- Email: [email protected]
EEG synchronization deficits in schizophrenia spectrum disorders
International Congress Series 1232 (2002) 697 – 703
EEG synchronization deficits in schizophrenia spectrum disorders Brian F. O’Donnell a,*, M.A. Wilt a, C.A. Brenner a, T.A. Busey a, J.S. Kwon b b
a Department of Psychology, Indiana University, 1101 E. 10th Street, Bloomington, IN 47405, USA Department of Psychiatry, Seoul National University Medical College, Youngon-Dong, Chongno-Gu, Seoul 110-799, South Korea
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. D 2002 Elsevier Science B.V. All rights reserved. Keywords: EEG; Event-related potentials; Synchronization; Schizophrenia
1. Introduction Bleuler’s [1] conceptualization of schizophrenia, meaning ‘‘split mind’’, the loss of integration among different psychic functions as central to Subsequent investigators have sought to identify the neural substrates for integration. Andreasen [2] proposed that loss of synchrony, or the fluid,
*
Corresponding author. Tel.: +1-812-856-4164; fax: +1-812-844-4691. E-mail address: [email protected] (B.F. O’Donnell).
0531-5131/02 D 2002 Elsevier Science B.V. All rights reserved. PII: S 0 5 3 1 - 5 1 3 1 ( 0 1 ) 0 0 7 8 6 - 5
emphasized the illness. this loss of coordinated
698
B.F. O’Donnell et al. / International Congress Series 1232 (2002) 697–703
sequence of thoughts and action, is disrupted in schizophrenia. This disruption, which she termed 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 – 80 Hz). Whittington et al. [5] have noted that gamma oscillations can induce beta (12 – 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 13 medicated male patients affected by schizophrenia and 13 male control subjects (see Ref. [7] for detailed methods). The stimuli were 1-ms duration
B.F. O’Donnell et al. / International Congress Series 1232 (2002) 697–703
699
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/s 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 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 –82 Hz). This modulation technique, developed by Lins and Picton [11], allows the concurrent use of more than one modulation frequency. 2.2.1. 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, 51, 31 and 11 Hz. The other four were delivered with a 500-Hz carrier pitch and were modulated at 42, 22, 82 and 62 Hz. 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– 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. 2.2.2. 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 Fig. 1, ( F(1,15)=7.85, p=0.01). 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<0.001). There was also a trend for a group by stimulus interaction ( F(7,105)=1.79, p=0.10). Post-hoc contrasts showed that schizophrenia spectrum subjects exhibited lower response power to the 42-Hz ( p=0.05) and 62-Hz frequencies ( p=0.02). 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
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Fig. 1. EEG Power and frequency of modulated tones in normal control (NC) and schizophrenia (SZ) subjects, with an asterisk indicating a significant group difference.
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. 2.3.1. Methods A rapidly flickering black and white patch subtending 4.9j 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 – 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. 2.3.2. Power analysis Fig. 2 shows the event-related potentials (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 among 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=0.02). There was a group X stimulus interaction ( F(1,14)=19.56,
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Fig. 2. Averaged evoked potentials for the schizophrenic and control groups to 21-Hz flicker.
p=0.001), indicating that patients showed a marked reduction in EEG power at 21 Hz, but not at 28 Hz (Fig. 3). 2.3.3. Phase synchronization analysis The results above suggest that patients with schizophrenia show a marked deficit in visual EEG 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.
Fig. 3. EEG power at 21- and 28-Hz flicker rates in normal (NC) and schizophrenic (SZ) groups.
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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 0.53F0.30 (meanFS.D.) for control subjects, and 0.19F0.06 for the schizophrenic subjects, t(13)=3.15, p=0.008. 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– 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].
Acknowledgements This research was supported by NARSAD Young Investigator Awards (BFO), a National Defense Science and Engineering Graduate Fellowship (MAW), a NIMH B/Start
B.F. O’Donnell et al. / International Congress Series 1232 (2002) 697–703
703
Award (RO3-MH63112-01, BFO), and a NIH-NIMH Clinical Science Training Grant Predoctoral Fellowship (T32 MH17146-17, CAB). We thank Paul Lysaker and Colleen Brenner for their assistance in patient diagnosis and data recording.
References [1] E. Bleuler, Dementia Praecox or the Group of Schizophrenias, International Univ. Press, New York, 1950, Zinkin, J. (trans.). [2] N.C. Andreasen, A unitary model of schizophrenia: Bleuler’s ‘‘Fragmented Phrene’’ as Schizencephaly, Am. J. Psychiatry 56 (1999) 781 – 787. [3] D.O. Hebb, The Organization of Behavior, Wiley, New York, 1949. [4] W. Singer, Neural synchrony: a versatile code for the definition of relations? Neuron 24 (1999) 49 – 65. [5] M.A. Whittington, H.J. Faulkner, H.C. Doheny, R.D. Traub, Neuronal fast oscillations as a target site for psychoactive drugs, Pharm. Ther. 86 (2000) 171 – 190. [6] H.C. Grunze, D.G. Rainnie, M.E. Hasselmo, E. Barkai, E.F. Hearn, R.W. McCarley, R.W. Greene, NMDAdependent modulation of CA1 local circuit inhibition, J. Neurosci. 16 (1996) 2034 – 2043. [7] J.S. Kwon, B.F. O’Donnell, G.V. Wallenstein, R.W. Greene, Y. Hirayasu, P.G. Nestor, M.E. Hasselmo, G.F. Potts, M.E. Shenton, R.W. McCarley, Gamma frequency-range abnormalities to auditory stimulation in schizophrenia, Arch. Gen. Psychiatry 56 (1999) 1001 – 1005. [8] J.W. Olney, N.B. Farber, Glutamate receptor dysfunction and schizophrenia, Arch. Gen. Psychiatry 52 (1995) 998 – 1007. [9] F.M. Benes, Emerging principles of altered neural circuitry in schizophrenia, Brain Res. Rev. 31 (2000) 251 – 269. [10] D.A. Lewis, GABAergic local circuit neurons and prefrontal cortical dysfunction in schizophrenia, Brain Res. Rev. 31 (2000) 270 – 276. [11] O.G. Lins, T.W. Picton, Auditory steady-state responses to multiple simultaneous stimuli, Electroencephalogr. Clin. Neurophysiol. 96 (1995) 420 – 432. [12] J.P. Lachaux, E. Rodriguez, J. Martinerie, F.J. Vaerla, Measuring phase synchrony in brain signals, Hum. Brain Mappi. 8 (1999) 194 – 208. [13] Y. Jin, S.G. Potkin, C.A. Sandman, W.E. Bunney, Electroencephalographic photic driving in patients with schizophrenia and depression, Biol. Psychiatry 41 (1997) 496 – 499. [14] A.R. Haig, E. Gordon, V. De Pascalis, R.A. Meares, H. Bahramali, A. Harris, Gamma activity in schizophrenia: evidence of impaired network binding? Clin. Neurophysiol. 111 (2000) 1461 – 1468. [15] R.B. Silberstein, P. Line, A. Pipingas, D. Copolov, P. Harris, Steady-state visually evoked potential topography during the performance task in normal controls and schizophrenia, Clin. Neurophysiol. 111 (2000) 850 – 857. [16] G. Tononi, G.M. Edelman, Schizophrenia and the mechanisms of conscious integration, Brain Res. Rev. 31 (2000) 391 – 400. [17] L.D. Selemon, G. Rajkowska, P.S. Goldman-Rakic, Abnormally high neuronal density in the schizophrenic cortex, Arch. Gen. Psychiatry 52 (1995) 805 – 818. [18] B.F. O’Donnell, J.M. Swearer, L.T. Smith, P.G. Nestor, M.E. Shenton, R.W. McCarley, Selective deficits in visual perception and recognition in schizophrenia, Am. J. Psychiatry 153 (1996) 687 – 692. [19] M.F. Green, K.H. Nuechterlein, B. Breitmeyer, J. Mintz, Backward masking in unmedicated schizophrenic patients in psychotic remission: possible reflection of aberrant cortical oscillation, Am. J. Psychiatry 156 (1999) 1367 – 1373.
EEG synchronization deficits in schizophrenia spectrum disorders Brian F. O’Donnell a,*, M.A. Wilt a, C.A. Brenner a, T.A. Busey a, J.S. Kwon b b
a Department of Psychology, Indiana University, 1101 E. 10th Street, Bloomington, IN 47405, USA Department of Psychiatry, Seoul National University Medical College, Youngon-Dong, Chongno-Gu, Seoul 110-799, South Korea
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. D 2002 Elsevier Science B.V. All rights reserved. Keywords: EEG; Event-related potentials; Synchronization; Schizophrenia
1. Introduction Bleuler’s [1] conceptualization of schizophrenia, meaning ‘‘split mind’’, the loss of integration among different psychic functions as central to Subsequent investigators have sought to identify the neural substrates for integration. Andreasen [2] proposed that loss of synchrony, or the fluid,
*
Corresponding author. Tel.: +1-812-856-4164; fax: +1-812-844-4691. E-mail address: [email protected] (B.F. O’Donnell).
0531-5131/02 D 2002 Elsevier Science B.V. All rights reserved. PII: S 0 5 3 1 - 5 1 3 1 ( 0 1 ) 0 0 7 8 6 - 5
emphasized the illness. this loss of coordinated
698
B.F. O’Donnell et al. / International Congress Series 1232 (2002) 697–703
sequence of thoughts and action, is disrupted in schizophrenia. This disruption, which she termed 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 – 80 Hz). Whittington et al. [5] have noted that gamma oscillations can induce beta (12 – 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 13 medicated male patients affected by schizophrenia and 13 male control subjects (see Ref. [7] for detailed methods). The stimuli were 1-ms duration
B.F. O’Donnell et al. / International Congress Series 1232 (2002) 697–703
699
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/s 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 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 –82 Hz). This modulation technique, developed by Lins and Picton [11], allows the concurrent use of more than one modulation frequency. 2.2.1. 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, 51, 31 and 11 Hz. The other four were delivered with a 500-Hz carrier pitch and were modulated at 42, 22, 82 and 62 Hz. 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– 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. 2.2.2. 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 Fig. 1, ( F(1,15)=7.85, p=0.01). 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<0.001). There was also a trend for a group by stimulus interaction ( F(7,105)=1.79, p=0.10). Post-hoc contrasts showed that schizophrenia spectrum subjects exhibited lower response power to the 42-Hz ( p=0.05) and 62-Hz frequencies ( p=0.02). 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
700
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Fig. 1. EEG Power and frequency of modulated tones in normal control (NC) and schizophrenia (SZ) subjects, with an asterisk indicating a significant group difference.
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. 2.3.1. Methods A rapidly flickering black and white patch subtending 4.9j 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 – 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. 2.3.2. Power analysis Fig. 2 shows the event-related potentials (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 among 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=0.02). There was a group X stimulus interaction ( F(1,14)=19.56,
B.F. O’Donnell et al. / International Congress Series 1232 (2002) 697–703
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Fig. 2. Averaged evoked potentials for the schizophrenic and control groups to 21-Hz flicker.
p=0.001), indicating that patients showed a marked reduction in EEG power at 21 Hz, but not at 28 Hz (Fig. 3). 2.3.3. Phase synchronization analysis The results above suggest that patients with schizophrenia show a marked deficit in visual EEG 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.
Fig. 3. EEG power at 21- and 28-Hz flicker rates in normal (NC) and schizophrenic (SZ) groups.
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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 0.53F0.30 (meanFS.D.) for control subjects, and 0.19F0.06 for the schizophrenic subjects, t(13)=3.15, p=0.008. 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– 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].
Acknowledgements This research was supported by NARSAD Young Investigator Awards (BFO), a National Defense Science and Engineering Graduate Fellowship (MAW), a NIMH B/Start
B.F. O’Donnell et al. / International Congress Series 1232 (2002) 697–703
703
Award (RO3-MH63112-01, BFO), and a NIH-NIMH Clinical Science Training Grant Predoctoral Fellowship (T32 MH17146-17, CAB). We thank Paul Lysaker and Colleen Brenner for their assistance in patient diagnosis and data recording.
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