Human brain evoked potentials and discrimination of short acoustic stimuli with various frequency

We found that the mismatch negativity (MMM) was absent in evoked potentials in passive condition for frequency deviant acoustical stimuli when stimulus duration was only 11-30 ms. But it was shown that it is possible for participants to fairly well discriminate these stimuli and the component N2b in RP was generated without preceding MMN. Processing negativity also was absent in potentials by the minimal stimulus duration (11 ms). Auditory discrimination nevertheless was still possible, but reaction time and number of committed errors increased significantly.     

Neural networks simulating the frequency discrimination of hearing for non-stationary short tone stimuli

This paper addresses the question of frequency discrimination of hearing for non-stationary (short) tone stimuli (duration 125 ms). Shortening of the stimulus duration leads to widening of the frequency spectrum of the tone. It can be shown that for hearing no acoustical uncertainty relation holds and thus some nonlinear elements must be present in hearing physiology. We present neurophysiological and psychoacoustical findings supporting the hypothesis that frequency discrimination of non-stationary short tone stimuli is performed in neural networks of the auditory system. Neural network architectures that could process the temporal and place excitation patterns originating in the cochlea are suggested. We show how these networks (temporal coincidence network processing the temporal code and lateral inhibition network processing the place code) can be combined to show performance consistent with auditory physiology. They might explain the frequency discrimination of hearing for non-stationary short tone stimuli. We show the fitting of psychophysical relations based on these networks with the experimentally determined data.     

Perceptual categories for auditory motion as reflected in mismatch negativity

Auditory evoked response and mismatch negativity potential have been studied using the reversed oddball paradigm of standard and deviant stimulus presentation. In the experiments, three types of spatial sound stimuli (stationary and moving gradually or abruptly from the head midline) were presented in three configurations. In each configuration, one stimulus type served as the standard one, and the other two, as deviants. The reversal of the configuration of the presentation of the standard and deviant stimuli was shown to significantly influence the evoked response and mismatch negativity. The results are discussed as possible evidence of the categorical perception of auditory motion at early stages of sound processing in the hearing system.     

Dual role of MutS glutamate 38 in DNA mismatch discrimination and in the authorization of repair

MutS plays a critical role in DNA mismatch repair in Escherichia coli by binding to mismatches and initiating repair in an ATP-dependent manner. Mutational analysis of a highly conserved glutamate, Glu38, has revealed its role in mismatch recognition by enabling MutS to discriminate between homoduplex and mismatched DNA. Crystal structures of MutS have shown that Glu38 forms a hydrogen bond to one of the mismatched bases. In this study, we have analyzed the crystal structures, DNA binding and the response to ATP binding of three Glu38 mutants. While confirming the role of the negative charge in initial discrimination, we show that in vivo mismatch repair can proceed even when discrimination is low. We demonstrate that the formation of a hydrogen bond by residue 38 to the mismatched base authorizes repair by inducing intramolecular signaling, which results in the inhibition of rapid hydrolysis of distally bound ATP. This allows formation of the stable MutS-ATP-DNA clamp, a key intermediate in triggering downstream repair events.     

Moving sound source discrimination in humans: Mismatch negativity and psychophysics

The ability to discriminate moving sounds sources with different dynamic properties was studied in humans. Mismatch negativity was studied in an experiment on dichotic stimulation, with deviant stimuli simulating the instantaneous movement of the auditory image to the right or left of the head midline in the horizontal plane. Standard stimuli simulated continuous movement of the sound source to the right or to the left to the same angular distances. It was also established that both deviant stimuli caused mismatch negativity, its parameters being independent on the direction of sound movement. Psychophysical testing of the same group of subjects showed that discrimination between the stimuli was below the psychophysical threshold. The results obtained are discussed from the point of view of current theories of moving sound localization. The correlation between the objective and subjective levels of discrimination of moving auditory images are discussed.     

Optimization of single-base-pair mismatch discrimination in oligonucleotide microarrays

The discrimination between perfect-match and single-base-pair-mismatched nucleic acid duplexes was investigated by using oligonucleotide DNA microarrays and nonequilibrium dissociation rates (melting profiles). DNA and RNA versions of two synthetic targets corresponding to the 16S rRNA sequences of Staphylococcus epidermidis (38 nucleotides) and Nitrosomonas eutropha (39 nucleotides) were hybridized to perfect-match probes (18-mer and 19-mer) and to a set of probes having all possible single-base-pair mismatches. The melting profiles of all probe-target duplexes were determined in parallel by using an imposed temperature step gradient. We derived an optimum wash temperature for each probe and target by using a simple formula to calculate a discrimination index for each temperature of the step gradient. This optimum corresponded to the output of an independent analysis using a customized neural network program. These results together provide an experimental and analytical framework for optimizing mismatch discrimination among all probes on a DNA microarray.     

Mechanisms and functions of DNA mismatch repair

DNA mismatch repair （MMR） is a highly conserved biological pathway that plays a key role in maintaining genomic stability. The specificity of MMR is primarily for base-base mismatches and insertion/deletion mispairs generated during DNA replication and recombination. MMR also suppresses homeologous recombination and was recently shown to play a role in DNA damage signaling in eukaryotic cells. Escherichia coli MutS and MutL and their eukaryotic homologs, MutSα and MutLα, respectively, are key players in MMR-associated genome maintenance. Many other protein components that participate in various DNA metabolic pathways, such as PCNA and RPA, are also essential for MMR. Defects in MMR are associated with genome-wide instability, predisposition to certain types of cancer including hereditary non-polyposis colorectal cancer, resistance to certain chemotherapeutic agents, and abnormalities in meiosis and sterility in mammalian systems.     

Mismatch negativity in the brain evoked potentials induced by short duration acoustic stimuli in adolescents in the norm and those with attention deficit

The effect of stimulus duration on the mismatch negativity of the auditory event-related potentials was studied in healthy children and those with attention-deficit symptoms. The minimum stimulus duration with which a MMN was elicited by frequency deviant was 50 ms in healthy children. The MMN was absent with shorter stimuli (11 ms and 30 ms). These parametres are close to those in adults. As to children with attention-deficit symptoms the MMN was insignificant with all tested stimulus durations (11 ms, 30 ms, 50 ms).     

Sequential grouping of tone sequence as reflected by the mismatch negativity

The human sequential grouping that organizes parts of tones into a group was examined by the mismatch negativity (MMN), a component of event-related potentials that reveals the sensory memory process. The sequential grouping is accomplished by the combinations of some factors, e.g., temporal and frequency proximity principles. In this study, auditory oddball stimuli in which each of the stimuli consisted of series of tone bursts, were applied to the subjects, and the MMN elicited by the deviation of the frequency of the last tone in the stimulus was investigated. The relationship between the expected phenomena of sequential grouping of tones and observed magnitudes of MMN was evaluated. It was shown that the magnitudes of MMN changed according to the configuration (number of tones, frequency) of tone sequence to be stored. This result suggested that the sequential grouping of presented tones was achieved on the preattentive auditory sensory memory process. It was also shown that the relative change of MMN magnitudes corresponded to the conditions of sequential grouping, which had been proposed by the auditory psychophysical studies. The investigation of MMN properties could reveal the nature of auditory sequential grouping.This study was approved by the Ethics Committee on Clinical Investigation, Graduate School of Engineering, Tohoku University and was carried out in accordance with the policy of the Declaration of Helsinki.     

Stability and mismatch discrimination of locked nucleic acid-DNA duplexes

Locked nucleic acids (LNA; symbols of bases, +A, +C, +G, and +T) are introduced into chemically synthesized oligonucleotides to increase duplex stability and specificity. To understand these effects, we have determined thermodynamic parameters of consecutive LNA nucleotides. We present guidelines for the design of LNA oligonucleotides and introduce free online software that predicts the stability of any LNA duplex oligomer. Thermodynamic analysis shows that the single strand-duplex transition is characterized by a favorable enthalpic change and by an unfavorable loss of entropy. A single LNA modification confines the local conformation of nucleotides, causing a smaller, less unfavorable entropic loss when the single strand is restricted to the rigid duplex structure. Additional LNAs adjacent to the initial modification appear to enhance stacking and H-bonding interactions because they increase the enthalpic contributions to duplex stabilization. New nearest-neighbor parameters correctly forecast the positive and negative effects of LNAs on mismatch discrimination. Specificity is enhanced in a majority of sequences and is dependent on mismatch type and adjacent base pairs; the largest discriminatory boost occurs for the central +C·C mismatch within the +T+C+C sequence and the +A·G mismatch within the +T+A+G sequence. LNAs do not affect specificity in some sequences and even impair it for many +G·T and +C·A mismatches. The level of mismatch discrimination decreases the most for the central +G·T mismatch within the +G+G+C sequence and the +C·A mismatch within the +G+C+G sequence. We hypothesize that these discrimination changes are not unique features of LNAs but originate from the shift of the duplex conformation from B-form to A-form.     

Differentiation of schizophrenia patients from healthy subjects by mismatch negativity and neuropsychological tests

Background

Schizophrenia is a heterogeneous disorder with diverse presentations. The current and the proposed DSM-V diagnostic system remains phenomenologically based, despite the fact that several neurobiological and neuropsychological markers have been identified. A multivariate approach has better diagnostic utility than a single marker method. In this study, the mismatch negativity (MMN) deficit of schizophrenia was first replicated in a Han Chinese population, and then the MMN was combined with several neuropsychological measurements to differentiate schizophrenia patients from healthy subjects.

Methodology/Principal Findings

120 schizophrenia patients and 76 healthy controls were recruited. Each subject received examinations for duration MMN, Continuous Performance Test, Wisconsin Card Sorting Test, and Wechsler Adult Intelligence Scale Third Edition (WAIS-III). The MMN was compared between cases and controls, and important covariates were investigated. Schizophrenia patients had significantly reduced MMN amplitudes, and MMN decreased with increasing age in both patient and control groups. None of the neuropsychological indices correlated with MMN. Predictive multivariate logistic regression models using the MMN and neuropsychological measurements as predictors were developed. Four predictors, including MMN at electrode FCz and three scores from the WAIS-III (Arithmetic, Block Design, and Performance IQ) were retained in the final predictive model. The model performed well in differentiating patients from healthy subjects (percentage of concordant pairs: 90.5%).

Conclusions/Significance

MMN deficits were found in Han Chinese schizophrenia patients. The multivariate approach combining biomarkers from different modalities such as electrophysiology and neuropsychology had a better diagnostic utility.     

Design of LNA probes that improve mismatch discrimination

Locked nucleic acids (LNA) show remarkable affinity and specificity against native DNA targets. Effects of LNA modifications on mismatch discrimination were studied as a function of sequence context and identity of the mismatch using ultraviolet (UV) melting experiments. A triplet of LNA residues centered on the mismatch was generally found to have the largest discriminatory power. An exception was observed for G–T mismatches, where discrimination decreased when the guanine nucleotide at the mismatch site or even the flanking nucleotides were modified. Fluorescence experiments using 2-aminopurine suggest that LNA modifications enhance base stacking of perfectly matched base pairs and decrease stabilizing stacking interactions of mismatched base pairs. LNAs do not change the amount of counterions (Na⁺) that are released when duplexes denature. New guidelines are suggested for design of LNA probes, which significantly improve mismatch discrimination in comparison with unmodified DNA probes.     

A mismatch negativity elicited with stationary and moving auditory images of different azimuth positions

Characteristics of mismatch negativity elicited by dichotic stimulation were examined using deviant stimuli simulating movement of fused auditory images towards the standard stimuli or in the reverse direction. The effect of stationary deviants localized at 90 degrees in respect to standards was also measured. The standard stimuli were localized near either of ears or along the head midline. The spatial locations were produced by introducing interaural time differences into the click trains. All deviant stimuli evoked the mismatch negativity. The deviants moving from standards seem to evoke the lowest mismatch negativity with the longest latency at all azimuthal locations of standard stimuli. Besides, the deviant shift from standards proved to be the only direction at which the characteristics of mismatch negativity depended upon the standard's azimuth. It is seems that the discrimination of interaural time delay is essentially dependent on the pattern of interaural delay changes at the moment when the deviant occurs.     

Enhanced thermal stability and mismatch discrimination of mutation-carrying DNA duplexes and their kinetic and thermodynamic properties in microchannel laminar flow

This article reports the enhancement of thermal stability involving normal duplex and mutation-carrying DNA duplexes in microchannel laminar flow. The application of an in-house temperature-controllable microchannel-type flow cell is demonstrated for improved discrimination of mismatch base pairs such as A-G and T-G that are difficult to distinguish due to the rather small thermal destabilizations. Enhancement in thermal stability is reflected by an increased thermal melting temperature achieved in microchannel laminar flow as compared with batch reactions. To examine the kinetics and thermodynamics of duplex-coil equilibrium of DNA oligomers, denaturation-renaturation hysteresis curves were measured. The influence of microchannel laminar flow on DNA base mismatch analysis was described from the kinetic and thermodynamic perspectives. An increasing trend was observed for association rate constant as flow rate increased. In contrast, an apparent decrease in dissociation rate constant was observed with increasing flow rate. The magnitudes of the activation energies of dissociation were nearly constant for both the batch and microchannel laminar flow systems at all flow rates. In contrast, the magnitudes of activation energies of association decreased as flow rate increased. These results clearly show how microchannel laminar flow induces change in reaction rate by effecting change in activation energy. We anticipate, therefore, that this approach based on microchannel laminar flow system holds great promise for improved mismatch discrimination in DNA analyses, particularly on single-base-pair mismatch, by pronouncedly enhancing thermal stability.     

Integration of consonant and pitch processing as revealed by the absence of additivity in mismatch negativity

Consonants, unlike vowels, are thought to be speech specific and therefore no interactions would be expected between consonants and pitch, a basic element for musical tones. The present study used an electrophysiological approach to investigate whether, contrary to this view, there is integrative processing of consonants and pitch by measuring additivity of changes in the mismatch negativity (MMN) of evoked potentials. The MMN is elicited by discriminable variations occurring in a sequence of repetitive, homogeneous sounds. In the experiment, event-related potentials (ERPs) were recorded while participants heard frequently sung consonant-vowel syllables and rare stimuli deviating in either consonant identity only, pitch only, or in both dimensions. Every type of deviation elicited a reliable MMN. As expected, the two single-deviant MMNs had similar amplitudes, but that of the double-deviant MMN was also not significantly different from them. This absence of additivity in the double-deviant MMN suggests that consonant and pitch variations are processed, at least at a pre-attentive level, in an integrated rather than independent way. Domain-specificity of consonants may depend on higher-level processes in the hierarchy of speech perception.