Effects of olanzapine on auditory P300 and mismatch negativity (MMN) in schizophrenia spectrum disorders

We investigated effects of olanzapine (5-10 mg/day) on passive and active attention in 11 patients with schizophrenia spectrum disorders and 15 healthy controls by using auditory evoked potentials (AEPs) mismatch negativity (MMN) and P300. AEPs were elicited during active and passive auditory "oddball" paradigms before, after 2 weeks and 4 weeks of olanzapine treatment. Baseline P300 amplitudes, but not MMN, were significantly reduced in patients compared with controls. Although clinical signs improved significantly measured by Positive and Negative Syndrome Scale (PANSS), olanzapine had no significant effects on latencies and amplitudes of MMN and P300. Thus, olanzapine does not have effects on active and passive attention in patients with schizophrenia spectrum disorders. Four weeks olanzapine treatment may be insufficient for the improvement of cognitive dysfunction in terms of inability to focus on relevant stimuli in these patients.     

Stability of the mismatch negativity under different stimulus and attention conditions.

OBJECTIVE: Mismatch negativities (MMN) elicited by frequency and duration changes in a sequence of repetitive tones were recorded in test and retest sessions from 45 subjects. METHODS: Tones presented with a stimulus onset asynchrony (SOA) of 0.5 s were to be ignored while attention had no instructed focus in one group and was directed to an active visual vigilance task in a second group of subjects. RESULTS: MMN amplitude was larger for duration deviants, the focus of attention had no systematic effect. Individual replicability of the MMN amplitudes was generally better when duration deviants were used. In addition, directing attention to the visual task increased the retest reliability of the duration deviance MMN. In this condition, the test-retest correlation coefficients were above 0.8 at all frontal scalp sites (0.87 at F4). CONCLUSIONS: The study shows that the deviant type as well as the attentional condition may have substantial effects on the stability and replicability of MMN potentials. The choice of the appropriate task condition is essential for using the MMN in group comparisons and as a diagnostic tool in individual cases.     

The effect of visual task difficulty and attentional direction on the detection of acoustic change as indexed by the Mismatch Negativity

Näätänen's model of auditory processing purports that attention does not affect the MMN. The present study investigates this claim through two different manipulations. First, the effect of visual task difficulty on the passively elicited MMN is assessed. Second, the MMNs elicited by stimuli under attended and ignored conditions are compared. In Experiment 1, subjects were presented with mixed sequences of equiprobable auditory and visual stimuli. The auditory stimuli consisted of standard (80 dB SPL 1000 Hz), frequency deviant (1050 Hz), and intensity deviant (70 dB SPL) tone pips. In a first instance, subjects were instructed to ignore the auditory stimulation and engage in an easy and difficult visual discrimination task (focused condition). Subsequently, they were asked to attend to both modalities and detect visual and auditory deviant stimuli (divided condition). The results indicate that the passively elicited MMN to frequency and intensity deviants did not significantly vary with visual task difficulty, in spite of the fact that the easy and difficult tasks showed a wide variation in performance. The manipulation of the attentional direction (focused vs. divided conditions) did result in a significant effect on the MMN elicited by the intensity, but not frequency, deviant. The intensity MMN was larger at frontal sites when subjects' attention was directed to both modalities as compared to only the visual modality. The attentional effect on the MMN to the intensity deviants only may be due to the specific deviant feature or the poorer perceptual discriminability of this deviant from the standard. Experiment 2 was designed to address this issue. The methods of Experiment 2 were identical to those of Experiment 1 with the exception that the intensity deviant (60 dB SPL) was made to be more perceptible than the frequency deviant (1016 Hz) when compared to the standard stimulus (80 dB SPL 1000 Hz). The results of Experiment 2 also demonstrated that the passively elicited MMN was not affected by large variations in visual task difficulty; this provides convincing evidence that the MMN is independent of visual task demands. Similarly to Experiment 1, the direction of attention again had a significant effect on the MMN. In Experiment 2, however, the frequency MMN (and not the intensity MMN) was larger at frontal sites during divided attention compared to focused visual attention. The most parsimonious explanation of these results is that attention enhances the discriminability of the deviant from the standard background stimulation. As such, small acoustic changes would benefit from attention whereas the discriminability of larger changes may not be significantly enhanced.     

Development of auditory sensory memory from 2 to 6 years: an MMN study

Short-term storage of auditory information is thought to be a precondition for cognitive development, and deficits in short-term memory are believed to underlie learning disabilities and specific language disorders. We examined the development of the duration of auditory sensory memory in normally developing children between the ages of 2 and 6 years. To probe the lifetime of auditory sensory memory we elicited the mismatch negativity (MMN), a component of the late auditory evoked potential, with tone stimuli of two different frequencies presented with various interstimulus intervals between 500 and 5,000 ms. Our findings suggest that memory traces for tone characteristics have a duration of 1-2 s in 2- and 3-year-old children, more than 2 s in 4-year-olds and 3-5 s in 6-year-olds. The results provide insights into the maturational processes involved in auditory sensory memory during the sensitive period of cognitive development.     

Auditory organization of sound sequences by a temporal or numerical regularity--a mismatch negativity study comparing musicians and non-musicians

The human auditory system can encode regularities in the acoustic environment without the requirement of attention. We investigated whether the auditory system of musicians is more sensitive than that of non-musicians in encoding complex regularities. We presented tone sequences containing either a temporal or a numerical regularity. The sequence with the temporal regularity could be divided into segments of a constant duration while the segments contained a varying number of tones. The sequence with the numerical regularity, on the other hand, could be divided into segments containing a constant number of tones while the segments varied in duration. Auditory encoding of the regularity was determined by measuring whether an occasional segment lengthening, either in time or by number elicited the mismatch negativity (MMN). In both musicians and non-musicians, an MMN was elicited when the temporal regularity was violated. In contrast, only in musicians an MMN was elicited to violations of the numerical regularity. The results show that temporal processing is of general importance in audition since at an involuntary auditory processing stage a complex temporal regularity can be encoded irrespective of musical expertise. Furthermore, the auditory system of professional musicians can encode a numerical regularity without attention being required reflecting the functional importance of beat tracking in the perceptual organization of music.     

Deviance-related electrophysiological activity in mice: is there mismatch negativity in mice?

OBJECTIVE: Mismatch negativity (MMN) is an auditory event-related potential (ERP) that provides an index of auditory sensory memory and has become an important tool to investigate auditory sensory memory in cognitive neuroscience and disorders such as schizophrenia and dyslexia. The development of a mouse model of human MMN would permit to investigate the molecular biology of normal and dysfunctional MMN generation. However, the presence of MMN-like electrophysiological activity in mice has not been demonstrated. METHODS: Deviance-related ERPs were recorded in awake mice using 3 frequency deviance paradigms and one duration deviance paradigm. These paradigms were modelled after paradigms used in human studies to characterize MMN. RESULTS: Significant deviance-related activity was observed in all paradigms. However, in all frequency deviance paradigms this activity manifested as an enhancement of similar activity to the standard due to differences in stimulation rate between deviant and standard stimuli rather than qualitatively different MMN-like activity. In the duration deviance paradigm negative deflections were observed that showed characteristics typical of human MMN. CONCLUSIONS: MMN-like activity can be observed in mice in duration deviance paradigms. In frequency deviance paradigms effects of different stimulation rates of deviant and standard stimuli seem to be the main determinants of deviance-related activity. SIGNIFICANCE: Investigations of MMN-like ERPs in mice may permit to investigate the molecular basis for normal and abnormal MMN generation in neuropsychiatric disorders and dyslexia.     

Visual mismatch negativity among patients with schizophrenia

Event related potentials (ERPs) provide an insight into sensory and cognitive processes in health and disease. Studies of an ERP negative amplitude deflection elicited by a change in a series of auditory stimuli is known as mismatch negativity (MMN). The generation of MMN is impaired in schizophrenia. Its deficit is associated with lower everyday functioning and may be also interpreted as the marker of progression in schizophrenia. MMN elicited by visual stimuli (vMMN) was described by several research teams, but it has not been investigated in schizophrenia as yet. Using a motion-direction paradigm, we elicited visual MMN in 24 patients with schizophrenia and schizoaffective disorder. The vMMN was computed as differences in areas under curve of visual ERPs to standard and deviant motion-direction stimuli recorded from midline derivations at the interval of 100-200 ms. They were compared between groups of patients with schizophrenia and healthy controls. The significantly smaller vMMN indicated an impaired generation of mismatch negativity in patients with schizophrenia. In secondary analyses there was an association of vMMN impairment among patients with higher dose of medication, lower level of functioning and the presence of deficit syndrome. This impairment appears analogous to the impairment of MMN in the auditory domain and is probably related to early visual information processing. Its relationship to cognitive functioning of patients with schizophrenia deserves further attention.     

Mismatch negativity (MMN) in multiple sclerosis: an event-related potentials study in 46 patients.

OBJECTIVE: To assess pre-attentive detection mechanisms indexed by MMN component of auditory Event-Related Potentials (ERPs) in Multiple Sclerosis (MS) patients. METHODS: 46 MS patients (mean age 43.7 years, mean disease duration 10.1 years, mean EDSS 4.6) and 46 matched controls were assessed with ERPs elicited by a passive oddball paradigm using duration deviants. Auditory P50, N1, P2 components were recorded. MMN and P3a components were calculated as the difference potential between deviants and standard stimuli. Eighteen of these 46 patients underwent also global psychometrical assessment and were sorted in cognitively normal and impaired patients. ERPs of these two groups of patients were compared. RESULTS: MS patients showed reduced MMN and P3a areas as compared to controls, besides exogenous N1-P2 complex amplitude reduction. Among the 18 patients investigated with neuropsychological testings, six were cognitively impaired and 12 cognitively unimpaired. Patients with a global cognitive impairment had reduced MMN as compared to cognitively unimpaired patients. CONCLUSIONS: Auditory MMN and P3a components of auditory ERPs are altered in MS patients. MMN alterations are more pronounced in cognitively impaired patients. SIGNIFICANCE: MMN and P3a areas reduction suggests that MS patients are prone to pre-attentive auditory information processing deficits, besides previously described controlled information processing difficulties. Moreover, MMN alterations may represent an objective index of cognitive disturbances in MS patients.     

阿立哌唑对精神分裂症患者失匹配性负波电位的影响

目的 探讨阿立哌唑对精神分裂症患者失匹配性负波电位(MMN)的影响.方法 随机选自18～65岁符合DSM-精神分裂症标准患者30例作为研究组,30例健康人作为对照组.研究组于阿立哌唑治疗前、4,8周后予MMN检测,同时予PANSS评定病情严重程度.对照组入组时预MMN检测.观察MMN波幅、潜伏期的变化.结果 研究组在治疗4,8周后PANSS量表分低于基线水平(均P＜0.05).研究组频率偏离MMN波幅及持续时间偏离MMN波幅均低于对照组(均P＜0.05).将MMN型与治疗时间层面作为组间因素的重复测量的方差分析显示,研究组频率偏离MMN与持续时间偏离MMN两组波幅间交互作用不显著;治疗时间层面间存在显著效应.治疗8周后MMN波幅比基线水平、治疗4周后明显升高(均P＜0.05).结论 精神分裂症患者存在认知功能损害,MMN提供了阿立哌唑能够改善精神分裂症认知功能的证据.     

The mismatch negativity (MMN) in basic research of central auditory processing: A review

In the present article, the basic research using the mismatch negativity (MMN) and analogous results obtained by using the magnetoencephalography (MEG) and other brain-imaging technologies is reviewed. This response is elicited by any discriminable change in auditory stimulation but recent studies extended the notion of the MMN even to higher-order cognitive processes such as those involving grammar and semantic meaning. Moreover, MMN data also show the presence of automatic intelligent processes such as stimulus anticipation at the level of auditory cortex. In addition, the MMN enables one to establish the brain processes underlying the initiation of attention switch to, conscious perception of, sound change in an unattended stimulus stream.     

Fast vigilance decrement in closed head injury patients as reflected by the mismatch negativity (MMN)

Event-related potentials (ERPs) were measured from 24 chronic closed head injury (CHI) patients and 18 age- and education-matched controls. The oddball paradigm was applied while subjects were watching a silent movie. The standard (p=0.8) sound of 75 ms duration had a basic frequency of 500 Hz with harmonic partials of 1000 Hz and 1500 Hz, whereas these frequencies for the pitch deviant were each 10% higher. The frequencies of the duration deviant matched with those of the standard but was 25 ms in duration. The MMN (mismatch negativity), generated by the brain's automatic auditory change-detector mechanism, was elicited by both deviants. No significant differences in the MMN latency or amplitude for either pitch or duration deviants were found between the groups. However, the MMN amplitude for the pitch deviant decreased in the patient group during the experiment considerably faster than in controls, suggesting a faster vigilance decrement in the patients.     

The mismatch negativity (MMN) response to complex tones and spoken words in individuals with aphasia

Background: The mismatch negativity (MMN) is a fronto-centrally distributed event-related potential (ERP) that is elicited by any discriminable auditory change. It is an ideal neurophysiological tool for measuring the auditory processing skills of individuals with aphasia because it can be elicited even in the absence of attention. Previous MMN studies have shown that acoustic processing of tone or pitch deviance is relatively preserved in aphasia, whereas the basic acoustic processing of speech stimuli can be impaired (e.g., auditory discrimination). However, no MMN study has yet investigated the higher levels of auditory processing, such as language-specific phonological and/or lexical processing, in individuals with aphasia. Aims: The aim of the current study was to investigate the MMN responses of normal and language-disordered subjects to tone stimuli and speech stimuli that incorporate the basic auditory processing (acoustic, acoustic-phonetic) levels of non-speech and speech sound processing, and also the language-specific phonological and lexical levels of spoken word processing. Furthermore, this study aimed to correlate the aphasic MMN data with language performance on a variety of tasks specifically targeted at the different levels of spoken word processing. Methods & Procedures: Six adults with aphasia (71.7 years ±3.0) and six healthy age-, gender-, and education-matched controls (72.2 years ±5.4) participated in the study. All subjects were right-handed and native speakers of English. Each subject was presented with complex harmonic tone stimuli, differing in pitch or duration, and consonant-vowel (CV) speech stimuli (non-word /de:/ versus real word /deI/). The probability of the deviant for each tone or speech contrast was 10%. The subjects were also presented with the same stimuli in behavioural discrimination tasks, and were administered a language assessment battery to measure their auditory comprehension skills. Outcomes & Results: The aphasic subjects demonstrated attenuated MMN responses to complex tone duration deviance and to speech stimuli (words and non-words), and their responses to the frequency, duration, and real word deviant stimuli were found to strongly correlate with performance on the auditory comprehension section of the Western Aphasia Battery (WAB). Furthermore, deficits in attentional lexical decision skills demonstrated by the aphasic subjects correlated with a word-related enhancement demonstrated during the automatic MMN paradigm, providing evidence to support the “word advantage effect”, thought to reflect the activation of language-specific memory traces in the brain for words. Conclusions: These results indicate that the MMN may be used as a technique for investigating general and more specific auditory comprehension skills of individuals with aphasia, using speech and/or non-speech stimuli, independent of the individual's attention. The combined use of the objective MMN technique and current clinical language assessments may result in improved rehabilitative management of aphasic individuals.     

A modified oddball paradigm "cross-modal delayed response" and the research on mismatch negativity

A modified oddball paradigm was developed to facilitate the focus of attention and to minimize target effects on deviant-related components of auditory and visual event-related potentials (ERPs) elicited with long interstimulus intervals. Subjects were required to focus on either the visual or auditory stimulus in each stimulus block. Deviant-related components were obtained by subtracting ERPs of the standard stimulus from that of the deviant stimulus for each modality with each stimulus condition. Results showed that auditory mismatch negativity (MMN) and a visual early deviant related negativity (DRN1) were elicited both when stimuli were attended and unattended. In contrast, N2b and P3 were produced only under the attended condition. In comparison of attended MMN and unattended MMN at three time windows (100-150 ms, 150-200 ms, and 200-250 ms) of MMN zone, different scalp distributions were shown, depending on the time windows. This result suggests that the attended auditory MMN is a mixed wave, consisting of genuine MMN, N2b, and possible P165. The effect of attention on MMN may stem from the contamination of these overlapping components. With the present paradigm, at least three sensory memory traces have to be maintained simultaneously in multiple sensory modalities to support automatic processing.     

An electrophysiological and behavioral investigation of involuntary attention towards auditory frequency,duration and intensity changes

We measured behavior and event-related brain potentials (ERPs) in 12 subjects performing on an audio-visual distraction paradigm to investigate the cerebral mechanisms of involuntary attention towards stimulus changes in the acoustic environment. Subjects classified odd/even numbers presented on a computer screen 300 ms after the occurrence of a task-irrelevant auditory stimulus, by pressing the corresponding response button. Auditory stimuli were standard tones (600 Hz, 200 ms, 85 dB; P=0.8) or deviant tones (P=0.2), these differing from the standard either in frequency (700 Hz), duration (50 ms) or intensity (79 dB), in separate blocks. In comparison to performance to visual stimuli following the standard tones, reaction time increased by 24 ms (F(1,11)=10.91, P<0.01) and hit rate decreased by 4.6% (F(1,11)=35.47, P<0.001) to visual stimuli following the deviant tones, indicating behavioral distraction. ERPs revealed the mismatch negativity (MMN) elicited to deviant tones, which was larger for the duration deviant than for the frequency and intensity deviants (F(2,22)=19.43, P<0.001, epsilon =0.83), and which had different scalp distribution for all three deviant conditions (F(16,176)=2.40, P<0.05, epsilon =0.12). As the shorter duration and softer intensity deviant tones were unlikely to engage fresh neurons responding to their specific physical features, the present results indicate that a genuine change detection mechanism is involved in triggering attention switching towards sound changes, and suggest a largely distributed neural network of the auditory cortex underlying such involuntary attention switching.     

Temporal integration of deviant sound in automatic detection reflected by mismatch negativity

Mismatch negativity (MMN) is an event-related potential that is elicited by deviant sounds that are presented along with frequent sounds in the absence of attention. Auditory MMN is generated by the comparison process between sensory memory trace of a frequent auditory event and a deviant event. It is well known that frequent sounds are encoded in memory trace and processed as a single unit within 160-170 ms. This study examined whether deviant sound would be similarly processed as a temporal unit. Twelve healthy men were presented with relatively short standard sounds and relatively long deviant sounds that contained an omitted (i.e. silent) part. Three types of deviant sounds were designed to vary in duration. The MMN amplitude was gradually enhanced from the short to long duration deviant events that contained an omitted part. In contrast, MMN latency showed no significant differences among the deviants. These findings show that deviant sounds are also processed as a unitary event.     

Cortical speech and non‐speech discrimination in relation to cognitive measures in preschool children

Effective speech sound discrimination at preschool age is known to be a prerequisite for the development of language skills and later literacy acquisition. However, the speech specificity of cortical discrimination skills in small children is currently not known, as previous research has either studied speech functions without comparison with non‐speech sounds, or used much simpler sounds such as harmonic or sinusoidal tones as control stimuli. We investigated the cortical discrimination of five syllable features (consonant, vowel, vowel duration, fundamental frequency, and intensity), covering both segmental and prosodic phonetic changes, and their acoustically matched non‐speech counterparts in 63 6‐year‐old typically developed children, by using a multi‐feature mismatch negativity (MMN) paradigm. Each of the five investigated features elicited a unique pattern of differentiating negativities: an early differentiating negativity, MMN, and a late differentiating negativity. All five studied features showed speech‐related enhancement of at least one of these responses, suggesting experience‐related neural commitment in both phonetic and prosodic speech processing. In addition, the cognitive performance and language skills of the children were tested extensively. The speech‐related neural enhancement was positively associated with the level of performance in several neurocognitive tasks, indicating a relationship between successful establishment of cortical memory traces for speech and enhanced cognitive functioning. The results contribute to the understanding of typical developmental trajectories of linguistic vs. non‐linguistic auditory skills, and provide a reference for future studies investigating deficits in language‐related disorders at preschool age.     

Effects of NMDA receptor antagonist memantine on mismatch negativity

Mismatch negativity (MMN) and its magnetic counterpart (MMNm) have been shown to be altered in patients with various psychiatric and neurological disorders, e.g. Alzheimer's disease and schizophrenia, indicating deficits in involuntary attention. N-Methyl-D-aspartate (NMDA) receptor-mediated glutamate dysfunction is suggested to underlie these deficits. However, the role of NMDA receptors in involuntary attention is poorly understood. Memantine is an NMDA receptor antagonist that has been demonstrated to be effective in the treatment of patients with Alzheimer's disease. We aimed to investigate whether a single dose of memantine would affect MMN/MMNm in healthy subjects studied with simultaneous electroencephalography (EEG) and magnetoencephalography (MEG). Monaural left-ear auditory stimuli were presented in a passive oddball paradigm with infrequent deviant tones differing in frequency and duration. Neuronal activity was recorded in 13 healthy subjects after oral administration of 30mg of memantine or placebo in a randomized, double-blind, cross-over design. MMNm was analyzed using equivalent current dipoles. MMN was evaluated from frontocentral electrodes. Memantine lowered subjects' arousal level as measured by visual analog scales, and enhanced the amplitude of MMN in EEG. No differences in MMN latency were observed in MEG or EEG. Memantine did not affect the location, strength, amplitude or latency of MMNm, P1m, and N1m components. No changes in amplitude or latency were observed for P1 and N1 peaks. These results indicate that memantine affects involuntary attention without otherwise changing auditory processing of the stimuli. As memantine-induced changes in MMN were detected only in EEG, we suggest that the effect is mostly related to the frontal cortex.     

Do tone duration changes that elicit the mismatch negativity also affect the preceding middle latency responses?

The human brain can automatically detect sound changes. Previous studies have reported that rare sounds presented within a sequence of repetitive sounds elicit the mismatch negativity (MMN) in the absence of attention in the latency range of 100–250 ms. On the other hand, a previous study discovered that occasional changes in sound location enhance the middle latency response (MLR) elicited in the latency range of 10–50 ms. Several studies have reported an increase in the amplitude of the MLR within the frame of oddball paradigms such as frequency and location changes. However, few studies have been conducted on paradigms employing a duration change. The purpose of the present study was to examine whether the peak amplitudes of the MLR components are enhanced by a change in duration. Twenty healthy Japanese men (age: 23.9 ± 2.9 years) participated in the present study. We used an oddball paradigm that contained standard stimuli with a duration of 10 ms and deviant stimuli with a duration of 5 ms. The peak amplitudes of the MLR for the deviant stimuli were then compared with those for the standard stimuli. No changes were observed in the peak amplitude of the MLR resulting from a duration change, whereas a definite MMN was elicited. The amplitude of the MLR was increased within the frame of oddball paradigms such as frequency and location changes. By contrast, the amplitude of the MLR was not changed within the duration change oddball paradigm that elicited the MMN.     

艾司西酞普兰对抑郁症患者认知功能的影响：失匹配负电位的评价

实验对30例抑郁症患者及与其年龄、性别、教育程度相匹配的30名健康对照的事件相关电位失匹配性负波进行检测,发现抑郁症患者频率偏离以及时间偏离失匹配负波电位波幅均低于健康对照,说明抑郁症患者存在听觉注意认知加工过程的异常,即认知功能缺陷。经艾司西酞普兰治疗8周后,抑郁症患者的频率偏离以及时间偏离失匹配负波电位波幅明显提高,HAMD量表评分明显降低。表明艾司西酞普兰可改善抑郁症患者的认知功能,失匹配负电位可以作为认知功能状态以及治疗效果评价的神经电生理指标。     

Differentiating ERAN and MMN: an ERP study

In the present study, the early right-anterior negativity (ERAN) elicited by harmonically inappropriate chords during listening to music was compared to the frequency mismatch negativity (MMN) and the abstract-feature MMN. Results revealed that the amplitude of the ERAN, in contrast to the MMN, is specifically dependent on the degree of harmonic appropriateness. Thus, the ERAN is correlated with the cognitive processing of complex rule-based information, i.e. with the application of music-syntactic rules. Moreover, results showed that the ERAN, compared to the abstract-feature MMN, had both a longer latency, and a larger amplitude. The combined findings indicate that ERAN and MMN reflect different mechanisms of pre-attentive irregularity detection, and that, although both components have several features in common, the ERAN does not easily fit into the classical MMN framework. The present ERPs thus provide evidence for a differentiation of cognitive processes underlying the fast and pre-attentive processing of auditory information.