Do high or low doses of anxiolytics and hypnotics affect mismatch negativity in schizophrenic subjects? An EEG and MEG study
Introduction
Since the early clinical description by Bleuler (1911), it has been recognized that attentional deficits are one of the primary dysfunctions in schizophrenic psychopathology. The advent of event-related brain potential (ERP) studies has enabled an electrophysiological assessment of attentional dysfunction in schizophrenia. Earlier investigations focused on the evaluation of conscious, controlled aspects of attention in schizophrenia, and thus abnormalities of P300 (Roth et al., 1981, Kutcher et al., 1987, McCarley et al., 1989), N2b (Brecher et al., 1987), and the processing negativity (Michie et al., 1990) component of ERPs have been repeatedly reported. However, in 1991 Shelley et al. (1991) reported on impaired mismatch negativity (MMN) in response to a duration change of tones, an ERP index of auditory preattentive processing (Näätänen et al., 1978) in schizophrenia. Subsequent studies have replicated a reduction in MMN amplitude in response to a duration (Catts et al., 1995, Kasai et al., 1999c, Javitt et al., 2000b, Michie et al., 2000, Todd et al., 2000) and frequency (Javitt et al., 1993, Javitt et al., 1995, Javitt et al., 1998, Javitt et al., 2000a, Javitt et al., 2000b, Shutara et al., 1996, Alain et al., 1998, Hirayasu et al., 1998, Umbricht et al., 1998, Shelley et al., 1999) changes of tones in schizophrenia, although others did not find a significant reduction in the MMN in response to a frequency change of tones (O'Donnell et al., 1994, Kathmann et al., 1995, Oades et al., 1996, Kirino and Inoue, 1999). Recently, magnetoencephalography (MEG) (Kreitschmann-Andermahr et al., 1999) and functional magnetic resonance imaging (Wible et al., 2001) investigations have also demonstrated abnormalities of auditory mismatch detection in response to frequency changes of tones in schizophrenia.
Regarding the effects of psychotropic drugs on the MMN in schizophrenia, several reports have described no significant correlation between reported MMN amplitudes and the dose of neuroleptics administered to patients with chronic schizophrenia (Shelley et al., 1991, Shutara et al., 1996, Kasai et al., 1999c, Michie et al., 2000, Todd et al., 2000). Catts et al. (1995) and Javitt et al. (1995) independently found no significant difference in MMN amplitude between medicated and neuroleptic-free patients. Umbricht et al., 1998, Umbricht et al., 1999 showed that MMN reduction was not ameliorated by either typical (haloperidol) or atypical (clozapine or risperidone) medication. These reports provide a consensus that neuroleptics have no effect on MMN amplitude in schizophrenia. On the other hand, there is evidence from primate and human studies indicating that the interplay between excitatory glutamatergic and inhibitory GABAergic neurons regulates MMN generation (Javitt et al., 1996, Umbricht et al., 2000). Supporting this hypothesis, Nakagome et al. (1998) reported MMN amplitude reduction in the morning following administration of triazolam in normal subjects. Furthermore, Smolnik et al. (1998) observed a tendency towards an increase in MMN amplitude after the administration of the benzodiazepine antagonist, flumazenil, in normal subjects although the effect was not statistically significant. Considering that a substantial proportion of patients with schizophrenia receive anxiolytics and hypnotics to reduce the comorbid symptoms of anxiety and sleep disturbances, respectively (Carpenter et al., 1999, Hardy et al., 1999, Ito et al., 1999, Voirol et al., 1999), and that these drugs have affinity to GABAA receptors (Schroder et al., 1997, Fujita et al., 1999), we need to assess the possibility that anxiolytics/hypnotics might have some effect on MMN amplitude in schizophrenic patients. However, to our knowledge, only one preliminary study from our group (Murakami et al., 2001) has evaluated the possible effects of anxiolytics/hypnotics on the MMN in schizophrenic patients. Using a 16-channel montage, Murakami et al. compared the MMN and N2b in response to pure-tone stimuli between two subgroups of schizophrenic patients, one comprised of patients who did not receive benzodiazepines (benzodiazepine-off group; n=7) and the other of those who were administered benzodiazepines during daytime (benzodiazepine-on group; n=7). They found no significant differences in MMN and N2b amplitudes between the two subgroups, whereas the N2b latency was significantly prolonged in the benzodiazepine-on group relative to the benzodiazepine-off group. These results suggested that benzodiazepine had no marked effects on the MMN amplitude/latency in schizophrenia. The present study is an extension of our preliminary study; here, we determine whether the dose of anxiolytics/hypnotics affects MMN (or its magnetic counterpart, MMNm) amplitude (or MMNm power)/latency/topography (or laterality) in response to pure-tone and speech sounds in two new groups of patients with schizophrenia, using ERP and MEG recordings, respectively.
Section snippets
Subjects
Twenty-three right-handed (determined using the Edinburgh Inventory (Oldfield, 1971); we used a laterality index ≥0.8 as the cutoff for right-handedness), medicated outpatients with schizophrenia participated in this part of the study. Sixteen were male and 7 were female. This study is a post hoc analysis of our previous study comparing MMN between these 23 schizophrenic patients and 28 healthy subjects (Kasai et al., 2001a). Diagnosis was determined according to DSM-IV criteria (American
Results of ERP recording
The repeated measures ANOVA of MMN amplitude showed no significant main effects of group or interactions between group and any other factors: the main effect of group, F(1,21)=0.953, not significant (n.s.); group-by-condition interaction, F(2,42)=1.17, n.s.; group-by-hemisphere interaction, F(1,21)=0.042, n.s.; group-by-channel interaction, F(21,441)=0.577, n.s.; group-by-condition-by-hemisphere interaction, F(2,42)=0.342, n.s.; group-by-condition-by-channel interaction, F(42,882)=1.10, n.s.;
Discussion
The results of this study can be summarized as follows. (1) There were no differences in MMN amplitude (MMNm power), latency, effect of type of stimuli (nonverbal, verbal), or topography (laterality) between schizophrenic patients who received high and low doses of anxiolytics/hypnotics. (2) There were no significant correlations between MMN amplitude (MMNm power) or latency and dose of anxiolytics/hypnotics. Our results support our preliminary finding that there is no effect of benzodiazepines
Acknowledgements
This study was supported in part by a grant-in-aid for Scientific Research (No. 11680836) from the Japan Society for the Promotion of Science and a grant-in-aid for Scientific Research (C12670928) from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and by grants from the Welfide Medicinal Research Foundation, Japan and from the Uehara Memorial Foundation, Japan. The authors also gratefully acknowledge the technical support of Dr. S.F. Huang, and the administrative
References (65)
- et al.
Processing of auditory stimuli during visual attention in patients with schizophrenia
Biol Psychiatry
(1998) - et al.
Differential changes in frontal and sub-temporal components of mismatch negativity
Int J Psychophysiol
(1999) - et al.
Changes of benzodiazepine receptors during chronic benzodiazepine administration in humans
Eur J Pharmacol
(1999) - et al.
Impairment of early cortical processing in schizophrenia: an event-related potential confirmation study
Biol Psychiatry
(1993) - et al.
Impaired mismatch negativity (MMN) generation in schizophrenia as a function of stimulus deviance, probability, and interstimulus/interdeviant interval
Electroenceph clin Neurophysiol
(1998) - et al.
Associated deficits in mismatch negativity generation and tone matching in schizophrenia
Clin Neurophysiol
(2000) - et al.
Mismatch negativity and N2b attenuation as an indicator for dysfunction of the preattentive and controlled processing for deviance detection in schizophrenia: a topographic event-related potential study
Schizophr Res
(1999) - et al.
Delayed peak latency of the mismatch negativity in schizophrenics and alcoholics
Biol Psychiatry
(1995) - et al.
Impaired sensory processing in male patients with schizophrenia: a magnetoencephalographic study of auditory mismatch detection
Schizophr Res
(1999) - et al.
Reference-free identification of components of checkboard-evoked multichannel potential fields
Electroenceph clin Neurophysiol
(1980)
Spatial analysis of evoked potentials in man: a review
Prog Neurobiol
Intracranial identification of an electric frontal-cortex response to auditory stimulus change: a case study
Brain Res Cogn Brain Res
Duration and frequency mismatch negativity in schizophrenia
Clin Neurophysiol
Early selective-attention effect on evoked potential reinterpreted
Acta Psychol
Auditory event-related potential (ERP) and difference-wave topography in schizophrenia patients with/without active hallucinations and delusions: a comparison with young obsessive-compulsive disorder (OCD) and healthy subjects
Int J Psychophysiol
Auditory ERPs to non-target stimuli in schizophrenia: relationship to probability, task demands, and target ERPs
Int J Psychophysiol
The assessment and analysis of handedness: the Edinburgh inventory
Neuropsychologia
Low resolution electromagnetic tomography: a new method for localizing electrical activity in the brain
Int J Psychophysiol
Separate time behaviors of the temporal and frontal mismatch negativity sources
Neuroimage
Habituation of the auditory evoked field component N100m in male patients with schizophrenia
J Psychiatr Res
Auditory event-related potentials in schizophrenia and depression
Psychiatry Res
Benzodiazepine receptor distribution and diazepam binding in schizophrenia: an exploratory study
Psychiatry Res
Mismatch negativity: an index of a preattentive processing deficit in schizophrenia
Biol Psychiatry
Diminished responsiveness of ERPs in schizophrenic subjects to changes in auditory stimulation parameters: implications for theories of cortical dysfunction
Schizophr Res
Auditory sensory memory in schizophrenia: inadequate trace formation?
Psychiatry Res
Effects of clozapine on auditory event-related potentials in schizophrenia
Biol Psychiatry
Processing of novel sounds and frequency changes in the human auditory cortex: magnetoencephalographic recordings
Psychophysiology
DSM-IV: Diagnostic and statistical manual of mental disorders
Dementia praecox or the group of schizophrenias
The N2 component of the event-related potential in schizophrenic patients
Electroenceph clin Neurophysiol
Diazepam treatment of early signs of exacerbation in schizophrenia
Am J Psychiatry
Brain potential evidence for an auditory sensory memory deficit in schizophrenia
Am J Psychiatry
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2015, International Journal of PsychophysiologyCitation Excerpt :An adequate NMDA-receptor function is a critical element in memory-trace formation at different hierarchical levels of the environmental representations and, hence, a central prerequisite of intact cognitive functioning (Baldeweg and Hirsch, 2014; Näätänen et al., 2011, 2014). Furthermore, the MMN can also be used for testing the treatment response in clinical trials (Baldeweg et al., 2006; Higuchi et al., 2010; Kasai et al., 2002; Fisher et al., 2012a; Inami et al., 2005) and as a tool of translational animal research for testing and developing animal models of psychosis and pharmacological agents (Nakamura et al., 2011; Gil-da-Costa et al., 2013; Ehrlichman et al., 2009; Javitt et al., 1994, 1996, 2012; Astikainen et al., 2011; see also Csépe et al., 1987; Kraus et al., 1994; for reviews, see Nagai et al., 2013; Todd et al., 2013). In conclusion, this review has shown that MMN deficiency at least in clinically at-risk individuals indexes a greatly increased psychosis risk and, in psychosis itself, a core aspect of it, viz., decreased brain plasticity and associated cognitive and functional decline.
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2013, Schizophrenia ResearchCitation Excerpt :Third, MMN provides accurate characterization of sensory network dysfunction. This is important since medication, attention, and motivation have little effect on MMN (Catts et al., 1995; Michie et al., 2000; Michie, 2001; Kasai et al., 2002; Rissling et al., 2012). Fourth, MMN has a distributed neural architecture and therefore serves as a reliable probe of auditory network dysfunction (Takahashi et al., 2012).