University of Pennsylvania
Departmental Papers (BE)Department of Bioengineering
Ketamine Modulates Theta and Gamma
Maciej T. Lazarewicz
University of Pennsylvania
Richard S. Ehrilichman
University of Pennsylvania
Christina R. Maxwell
University of Pennsylvania
Michael J. Gandal
University of Pennsylvania, firstname.lastname@example.org
Leif H. Finkel
University of Pennsylvania
See next page for additional authors
Lazarewicz, M.T., R.S. Ehrlichman, C.R. Maxwell, M.J. Gandal, L.H. Finkel and S.J. Siegel. (2009). "Ketamine Modulates Theta and Gamma
Oscillations."Journal of Cognitive Neuroscience.Vol. 22(7). pp. 1452-1464.
© 2009 Massachusetts Institute of Technology
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Maciej T. Lazarewicz, Richard S. Ehrilichman, Christina R. Maxwell, Michael J. Gandal, Leif H. Finkel, and
Steven J. Siegel
This journal article is available at ScholarlyCommons:http://repository.upenn.edu/be_papers/165
Ketamine Modulates Theta and Gamma Oscillations
Maciej T. Lazarewicz, Richard S. Ehrlichman, Christina R. Maxwell,
Michael J. Gandal, Leif H. Finkel, and Steven J. Siegel
■ Ketamine, an N-methyl-D-aspartate (NMDA) receptor gluta-
when applied in subanesthetic doses. In EEG studies, ketamine
affects sensory gating and alters the oscillatory characteristics of
neuronal signals ina complexmanner. Weinvestigated the effects
of ketamine on in vivo recordings from the CA3 region of mouse
hippocampus referenced to the ipsilateral frontal sinus using a
paired-click auditory gating paradigm. One issue of particular in-
terest was elucidating the effect of ketamine on background net-
work activity, poststimulus evoked and induced activity. We find
that ketamine attenuates the theta frequency band in both back-
groundactivity andinpoststimulusevoked activity. Ketamine also
recordings. In the gamma frequency range, ketamine enhances
Two main hypotheses for the pathogenesis of schizo-
phrenia focus on disorders of dopamine (Abi-Dargham
et al., 2002; Carlsson,Waters,Waters,&Carlsson,2000;Akil
tamate mechanisms (Coyle, 2006; Tamminga, 1998). Many
of the changes in the glutamatergic dysfunction model are
reported in hippocampus (Reynolds & Harte, 2007). Keta-
several symptoms and cognitive deficits associated with
schizophrenia (Lahti, Weiler, Tamara Michaelidis, Parwani,
& Tamminga, 2001). Ketamine models both the hyperdo-
paminergic and hypoglutamatergic putative mechanisms
tionofketamineisaccepted asa modelofpsychosisand is
correlated with both positive and negative symptoms of
schizophrenia in both humans (Adler et al., 1999) and ani-
mals (Adams & Moghaddam, 1998). At pharmacologically
relevant concentrations, ketamine acts as a noncompeti-
tor. This mechanism is considered responsible for the
schizophrenia-like symptoms (Tsai & Coyle, 2002) and is
linked to the disinhibition of hippocampal interneurons
(Lewis & Moghaddam, 2006; Greene, 2001). Enhancement
of NMDA receptor action is implicated in reducing some
of the positive symptoms of schizophrenia (Wood, 2005),
Ketamine at subanesthetic doses has been extensively
studied as a model of glutamatergic dysfunction in animal
models of schizophrenia (Bubenikova-Valesova, Horacek,
Vrajova, & Hoschl, 2008; Becker et al., 2003; Moghaddam
& Jackson, 2003; Mansbach & Geyer, 1991). Loss of gluta-
mate receptor function is believed to underlie a range of
cognitive and sensory deficits associated with the disease
(Coyle, 2006). Ketamine has been shown to alter both glu-
tamatergic and dopaminergic neurotransmission, in brain
pus, medial septum, thalamus, and brain stem among oth-
ers (Becker et al., 2003). Specifically interesting are the
effects that ketamine has on gamma oscillations, as they
tures of incoming sensory information (Gray & Singer,
1989) as well as coordinating the activity of local neuronal
oscillations have also been linked to information process-
ing (Gray & Singer, 1989), consciousness (Engel, Fries, &
1993),and memory(Kaiser& Lutzenberger,2005;Howard
2003; Tallon-Baudry, Bertrand, Peronnet, & Pernier, 1998).
Bertrand, 1999) and activation of associative memories
(Miltner, Braun, Arnold, Witte, & Taub, 1999; Pulvermuller,
Lutzenberger, & Preissl, 1999). Stimulus evoked gamma-
band responses have been suggested to reflect synchro-
nously active neural assemblies and the precise temporal
oscillations correlates with working memory during the
n-back task in humans (Sederberg et al., 2006; Howard
University of Pennsylvania, Philadelphia
© 2009 Massachusetts Institute of Technology Journal of Cognitive Neuroscience 22:7, pp. 1452–1464
et al., 2003). In patients with schizophrenia, this correla-
tion is disturbed (Cho, Konecky, & Carter, 2006). A recent
clinical paper has shown that increasing gamma oscilla-
tions with a novel GABA type A agonist correlates with in-
creased cognitive performance in schizophrenic patients
(Lewis et al., 2008). Several studies have demonstrated in-
pocampus in vivo (Hinman, Sabolek, & Chrobak, 2007; Ma
& Leung, 2007). Because ketamine acts through blocking
glutamatergic receptors and has an inhibitory effect on
cells, it is perhaps unexpected to see an increase of gamma
power. However, in hippocampus, NMDA receptors are
located not only on pyramidal cells but also on several
(O-LM) cells (Nyiri, Stephenson, Freund, & Somogyi, 2003;
that ketamine may be acting to increase gamma power via
integration (Bland & Oddie, 2001; OʼKeefe & Recce, 1993),
emotion (Gray, 1982), and formation and recall of episodic
2006; Vertes,2005), as well as working and long-term mem-
ory encoding (Klimesch, Freunberger, Sauseng, & Gruber,
2008). It was suggested that restoring theta-range rhythmic-
ity restores hippocampal function (McNaughton, Ruan, &
Woodnorth, 2006). The theta rhythm may also play a role
encoding of selected information and additionally “filtering-
out” interfering inputs (Vinogradova, 1995). A relationship
lished in hippocampus (Canolty et al., 2006; Bragin et al.,
In this article, we analyze data acquired in an auditory
paired-click gating paradigm. This experimental design
has been extensively investigated in normal cognitive and
schizophrenic studies (Brockhaus-Dumke, Mueller, Faigle,
& Klosterkoetter, 2008). In this auditory gating paradigmin
healthy subjects and animals, the ratio of EEG responses of
the second click to the first click is significantly less than
one, what is called “sensory gating.” In patients diagnosed
with schizophrenia, this sensory gating phenomenon is re-
duced or abolished (the ratio is close to one). Several stud-
ies suggest that gating ratio abnormalities in schizophrenia
are actually mediated by reductions in the first click re-
sponse in unmedicated patients, rather than increased am-
plitude of the second (Clementz & Blumenfeld, 2001; Jin
et al., 1997; Jin & Potkin, 1996; Adler, Rose, & Freedman,
1986; Freedman,Adler,Waldo, Pachtman,& Franks,1983).
macological response properties using this configuration
(Ehrlichman, Maxwell, Majumdar, & Siegel, 2008; Halene
& Siegel, 2008; Rabin et al., 2008; Metzger, Maxwell, Liang,
Liang, Trief, et al., 2006; Maxwell, Liang, et al., 2006; Siegel
Abel, & Siegel, 2004; Maxwell, Liang, et al., 2004; Umbricht
et al., 2004; Umbricht, Latanov, Vissotksi, Nitsch, & Lipp,
2002; Stevens, Kem, & Freedman, 1999; Stevens, Kem,
et al., 1996; Stevens, Meltzer, & Rose, 1995). In animals,
acute injection of ketamine similarly affects this ratio, as
(Ehrlichman et al., 2008; Maxwell, Ehrlichman, Liang,
Trief, et al., 2006; Connolly et al., 2003, 2004). As such,
ketamine may represent a model of altered circuitry in
schizophrenia. We use the auditory paired-click paradigm
to elucidatethe contributionsof background,evoked,and
induced power changes whose interaction obscure the
role of altered glutamatergic responses following ketamine
(using 5 vs. 20 mg/kg) application.
C57BL/6Hsd (B6) male mice (n = 20) were obtained at
8 weeks of age from Harlan (Indianapolis, IN). All proto-
cols were performed in accordance with University Labo-
ratory Animal Resources guidelines and were approved
by the Institutional Animal Care and Use Committee.
Testing was conducted between 10 and 13 weeks of age.
Mice were housed three to four per cage in a light- and
temperature-controlled Association for Assessment and
facility. All efforts were made to minimize animal number
and suffering. Water and standard rodent chow were avail-
able ad lib. Experiments were conducted during the light
phase between the hours of 0900 and 1300. Mice were ac-
climated to the housing facility for at least 1 week prior to
less otherwise stated. Although the ketamine doses used in
dose, we assessed their effects on locomotor activity to con-
trol for possible motor effects on EEG. Mice (n = 6/group,
forthesamedurationas recording ofERPs accordingtopre-
activity testing room in their home cages for a habituation
period of 15 min prior to testing. Animals were placed in
automated locomotor activity frames that creates a grid of
(31 cm length, 19 cm width, 16 cm height) (Med Associates,
Lazarewicz et al.1453
St. Albans, VT, USA). Data were collected over a total period
of 30 min using a personal computer.
Animals underwent stereotaxic implantation of electrode
assemblies (PlasticsOne, Roanoke, VA) for nonanesthe-
tized recording of auditory ERPs as previously reported
(Maxwell, Ehrlichman, Liang, Trief, et al., 2006; Connolly
et al., 2003, 2004; Maxwell,Kanes,etal.,2004;Siegeletal.,
polar recording electrodes were placed in the CA3 hippo-
to the ipsilateral frontal sinus (negative polarity) to reflect
whole-brain electrical activity. Electrode localization in CA3
& Glickstein, 1976). ERPs recorded from this electrode con-
from the Cz scalp location as illustrated in the third figure
from a prior publication (Siegel et al., 2003). The electrode
pedestal was secured to the skull using dental cement and
cyanoacrylate glue. EEGs were recorded 2 weeks after elec-
trode surgery, as described below.
EEGs were recorded during the presentation of a paired-
between 1 and 500 Hz during collection. Stimuli were gen-
through speakers attached to the cage top. All recordings
in a Faraday cage 15 min before stimulus onset. A series of
50 pairs of white noise clicks (10 msec in duration each)
with a 500-msec interstimulus interval were presented
ground of 70 dB. Testing commenced 5 min after intra-
peritoneal injection for each treatment group.
Data analysis was performed using MatLab (MathWorks,
Natick, MA) and JMP (SAS, Cary, NC) software. Four mice
were rejected from the study because of severe recording
artifacts. Two groupsofeight micewereeachanalyzedun-
der two conditions: after saline and after ketamine injec-
tion using a within-subjects experimental design. The first
and 2.5 sec relative to the first click were extracted from
the continuous data. Individual sweeps were rejected for
movement artifact on the basis of a criterion of two times
the root-mean-squared amplitude per mouse. The mean
number of trials in each condition was not significantly
different. ERPs for the first and the second clicks were
obtained by averaging epochs centered at Time 0 and
500 msec to 0 μV, respectively. For each epoch, power
was calculated by the EEGLAB MatLab toolbox (Delorme
& Makeig, 2004) using Morlet wavelets in 91 logarithmi-
cally spaced frequency bins between 2.4 and 150 Hz, with
of 685 msec were dropped from both sides of the epoch.
andtakingthepower of thataverageddata.For inducedac-
tivity,thepower of individualtrialswastakenandaveraged,
and then the part attributable to evoked activity was sub-
tracted. In order to compute the power spectral density,
the mean of total power between −1100 and −100 msec
was averaged. Event-related spectral perturbations (ERSP)
were calculated by averaging power relative to the mean
Figure 1. Demonstration of electrode placement in hippocampus.
(A) Positive electrode tips are marked using Perlʼs iron reaction. Four
examples are shown with the characteristic staining for iron adjacent to
CA3. (B) Gamma power is modulated by theta oscillation phase. The
gray line represents a grand averageof gamma power(30–50Hz) aligned
to the peak of the theta power (3–12 Hz). The black line shows gamma
activity that is not aligned to the theta oscillations. The peak of the
gamma is shifted 10 msec from the peak of the theta with secondary
peak locations compatible with 7–8 Hz oscillations.
1454 Journal of Cognitive NeuroscienceVolume 22, Number 7
baseline between −1100 and −100 msec. To confirm our
results, we estimated the envelope of the amplitude of
band-pass filtered signal using analytical amplitude as pre-
viously performed by Freeman (2004). Briefly, the raw sig-
nal was band-pass filtered using a two-way least-squares
FIR filter in three frequency ranges: low theta (3–5 Hz),
the signal envelope was extracted by calculating the module
of the Hilbert transform. Statistical analysis was performed
using the permutation method (Westfall & Young, 1993)
with 10,000 iterations. Nonpaired and paired t tests were
used for the saline/ketamine factor, and the after-event/
baseline factor, respectively. This method keeps the family-
wise error type II at the desired level for multiple compar-
isons in the time or frequency domain. We do not report
statistically significant changes shorter then 10 msec. For
evoked power analysis, the ANOVA repeated measure of
averaged squared analytical amplitude was calculated
using JMP in time intervals 0–60 and 515–575 msec. The
power of statistical test was stronger in the case of the
power spectral density than analytical amplitude because
the former contains data accumulated over relatively long
There was no effect of ketamine on locomotor activity at
these subanesthetic doses [F(2, 15) = 1.67, p = .22;
mean ± SEM: saline 2721 ± 333.7, 5 mg/kg ketamine
2270 ± 341.9, 20 mg/kg ketamine 3324 ± 524.5]. The
qualitative pattern of ERPs is demonstrated in Figure 2.
The authors have previously published the effects of ke-
tamine on the amplitude and latency of time-locked aver-
aged activity in the time domain (Maxwell, Ehrlichman,
Liang, Trief, et al., 2006; Connolly et al., 2004; Siegel et al.,
main to extend previous findings. Examples of single-trial
recordings are shown in Figure 3. A clear change of rhythm
due to the auditory clicks is evident in the saline condition.
In the ketamine condition, a change in rhythm is almost
nonexistent. Figure 1B demonstrates the pattern of theta-
modulated gamma activity present in these recordings, in-
dicating a large contribution of hippocampal activity to the
To investigate the effect of ketamine on background activ-
ityunrelatedtothestimulus, theaverage powerwas calcu-
lated before the first click in the time window −1100 to
−100 msec (Figure 4).
The dosage of 5 mg/kg ketamine yields a statistically sig-
nificant increase in power in frequency range 33–93 Hz
( p < .001) including the gamma range (30–80 Hz).
thefrequency range26.5–143 Hz ( p < .001)includingthe
gamma range. We note a statistically significant decrease
in power within the frequency range 2.5–21 Hz ( p <
.001), which includes parts of the delta, theta, alpha, and
beta frequency bands. The two curves cross near 23.5 Hz.
power did not show a statistically significant effect between
saline and 5 mg/kg ketamine (p > .05).
(3–5 Hz) [F(1,7) = 14.5, p < .01]and high theta(6–12Hz)
p < .001].
Using induced ERSPs, two main effects (p < .001) are vis-
of power near 20–40 msec in the 15–150 Hz frequency
range, and a strong depression starting near 160 msec
and lasting over 1 sec is pronounced in the 3–20 Hz fre-
quency range. This depression has three visible peaks, the
first two of which are near 300 msec at 4 Hz and 10 Hz
Figure 2. ERPs during the auditory paired-click task after saline (black
lines) and ketamine (gray lines) injections with (A) 5 mg/kg and (B)
20 mg/kg. Left panel responses are shifted to 0 μV at the time of the
first click (at 0 sec), and right panel responses are shifted to 0 μV at the
time of the second click (at 0.5 sec). Inset shows zoom at 0–50 msec in
each panel. ERPs were calculated averaged over 50 trials and across
Lazarewicz et al.1455
is less pronounced, and in the 20-mg/kg ketamine condi-
tion, the late theta depression is lost.
To further quantify these changes, we calculated square
analytic amplitude (Freeman, 2004) in three frequency
in the gamma frequency range (135–155, 335–350, and
595–605 msec), there is no significant difference between
for low theta, a significant attenuationofanalytic amplitude
In the ketamine condition for low theta, the depression
is slightly longer and localized in the time interval 125–
from baseline is localized in the intervals 115–500, 600–920,
the power is depressed in the time interval 155–705 msec.
from the baseline in the saline condition during 6–45 msec
and in the ketamine condition during 10–36 msec.
In contrast to 5 mg/kg, signal power at 20 mg/kg in the
ferent for all calculated time intervals. Low thetaʼs depres-
sion from baseline in the saline condition is pronounced in
the time interval 200–755 msec, but there is no statistically
significantdeviationfrom the baselineintheketaminecon-
dition. For high theta, the two conditions are different ex-
cept for twotimeintervals: 185–850 and970–1360msec. In
the saline condition, power is depressed during the long
power is depressed only briefly at 660–740 msec. For the
gamma frequency range, the two conditions are statistically
(14–52 msec) within which both the saline and ketamine
conditions are attenuated during 10–47 and 13–29 msec,
respectively. In the saline condition, for the gamma range
during the time interval 100–1100 msec, power has inter-
mittent depression from baseline that is not present in the
ketamine condition, nor in the 5-mg/kg dataset.
Our results suggest the following findings.
• Ketamine produces a marked decrease in background
theta (3–7 Hz, 8–12 Hz), and an increase in background
gamma power (30–80 Hz).
evoked power is increased.
• Induced responses in the gamma range have similar
characteristics to background gamma power and evoked
Figure 4. Power spectral densities calculated for intervals between
−1100 and −100 msec before the first click (background data). Saline
(black lines) and ketamine (gray lines) injection with (A) 5 mg/kg and
(B) 20 mg/kg. Horizontal lines with star above represent frequency
ranges with statistically significant differences between saline and
ketamine conditions with p < .001. At (A) horizontal bar spreads from
33 to 95 Hz. At (B) the curve intersection is located about 23.5 Hz.
Figure 3. Example of five
consecutive raw single-trial
recordings (A) after saline and
(B) ketamine injection.
Horizontal scale line represents
500 msec and vertical line
represents 250 μV. Two vertical
lines represent the first and the
second auditory clicks.
1456Journal of Cognitive Neuroscience Volume 22, Number 7
Figure 5. Evoked ERSPs.
Colors represent average
deviation in decibels (dB) from
the mean baseline before the
first click. (A) After saline
(pre 5 mg ketamine), (B) after
5 mg/kg ketamine injection,
(C) after saline (pre 20 mg
ketamine), and (D) after
20 mg/kg ketamine injection.
Figure 6. Evoked analytic
amplitude calculated for three
frequency bands: low theta
(3–5 Hz), high theta (6–12 Hz),
and gamma (30–80 Hz) after
saline (green lines) and
ketamine (red lines) injections
with (A) 5 mg/kg and (B)
20 mg/kg. Width of the line
indicates standard error of
measurement (SEM). Stars
mean statistically significant
difference between saline and
ketamine conditions (*p < .05,
**p < .01, ***p < .001).
Lazarewicz et al.1457
Figure 7. Induced ERSPs.
Colors represent average
deviation in decibels (dB) from
the mean baseline before the
first click. (A) After saline
(pre 5 mg ketamine), (B)
5 mg/kg ketamine injection,
(C) saline (pre 5 mg ketamine),
(D) 20 mg/kg ketamine
injection. Only statistically
significant results are shown
( p < .05). Black contour
indicates statistical significance
at the level of ( p < .001).
Figure 8. Induced analytic
amplitude calculated for three
frequency bands: low theta
(3–5 Hz), high theta (6–12 Hz),
and gamma (30–80 Hz) after
saline (green lines) and
ketamine (red lines) injections
with (A) 5 mg/kg and (B)
20 mg/kg. Horizontal bars
represent time ranges with
differences between saline and
ketamine conditions (black
line), saline condition and saline
mean baseline (green line), and
ketamine condition and
ketamine mean baseline (red
line) with p < .01. Width of the
line indicates standard error of
1458 Journal of Cognitive Neuroscience Volume 22, Number 7
responses. However changes relative to the background
are reduced by ketamine.
persists for roughly 1000 msec in control animals, but
this suppression is lost following ketamine.
Theta and Gamma Oscillations
Weinvestigated theeffect ofketamine duringthe auditory
paired-click paradigm using two doses (5 and 20 mg/kg).
We analyzed the relationship between background, evoked,
and induced power before and after the auditory stimulus
and their alteration in the presence of ketamine. We have
specifically focused on the theta and gamma frequency
ranges.Our results demonstrate that ketamine, in subanes-
theticdoses,produces complexchanges inthenetworkos-
cillatoryactivity ofneurons,specificallyin theta and gamma
frequency ranges. These perturbations affected ongoing,
background activity as well as event-related activities. Addi-
to move in opposite directions, which may be explained by
et al., 1995; Llinas & Ribary, 1993; Soltesz & Deschenes,
1993; Woolley & Timiras, 1965). Of special note, ketamine
ing only a short depressed activity after the second click lo-
cated in the high theta frequency range. This may correlate
with recent human EEG data showing a decrease in the
group and an attenuation of this decrease in patients with
schizophrenia (Ford, Roach, Hoffman, & Mathalon, 2008).
ing NMDA receptors, these data support their role in medi-
ating the balance between theta and gamma responses to
sensory stimuli with implications for dysfunction in schizo-
phrenia. We also observed that ketamine produced changes
in the prestimulus power content, indicating that the state
of the animal brain changed independent of the auditory
stimuli used in the experiment. This makes the analysis of
the event-related changes more complex, as changes in
power relative to the background may depend upon their
frequencies, including the theta range (low: 3–5 Hz; high:
6–12 Hz). The transition point between decrease and in-
subanesthetic concentration of 5 mg/kg ketamine, the
only statistically significant change was the gamma power
amplification. The increase of in vivo gamma power after
ketamine administration in hippocampus was previously
encephalography studies suggested a positive correlation
toms such as hallucinations (Sperling, Bleich, Maihofner, &
Reulbach, 2009; Ince, Goksu, Pellizzer, Tewfik, & Stephane,
studies suggest an opposite change in theta power than that
reported here. It is not possible to evaluate the effects of
ketamine on constructs such as hallucinations in our ani-
symptomatic exacerbations in humans. Consistent with
our results, Chrobak, Hinman, and Sabolek (2008) also
demonstrated ketamine-induced changes in theta and
phase relationship in hippocampus.
Ketamine Mode of Action on Local Circuits
campus is the main generator of theta rhythms (Buzsaki,
2002) and some investigators have argued that hippocam-
pus contributes strongly to gating (Adler, Hoffer, Wiser, &
of gamma oscillations is significantly higher in hippocam-
pus than in the rest of the brain (Bartos, Vida, & Jonas,
2007). We propose that hippocampus contributes heavily
to theactivity in ourrecordings.Therefore,understanding
the effect of ketamine on local hippocampal circuits may
help interpret the observed changes in gamma and theta
oscillatory power. We speculate that dysfunction of the
glutamatergic system in schizophrenia affects theta/gamma
oscillationson the levelofthislocalcircuit.In particular,we
speculate that a disruption in the interaction between dif-
ferent subtypes of interneurons and pyramidal cells may
mediate our observed oscillatory findings. This circuit
has been shown to be disrupted in schizophrenia (Lewis,
a key generator of oscillatory activity in neuronal popula-
tions in vivo (Bartos et al., 2007). Ketamine likely targets
NMDA receptors located at hippocampal interneurons
(Greene, 2001), with an emphasis on O-LM cells (Tort,
Rotstein, Dugladze, Gloveli, & Kopell, 2007) that contain
an abundance of NMDA receptors (Nyiri et al., 2003; Hajos
to NMDA-receptor antagonists than pyramidal cells at low
doses (Grunze et al., 1996).
Wereport significantchangesin background gamma (in-
creased) and background theta (decreased) activity with
ketamine administration. In interpreting these results, it is
interesting to note that at the level of hippocampus mod-
ulation of gamma and theta oscillations has been shown
to be coupled. Data from in vitro preparations indicate that
theta oscillations may be masked or inhibited by the pres-
ence of gamma oscillations (Gillies et al., 2002). An implica-
tion of this finding is that disruption of the hippocampal
theta generator would have a secondary effect of unmask-
ing power in this frequency band. Although the precise
mechanism of theta generation is unknown, hippocampal
Lazarewicz et al. 1459
O-LM cells are thought to be integrally involved (Traub,
Bibbig, LeBeau, Buhl, & Whittington, 2004). O-LM cells
are also known to contain an abundance of NMDA recep-
sion. The failure of the theta generator as a mechanismfor
ment with the hypothesis that event-related theta oscilla-
tions have a double function in information processing:
“filtering in” the first click, and “filtering out” the second
click(Vinogradova,1995).Althoughthis is aplausible mech-
anistic explanation of our findings, further experimental
work and computational modeling will be required to so-
lidify these connections.
Absolute vs. Relative Power
There is some variability in the literature regarding abnor-
animal models of the disorder. In human EEG studies,
there are reports of a gamma power decrease in schizo-
phrenia patients (Ferrarelli et al., 2008; Gallinat, Winterer,
Herrmann, & Senkowski, 2004), simultaneous decreases
in the left hemisphere and frontal sites and an increase
in right hemisphere and parieto-occipital sites (Haig et al.,
symptoms, and an increase in gamma power associated
with positive symptoms (Herrmann & Demiralp, 2005;
Lee et al., 2003).
Taking into account that, in an animal model of the dis-
order after acute injection of ketamine, a complex spec-
trum of changes is observed, we explored possible causes
for the complexities regarding increases and decreases in
signal power in the theta and gamma frequency ranges.
Several measured or calculated values can be confused if
not fully qualified: total power, evoked power, induced
power, absolute power, and power relative to the back-
ground. First, using “relative to the background” versus
“absolute change in power” may introduce divergent re-
sults, especially in taskswhere thefirst factorisan external
stimulus and the second factor is saline versus drug condi-
tion. In our data, the induced gamma power is a good ex-
ample of this situation (Figure 8B). Short increases in the
induced gamma power just after the first click reach statis-
tically the same absolute value in the saline and ketamine
condition, but the relative changes are different because
they start from different prestimulus baselines. The total
power in that case behaves identically (data not shown).
Additionally, four combinations of experimental condi-
tions exist: before auditory stimulus when saline is in-
jected, after auditory stimulus when saline is injected,
before auditory stimulus when ketamine is injected, after
four conditions, total/induced power of the field poten-
tial may differ. If A and B are two of these conditions and
the background/induced power is larger in Condition B
(Figure 9D, red color) than in Condition A (Figure 9D,
green color), and relative-to-the-background change in
power is larger in Condition A, it still may not be large
in the Condition A, than in the Condition B. Therefore, a
comparison of relative changes of power needs to be evalu-
ated in the context of changes of the background power.
This complication does not apply to evoked power because
the background evoked power comes close to zero.
In an animal model of schizophrenia, it is possible to
perform a within-subjects experiment in which measure-
ments of power are taken in all four conditions for each
mouse. Human data in schizophrenia research come from
after stimulus in a between-subjects experiment. It is not
possible to make within-subject comparisons between
control and schizophrenia conditions. Therefore, it is pos-
sible that, in the human experiments, the relative and ab-
solute changes of power may be confounded, taking into
account the large variability of spontaneous (background)
power levels within a control and patient group. Data re-
are mixed. Some studies suggest reductions in gamma ac-
tivity using a gamma frequency stimulus to evaluate en-
trainment. Others show reductions in evoked power,
albeit after removal of baseline activity (Spencer et al.,
2003, 2004; Kwon et al., 1999). Our group has found in-
creased gamma power in schizophrenia, which is due to
the increase in baseline (Turetsky & Siegel, 2007;Turetsky,
McGue, Ramsey, Siegel, & Gur, 2006). Indeed, the variabil-
ity in findings is largely a function of how each group han-
dles background activity as its removal yields a reduction,
but its inclusion yields the opposite finding.
by intracranial electrode) is associated with the global de-
by breaking down the long-range synchronization in this
frequency range (Yeragani, Cashmere, Miewald, Tancer,
& Keshavan, 2006). It is conceivable that local changes in
oscillations, such as an increase in gamma, may break down
Figure 9. Summary of the absolute and relative changes in power
before and after an event in the saline (green) and ketamine (red)
conditions. (A) Theta evoked power, (B) gamma evoked power,
(C) theta induced power, (D) gamma induced power.
1460 Journal of Cognitive NeuroscienceVolume 22, Number 7
the mechanisms for long-range synchronization, or in-
versely, the loss of long-range synchronization may cause
a local, compensatory increase in gamma power. This
may explain the decrease in gamma power in EEG record-
ings in patients with schizophrenia and the increase in
phrenia. Another explanation may be that the effect of ke-
tamine depends upon brain area and cortical layer (Roopun
et al., 2008). An increase in gamma power after ketamine
administration has also been found in neocortex (Pinault,
2008). In contrast, decreases in gamma power are seen
in vitro in medial-temporal structures (Cunningham et al.,
2006; Uhlhaas et al., 2006). Functional variability along the
longitudinal axis of hippocampus has also been described
(Kjelstrup et al., 2008); therefore, further investigation of
ketamine action in these regions may confirm some of
The use ofa bipolar configuration spanninga negativepole
adjacent to frontal cortex and a positive pole in hippocam-
tion allows for a better translation to human EEG, which is
figuration does not allow for isolation of signals to a single,
unitary source. As such, we are not suggesting that the ob-
served EEG spectral analysis reflects only hippocampal ac-
tivity. Rather, it reflects the gestalt of EEG signals that
is most sensitive to the structures closest to the electrode
tips, and therefore, does include activity from both hippo-
campus and frontal cortex. Because our goal is to examine
the extent to which ketamine recapitulates the changes in
is able to address the primary question posed in this study.
tions of these abnormalities.
gamma frequency oscillations display opposing effects that
suggest possible fundamental alterations in information
processing in schizophrenia.
Supported by NIH Conte Center MH-064045064045 and R01
DA023210-01. We thank Marieke van Vugt for fruitful discussion
about permutation methods, and Mark Lippmann for helpful
discussions and comments on the manuscript.
Reprint requests should be sent to Maciej T. Lazarewicz, Neuro-
engineering Laboratory, Department of Bioengineering, Univer-
sity of Pennsylvania, Room 240 Skirkanich Hall, 210 S. 33rd Street,
Philadelphia, PA 19104, or via e-mail: firstname.lastname@example.org.
Abi-Dargham, A., Mawlawi, O., Lombardo, I., Gil, R., Martinez,
D., Huang, Y., et al. (2002). Prefrontal dopamine D1
receptors and working memory in schizophrenia. Journal
of Neuroscience, 22, 3708–3719.
Adams, B., & Moghaddam, B. (1998). Corticolimbic dopamine
neurotransmission is temporally dissociated from the
cognitive and locomotor effects of phencyclidine. Journal
of Neuroscience, 18, 5545–5554.
Adler, C. M., Malhotra, A. K., Elman, I., Goldberg, T., Egan, M.,
Pickar, D., et al. (1999). Comparison of ketamine-induced
thought disorder in healthy volunteers and thought disorder
in schizophrenia. American Journal of Psychiatry, 156,
Adler, L. E., Hoffer, L. D., Wiser, A., & Freedman, R. (1993).
Normalization of auditory physiology by cigarette smoking
in schizophrenic patients. American Journal of Psychiatry,
Adler, L.E., Rose, G.,& Freedman,R. (1986).Neurophysiological
studies of sensory gating in rats: Effects of amphetamine,
phencyclidine, and haloperidol. Biological Psychiatry, 21,
Akil, M., Pierri, J. N., Whitehead, R. E., Edgar, C. L., Mohila, C.,
Sampson, A. R., et al. (1999). Lamina-specific alterations in
the dopamine innervation of the prefrontal cortex in
schizophrenic subjects. American Journal of Psychiatry,
Bartos, M., Vida, I., & Jonas, P. (2007). Synaptic mechanisms of
synchronized gamma oscillations in inhibitory interneuron
networks. Nature Reviews Neuroscience, 8, 45–56.
Becker, A., Peters, B., Schroeder, H., Mann, T., Huether, G., &
Grecksch, G. (2003). Ketamine-induced changes in rat
behaviour: A possible animal model of schizophrenia.
Progress in Neuro-psychopharmacology & Biological
Psychiatry, 27, 687–700.
Bland, B. H., & Oddie, S. D. (2001). Theta band oscillation and
synchrony in the hippocampal formation and associated
structures: The case for its role in sensorimotor integration.
Behavioural Brain Research, 127, 119–136.
Bragin, A., Jando, G., Nadasdy, Z., Hetke, J., Wise, K., &
Buzsaki, G. (1995). Gamma (40–100 Hz) oscillation in the
hippocampus of the behaving rat. Journal of Neuroscience,
Brockhaus-Dumke, A., Mueller, R., Faigle, U., & Klosterkoetter,
J. (2008). Sensory gating revisited: Relation between brain
oscillations and auditory evoked potentials in schizophrenia.
Schizophrenia Research, 99, 238–249.
Bubenikova-Valesova, V., Horacek, J., Vrajova, M., & Hoschl, C.
(2008). Models of schizophrenia in humans and animals
based on inhibition of NMDA receptors. Neuroscience and
Biobehavioral Reviews, 32, 1014–1023.
Buhl, E. H., Szilagyi, T., Halasy, K., & Somogyi, P. (1996).
Physiological properties of anatomically identified basket and
bistratified cells in the CA1 area of the rat hippocampus
in vitro. Hippocampus, 6, 294–305.
Buzsaki, G. (2002). Theta oscillations in the hippocampus.
Neuron, 33, 325–340.
Canive, J. M., Lewine, J. D., Edgar, J. C., Davis, J. T., Miller, G. A.,
Torres, F., et al. (1998). Spontaneous brain magnetic activity
in schizophrenia patients treated with aripiprazole.
Psychopharmacology Bulletin, 34, 101–105.
Canolty, R. T., Edwards, E., Dalal, S. S., Soltani, M., Nagarajan,
S. S., Kirsch, H. E., et al. (2006). High gamma power is phase-
locked to theta oscillations in human neocortex. Science,
Carlsson, A., Waters, N., Waters, S., & Carlsson, M. L. (2000).
Network interactions in schizophrenia—Therapeutic
Lazarewicz et al.1461
implications. Brain Research, Brain Research Reviews, 31,
Cho, R. Y., Konecky, R. O., & Carter, C. S. (2006). Impairments
in frontal cortical gamma synchrony and cognitive control in
schizophrenia. Proceedings of the National Academy of
Sciences, U.S.A., 103, 19878–19883.
Chrobak, J. J., & Buzsaki, G. (1998). Operational dynamics in
the hippocampal–entorhinal axis. Neuroscience and
Biobehavioral Reviews, 22, 303–310.
Chrobak, J. J., Hinman, J. R., & Sabolek, H. R. (2008). Revealing
past memories: Proactive interference and ketamine-induced
memory deficits. Journal of Neuroscience, 28,
Clementz, B. A., & Blumenfeld, L. D. (2001). Multichannel
electroencephalographic assessment of auditory evoked
response suppression in schizophrenia. Experimental Brain
Research, 139, 377–390.
Connolly, P. M., Maxwell, C., Liang, Y., Kahn, J. B., Kanes, S. J.,
Abel, T., et al. (2004). The effects of ketamine vary among
inbred mouse strains and mimic schizophrenia for the P80,
but not P20 or N40 auditory ERP components.
Neurochemical Research, 29, 1179–1188.
Connolly, P. M., Maxwell, C. R., Kanes, S. J., Abel, T., Liang, Y.,
Tokarczyk, J., et al. (2003). Inhibition of auditory evoked
potentials and prepulse inhibition of startle in DBA/2J
and DBA/2Hsd inbred mouse substrains. Brain Research,
Coyle, J. T. (2006). Substance use disorders and schizophrenia:
A question of shared glutamatergic mechanisms.
Neurotoxicity Research, 10, 221–233.
Cunningham, M. O., Hunt, J., Middleton, S., LeBeau, F. E.,
Gillies, M. J., Davies, C. H., et al. (2006). Region-specific
reduction in entorhinal gamma oscillations and parvalbumin-
immunoreactive neurons in animal models of psychiatric
illness. Journal of Neuroscience, 26, 2767–2776.
Delorme, A., & Makeig, S. (2004). EEGLAB: An open source
toolbox for analysis of single-trial EEG dynamics including
independent component analysis. Journal of Neuroscience
Methods, 134, 9–21.
Ehrlichman, R. S., Maxwell, C. R., Majumdar, S., & Siegel, S. J.
(2008). Deviance-elicited changes in event-related potentials
are attenuated by ketamine in mice. Journal of Cognitive
Neuroscience, 20, 1403–1414.
Engel, A. K., Fries, P., & Singer, W. (2001). Dynamic predictions:
Oscillations and synchrony in top–down processing. Nature
Reviews Neuroscience, 2, 704–716.
Fehr, T., Kissler, J., Moratti, S., Wienbruch, C., Rockstroh, B., &
Elbert, T. (2001). Source distribution of neuromagnetic slow
waves and MEG-delta activity in schizophrenic patients.
Biological Psychiatry, 50, 108–116.
Fehr, T., Kissler, J., Wienbruch, C., Moratti, S., Elbert, T.,
Watzl, H., et al. (2003). Source distribution of neuromagnetic
slow-wave activity in schizophrenic patients—Effects of
activation. Schizophrenia Research, 63, 63–71.
Ferrarelli, F., Massimini, M., Peterson, M. J., Riedner, B. A.,
Lazar, M., Murphy, M. J., et al. (2008). Reduced evoked
gamma oscillations in the frontal cortex in schizophrenia
patients: A TMS/EEG study. American Journal of Psychiatry,
Ford, J. M., Roach, B. J., Hoffman, R. S., & Mathalon, D. H.
(2008). The dependence of P300 amplitude on gamma
synchrony breaks down in schizophrenia. Brain Research,
Freedman, R., Adler, L. E., Waldo, M. C., Pachtman, E., & Franks,
R. D. (1983). Neurophysiological evidence for a defect in
inhibitory pathways in schizophrenia: Comparison of
medicated and drug-free patients. Biological Psychiatry, 18,
Freeman, W. J. (2004). Origin, structure, and role of
background EEG activity: Part 1. Analytic amplitude. Clinical
Neurophysiology, 115, 2077–2088.
Gallinat, J., Winterer, G., Herrmann, C. S., & Senkowski, D.
(2004). Reduced oscillatory gamma-band responses in
unmedicated schizophrenic patients indicate impaired
frontal network processing. Clinical Neurophysiology, 115,
Gillies, M. J., Traub, R. D., LeBeau, F. E., Davies, C. H., Gloveli,
T., Buhl, E. H., et al. (2002). A model of atropine-resistant
theta oscillations in rat hippocampal area CA1. Journal of
Physiology, 543, 779–793.
Gray, C. M., & Singer, W. (1989). Stimulus-specific neuronal
oscillations in orientation columns of cat visual cortex.
Proceedings of the National Academy of Sciences, U.S.A.,
Gray, J. A. (1982). The neuropsychology of anxiety: An enquiry
into the functions of the septo-hippocampal system. Oxford:
Oxford University Press.
Greene, R. (2001). Circuit analysis of NMDAR hypofunction in
the hippocampus, in vitro, and psychosis of schizophrenia.
Hippocampus, 11, 569–577.
Grunze, H. C., Rainnie, D. G., Hasselmo, M. E., Barkai, E.,
Hearn, E. F., McCarley, R. W., et al. (1996). NMDA-dependent
modulation of CA1 local circuit inhibition. Journal of
Neuroscience, 16, 2034–2043.
Gunduz-Bruce, H. (2009). The acute effects of NMDA
antagonism: From the rodent to the human brain. Brain
Research Reviews, 60, 279–286.
Haig, A. R., Gordon, E., De Pascalis, V., Meares, R. A., Bahramali,
H., & Harris, A. (2000). Gamma activity in schizophrenia:
Evidence of impaired network binding? Clinical
Neurophysiology, 111, 1461–1468.
Hajos, N., Freund, T. F., & Mody, I. (2002). Comparison of
single NMDA receptor channels recorded on hippocampal
principal cells and oriens/alveus interneurons projecting to
stratum lacunosum–moleculare (O-LM cells). Acta Biologica
Hungarica, 53, 465–472.
Halene, T. B., & Siegel, S. J. (2008). Antipsychotic-like
properties of phosphodiesterase 4 inhibitors: Evaluation of
with auditory event-related potentials and prepulse inhibition
of startle. Journal of Pharmacology and Experimental
Therapeutics, 326, 230–239.
Herrmann, C. S., & Demiralp, T. (2005). Human EEG gamma
oscillations in neuropsychiatric disorders. Clinical
Neurophysiology, 116, 2719–2733.
Herrmann, C. S., Munk, M. H., & Engel, A. K. (2004). Cognitive
functions of gamma-band activity: Memory match and
utilization. Trends in Cognitive Sciences, 8, 347–355.
Hinman, J. R., Sabolek, H. R., & Chrobak, J. J. (2007). Ketamine
induced proactive interference between working and
episodic memories in the rat: Relation to hippocampal
theta. Paper presented at the Society for Neuroscience,
San Diego, CA.
Howard, M. W., Rizzuto, D. S., Caplan, J. B., Madsen, J. R.,
Lisman, J., Aschenbrenner-Scheibe, R., et al. (2003). Gamma
oscillations correlate with working memory load in humans.
Cerebral Cortex, 13, 1369–1374.
Ince, N. F., Goksu, F., Pellizzer, G., Tewfik, A., & Stephane, M.
(2008). Selection of spectro-temporal patterns in
multichannel MEG with support vector machines for
schizophrenia classification. Conference Proceedings:
Annual International Conference of the IEEE
Engineering in Medicine and Biology Society, 1,
Ishii, R., Shinosaki, K., Ikejiri, Y., Ukai, S., Yamashita, K.,
Iwase, M., et al. (2000). Theta rhythm increases in left
1462 Journal of Cognitive NeuroscienceVolume 22, Number 7
superior temporal cortex during auditory hallucinations in
schizophrenia: A case report. NeuroReport, 11, 3283–3287.
Jacobs, J., Hwang, G., Curran, T., & Kahana, M. J. (2006). EEG
oscillations and recognition memory: Theta correlates of
memory retrieval and decision making. Neuroimage, 32,
Jin, Y., & Potkin, S. G. (1996). P50 changes with visual
interference in normal subjects: A sensory distraction model
for schizophrenia. Clinical Electroencephalography, 27,
Jin, Y., Potkin, S. G., Patterson, J. V., Sandman, C. A., Hetrick,
W. P., & Bunney, W. E., Jr. (1997). Effects of P50 temporal
variability on sensory gating in schizophrenia. Psychiatry
Research, 70, 71–81.
Kaiser, J., & Lutzenberger, W. (2005). Cortical oscillatory activity
and the dynamics of auditory memory processing. Reviews in
the Neurosciences, 16, 239–254.
Kjelstrup, K. B., Solstad, T., Brun, V. H., Hafting, T., Leutgeb, S.,
Witter, M. P., et al. (2008). Finite scale of spatial
representation in the hippocampus. Science, 321, 140–143.
Klimesch, W., Freunberger, R., Sauseng, P., & Gruber, W.
(2008). A short review of slow phase synchronization and
memory: Evidence for control processes in different memory
systems? Brain Research, 1235, 31–44.
Koh, D. S., Geiger, J. R., Jonas, P., & Sakmann, B. (1995).
Ca(2+)-permeable AMPA and NMDA receptor channels in
basket cells of rat hippocampal dentate gyrus. Journal of
Physiology, 485, 383–402.
Kwon, J. S., OʼDonnell, B. F., Wallenstein, G. V., Greene, R. W.,
Hirayasu, Y., Nestor, P. G., et al. (1999). Gamma frequency-
range abnormalities to auditory stimulation in schizophrenia.
Archives of General Psychiatry, 56, 1001–1005.
LaBossiere, E., & Glickstein, M. (1976). Histological processing
for the neural science. Springfield, IL: Charles C. Thomas.
Lahti, A. C., Weiler, M. A., Tamara Michaelidis, B. A., Parwani, A.,
& Tamminga, C. A. (2001). Effects of ketamine in normal and
schizophrenic volunteers. Neuropsychopharmacology, 25,
Lee, K. H., Williams, L. M., Haig, A., & Gordon, E. (2003).
“Gamma (40 Hz) phase synchronicity” and symptom
dimensions in schizophrenia. Cognitive Neuropsychiatry,
Lewis, D. A., Cho, R. Y., Carter, C. S., Eklund, K., Forster, S.,
Kelly, M. A., et al. (2008). Subunit-selective modulation of
GABA type A receptor neurotransmission and cognition
in schizophrenia. American Journal of Psychiatry, 165,
Lewis, D. A., Hashimoto, T., & Volk, D. W. (2005). Cortical
inhibitory neurons and schizophrenia. Nature Reviews
Neuroscience, 6, 312–324.
Lewis, D. A., & Moghaddam, B. (2006). Cognitive dysfunction in
schizophrenia: Convergence of gamma-aminobutyric acid
and glutamate alterations. Archives of Neurology, 63,
Llinas, R., & Ribary, U. (1993). Coherent 40-Hz oscillation
characterizes dream state in humans. Proceedings of the
National Academy of Sciences, U.S.A., 90, 2078–2081.
Ma, J., & Leung, L. S. (2007). The supramammillo-septal-
hippocampal pathway mediates sensorimotor gating
impairment and hyperlocomotion induced by MK-801
and ketamine in rats. Psychopharmacology (Berlin), 191,
Mansbach, R. S., & Geyer, M. A. (1991). Parametric
determinants in pre-stimulus modification of acoustic startle:
Interaction with ketamine. Psychopharmacology (Berlin),
Maxwell, C. R., Ehrlichman, R. S., Liang, Y., Gettes, D. R., Evans,
D. L., Kanes, S. J., et al. (2006). Corticosterone modulates
auditory gating in mouse. Neuropsychopharmacology, 31,
Maxwell, C. R., Ehrlichman, R. S., Liang, Y., Trief, D., Kanes, S. J.,
Karp, J., et al. (2006). Ketamine produces lasting disruptions
in encoding of sensory stimuli. Journal of Pharmacology
and Experimental Therapeutics, 316, 315–324.
Maxwell, C. R., Kanes, S. J., Abel, T., & Siegel, S. J. (2004).
Phosphodiesterase inhibitors: A novel mechanism for
receptor-independent antipsychotic medications.
Neuroscience, 129, 101–107.
Maxwell, C. R., Liang, Y., Kelly, M. P., Kanes, S. J., Abel, T., &
Siegel, S. J. (2006). Mice expressing constitutively active
Gsalpha exhibit stimulus encoding deficits similar to those
observed in schizophrenia patients. Neuroscience, 141,
Maxwell, C. R., Liang, Y., Weightman, B. D., Kanes, S. J., Abel, T.,
Gur, R. E., et al. (2004). Effects of chronic olanzapine and
haloperidol differ on the mouse N1 auditory evoked
potential. Neuropsychopharmacology, 29, 739–746.
McBain, C. J., & Dingledine, R. (1993). Heterogeneity of
synaptic glutamate receptors on CA3 stratum radiatum
interneurones of rat hippocampus. Journal of Physiology,
McNaughton, N., Ruan, M., & Woodnorth, M. A. (2006).
Restoring theta-like rhythmicity in rats restores initial
learning in the Morris water maze. Hippocampus, 16,
Metzger, K. L., Maxwell, C. R., Liang, Y., & Siegel, S. J. (2007).
Effects of nicotine vary across two auditory evoked potentials
in the mouse. Biological Psychiatry, 61, 23–30.
Miltner, W. H., Braun, C., Arnold, M., Witte, H., & Taub, E.
(1999). Coherence of gamma-band EEG activity as a basis for
associative learning. Nature, 397, 434–436.
Moghaddam, B., & Jackson, M. E. (2003). Glutamatergic animal
models of schizophrenia. Annals of the New York Academy
of Sciences, 1003, 131–137.
Nyiri, G., Stephenson, F. A., Freund, T. F., & Somogyi, P. (2003).
Large variability in synaptic N-methyl-D-aspartate receptor
density on interneurons and a comparison with pyramidal-cell
spines in the rat hippocampus. Neuroscience, 119, 347–363.
OʼKeefe, J., & Recce, M. L. (1993). Phase relationship between
hippocampal place units and the EEG theta rhythm.
Hippocampus, 3, 317–330.
Phillips, J. M., Ehrlichman, R. S., & Siegel, S. J. (2007).
Mecamylamine blocks nicotine-induced enhancement of the
P20 auditory event-related potential and evoked gamma.
Neuroscience, 144, 1314–1323.
Pinault, D. (2008). N-methyl-D-aspartate receptor antagonists
ketamine and MK-801 induce wake-related aberrant gamma
oscillations in the rat neocortex. Biological Psychiatry, 63,
Pulvermuller, F., Lutzenberger, W., & Preissl, H. (1999). Nouns
and verbs in the intact brain: Evidence from event-related
potentials and high-frequency cortical responses. Cerebral
Cortex, 9, 497–506.
Rabin, C., Liang, Y., Ehrlichman, R. S., Budhian, A., Metzger,
K. L., Majewski-Tiedeken, C., et al. (2008). In vitro and in vivo
demonstration of risperidone implants in mice.
Schizophrenia Research, 98, 66–78.
Reynolds, G. P., & Harte, M. K. (2007). The neuronal pathology
of schizophrenia: Molecules and mechanisms. Biochemical
Society Transactions, 35, 433–436.
Rodriguez, E., George, N., Lachaux, J. P., Martinerie, J., Renault,
B., & Varela, F. J. (1999). Perceptionʼs shadow: Long-distance
synchronization of human brain activity. Nature, 397,
Roopun, A. K., Cunningham, M. O., Racca, C., Alter, K., Traub,
R. D., & Whittington, M. A. (2008). Region-specific changes in
Lazarewicz et al.1463
gamma and beta2 rhythms in NMDA receptor dysfunction Download full-text
models of schizophrenia. Schizophrenia Bulletin, 34, 962–973.
Sederberg, P. B., Gauthier, L. V., Terushkin, V., Miller, J. F.,
Barnathan, J. A., & Kahana, M. J. (2006). Oscillatory correlates
of the primacy effect in episodic memory. Neuroimage, 32,
Sederberg, P. B., Kahana, M. J., Howard, M. W., Donner, E. J., &
Madsen, J. R. (2003). Theta and gamma oscillations during
encoding predict subsequent recall. Journal of Neuroscience,
Siegel, S. J., Connolly, P., Liang, Y., Lenox, R. H., Gur, R. E.,
Bilker, W. B., et al. (2003). Effects of strain, novelty, and
NMDA blockade on auditory-evoked potentials in mice.
Neuropsychopharmacology, 28, 675–682.
Siegel, S. J., Maxwell, C. R., Majumdar, S., Trief, D. F.,
Lerman, C., Gur, R. E., et al. (2005). Monoamine reuptake
inhibition and nicotine receptor antagonism reduce
amplitude and gating of auditory evoked potentials.
Neuroscience, 133, 729–738.
Soltesz, I., & Deschenes, M. (1993). Low- and high-frequency
membrane potential oscillations during theta activity in CA1
and CA3 pyramidal neurons of the rat hippocampus under
ketamine–xylazine anesthesia. Journal of Neurophysiology,
Spencer, K. M., Nestor, P. G., Niznikiewicz, M. A., Salisbury,
D. F., Shenton, M. E., & McCarley, R. W. (2003). Abnormal
neural synchrony in schizophrenia. Journal of Neuroscience,
Spencer, K. M., Nestor, P. G., Perlmutter, R., Niznikiewicz, M. A.,
Klump, M. C., Frumin, M., et al. (2004). Neural synchrony
indexes disordered perception and cognition in schizophrenia.
Proceedings of the National Academy of Sciences, U.S.A., 101,
Sperling, W., Bleich, S., Maihofner, C., & Reulbach, U. (2009).
Auditory hallucinations in schizophrenia—Outcry of a
diseased brain? Medical Hypotheses, 72, 213–216.
Sperling, W., Vieth, J., Martus, M., Demling, J., & Barocka, A.
(1999). Spontaneous slow and fast MEG activity in male
schizophrenics treated with clozapine. Psychopharmacology
(Berlin), 142, 375–382.
Stevens, K. E., Freedman, R., Collins, A. C., Hall, M., Leonard, S.,
Marks, M. J., et al. (1996). Genetic correlation of inhibitory
gating of hippocampal auditory evoked response and
a-bungerotoxin-binding nicotinic cholinergic receptors
in inbred mouse strains. Neuropsychopharmacology, 15,
Stevens, K. E., Kem, W. R., & Freedman, R. (1999). Selective
alpha 7 nicotinic receptor stimulation normalizes chronic
cocaine-induced loss of hippocampal sensory inhibition in
C3H mice. Biological Psychiatry, 46, 1443–1450.
Stevens, K. E., Kem, W. R., Mahnir, V. M., & Freedman, R.
(1998). Selective alpha7-nicotinic agonists normalize
inhibition of auditory response in DBA mice.
Psychopharmacology (Berlin), 136, 320–327.
Stevens, K. E., Meltzer, J., & Rose, G. M. (1995). Nicotinic
cholinergic normalization of amphetamine-induced loss of
auditory gating in freely moving rats. Psychopharmacology
(Berlin), 119, 163–170.
Stevens, K. E., & Wear, K. D. (1997). Normalizing effects of
nicotine and a novel nicotinic agonist on hippocampal
auditory gating in two animal models. Pharmacology,
Biochemistry and Behavior, 57, 869–874.
Tallon-Baudry, C., Bertrand, O., Peronnet, F., & Pernier, J.
(1998). Induced gamma-band activity during the delay of a
visual short-term memory task in humans. Journal of
Neuroscience, 18, 4244–4254.
Tallon-Baudry, C., Kreiter, A., & Bertrand, O. (1999). Sustained
and transient oscillatory responses in the gamma and beta
bands in a visual short-term memory task in humans. Visual
Neuroscience, 16, 449–459.
Tamminga, C. A. (1998). Schizophrenia and glutamatergic
transmission. Critical Reviews in Neurobiology, 12, 21–36.
Tiitinen, H., Sinkkonen, J., Reinikainen, K., Alho, K., Lavikainen,
J., & Naatanen, R. (1993). Selective attention enhances the
auditory 40-Hz transient response in humans. Nature, 364,
Tort, A. B., Rotstein, H. G., Dugladze, T., Gloveli, T., & Kopell,
N. J. (2007). On the formation of gamma-coherent cell
assemblies by oriens lacunosum–moleculare interneurons in
the hippocampus. Proceedings of the National Academy of
Sciences, U.S.A., 104, 13490–13495.
Traub, R. D., Bibbig, A., LeBeau, F. E., Buhl, E. H., &
Whittington, M. A. (2004). Cellular mechanisms of neuronal
population oscillations in the hippocampus in vitro. Annual
Review of Neuroscience, 27, 247–278.
Tsai, G., & Coyle, J. T. (2002). Glutamatergic mechanisms in
schizophrenia. Annual Review of Pharmacology and
Toxicology, 42, 165–179.
Turetsky, B. I., McGue, C., Ramsey, L., Siegel, S. J., & Gur, R. E.
(2006). Persistent auditory-evoked gamma band
oscillations in schizophrenia. Paper presented at the Society
of Biological Psychiatry.
Turetsky, B. I., & Siegel, S. J. (2007). Persistent auditory-evoked
gamma band oscillations in schizophrenia. Paper
presented at the American College of
Maurer, K., et al. (2006). Dysfunctional long-range coordination
of neural activity during Gestalt perception in schizophrenia.
Journal of Neuroscience, 26, 8168–8175.
Umbricht, D., Vyssotky, D., Latanov, A., Nitsch, R., Brambilla, R.,
DʼAdamo, P., et al. (2004). Midlatency auditory event-related
potentials in mice: Comparison to midlatency auditory ERPs
in humans. Brain Research, 1019, 189–200.
Umbricht, D. S., Latanov, A., Vissotksi, D., Nitsch, R., & Lipp,
H. P. (2002). Development of a mouse model of deficits in
prettentive auditory processing in schizophrenia. Biological
Psychiatry, 51, 64S.
Vertes, R. P. (2005). Hippocampal theta rhythm: A tag for short-
term memory. Hippocampus, 15, 923–935.
Vidal, J. R., Chaumon, M., OʼRegan, J. K., & Tallon-Baudry, C.
(2006). Visual grouping and the focusing of attention induce
gamma-band oscillations at different frequencies in human
magnetoencephalogram signals. Journal of Cognitive
Neuroscience, 18, 1850–1862.
Vinogradova, O. S. (1995). Expression, control, and probable
functional significance of the neuronal theta-rhythm.
Progress in Neurobiology, 45, 523–583.
Weinberger, D. R., Berman, K. F., & Illowsky, B. P. (1988).
Physiological dysfunction of dorsolateral prefrontal cortex in
schizophrenia: III. A new cohort and evidence for a
monoaminergic mechanism. Archives of General Psychiatry,
Westfall, P. H., & Young, S. S. (1993). On adjusting p-values for
multiplicity. Biometrics, 49, 941–944.
Wood, P. L. (2005). The NMDA receptor complex: A long and
winding road to therapeutics. IDrugs, 8, 229–235.
Woolley, D. E., & Timiras, P. S. (1965). Prepyriform electrical
activity in the rat during high altitude exposure.
Electroencephalography and Clinical Neurophysiology, 18,
Yeragani, V. K., Cashmere, D., Miewald, J., Tancer, M., &
Keshavan, M. S. (2006). Decreased coherence in higher
frequency ranges (beta and gamma) between central and
frontal EEG in patients with schizophrenia: A preliminary
report. Psychiatry Research, 141, 53–60.
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