunctional neural
(34) is also consistent with decreased local circuit inhibition.
Of particular interest are the findings that the inhibitory
connections that chandelier cells make onto pyramidal cells are
initial segment of pyramidal cells, chandelier cells are in an
excellent position to control the timing of pyramidal cell spikes
(40). Furthermore, pyramidal cell excitability is strongly influ-
enced by chandelier cell input (41), so decreased inhibitory
output from chandelier cells could increase the excitability of
pyramidal cells, while decreasing synchrony between them.
Consistent with this model and the evidence for N-methyl-D-
aspartate receptor hypofunction in schizophrenia (5), an N-
methyl-D-aspartate antagonist has been shown to increase the
and NVH patients at O1.
SZ symptom analyses. (A) Correlations between symptom scales (y
www.pnas.org?cgi?doi?10.1073?pnas.0406074101 Spencer et al.
excitability of pyramidal cells while decreasing spike bursts (42), Download full-text
which may play a role in synchronizing cell assemblies.
Dysfunctional thalamocortical circuitry could also play a role
in abnormal ?-band synchronization in schizophrenia (10).
Thalamocortical loops are likely to be involved in synchronizing
cortical circuits in the ? band (43, 44), because thalamocortical
projections influence the membrane potential of cortical pyra-
midal neurons and hence their propensity for ?-band oscillations
(31). There is evidence for structural abnormalities in thalamic
nuclei at the macroscopic and microscopic scales in schizophre-
nia, as well as N-methyl-D-aspartate receptor abnormalities (45).
In the future the possibility of correlations between high and low
frequency bands should be examined, because Llina ´s et al. (46)
have proposed that such correlations are signs of abnormal
In summary, these data support the hypothesis that abnormal
?-band synchrony in schizophrenia reflects neural circuit dys-
function that is related to the symptomatology of this disorder.
This work was supported by a Veterans Affairs Research Enhancement
Award Program, a Veterans Affairs Merit Award, and National Institute
of Mental Health Grant R01 40799 (to R.W.M.); a Veterans Affairs
Merit Award (to P.G.N. and M.A.N.); and a Young Investigator Award
(to K.M.S.) from the National Alliance for Research on Schizophrenia
and Depression. K.M.S. is a Research Enhancement Award Program
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