EEG Synchronization Deficits in
Schizophrenia Spectrum Disorders
Brian F. O’Donnella, M. A. Wilt a, C. A. Brenner a, T.A. Busey a, J. S. Kwon b
a
Department of Psychology, Indiana University, Bloomington, IN, 47405, USA
b
Department of Psychiatry, Seoul National University Medical College, Youngon-Dong, Chongno-Gu,
Seoul, 110-799, KOREA
Correspondence regarding this article should be sent to Brian F. O’Donnell, Department of
Psychology, Indiana University, Bloomington, IN 47405. Phone: 812 856 4164; FAX 812 844 4691;
email: bodonnel@indiana.edu.
In press, Proceedings of the 12th World Congress of the International Society of Brain
Electromagnetic Topography, K. Hirata, Ed. Elsevier: Netherlands.
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Abstract
Neural synchronization may have a critical role in the integration of information within and across cerebral
structures. Synchronization, particularly at gamma range frequencies, is thought to be dependent on
GABAergic interneurons, which may be disturbed in schizophrenia. We report that patients with
schizophrenia show severe disruption of electroencephalogram (EEG) measures of neural synchronization
to periodic auditory and visual stimulation. Both EEG power and phase synchronization to temporally
modulated signals were affected in the beta or gamma frequency ranges. These findings are consistent with
GABAergic dysregulation in schizophrenia which disrupts neural synchronization. A deficit in neural
synchronization at high firing frequencies could contribute to behavioral disturbances of perceptual and
temporal integration observed in this disorder.
Key words: EEG, event-related potentials, synchronization, schizophrenia
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1. Introduction
Bleuler’s conceptualization of schizophrenia, meaning “split mind”, emphasized the loss of
integration among different psychic functions as central to the illness [1]. Subsequent investigators have
sought to identify the neural substrates for this loss of integration. Andreasen [2] proposed that loss of
synchrony, or the fluid, coordinated sequence of thoughts and action, is disrupted in schizophrenia. This
disruption, which she terms cognitive dysmetria, may be due to neurodevelopmental anomalies which
affect circuits integrating cortical regions with the cerebellum through thalamic nuclei.
What might be the cellular basis for such failures of integration? Hebb [3] hypothesized that
percepts may be mediated by reverberatory traces within an assembly of interconnected neurons.
Synchronized activation of an assembly of neurons could result in permanent alterations in neural
transmission, which might be the basis of associative learning. Recent cellular studies suggest that
transient synchronization of neural firing indeed plays an important role in integration of perceptual
features, of events across time, and of features associated in learning [4; 5]. For example, perception of a
cloud moving across the sky entails neural representations of texture, color, luminance, motion and
contours. The neural circuits involved in each of these features are spatially distributed across the visual
cortex. Therefore, the features must be “bound” or integrated to form a stable representation, and this
process appears to require transient synchronization of neural firing among neurons in the cortex and
possibly the thalamus at the gamma range (25 to 80 Hz). Whittington et al. [5] have noted that gamma
oscillations can induce beta (12 to 25 Hz) activity, which may represent a neuronal network correlate of
cognitive binding. Disruption of neural synchrony could therefore lead to abnormalities in perceptual
binding and associative learning.
The cellular mechanisms involved in synchronization are complex. Different mechanisms may
modulate oscillations in different parts of the brain [5]. Gamma aminobutyric acid (GABA) inhibitory
interneurons appear to be important in producing synchronization in local circuits, and can modulate firing
rates of projections neurons [5]. GABAergic neurons are highly sensitive to N-methyl-D-aspartate
(NMDA) antagonists [6]. Furthermore, there is extensive evidence of NMDA dysregulation in
schizophrenia [7; 8], and GABAergic neuron abnormalities or cell loss [9; 10]. Hence, if gamma range
synchronization is dependent in part on GABAergic drive on projection neurons, then neural
synchronization would likely be disrupted in schizophrenia.
In order to test whether neural circuits in schizophrenic patients could support normal neural
synchronization at specific frequencies, we evaluated synchronization of the electroencephalogram (EEG)
to stimuli presented at varying temporal frequencies, including frequencies in the beta and gamma ranges.
These externally entrained EEG responses are often termed “steady state potentials [11].” Testing the
capacity of neural circuits to support gamma range entrainment provides a method to determine the
relationship of the power or phase of the output (EEG) to the characteristics of the periodic input.
2. Experimental studies of EEG synchronization in schizophrenia
2.1 Auditory Synchronization to Click Trains in Schizophrenia
In order to test whether neural circuits in schizophrenia could support normal gamma
synchronization, we evaluated power of electroencephalographic (EEG) entrainment to periodic auditory
stimuli in thirteen medicated male patients affected by schizophrenia and thirteen male control subjects (see
[7] for detailed methods). The stimuli were 1 msec duration clicks, presented as trains of clicks with a
duration of 500 ms. The rate of presentation of the clicks was either 20, 30, or 40 clicks/second in each
block.
After averaging across trials within a block to isolate the synchronized EEG response, a Fast
Fourier Transform (FFT) was used to generate a power spectrum on the 512 ms epoch after stimulus onset.
EEG power to the stimulating frequency was compared between groups for each rate. Analysis of variance
revealed a main effect of stimulus (p< 0.001), with 40 Hz stimulation producing greater power than 20 or
30 Hz. There was also an interaction of group by stimulus (p < 0.05), indicating that the control group had
greater power at 40 Hz than the SZ group (t = 2.51, p < 0.05). These findings suggest a decrease in the
ability of auditory networks to maintain synchronous activity of neuronal firing at 40 Hz, but not lower,
frequencies in schizophrenia.
2.2
Auditory synchronization to amplitude modulated tones.
The previous study suggested that patients with schizophrenia showed a deficit at 40 Hz
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compared to lower stimulation rates. In our second study, amplitude modulated tones were used to elicit
EEG synchronization across a broad range of stimulation frequencies (11 to 82 Hz). This modulation
technique, developed by Picton and colleagues [11], allows concurrent use of more than one modulation
frequency.
Methods. Carrier tones modulated different frequencies were used as stimuli. A total of eight
tones were presented at 86 dB SPL, each with a different modulation rate. Four were delivered with a 1000
Hz carrier pitch and were modulated at 71 Hz, 51 Hz, 31 Hz and 11 Hz. The other four were delivered with
a 500 Hz carrier pitch and were modulated at 42 Hz, 22 Hz, 82Hz and 62Hz. Two tones with a different
carrier pitch and modulation rate were presented simultaneously, one to each ear, in a series of four blocks.
The duration of each tone was 1000 ms, the ISI was 250 ms, and there were 196 tones in each block. Nine
medicated patients with schizophrenia or schizoaffective disorder, and eight healthy control subjects were
tested. EEG was recorded at sampling rate of 1000 Hz (1 to 200 Hz bandpass) and averaged across trials
over a 1024 ms recording epoch after stimulus onset to isolate phase locked responses. The power of the
response at the Fz electrode site was computed at each target frequency using the FFT.
Results. A mixed model ANOVA was used to evaluate the factors of group [2] and stimulus
frequency [8]. The ANOVA revealed a main effect of group, indicating that patients showed lower power
at stimulus frequencies than control subjects as shown in Figure 1, (F(1, 15) = 7.85, p = .01). There was an
effect of stimulus, indicating that the magnitude of the response varied by stimulus, with the largest peak in
the gamma range at 42 Hz in both groups (F(7, 105) = 6.02, p < .001). There was also a trend for a group
by stimulus interaction (F(7, 105) = 1.79, p = .10). Post-hoc contrasts showed that schizophrenia spectrum
subjects exhibited lower response power to the 42 Hz (p = .05) and 62 Hz frequencies (p = .02).
Figure 1 about here
These results suggest that the synchronization deficit obtained from click stimuli in schizophrenia
is also obtained using amplitude modulated tones as stimuli, but that the breadth of the deficit extends over
a broad range of modulation frequencies, with the most reliable differences obtained at higher temporal
frequencies.
2.3 Visual Power and Phase Synchronization in Schizophrenia
The preceding data and models suggest that patients with schizophrenia exhibit a severe deficit in
synchronizing at gamma range frequencies in the auditory domain. We next evaluated whether
synchronization deficits might also occur in the visual modality.
Methods. A rapidly flickering black and white patch subtending 4.9 degrees of visual angle was
used to entrain EEG in eight medicated patients with schizophrenia and eight control subjects. Two
flicker rates were analyzed, 21 and 28 Hz. The duration of the flickering stimulus was 2000 ms, with a 200
ms ISI. EEG was recorded at a sampling rate of 500 Hz and a bandpass of 0.3 to 200 Hz. EEG was
segregated into 2048 ms epochs prior to the FFT. Single trial power spectra were calculated after artifact
rejection, and power spectra were averaged across trials at the flicker frequency for that condition.
Figure 2 about here
2.3.1 Power analysis
Figure 2 shows the ERP averaged within schizophrenic and control groups to the 21 Hz flickering
stimulus at Oz, where the response was largest. The onset of the stimulus was followed by a P1
component. Subsequently, the control subjects showed synchronization to the stimulus flicker, while
synchronization in patients was much less apparent. An ANOVA on power values to each stimulus
frequency showed a main effect of stimulus, in that the 21 Hz response was larger than the 28 Hz response
(F(1,14) = 7.42, p = .02). There was a group X stimulus interaction (F(1, 14) = 19.56, p = .001), indicating
that patients showed a marked reduction in EEG power at 21 Hz, but not at 28 Hz (Figure 3).
Figure 3 about here
2.3.2 Phase synchronization Analysis
The results above suggest that patients with schizophrenia show a marked deficit in visual EEG
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synchronization at 21 Hz. It is possible, however, that patients synchronize with the input frequency, but
that the amplitude of the response is much lower than in normal subjects. In order to evaluate phase
synchronization independent of response amplitude, we applied a new method for measuring instantaneous
frequency synchronization between EEG signals, called phase locking statistics. Phase locking statistics
were developed by Lachaux et al. [12] to measure the intertrial variability of instantaneous phase between
two signals across multiple trials. This measure is called the phase locking value, which varies between 1
for signals completely in phase, and 0 in the absence of phase synchronization. For a frequency of interest,
phase locking analysis yields values for each sample point. For statistical comparison between control and
patient groups, the average phase locking value was calculated between the input signal (i.e.a sine wave at
the frequency of stimulation), and EEG recorded at Oz.
The phase locking value for the relationship between EEG activity at Oz and the input signal was
greater in normal subjects (N=7) than in SZ subjects (N=8) over the 2000 ms period of stimulation. The
mean phase locking value computed over the 300 to 600 ms interval after stimulus onset was 0.53 + .30
(mean + SD) for control subjects, and 0.19 + .06 for the schizophrenic subjects, t(13) = 3.15, p = .008.
These results indicate that patients show reduced phase synchronization with the input signal across the
period of stimulation independent of the magnitude of the response.
3. Discussion
Neural synchronization to periodic stimuli either in the auditory or the visual modality is severely
disrupted in medicated patients with schizophrenia spectrum disorders. Instantaneous phase
synchronization was affected in the visual modality, indicating that the deficit was not simply due to
reduced amplitude of the steady state response. Kwon et al. [7] also reported phase synchronization
disturbances in the auditory modality. These results are consistent with other studies showing EEG
synchronization deficits in schizophrenia. Patients with schizophrenia showed decreased power during
photic driving at 7.2, 8.3, 9.0, and 9.6 Hz, while depressed patients showed increased power compared to
control subjects [13]. Other studies have shown disturbed EEG power or coherence in schizophrenia
during task related stimulus processing [14; 15]. The relationship of externally entrained EEG
synchronization to transient, task related synchronization in patients with schizophrenia remains to be
elucidated.
The neural substrates of these disturbances in EEG synchronization in schizophrenia are of
interest in terms of the pathophysiology of the illness. GABAergic interneurons appear to be affected in
some patients with schizophrenia, either due to cell damage in some cortical regions, or dysfunction
secondary to NMDA or dopamine receptor abnormalities [6; 7; 8: 9; 10]. It is possible that reduced
inhibitory drive by GABAergic neurons may contribute to the synchronization disturbances detected in the
present studies. Another possibility is that synchronization is due to reduction in cellular connectivity [16].
Disturbances of connectivity have been inferred from neuropathological evidence of increased neuronal
density in occipital area 17 and frontal lobe regions [17].
From a theoretical perspective, a loss in the capacity of the brain for accurate neural
synchronization would have pervasive effects on perceptual integration, temporal processing, and
associative learning. Deficits in synchronization could result in a global cognitive dysmetria [2] from loss
of coordination among brain systems. Asynchronous processing would also interfere with transmission of
transient or high temporal frequency information, and thus contribute to behavioral deficits noted for tasks
which require rapid temporal integration, such as motion perception [18] and backward masking
performance [19].
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4. Acknowledgements.
This research was supported by NARSAD Young Investigator Awards (BFO), a National Defense
Science and Engineering Graduate Fellowship (MAW), a NIMH B/Start Award (RO3 -MH63112-01,
BFO), and a NIH-NIMH Clinical Science Training Grant Predoctoral Fellowship (T32 MH17146-17,
CAB). We thank Paul Lysaker for assistance in patient diagnosis.
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Research Reviews 2000;31:391-400.
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Figure Legends
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P o w e r(V )
Power at Fz
0.2
0.18
0.16
0.14
0.12
0.1
0.08
0.06
0.04
0.02
0
NC ( n= 8)
S Z ( n= 9)
22Hz
31Hz
42Hz*
51Hz
62Hz*
71Hz
82Hz
S t im u lu s F r eq u en cy
Figure 1. EEG Power and frequency of modulated tones in normal control (NC) and schizophrenia (SZ)
subjects, with an asterisk indicating a significant group difference.
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Figure 2. Averaged evoked potentials for the schizophrenic and control groups to 21 Hz flicker.
Figure 3. EEG power at 21 Hz and 28 Hz flicker rates in normal (NC) and schizophrenic (SZ) groups.
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