Impairments in frontal cortical ? synchrony
and cognitive control in schizophrenia
R. Y. Cho*†, R. O. Konecky*†, and C. S. Carter*‡§
*Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213;†Center for the Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, PA
15260; and‡Departments of Psychiatry and Psychology and Imaging Research Center, University of California, Davis, CA 95616
Communicated by Edward G. Jones, University of California, Davis, CA, October 25, 2006 (received for review June 27, 2006)
A critical component of cognitive impairments in schizophrenia can
be characterized as a disturbance in cognitive control, or the ability
to guide and adjust cognitive processes and behavior flexibly in
accordance with one’s intentions and goals. Cognitive control
impairments in schizophrenia are consistently linked to specific
disturbances in prefrontal cortical functioning, but the underlying
neurophysiologic mechanisms are not yet well characterized. Syn-
chronous ?-band oscillations have been associated with a wide
range of perceptual and cognitive processes, raising the possibility
that they may also help entrain prefrontal cortical circuits in the
service of cognitive control processes. In the present study, we
measured induced ?-band activity during a task that reliably
engages cognitive control processes in association with prefrontal
cortical activations in imaging studies. We found that higher
cognitive control demands were associated with increases in in-
duced ?-band activity in the prefrontal areas of healthy subjects
but that control-related modulation of prefrontal ?-band activity
was absent in schizophrenia subjects. Disturbances in ?-band
activity in patients correlated with illness symptoms, and ?-band
activity correlated positively with performance in control subjects
but not in schizophrenia patients. Our findings may provide a
link between previously reported postmortem abnormalities in
thalamofrontocortical circuitry and alterations in prefrontal activ-
ity observed in functional neuroimaging studies. They also suggest
that deficits in frontal cortical ?-band synchrony may contribute to
the cognitive control impairments in schizophrenia.
cognition ? ? oscillations ? prefrontal cortex
debilitating disorder (1). One critical set of deficits can be charac-
terized as a disturbance in cognitive control, or the ability to guide
and adjust cognitive processes and behavior flexibly in accordance
with one’s intentions and goals. As shown in functional magnetic
resonance imaging (fMRI) studies, cognitive control processes are
supported by the dorsolateral prefrontal cortex (DLPFC) (2–4),
and they are impaired in schizophrenia in association with distur-
bances in DLPFC activity (5–7). However, although disturbed PFC
activity and cognition in schizophrenia are well established, little is
known about the nature of the underlying neurophysiologic
Studies of the fMRI blood oxygen level-dependent (BOLD)
signal suggest that high-frequency localized neuronal synchrony
drives BOLD responses (8), raising the possibility that disturbances
in high-frequency neural synchrony may give rise to the impaired
prefrontal cortical activations observed in fMRI studies in schizo-
phrenia. This notion is supported by postmortem work in schizo-
phrenia showing that chandelier cell interneurons, which have the
anatomic and electrophysiologic properties to coordinate fast os-
cillations in pyramidal neurons, are functionally impaired in the
PFC function may be caused by an alteration in high-frequency
Synchronization of cortical neuronal activity in the ? band
(30–80 Hz) appears to be important for a wide range of perceptual
ognitive impairments are a core feature of schizophrenia and
one of the strongest predictors of functional outcome in this
and cognitive processes. Studies of perception show that visual
stimuli can elicit ?-band synchrony in animals (10, 11) and humans
(12, 13), and such synchronous ?-band activity may be critical for
perceptual feature binding (14). Moreover, findings of ?-band
synchrony extend to higher cognitive processes, such as associative
is found in association with a wide variety of perceptual and
for entraining networks of cortical neurons. By extension, ?-band
subserve cognitive control.
If frontal cortical ?-band oscillations are necessary for cognitive
control, then disturbances in the ?-band activity may lead to the
in schizophrenia have found disturbances in steady-state activity
(18), which refers to neural oscillations that are entrained to an
oscillating stimulus, whereas others found disturbed evoked ?
activity that derives from oscillations that are phase-locked to
presented stimuli (19, 20). Spencer and colleagues (21, 22) exam-
ined phase-locking to both stimuli and responses.
However, it is not clear how findings concerning stimulus-locked
responses are related to impaired cognitive control in schizophre-
nia. Higher-order cognitive processes are thought to be more
commonly associated with induced oscillatory activity (23) or
study, we thus measured induced ?-band activity during the Pre-
paring to Overcome Prepotency task, a paradigm that engages
healthy subjects and comparably less prefrontal cortical activity
control demands would elicit increases in prefrontal induced
?-band activity in healthy subjects but that this modulation of this
activity would be reduced in schizophrenia subjects.
Cognitive Task Description. For a description of the cognitive task,
see Fig. 1.
Behavioral Performance. Performance was compared (Fig. 2) by
using two-way repeated measures ANOVAs with diagnostic group
(schizophrenia vs. healthy control group) as a between-subject
factor and condition (high- vs. low-control) as a within-subject
factor. For error rates, this analysis revealed the main effects of
P ? 0.63), with a significant diagnostic group ? condition inter-
Author contributions: C.S.C. designed research; R.Y.C. and R.O.K. performed research;
R.O.K. contributed new reagents/analytic tools; R.Y.C., R.O.K., and C.S.C. analyzed data;
and R.Y.C., R.O.K., and C.S.C. wrote the paper.
The authors declare no conflict of interest.
Abbreviations: BOLD, blood oxygen level-dependent; PFC, prefrontal cortex; DLPFC, dor-
solateral PFC; EEG, electroencephalogram; fMRI, functional magnetic resonance imaging.
§To whom correspondence should be addressed. E-mail: firstname.lastname@example.org.
This article contains supporting information online at www.pnas.org/cgi/content/full/
© 2006 by The National Academy of Sciences of the USA
December 26, 2006 ?
vol. 103 ?
action (F ? 10.18, P ? 0.005). Planned comparisons of the
condition effect (high-control minus low-control error rates) be-
tween groups revealed that this interaction was driven by higher-
condition effects in the patient vs. control group (t ? 2.04, P ?
0.005, two-tailed). For reaction times, there were main effects of
diagnostic group (F ? 0.59, P ? 0.005) and condition (F ? 17.47,
P ? 0.001). There was no group ? condition interaction (F ? 0.89,
P ? 0.35).
Electroencephalogram (EEG). Induced ?-band oscillations. To test our
hypothesis that increased induced frontal ?-band activity would be
associated with cognitive control, we assessed induced ? over the
delay period (500–1,500 ms from cue onset), comparing high-
stimulus) vs. a low-control (respond in same direction indicated by
probe) trials. In comparing induced ?-band activity for controls vs.
0.05), one in a right frontal region (electrode 2 or AF8 in the 10/10
system; for conversion table, see ref. 24) and the other in a left
frontal region (electrode 21 or FC1 in the 10/10 system).
To rule out group differences in induced ?-band activity being
for the significant right and left frontal electrodes. Neither elec-
trode demonstrated significant within or between group (right
frontal, P ? 0.79; left frontal, P ? 0.73) differences in evoked ?
indexed, induced ? analyses were repeated with evoked ? averages
for each subject subtracted from the averaged per-trial wavelet-
(at P ? 0.05).
Induced ?- and ?-band oscillations. To examine the specificity of our
induced ? findings and rule out broader spectrum in-
creases, induced ? and ? activity was examined. In the ? band,
although controls showed no significant modulation by condition,
group comparisons showed patients with greater modulation by
condition for three electrodes (all P ? 0.05), in the parietoocciptal
area: electrodes 73, 92, and 95 (Oz, P8, and close to PO8, respec-
tively, in 10/10). In ?-band analyses, both groups tended to show
decreases in ?-band activity in frontal areas with increased control,
and the group comparison revealed that patients showed relatively
greater decreases (P ? 0.05) in ? in the right frontal region
(electrode 3, AF4 in 10/10).
To complement the ?- and ?-band analyses in assessing the
possibility of broad-spectrum modulations, a wavelet transform
across a broad range of frequencies (8–80 Hz) was performed for
the right and left frontal electrodes that were significant for the
across-group contrasts for ?-band activity (Fig. 3). The scalp map
but that only one electrode in each region (nonhomologous sites)
achieved significance (marked by circles). In both frontal regions,
there were increased modulations in controls vs. patients in the
lower-?-frequency band centered at ?45 Hz and 37 Hz in the right
cue, extending into the delay period, and are apparent in the
within-group contrasts for the controls but not for the patients. In
the right frontal electrode, there are also significant differences in
the ? and lower-? frequency range between controls and patients
over much of the delay period. These differences over the delay
period were the result of both modest increases in controls as well
as decreases in patients, especially at the end of the delay period.
The decrease in ? activity by increased control demand for patients
is consistent with similar decreases observed for electrode 3 (AF4),
which is directly adjacent to this right frontal electrode. Plots of the
power for each of the groups and conditions for the two frontal
electrodes [see supporting information (SI) Fig. 5] indicate what
gave rise to the within and between group statistics. The left
electrode had greater modulation of ?-band activity by condition
(high vs. low control) for controls compared with patients. For the
right frontal electrode, patients had overall greater power in
frequencies higher than ?25 Hz in both conditions. However, the
patients lacked the modulation by condition that the controls
Correlations of ?-band activity with clinical symptoms. Among the
symptom clusters of schizophrenia, Disorganization has been
shown to be most strongly negatively correlated with both behavior
between ?-band activity in electrodes 2 (AF8) and 21 (FC1) over
the early, middle, and late delay periods, and symptom scores for
Disorganization, as well as Reality Distortion and Poverty symp-
toms. For electrode 2 (AF8), the only significant finding was a
positive correlation between middle delay ?-band activity and
Reality Distortion (r ? 0.47, t ? 1.9, P ? 0.05, one-tailed). This
correlation seemed largely driven by one influential point, which,
when excluded, made the correlation nonsignificant (r ? 0.22, t ?
0.80, P ? 0.22, one-tailed). The largest correlations with Poverty
symptoms and Disorganization over any part of the delay were r ?
0.19 and r ? 0.04, respectively. For electrode 21 (FC1), the only
cues. (Right) High-control trials signaled by red cues.
between high- and low-control error rates compared with controls.
Cho et al.PNAS ?
December 26, 2006 ?
vol. 103 ?
no. 52 ?
significant result was an inverse correlation for late delay ? and
Disorganization (r ? ?0.45, t ? ?1.8, P ? 0.05, one-tailed). The
largest correlations with Reality Distortion and Poverty symptoms
Correlations of ?-band activity with behavioral performance.Toexamine
whether ?-band activity would be predictive of behavior, we per-
formed correlations between ?-band activity in electrodes 2 (AF8)
and 21 (FC1) during the early, middle, and late delay periods, and
performance during the high-control condition (separately for
patients and controls). For electrode 2 (AF8), controls showed a
relatively high correlation (r ? 0.54, t ? 2.6, P ? 0.01) between late
controls showed a nearly significant correlation between late delay
?-band activity accuracy (r ? 0.38, t ? 1.7, P ? 0.057). Controls
demonstrated no significant correlations with reaction times for
either electrode. Patients exhibited no significant correlations be-
tween ?-band activity and performance for either electrode. These
correlations with performance were repeated for low-control re-
lated ?-band activity with no significant findings for controls or
patients. To rule out the possibility that correlations between
Disorganization and ?-band activity in electrode 21 (FC1) were
obscuring a relationship between performance and ? activity in
patients, this latter correlation was redone, partialing out the effect
late delay ? activity increased from r ? 0.07 to 0.31, but it remained
nonsignificant (t ? 1.18, P ? 0.13, one-tailed).
?-Band synchronous oscillations have been associated with a wide
range of perceptual and cognitive processes. In this study, increases
in cognitive control demands were associated with increases in
This modulation of frontal cortical ? was diminished in schizophre-
nia subjects, with disturbances in ?-band activity correlating with
their Disorganization symptoms. Further, increases in ?-band ac-
tivity correlated with performance in controls but not patients.
These findings are consistent with the proposal that disturbances in
frontal induced ? synchrony¶may underlie the cognitive control
deficits observed in this disorder.
The modulation of induced prefrontal ? delay period activity in
association with cognitive control demands in controls comple-
ments previous EEG findings of working memory maintenance-
related ?-band activity (16, 17). Our findings suggest that synchro-
nous ?-cortical oscillations may support not only basic object
representations but also more abstract representations involved in
cognitive control, e.g., those that mediate stimulus–response rever-
sals that suppress prepotent tendencies. That prefrontal ? activity
that increases in right frontal delay activity are associated with
performance during trials requiring higher control, consistent with
previous findings relating increased delay-related DLPFC activa-
tions and decreased interference (3).
Schizophrenia subjects failed to show similar modulations of
prefrontal ? by control demands, both in the condition-related
contrasts and correlations with performance. These results are
¶‘‘Synchrony’’ can refer to ‘‘phase synchrony’’ that describes consistent phase relationships
with respect to a stimulus or response. In this context, however, we refer to the fact that
for increases in induced ? band power, clustered, similarly oriented groups of neurons
must fire at the same time with respect to each other on any given trial. These require-
ments are true for any detectable scalp EEG signal, as with regular event-related poten-
tials, but in this case, the synchronous activations modulate in an oscillatory manner.
the 30- to 80-Hz range used to define ? activity in the band-specific analyses, over the baseline (?200 to 0 ms), cue (0–500 ms), and delay (500–1,500 ms) periods
(x axis). (Left and Center) Statistical comparisons (Wilcoxon signed-rank test) of high- vs. low-control conditions. (Left) Controls. (Center) Patients. (Right) Group
comparison of the difference between the high- and low-control conditions (controls vs. patients; Mann–Whitney U test). Shown are negative log P values for
all plots. For display purposes, all values represent the statistical comparisons without multiple-comparison corrections. (Upper) Left frontal electrode. (Lower)
Right frontal electrode. The frontal scalp map is a summary map of group differences over the delay period, showing locations of the left and right electrodes
(circled; the back of the head is not shown because of very minimal activation differences). (Left and Center) Hot colors denote greater ? power for the high-
vs. low-control condition, and cool colors show the reverse. (Right) Hot colors denote controls having greater positive differences between the high- and
low-control conditions compared with patients, and cool colors show the reverse.
Frequency–time plots of within- and across-group comparisons of induced ?-band activity. All plots span frequencies 8–80 Hz (y axis), which includes
control condition for healthy control subjects plotted against late delay ?
power for the high-control condition in the right frontal region.
Correlation with performance. Shown are accuracy rates for high-
www.pnas.org?cgi?doi?10.1073?pnas.0609440103 Cho et al.
consistent with our fMRI study of schizophrenia subjects using the
Preparing to Overcome Prepotency task, which also showed re-
duced DLPFC modulation by control demands and a correlation
between DLPFC activation and performance in healthy controls
but not patients (7). In the current study, patients exhibited a
variable pattern of induced ?-band activity across the PFC (higher
on the right, lower on the left), analogous to similar variability in
fMRI studies of PFC function in schizophrenia (28), but the
consistent finding was a lack of modulation of induced ? by
cognitive control demands. Although patients did not exhibit
with symptoms suggested a relationship between ?-band distur-
negatively correlated with Disorganization symptoms but not Re-
ality Distortion or Poverty symptoms, consistent with similar cor-
relations between left DLPFC activation and Disorganization in
previous studies (6, 7). Right prefrontal ? activity correlated with
Reality Distortion, consistent with similar reports in the literature
suggest that disturbed modulation of prefrontal cortical ? syn-
chrony in subjects may underlie cognitive control disturbances as
well as possibly contributing to clinical symptoms.
The specificity of our findings of induced ?-band activity in
prefrontal regions for controls and schizophrenia subjects was
supported by a number of findings. First, analyses of evoked ?
showed that findings in the induced ? responses were not con-
founded by evoked activity. Second, the ?- and ?-bands did not
exhibit the same patterns of activity that were observed in the
?-band, ruling out broad-spectrum modulations. ?-Band analysis
showed greater decreases for high-control trials, consistent with
similar findings (30) for both controls and patients, with patients
showing greater such modulation in a right frontal region. The lack
of overlap in the directionality of ?-band and ?-band findings is
consistent with a report of an absence of any spatial or temporal
correlations between ?- and ?-band activity (31). Although Gevins
and colleagues (30) have shown frontal midline ?-band activity
modulating with memory load in healthy subjects, our control
subjects did not exhibit significant ?-band activity, perhaps because
of equal working memory demands across the two conditions.
Patients, however, did exhibit increased modulation in the pari-
etooccipital region compared with controls. The significance of
it may point to compensatory mechanisms in the absence of proper
entrainment of frontal ? activity.
Although our findings of disturbed prefrontal-induced ?-band
activity in schizophrenia are consistent with our previous fMRI
studies that used the same or similar tasks (5–7), there are some
possibly confounded by medication effects and chronicity. We are
currently studying first-episode, medication-naı ¨ve schizophrenia
subjects to address these possible confounds. Another possibility is
that the stimulus properties of the cues, namely, the colors that
indicated the low- vs. high-control trials (green vs. red, respectively;
cues were matched for size and luminance) may have had differ-
ential effects across groups. Previous reports (32) have noted
increased modulation of induced ?-synchrony in monkey visual
cortex by red over green stimuli. However, these responses quickly
dissipated after stimulus offset, suggesting that these ‘‘bottom-up’’
influences would not explain our results over the whole delay
trials to ensure that subjects were on task, implying that, whatever
more perceptually driven processes were occurring, subjects were
properly interpreting the cues. Future studies that counterbalance
cue color across subjects will more definitively answer this issue.
Our findings of disturbed ?-band synchrony in schizophrenia are
consistent with neurobiological findings in this disorder. Jones (33)
proposed that observed anatomical evidence for functional distur-
bances in thalamocortical circuits in schizophrenia first reported in
schizophrenia. Clearly, disturbances in either the thalamocortical
and/or corticothalamic projections could result in disruptions in
?-band thalamocortical oscillations. Reduced numbers of thalamo-
cortical projection neurons have been reported (34, 35) as well as
functional impairments in corticothalamic projections (36). One
intriguing possibility is that such disturbances in corticothalamic
also to increased ?-band activity as was found in the schizophrenia
subjects of this study. Llinas and colleagues (37) proposed that
increased inhibition or deafferentation of the thalamic relay cells
could lead to aberrant increases in ? rhythms. Specifically, they
proposed that the hyperpolarized state of relay neurons induced by
deafferentation or inhibition leads to periodic bursting at ? fre-
quency through deinactivation of T-type calcium channels and
feedback inhibition by thalamic reticular nucleus neurons. This
relay neuron hyperpolarization-dependent cycle gives rise to ?
rhythms during normal physiologic states such as sleep, but it is
proposed to occur pathologically in the context of neuropsychiatric
disorders, including schizophrenia. Another pathophysiologic
mechanism that implicates prefrontal cortical neurons is described
by Lewis and colleagues (38), who underscore the possible critical
role of functional disturbances in interneurons, the chandelier class
of GABA cells being one of the more consistently implicated. Each
chandelier cell exhibits fast-spiking, nonadapting firing patterns,
and it forms synapses onto the axon initial segments (near the site
it is thus enabled with both distinctive electrophysiologic properties
and strategic synaptic locations to modulate the electrical outflow
of a large number of pyramidal cells powerfully. Consequently,
disturbances in chandelier cell functioning could impair the ability
of cortical circuits to engage in high-frequency synchronous oscil-
lations, either locally or in coordination with the thalamus, consis-
current study. Interestingly, glutamate receptor hypofunction, a
pathophysiologic feature of schizophrenia (40), may lead to chan-
delier cell disturbances as a downstream consequence (41). Thus,
possibly related disturbances in both excitatory and inhibitory
neurotransmission may lead to disturbed ?-band synchrony in
In summary, we have demonstrated an association between
prefrontal cortical ?-band activity and cognitive control processes
that is present in healthy controls but absent in schizophrenia
subjects. Prefrontal ?-band activity was related to performance in
controls with suggestive correlations between disturbances in ?
activity and symptoms in patients. Although fMRI studies have
shown prefrontal disturbances in schizophrenia in association with
cognitive control impairments, this study provides EEG evidence
with improved temporal resolution and suggestive evidence that
disturbed ? synchrony may underlie the decreased activations
observed in imaging studies. EEG assessments of prefrontal ?
of prefrontal cortical circuits in tandem with behavioral measures
of cognitive control disturbances in schizophrenia. Assessments of
? synchrony may also help in assessing the efficacy of therapeutic
agents that aim at improving the functional integrity of cortical
circuits that subserve such coordinated activity.
Materials and Methods
Subjects. Eighteen healthy participants (17 right-handed) and 15
schizophrenia/schizoaffective disorder participants (14 right-
handed) participated in this study. Exclusion criteria consisted of a
lifetime history of seizures or significant head trauma, mental
retardation, substance use or abuse within the previous 6 months,
use of benzodiazepine or other anticonvulsants. Written informed
consent was completed before testing in accordance with the
Institutional Review Board at the University of Pittsburgh; partic-
Cho et al.PNAS ?
December 26, 2006 ?
vol. 103 ?
no. 52 ?
ipants were monetarily compensated when they completed the
study. All participants were 20–50 years old. Participants were
clinically stable, medicated outpatients with schizophrenia or
schizoaffective disorder, and they were recruited from a large,
Clinic, Pittsburgh, PA). Diagnoses were based on Structured Clin-
ical Interview for DSM-III-R (42), and we used DSM-IV criteria
for schizophrenia. Summary clinical ratings scores were derived
[following Barch et al. (ref. 26)] for Reality Distortion, Disorgani-
zation, and Poverty Symptoms from the Brief Psychiatric Rating
Scale [BPRS (ref. 43)] and the Scales for the Assessment of both
Positive and Negative Symptoms [SANS (ref. 44); SAPS (ref. 45)].
Patients’ average ratings (mean ?SD) were the following: Reality
Distortion, 2.55 ? 0.84; Disorganization, 1.77 ? 0.60; Poverty
Symptoms, 2.54 ? 0.52. Healthy controls were recruited through
hospital and community advertisements. Controls were inter-
viewed by using the nonpatient version of the Structured Clinical
Interview for DSM-III-R (46), and they were excluded for any
lifetime history of an Axis I disorder as well as a first-degree family
history of psychotic disorders. Comparisons made using t tests
determined that there were no significant differences between
controls and patients in the demographic variables of age [patients,
37.1 ? 9.0 years (SD); controls, 36 ? 6.2 years], gender
(patients, 9 males; controls, 10 males), and parental education
(patients, 14.0 ? 3.5 years; controls, 13.0 ? 3.4 years).
Procedure. Task. Stimuli were presented centrally on a computer
monitor by using E-Prime (Psychological Software Tools, Pitts-
(a green or red square; visual angle, 5.0°), delay period, probe (a
white arrow pointing left or right; visual angle, 1.6° ? 1.3°), and a
variable intertrial interval. Cues signaled conditions requiring low
vs. high degrees of cognitive control (referred to as the low- and
required to maintain the trial-type information and to prepare for
a response to the upcoming probe. For the low-control condition
(green cues), subjects were required to respond in the direction of
the arrow that followed (e.g., for a right-pointing arrow, press the
right button). For the high-control condition (red cues), subjects
were required to respond in the opposite direction (e.g., for a
right-pointing arrow, press the left button). For responses, subjects
pressed the left button on a button box with their left index finger,
and the right button with their right index finger. Cues were
response mappings of the low-control trials, thereby increasing the
control requirements during the high-control trials, the majority
(75%) of the trials were low-control with the remaining 25%
high-control. Both the cue and probe stimuli had durations of 500
ms. The delay period was fixed at 1,000 ms, during which subjects
were required to maintain fixation on a fixation cross presented
centrally on the screen. Intertrial intervals were randomized be-
each. Before experimentation, subjects practiced the task until at
least 90% accuracy was attained. For most subjects, one practice
block (24 trials) was sufficient.
carbon fiber electrode Geodesic Sensor Net (EGI, Eugene, OR)
a 0.1- to 100-Hz bandpass hardware filter. Electrode impedances
were kept at ?50 k?. All channels were referenced to Cz.
Offline processing. Forthe?-and?-bandanalyses,datawerefiltered
Filter (time constant, 0.0199s; slope, 12 dB/oct). For ?-band anal-
yses, data were filtered offline by using a 2- to 15-Hz bandpass.
Epochs were defined as ?400 to ?1,700 ms relative to the cue
onset. Error trials and epochs containing artifacts (EEG or elec-
trooculogram exceeding ?100 ?V) were excluded. Data were
re-referenced against the average reference (47).
Time–frequency transformation of the data. Time–frequency analyses
were carried out by using Brain Vision Analyzer (Brain Products
GmbH, Munich, Germany). The wavelet transformation was ap-
plied by using the complex Morlet wavelet, which is defined by
mo(x) ? c?e?x2
frequency parameter ?0with a Gaussian envelope exp(?x2/2) and
wavelet and determines the number of cycles present in each
wavelets, which remains constant across all frequency bands (thus,
lower frequency band wavelets will extend across a longer time
Wavelet analyses decomposed the signal between 8 and 100 Hz
(40 frequency steps) into its time–frequency components. Fre-
boundary as well as a central frequency. Thus, scales number from
1 through 40, going from lower to higher frequencies, respectively.
Because the parameter c determines the number of cycles, it also
determines how wide the each scale will be for the different
frequencies. For the ?- and ?-band analyses, power values from
and scale 2 (8.09- to 12.63-Hz bandwidth, 10.36-Hz central fre-
quency) were extracted, respectively. For ?-band analyses, the data
were bandpass-filtered (2–15 Hz) to include the ?-band. Scale 5
(4.94- to 7.72-Hz bandwidth, 6.33 central frequency) was extracted
to approximate ?-band. Data were referenced to a ?200 to ?50 ms
precue baseline interval for the ?-band data and to a ?300 to ?50
ms precue interval for the ?- and ?-bands because of the larger
not time-locked to the stimulus, and they are determined by
averaging the segments after they have been wavelet-transformed.
For evoked responses, which are time-locked to the stimulus, data
were first averaged for each condition (before wavelet transforma-
tion), with the resulting averages then being wavelet-transformed.
trials per condition, 5 patients were excluded from the analysis
(leaving 15 included in the analyses); all control subjects were
included. Controls averaged 194 low-control trials and 64 high-
control trials. Patients averaged 148 low-control and 50 high-
control trials. Because normality could not be assumed of the
spectral power distributions for each condition at each time point,
statistical contrasts of the high- vs. low-control conditions were
carried out by performing the nonparametric Wilcoxon signed-
ranks test for matched pairs for within-group contrasts and Mann–
Whitney U test for unmatched pairs for across-group comparisons.
The ? error was of concern because of the number of multiple
for the number of time points, the following correction was used,
involving an empirically derived estimate of the type I error. For
each of the three frequency bands (?, ?, and ?) on a per-electrode
basis, we segmented the data into 20 nonoverlapping bins of 48 ms
each, and we limited analysis to the delay period because this was
the interval most relevant to the hypothesis.
Such data reduction drastically reduces the number of com-
parisons. However, recognizing that even 20 comparisons is
relatively large, we derived empirical thresholds for significance
for each electrode by randomly permuting the data 1,000 times
and determining the number of bins that would have to be
?This central frequency is close to that of line noise (60 Hz). Although a 60-Hz notch filter
was used, imperfect filtering could lead to spurious results. As an extra check, for the
significant electrodes for the ? band analysis, data were reanalyzed by using a lower
sub-band of ? (38–48 Hz, central frequency of 43 Hz). The frontal electrodes retained
significance, which is perhaps not surprising given that most of the condition and group
related differences were seen in the lower range of ? (see Fig. 3).
www.pnas.org?cgi?doi?10.1073?pnas.0609440103Cho et al.
significant by the standard uncorrected test, to be above chance Download full-text
level (? ? 0.05). The thresholds involved the vast majority of
electrodes having ?6, 8, or 10 significant bins (of a possible total
of 20) for the ?-, ?-, and ?-band data, respectively. Deriving
thresholds in this manner helped accommodate any variability in
the noise characteristics across the electrode–frequency combi-
nations. All significant results reported in the text are based on
statistical tests with multiple-comparisons correction. For plot-
ting purposes only (Fig. 3), P values have been negative log-
transformed. All negative log P values shown in figures are
derived from uncorrected P values.
For the ?-band analyses, any significant frontal electrodes were
further examined by inspecting the ?-band power averages for the
high vs. low conditions, respectively. Also, to ensure that any
modulations in the induced ? responses were not actually the result
evoked averages as well as performing additional analyses by using
the induced averages as described above, but with the evoked
averages subtracted for each subject (25). Further, on each of these
electrodes, we conducted statistical tests across time–frequency
combinations that spanned the full cue-delay interval and fre-
For within-group contrasts of the high- vs. low-control condition ?
activity, Wilcoxon signed-ranks test for matched pairs was used,
with Mann–Whitney U test for unmatched pairs for across-group
Performance. To assess the clinical and behavioral relevance of any
group differences in ?-band activity, significant electrodes in the
group contrast were submitted to correlation analyses, probing for
any association with symptoms and performance.
Previous studies have shown that both poorer behavioral per-
formance (26) as well as decreased DLPFC activation (6) during
task trials requiring higher degrees of cognitive control are signif-
icantly and most strongly associated with the Disorganization
cluster of symptoms (48) in schizophrenia subjects. To check for
similar associations, we performed correlations between ?-band
activity over the delay period and symptom scores for Reality
Distortion, Disorganization, and Poverty Symptoms. Given the
temporally smoothed nature of fMRI BOLD, it is difficult to know
might give rise to the DLPFC activation correlations with Disor-
ganization symptoms. We therefore divided the delay period into
three bins, referenced with respect to cue stimulus offset: early
(0–332 ms), middle (333–664 ms), and late (665–996 ms). The ?
activity in each of these bins was correlated with the symptom
scores across schizophrenia subjects.
Similarly, previous reports of associations between DLPFC ac-
tivations and cognitive control (3) motivated checking for similar
correlations between ?-band activity during the early, middle, or
late delay period (as defined above) and performance during the
high-control trials. Correlations were performed separately for
controls and patients.
We thank Joseph M. Orr for help with graphics and data processing. This
work was supported by National Institute of Mental Health Grant
MH64190 and a Translational Clinical Scientist Award from the Bur-
roughs–Wellcome Foundation (to C.S.C.) and a National Alliance for
Research on Schizophrenia and Depression Young Investigator Award
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