Effect of the Temporal Window of Integration of Speech Sound on Mismatch Negativity.

Speech-sound stimuli have a complex structure, and it is unclear how the brain processes them. An event-related potential (ERP), known as mismatch negativity (MMN), is elicited when an individual's brain detects a rare sound. In this study, MMNs were measured in response to an omitted segment of a complex sound consisting of a Japanese vowel. The results indicated that the latency from onset in the right hemisphere was significantly shorter than that in the frontal midline and left hemispheres during left ear stimulation. Additionally, the results of latency from omission showed that the latency of stimuli omitted in the latter part of the temporal window of integration (TWI) was longer than that of stimuli omitted in the first part of the TWI. The mean peak amplitude was found to be higher in the right hemisphere than in the frontal midline and left hemispheres in response to left ear stimulation. In conclusion, the results of this study suggest that would be incorrect to believe that the stimuli have strictly the characteristics of speech-sound. However. the results of the interaction effect in the latencies from omission were insignificant. These results suggest that the detection time for deviance may not be related to the stimulus ear. However, the type of deviant stimuli on latencies was found to be significant. This is because the detection of the deviants was delayed when a deviation occurred in the latter part of the TWI, regardless of the stimulation of the ear.

Effect of oxytocin nasal spray on auditory automatic discrimination measured by mismatch negativity.

RATIONALE: As a treatment for cognitive dysfunction in schizophrenia, oxytocin nasal sprays potentially improve social cognition, facial expression recognition, and sense of smell. Mismatch negativity (MMN) is an event-related potential (ERP) reflecting auditory discrimination while MMN deficits reflect cognitive function decline in schizophrenia. OBJECTIVES: To determine whether oxytocin nasal spray affects auditory MMN METHODS: We measured ERPs in healthy subjects during an auditory oddball task, both before and after oxytocin nasal spray administration. Forty healthy subjects were randomly assigned to either the oxytocin or placebo group. ERPs were recorded during the oddball task for all subjects before and after a 24 international unit (IU) intranasal administration, and MMN was compared between the two groups. RESULTS: Participants who received oxytocin had significantly shorter MMN latencies than those who received a placebo. Oxytocin had no significant effect on the Change in MMN amplitude. CONCLUSIONS: The shortened MMN latencies that were observed after oxytocin nasal spray administration suggest that oxytocin may promote the comparison-decision stage.

Effects of single green tea ingestion on pharmacokinetics of nadolol in healthy volunteers.

AIMS: The aim of this study was to investigate the effects of a single green tea (GT), administered concomitantly or 1 hour before nadolol intake on nadolol pharmacokinetics. METHODS: In a randomized 3-phase crossover study, 11 healthy volunteers received an oral administration of nadolol with, or 1 hour after preingestion of brewed GT, or with water in a volume of 150 mL. RESULTS: Geometric mean ratio with 90% confidence interval for nadolol AUC0-48 was 0.371 (0.303-0.439) with concomitant GT. In addition, ingestion of GT 1 hour before nadolol administration resulted in a significant reduction of nadolol AUC0-48 with geometric mean ratio of 0.536 (0.406-0.665). There were no differences in time to maximal plasma concentration and renal clearance of nadolol among groups. CONCLUSION: These results suggest that single concomitant ingestion of GT substantially decreases plasma concentrations of nadolol. Moreover, the reduction in nadolol bioavailability could persist for at least 1 hour after drinking a cup of GT.

Estimation of frequency difference at which stream segregation precedes temporal integration as reflected by omission mismatch negativity.

Both stream segregation and temporal integration are considered important for auditory scene analysis in the brain. Several previous studies have indicated that stream segregation may precede temporal integration when both processes are required. In the present study, we utilized mismatch negativity (MMN)-which reflects automatic change detection-to systematically estimate the threshold of the frequency difference at which stream segregation occurs prior to temporal integration when these functions occur together during a state of inattention. Electroencephalography (EEG) data were recorded from 22 healthy Japanese men presented with six blocks of alternating high pure tones (high tones) and low pure tones (low tones). Only high tones were omitted with 5 % probability in all blocks. Our results indicated that stream segregation should cancel temporal integration of close sounds, as indicated by omission-MMN elicitation, when the frequency difference is 1000 Hz or larger.

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.

Sound frequency dependence of duration mismatch negativity recorded from awake rats.

AIMS: The brain function that detects deviations in the acoustic environment can be evaluated with mismatch negativity (MMN). MMN to sound duration deviance has recently drawn attention as a biomarker for schizophrenia. Nonhuman animals, including rats, also exhibit MMN-like potentials. Therefore, MMN research in nonhuman animals can help to clarify the neural mechanisms underlying MMN production. However, results from preclinical MMN studies on duration deviance have been conflicting. We investigated the effect of sound frequency on MMN-like potentials to duration deviance in rats. METHODS: Event-related potentials were recorded from an electrode placed on the primary auditory cortex of free-moving rats using an oddball paradigm consisting of 50-ms duration tones (standards) and 150-ms duration tones (deviants) at a 500-ms stimulus onset asynchrony. The sound frequency was set to three conditions: 3, 12, and 50 kHz. RESULTS: MMN-like potentials that depended on the short-term stimulus history of background regularity were only observed in the 12-kHz tone frequency condition. CONCLUSIONS: MMN-like potentials to duration deviance are subject to tone frequency of the oddball paradigm in rats, suggesting that rats have distinct sound duration recognition ability.

Investigation of betaine as a novel psychotherapeutic for schizophrenia.

BACKGROUND: Betaine is known to act against various biological stresses and its levels were reported to be decreased in schizophrenia patients. We aimed to test the role of betaine in schizophrenia pathophysiology, and to evaluate its potential as a novel psychotherapeutic. METHODS: Using Chdh (a gene for betaine synthesis)-deficient mice and betaine-supplemented inbred mice, we assessed the role of betaine in psychiatric pathophysiology, and its potential as a novel psychotherapeutic, by leveraging metabolomics, behavioral-, transcriptomics and DNA methylation analyses. FINDINGS: The Chdh-deficient mice revealed remnants of psychiatric behaviors along with schizophrenia-related molecular perturbations in the brain. Betaine supplementation elicited genetic background-dependent improvement in cognitive performance, and suppressed methamphetamine (MAP)-induced behavioral sensitization. Furthermore, betaine rectified the altered antioxidative and proinflammatory responses induced by MAP and in vitro phencyclidine (PCP) treatments. Betaine also showed a prophylactic effect on behavioral abnormality induced by PCP. Notably, betaine levels were decreased in the postmortem brains from schizophrenia, and a coexisting elevated carbonyl stress, a form of oxidative stress, demarcated a subset of schizophrenia with "betaine deficit-oxidative stress pathology". We revealed the decrease of betaine levels in glyoxylase 1 (GLO1)-deficient hiPSCs, which shows elevated carbonyl stress, and the efficacy of betaine in alleviating it, thus supporting a causal link between betaine and oxidative stress conditions. Furthermore, a CHDH variant, rs35518479, was identified as a cis-expression quantitative trait locus (QTL) for CHDH expression in postmortem brains from schizophrenia, allowing genotype-based stratification of schizophrenia patients for betaine efficacy. INTERPRETATION: The present study revealed the role of betaine in psychiatric pathophysiology and underscores the potential benefit of betaine in a subset of schizophrenia. FUND: This study was supported by the Strategic Research Program for Brain Sciences from AMED (Japan Agency for Medical Research and Development) under Grant Numbers JP18dm0107083 and JP19dm0107083 (TY), JP18dm0107129 (MM), JP18dm0107086 (YK), JP18dm0107107 (HY), JP18dm0107104 (AK) and JP19dm0107119 (KH), by the Grant-in-Aid for Scientific Research on Innovative Areas from the MEXT under Grant Numbers JP18H05435 (TY), JP18H05433 (AH.-T), JP18H05428 (AH.-T and TY), and JP16H06277 (HY), and by JSPS KAKENHI under Grant Number JP17H01574 (TY). In addition, this study was supported by the Collaborative Research Project of Brain Research Institute, Niigata University under Grant Numbers 2018-2809 (YK) and RIKEN Epigenetics Presidential Fund (100214-201801063606-340120) (TY).

Role of (-)-epigallocatechin gallate in the pharmacokinetic interaction between nadolol and green tea in healthy volunteers.

PURPOSE: The aim of the present study is to investigate a possible role of a single dose of (-)-epigallocatechin gallate (EGCG), the major catechin in green tea, for the pharmacokinetic interaction between green tea and nadolol in humans. METHODS: In a randomized three-phase crossover study, 13 healthy volunteers received single doses of 30 mg nadolol orally with water (control), or an aqueous solution of EGCG-concentrated green tea extract (GTE) at low or high dose. Plasma concentrations and urinary excretion of nadolol were determined up to 48 h. In addition, blood pressure and pulse rate were monitored. In vitro transport kinetic experiments were performed using human embryonic kidney 293 cells stably expressing organic anion transporting polypeptide (OATP)1A2 to evaluate the inhibitory effect of EGCG on OATP1A2-mediated substrate transport. RESULTS: Single coadministration of low and high dose GTE significantly reduced the plasma concentrations of nadolol. The geometric mean ratios with 90% CI for area under the plasma concentration-time curves from 0 to infinity of nadolol were 0.72 (0.56-0.87) for the low and 0.60 (0.51-0.69) for the high dose. There were no significant differences in Tmax, elimination half-life, and renal clearance between GTE and water phases. No significant changes were observed for blood pressure and pulse rate between phases. EGCG competitively inhibited OATP1A2-mediated uptake of sulphobromophthalein and nadolol with Ki values of 21.6 and 19.4 µM, respectively. CONCLUSIONS: EGCG is suggested to be a key contributor to the interaction of green tea with nadolol. Moreover, even a single coadministration of green tea may significantly affect nadolol pharmacokinetics.

Lack of pharmacokinetic interaction between fluvastatin and green tea in healthy volunteers.

PURPOSE: The objective of this study is to assess the effects of green tea and its major catechin component, (-)-epigallocatechin gallate (EGCG), on CYP2C9-mediated substrate metabolism in vitro, and the pharmacokinetics of fluvastatin in healthy volunteers. METHODS: The metabolism of diclofenac and fluvastatin in human recombinant CYP2C9 was investigated in the presence of EGCG. In a randomized three-phase crossover study, 11 healthy volunteers ingested a single 20-mg dose of fluvastatin with green tea extract (GTE), containing 150 mg of EGCG, along with water (300 mL), brewed green tea (300 mL), or water (300 mL) after overnight fasting. Plasma concentrations of fluvastatin and EGCG were measured by ultra-performance liquid chromatography with fluorescence detection and a single mass spectrometer. RESULTS: EGCG inhibited diclofenac 4'-hydroxylation and fluvastatin degradation with IC50 of 2.23 and 48.04 µM, respectively. Brewed green tea used in the clinical study also dose-dependently inhibited the metabolism of diclofenac and fluvastatin in vitro. However, no significant effects of GTE and brewed green tea were observed in plasma concentrations of fluvastatin. The geometric mean ratios with 90% CI for area under the plasma concentration-time curve (AUC0-∞) of fluvastatin were 0.993 (0.963-1.024, vs. brewed green tea) and 0.977 (0.935-1.020, vs. GTE). CONCLUSIONS: Although in vitro studies indicated that EGCG and brewed green tea produce significant inhibitory effects on CYP2C9 activity, the concomitant administration of green tea and fluvastatin in healthy volunteers did not influence the pharmacokinetics of fluvastatin.

Alteration of Duration Mismatch Negativity Induced by Transcranial Magnetic Stimulation Over the Left Parietal Lobe.

Mismatch negativity (MMN) is generated by a comparison between an incoming sound and the memory trace of preceding sounds stored in sensory memory without any attention to the sound. N100 (N1) is associated with the afferent response to sound onset and reflects early analysis of stimulus characteristics. MMN generators are present in the temporal and frontal lobe, and N1 generators are present in the temporal lobe. The parietal lobe is involved in MMN generation elicited by a change in duration. The anatomical network connecting these areas, lateralization, and the effect of the side of ear stimulation on MMN remain unknown. Thus, we studied the effects of low-frequency repetitive transcranial magnetic stimulation (rTMS) over the left parietal lobe on MMN and N1 in 10 healthy subjects. Low-frequency rTMS over the left parietal lobe decreased the amplitude of MMN following right ear sound stimulation, but the amplitude was unaffected with left ear sound stimulation. We observed no significant changes in the amplitude of N1 or the latency of MMN or N1. These results suggest that low-frequency rTMS over the left parietal lobe modulates the detection of early auditory changes in duration in healthy subjects. Stimulation that is contralateral to the side of the ear experiencing sound may affect the generation of duration MMN more than ipsilateral stimulation.

Temporal integration of segmented-speech sounds probed with mismatch negativity.

Deviant sounds occurring in a sequence of standard sounds, in the absence of attention, elicit an event-related potential known as mismatch negativity (MMN). Standard sounds are encoded in auditory sensory memory trace and processed as a single unit within 160-170 ms, where each unitary event stored is closely related to the temporal window of integration. The temporal window of integration of pure tone sound has already been reported. However, there are no reported correlations between segmented-speech sounds and a temporal unit. It is well known that pure tone sounds are predominantly recognized in the right hemisphere, whereas speech sounds are recognized in the left hemisphere. The aim of this study was to examine whether segmented-speech sounds were processed as a temporal unit like pure tone sounds and whether there were differences between right and left ear stimuli. Twenty-five right-handed healthy Japanese men participated in this study. Stimuli consisted of the vowel /a/ spoken by a Japanese female and the stimuli sequences were randomized from short standard sounds and three types of long deviant sounds. The stimuli were presented to both ears separately. All bilateral stimuli induced definite MMN with similar peak latencies. The MMN amplitude gradually enhanced from the short to the long duration deviant. There were no differences in MMN between the right and the left ear stimuli. These findings perhaps show that bilateral deviant segmented-speech sounds were processed equally as a temporal unit.

Deviance-Related Responses along the Auditory Hierarchy: Combined FFR, MLR and MMN Evidence.

The mismatch negativity (MMN) provides a correlate of automatic auditory discrimination in human auditory cortex that is elicited in response to violation of any acoustic regularity. Recently, deviance-related responses were found at much earlier cortical processing stages as reflected by the middle latency response (MLR) of the auditory evoked potential, and even at the level of the auditory brainstem as reflected by the frequency following response (FFR). However, no study has reported deviance-related responses in the FFR, MLR and long latency response (LLR) concurrently in a single recording protocol. Amplitude-modulated (AM) sounds were presented to healthy human participants in a frequency oddball paradigm to investigate deviance-related responses along the auditory hierarchy in the ranges of FFR, MLR and LLR. AM frequency deviants modulated the FFR, the Na and Nb components of the MLR, and the LLR eliciting the MMN. These findings demonstrate that it is possible to elicit deviance-related responses at three different levels (FFR, MLR and LLR) in one single recording protocol, highlight the involvement of the whole auditory hierarchy in deviance detection and have implications for cognitive and clinical auditory neuroscience. Moreover, the present protocol provides a new research tool into clinical neuroscience so that the functional integrity of the auditory novelty system can now be tested as a whole in a range of clinical populations where the MMN was previously shown to be defective.

Effects of Shakuyaku-Kanzo-to on Extrapyramidal Symptoms During Antipsychotic Treatment: A Randomized, Open-Label Study.

Extrapyramidal symptoms (EPS) are common adverse effects of antipsychotic treatment. This study examined the effects of the traditional Japanese herbal medicine (kampo) shakuyaku-kanzo-to on EPS during antipsychotic treatment. Twenty-two Japanese patients with psychiatric disorders who had developed EPS during antipsychotic treatment were randomly allocated to receive either shakuyaku-kanzo-to (7.5 g/d) or biperiden (3 mg/d) for 2 weeks. Extrapyramidal symptoms were evaluated using the Drug-Induced Extrapyramidal Symptom Scale (DIEPSS) and the Barnes Akathisia Rating Scale. Plasma levels of the monoamine metabolite homovanillic acid and serum prolactin levels were measured to investigate the mechanisms of action of shakuyaku-kanzo-to. Twenty of the 22 patients completed the study (10 patients in the shakuyaku-kanzo-to group and 10 patients in the biperiden group). There was a time effect on the Drug-Induced Extrapyramidal Symptom Scale total score (P < 0.01), suggesting that both shakuyaku-kanzo-to and biperiden decreased EPS. Notably, there was a time × drug interaction in dystonia, suggesting that shakuyaku-kanzo-to had a greater effect on dystonia compared with biperiden. No significant changes were observed in plasma homovanillic acid or serum prolactin levels after 2 weeks of treatment in either group. The effects of shakuyaku-kanzo-to on abnormal muscle tonus and dopamine D2 receptors may have contributed to improve EPS. These results suggest that shakuyaku-kanzo-to may be useful in decreasing EPS, especially dystonia, in patients undergoing treatment with antipsychotic agents.

Event-related potentials in patients with adult attention-deficit/hyperactivity disorder versus schizophrenia.

Event-related potentials (ERPs) such as Nd, N2b, and P300 in an attentional task and an auditory oddball task were compared among 54 adult AD/HD patients, 43 schizophrenic patients (SZ), and 40 healthy age-matched volunteers (HC). It is known that Nd, N2b, and P300 reflect selective attention, voluntary attention, and cognitive context updating respectively. The peak amplitude of P300 was significantly lower in the adult AD/HD and SZ groups than in the HC group. The peak latencies of late Nd, N2b, and P300 were significantly longer in the SZ group than in the HC and adult AD/HD groups. Thus, attenuated amplitude and prolonged latency of various ERP components in the SZ group suggest the possibility of impairment of basic mechanisms underlying cognitive processing. Unlike the SZ group, the adult AD/HD group exhibited reduced amplitude of P300 but not prolonged latency. These findings suggest the existence of a different type of cognitive dysfunction in the adult AD/HD group, which might be closely related to attentional function.

Memory trace dependence on number of stimuli in magnetic mismatch negativity.

Mismatch negativity (MMN) reflects a comparison process between a deviant stimulus and the memory trace of standard stimuli. Although this memory mechanism has been investigated by many research studies, the development of memory representation still remains unclear. In this study, we focused on the development of sound trace underlying the MMN response. We measured the magnetic counterpart of MMN (MMNm) in detail, when the neural trace of the standard sound was developed in accordance with the number of standard stimuli. When the number of standard stimuli increased, MMNm latency significantly shortened and the MMNm amplitude showed no significant change. Thus, the developmental effects on memory trace may differ between MMNm amplitude and MMNm latency.

Deviant matters: duration, frequency, and intensity deviants reveal different patterns of mismatch negativity reduction in early and late schizophrenia.

BACKGROUND: A reduction in the size of the auditory event-related potential component known as mismatch negativity (MMN) is a consistent finding in schizophrenia. This study was designed to test the hypothesis that sound intensity and duration might be more sensitive to MMN reduction early in the development of schizophrenia because of the computational complexity in extracting these two sound dimensions. METHODS: The MMN elicited to sounds deviating in duration, frequency, or intensity was measured in participants with a short (n = 14, mean 2.6 years) and longer length of illness (n = 29, mean 18.9 years) relative to healthy age-matched control subjects. RESULTS: For participants early in the illness, a clear reduction was evident in MMN to duration and intensity but not frequency deviants. A different pattern was observed in patients with a longer length of illness--that is, a reduction in frequency and in duration to a lesser degree but not intensity MMN. CONCLUSIONS: The results indicate a pronounced age-related decline in duration and intensity MMN in control subjects that might reduce the sensitivity of these indices in schizophrenia when measured later in the course of the illness. The MMN elicited to changes in different sound properties provides potentially complementary information on the onset and progression of neuropathological changes that underlie the reduction in MMN in schizophrenia.

The development of memory trace depending on the number of the standard stimuli.

The mismatch negativity (MMN) component of the event-related potentials reflects the automatic detection mechanism of sound change. MMN is elicited by a neuronal mismatch process between deviant (infrequent) auditory input and the sensory memory trace of the standard (frequent) stimuli. Although many previous studies have investigated MMN to reveal the sensory memory mechanism, the development of memory representation still remains unclear, in particular, the topographical aspect of the trace-development in sensory memory has not been clarified. We measured the frontal and the temporal MMN components, respectively, when the sound trace was developed as the number of standard stimuli was changed to 1, 3, 5 or 7. In this experiment, the inter-train interval was 15 sec. The stimulus train with the different frequency of 800 Hz, 900 Hz, or 1000 Hz was repeatedly presented. Thus, we reduced the influence of the previous train. For the first time, we found not only the enhanced amplitude but also the shortened latency for both MMN components when the number of standard stimuli was increased. These findings indicate that both frontal and temporal MMN components reflect the development of memory trace depending on the number of standard stimuli.

[Psychophysiological basis of smells].

There has been an increase in the use of psychophysiological techniques, especially event-related potentials (ERPs) to evaluate the effects of odor on the central nervous system. In the study of ERPs related to odor, there are two main methods of the odor presentation: (1) to investigate the olfactory ERP (OERP) or chemosensory ERP (CSERP), that is to calculate electrophysiological responses to odor stimulation as a trigger; (2) to compare ERP of mental functioning during the odor exposed condition with that of no odor exposure. The amplitude of contingent negative variation (CNV) varies with the odorant being present, when the odor is presented as a trigger and when it is administrated during a task. It is suggested that CNV changes depend on not only the odorant but the anticipation, expectation and emotion of the subject. The latency of the N1 component becomes shorter with increasing concentrations of odors. The N1 amplitude does not depend on the odor concentration while the amplitude of the auditory N1 strongly depends on the stimulus intensity. There is only one report that the olfactory mismatch negativity (MMN) is present in the CSERP. On the other hand, auditory MMN is not affected by odor administration. In relation to the P3 component, rare odors evoked a larger amplitude in contrast to frequent odors, as well as P3 evoked by other modalities. These ERP studies with odors are expected to be applied to such clinical settings as the differentiation between the anosmic patients and normosmic persons, the functional evaluation of patients with brain tumors, the earlier detection of dementia, and the objective evaluation of aromatherapy.

Time may be compressed in sound representation as replicated in sensory memory.

The flow of time in the real world may differ from the one in the neural representation of auditory scene stored in the sensory memory, because the encoded information is free from the rule of actual time. The sensory memory underlying the automatic discriminative system is reflected by the mismatch negativity (MMN). The time-wise image of preceding sounds is integrated into the sensory memory as a 160-170 ms epoch. We measured the mismatch field (MMNm) and the reaction time responding to the omitted segments incorporated into a complex sound. The main result was that the encoded period from early to late omitted segment was shorter than the actual one, suggesting that time may be compressed in the sound representation.

Sound perception affected by nonlinear variation of accuracy in memory trace.

The mismatch negativity (MMN) reflects the neural representation of the acoustic environment stored in sensory memory. The short phase of sensory memory corresponds to the temporal window of integration (TWI) which integrates the neighboring sounds into a unitary event. We measured the magnetic MMN (MMNm) and the discriminative reaction time (RT) responding to an omitted segment incorporated into a complex sound. Consequently, for the late omitted segments, the MMNm amplitudes were decreased, and those latencies and the RTs were prolonged. The percentages of the correct responses were also reduced for the late omitted segments. In sum, the discriminative sensitivity nonlinearly declined toward the end of the TWI, suggesting that the time-wise accuracy of the neural trace nonlinearly varies in sensory memory.