Low expression of the CCL5 gene and low serum concentrations of CCL5 in severe invasive group a streptococcal disease.

PURPOSE: Our objective was to elucidate host dependent factors of disease severity in invasive group A Streptococcal disease (iGAS) using transcriptome profiling of iGAS cases of varying degrees of severity at different timepoints. To our knowledge there are no previous transcriptome studies in iGAS patients. METHODS: We recruited iGAS cases from June 2018 to July 2020. Whole blood samples for transcriptome analysis and serum for biomarker analysis were collected at three timepoints representing the acute (A), the convalescent (B) and the post-infection phase (C). Gene expression was compared against clinical traits and disease course. Serum chemokine ligand 5 (CCL5, an inflammatory cytokine) concentration was also measured. RESULTS: Forty-five patients were enrolled. After disqualifying degraded or impure RNAs we had 34, 31 and 21 subjects at timepoints A, B, and C, respectively. Low expression of the CCL5 gene correlated strongly with severity (death or need for intensive care) at timepoint A (AUC = 0.92), supported by low concentrations of CCL5 in sera. CONCLUSIONS: Low gene expression levels and low serum concentration of CCL5 in the early stages of an iGAS infection were associated with a more severe disease course. CCL5 might have potential as a predictor of disease severity. Low expression of genes of cytotoxic immunity, especially CCL5, and corresponding low serum concentrations of CCL5 associated with a severe disease course, i.e. death, or need for intensive care, in early phase of invasive group A Streptococcal disease.

Enhanced neural mechanisms of set shifting in musically trained adolescents and young adults: converging fMRI, EEG, and behavioral evidence.

Musically trained individuals have been found to outperform untrained peers in various tasks for executive functions. Here, we present longitudinal behavioral results and cross-sectional, event-related potential (ERP), and fMRI results on the maturation of executive functions in musically trained and untrained children and adolescents. The results indicate that in school-age, the musically trained children performed faster in a test for set shifting, but by late adolescence, these group differences had virtually disappeared. However, in the fMRI experiment, the musically trained adolescents showed less activity in frontal, parietal, and occipital areas of the dorsal attention network and the cerebellum during the set-shifting task than untrained peers. Also, the P3b responses of musically trained participants to incongruent target stimuli in a task for set shifting showed a more posterior scalp distribution than control group participants' responses. Together these results suggest that the musician advantage in executive functions is more pronounced at an earlier age than in late adolescence. However, it is still reflected as more efficient recruitment of neural resources in set-shifting tasks, and distinct scalp topography of ERPs related to updating and working memory after childhood.

Neural discrimination of speech sound changes in a variable context occurs irrespective of attention and explicit awareness.

To process complex stimuli like language, our auditory system must tolerate large acoustic variance, like speaker variability, and still be sensitive enough to discriminate between phonemes and to detect complex sound relationships in, e.g., prosodic cues. Our study determined discrimination of speech sounds in input mimicking natural speech variability, and detection of deviations in regular pitch relationships (rule violations) between speech sounds. We investigated the automaticity and the influence of attention and explicit awareness on these changes by recording the neurophysiological mismatch negativity (MMN) and P3a as well as task performance from 21 adults. The results showed neural discrimination of phonemes and rule violations as indicated by MMN and P3a, regardless of whether the sounds were attended or not, even when participants could not explicitly describe the rule. While small sample size precluded statistical analysis of some outcomes, we still found preliminary associations between the MMN amplitudes, task performance, and emerging explicit awareness of the rule. Our results highlight the automaticity of processing complex aspects of speech as a basis for the emerging conscious perception and explicit awareness of speech properties. While MMN operates at the implicit processing level, P3a appears to work at the borderline of implicit and explicit.

Event-related brain responses while listening to entire pieces of music.

Brain responses to discrete short sounds have been studied intensively using the event-related potential (ERP) method, in which the electroencephalogram (EEG) signal is divided into epochs time-locked to stimuli of interest. Here we introduce and apply a novel technique which enables one to isolate ERPs in human elicited by continuous music. The ERPs were recorded during listening to a Tango Nuevo piece, a deep techno track and an acoustic lullaby. Acoustic features related to timbre, harmony, and dynamics of the audio signal were computationally extracted from the musical pieces. Negative deflation occurring around 100 milliseconds after the stimulus onset (N100) and positive deflation occurring around 200 milliseconds after the stimulus onset (P200) ERP responses to peak changes in the acoustic features were distinguishable and were often largest for Tango Nuevo. In addition to large changes in these musical features, long phases of low values that precede a rapid increase - and that we will call Preceding Low-Feature Phases - followed by a rapid increase enhanced the amplitudes of N100 and P200 responses. These ERP responses resembled those to simpler sounds, making it possible to utilize the tradition of ERP research with naturalistic paradigms.

Musicianship facilitates the processing of Western music chords--an ERP and behavioral study.

The present study addressed the effects of musicianship on neural and behavioral discrimination of Western music chords. In abstract oddball paradigms, minor chords and inverted major chords were presented in the context of major chords to musician and non-musician participants in a passive listening task (with EEG recordings) and in an active discrimination task. Both sinusoidal sounds and harmonically rich piano sounds were used. Musicians outperformed non-musicians in the discrimination task. Change-related mismatch negativity (MMN) was evoked to minor and inverted major chords in musicians only, and N1 amplitude was larger in musicians than non-musicians. While MMN was absent in non-musicians, both groups showed decreased N1 in response to minor compared to major chords. The results indicate that processing of complex musical stimuli is enhanced in musicians both behaviorally and neurally, but that major-minor chord categorization is present to some extent also in the absence of music training.

'I love Rock 'n' Roll'--music genre preference modulates brain responses to music.

The present study examined the effect of participants' music genre preference on the neural processes underlying evaluative and cognitive judgements of music using the event-related potential technique. To this aim, two participant groups differing in their preference for Latin American and Heavy Metal music performed a liking judgement and a genre classification task on a variety of excerpts of either music genre. A late positive potential (LPP) was elicited in all conditions between 600 and 900 ms after stimulus onset. During the genre classification task, an early negativity was elicited by the preferred compared to the non-preferred music at around 230-370 ms whereas the non-preferred genre was characterized by a larger LPP. The findings suggest that evaluative and cognitive judgements of music are accompanied by affective responses and that the valence of music may spontaneously modulate early processes of music categorization even when no overt liking judgement is required.

Informal musical activities are linked to auditory discrimination and attention in 2-3-year-old children: an event-related potential study.

The relation between informal musical activities at home and electrophysiological indices of neural auditory change detection was investigated in 2-3-year-old children. Auditory event-related potentials were recorded in a multi-feature paradigm that included frequency, duration, intensity, direction, gap deviants and attention-catching novel sounds. Correlations were calculated between these responses and the amount of musical activity at home (i.e. musical play by the child and parental singing) reported by the parents. A higher overall amount of informal musical activity was associated with larger P3as elicited by the gap and duration deviants, and smaller late discriminative negativity responses elicited by all deviant types. Furthermore, more musical activities were linked to smaller P3as elicited by the novel sounds, whereas more paternal singing was associated with smaller reorienting negativity responses to these sounds. These results imply heightened sensitivity to temporal acoustic changes, more mature auditory change detection, and less distractibility in children with more informal musical activities in their home environment. Our results highlight the significance of informal musical experiences in enhancing the development of highly important auditory abilities in early childhood.

Musical training facilitates the neural discrimination of major versus minor chords in 13-year-old children.

Music practice since childhood affects the development of hearing skills. An important classification in Western music is the chords' major-minor dichotomy. Its preattentive auditory discrimination was studied here using a mismatch negativity (MMN) paradigm in 13-year-olds with active hobbies, music-related (music group) or other (control group). In a context of root major chords, root minor chords and inverted major chords were presented infrequently. The interval structure of inverted majors differs more from root majors than the interval structure of root minors. However, the identity of the chords is the same in inverted and root majors (major), but different in root minors. The deviant chords introduced no new frequencies to the paradigm. Hence, an MMN caused by physical deviance was prevented. An MMN was elicited by the minor chords but not by the inverted majors. The MMN amplitude in the music group was larger than in the control group. Thus, the conceptual discrimination skills are present already in the preattentive processing level of the auditory cortex, and musical training can advance these skills.

Expertise in folk music alters the brain processing of Western harmony.

In various paradigms of modern neurosciences of music, experts of Western classical music have displayed superior brain architecture when compared with individuals without explicit training in music. In this paper, we show that chord violations embedded in musical cadences were neurally processed in a facilitated manner also by musicians trained in Finnish folk music. This result, obtained by using early right anterior negativity (ERAN) as an index of harmony processing, suggests that tonal processing is advanced in folk musicians by their long-term exposure to both Western and non-Western music.

The development of aesthetic responses to music and their underlying neural and psychological mechanisms.

In the field of psychology, the first studies in experimental aesthetics were conducted approximately 140 years ago. Since then, research has mainly concentrated on aesthetic responses to visual art. Both the aesthetic experience of music and, especially, its development have received rather limited attention. Moreover, until now, very little attention has been paid to the investigation of the aesthetic experience of music using neuroscientific methods. Aesthetic experiences are multidimensional and include inter alia sensory, perceptual, affective, and cognitive components. Aesthetic processes are usually experienced as pleasing and rewarding and are, thus, important and valuable experiences for many people. Because of their multidimensional nature, these processes employ several brain areas. In the present review, we examine important psychological and neural mechanisms that are believed to contribute to the development of aesthetic experiences of music. We also discuss relevant research findings. With the present review, we wish to provoke further discussion and possible future investigations as we consider the investigation of aesthetic experiences to be important both scientifically and with respect to potential clinical applications.

Top-down modulation of auditory processing: effects of sound context, musical expertise and attentional focus.

By recording auditory electrical brain potentials, we investigated whether the basic sound parameters (frequency, duration and intensity) are differentially encoded among speech vs. music sounds by musicians and non-musicians during different attentional demands. To this end, a pseudoword and an instrumental sound of comparable frequency and duration were presented. The accuracy of neural discrimination was tested by manipulations of frequency, duration and intensity. Additionally, the subjects' attentional focus was manipulated by instructions to ignore the sounds while watching a silent movie or to attentively discriminate the different sounds. In both musicians and non-musicians, the pre-attentively evoked mismatch negativity (MMN) component was larger to slight changes in music than in speech sounds. The MMN was also larger to intensity changes in music sounds and to duration changes in speech sounds. During attentional listening, all subjects more readily discriminated changes among speech sounds than among music sounds as indexed by the N2b response strength. Furthermore, during attentional listening, musicians displayed larger MMN and N2b than non-musicians for both music and speech sounds. Taken together, the data indicate that the discriminative abilities in human audition differ between music and speech sounds as a function of the sound-change context and the subjective familiarity of the sound parameters. These findings provide clear evidence for top-down modulatory effects in audition. In other words, the processing of sounds is realized by a dynamically adapting network considering type of sound, expertise and attentional demands, rather than by a strictly modularly organized stimulus-driven system.

Psychosocial stress attenuates general sound processing and duration change detection.

An EEG-compatible adaptation of the Trier Social Stress Test was developed to induce psychosocial stress in healthy subjects while investigating their auditory processing of unattended sounds and salivary levels of the stress hormone cortisol. The mismatch negativity (MMN) and N1/P2 were assessed using a multifeature paradigm, while subjects were attending to visual tasks with high or low attentional workload. Only the responses to duration change were affected by the stress manipulation. Cortisol levels during stress were inversely related to the MMN amplitudes of duration deviants. During anticipatory stress, responses to the standard tones (general sound processing) increased, but their amplitude was not correlated with cortisol levels. We found that psychosocial stressor anticipation attenuates both general and deviance-specific sound processing, suggesting that cortisol interferes with cortical memory-trace formation.

Practice strategies of musicians modulate neural processing and the learning of sound-patterns.

Previous studies suggest that pre-attentive auditory processing of musicians differs depending on the strategies used in music practicing and performance. This study aimed at systematically revealing whether there are differences in auditory processing between musicians preferring and not-preferring aural strategies such as improvising, playing by ear, and rehearsing by listening to records. Participants were assigned to aural and non-aural groups according to how much they employ aural strategies, as determined by a questionnaire. The change-related mismatch negativity (MMN) component of event-related brain potentials (ERPs) was used to probe pre-attentive neural discrimination of simple sound features and melody-like patterns. Further, the musicians' behavioral accuracy in sound perception was tested with a discrimination task and the AMMA musicality test. The data indicate that practice strategies do not affect musicians' pre-attentive neural discrimination of changes in simple sound features but do modulate the speed of neural discrimination of interval and contour changes within melody-like patterns. Moreover, while the aural and non-aural groups did not differ in their initial neural accuracy for discriminating melody-like patterns, they differed after a focused training session. A correlation between behavioral and neural measures was also obtained. Taken together, these results suggest that auditory processing of musicians who prefer aural practice strategies differs in melodic contour and interval processing and perceptual learning, rather than in simple sound processing, in comparison to musicians preferring other practice strategies.

Selective tuning of cortical sound-feature processing by language experience.

In 'quantity-languages', such as Japanese or Finnish, sound duration is linguistically relevant. We showed that quantity-language speakers were superior to speakers of a non-quantity language in discriminating the duration of even non-speech sounds. In contrast, there was no group difference in the discrimination of sound frequency. This result, obtained both by behavioural and neural indices at attentive and automatic levels of processing, indicates precise feature-specific tuning of the auditory-cortex functions by the mother tongue.

Frequency specific impairment of automatic pitch change detection by fMRI acoustic noise: an MEG study.

The loud acoustic noise produced by the magnetic resonance scanner is a major source of interference in auditory fMRI research. Whole-head magnetoencephalography (MEG) was used to investigate the interaction between the frequency range of auditory stimulation and fMRI acoustic noise. Pure tones and 3-harmonic complexes varying between 240 and 1240 Hz in frequency were presented while participants attended to a silent subtitled film. Continuous fMRI acoustic noise was presented during half of the blocks. The activity in six regions of interest was analyzed in 100-200 and 200-300 ms time windows to evaluate the magnetic counterparts of the mismatch negativity (MMN) and P3a brain responses. The results suggested that fMRI noise significantly reduced the amplitude of these responses. The effect of the noise on the automatic processing of the tones was more prominent for the tones with frequencies higher than 500 Hz. It is recommended that in the MMN protocols using continuous fMRI acquisition the sound stimuli should be spectrally separated from the fMRI scanner noise spectrum.

Auditory sensory memory disorder in dyslexic adults as indexed by the mismatch negativity.

Deficient temporal discrimination and vulnerability to masking effects caused by rapidly succeeding or simultaneous sounds might be one factor underlying the phonological difficulties in dyslexia. We evaluated cortical auditory discrimination in dyslexia by recording the mismatch negativity (MMN) for a simple pitch change, for an order reversal of tone pairs, and for tone-pair order reversals, with a third tone either preceding or following the tone pairs. It was found that when an additional tone followed the pairs the MMN amplitude was attenuated, suggesting elevated backward-masking effects in the auditory cortex of dyslexic individuals. In addition, the MMN elicited by pitch change was diminished over the left hemisphere of the dyslexic individuals suggesting left hemisphere auditory dysfunction. These results suggest impaired cortical discrimination of sounds and lowered tolerance for the masking effects of rapidly following sounds in dyslexia.

Are different kinds of acoustic features processed differently for speech and non-speech sounds?

This study examined how changes in different types of acoustic features are processed in the brain for both speech and non-speech sounds. Event-related potentials (ERPs) were recorded in native Finnish speakers presented with sequences of repetitive vowels (/e/) or complex harmonical tones interspersed with infrequent changes in duration, frequency and either a vowel change (/o/ for vowel sequences) or a double deviant (frequency+duration change for tone sequences). The stimuli were presented monaurally in separate blocks to either the left or right ear. The results showed that speech stimuli were more efficiently processed than harmonical tones as reflected by an enhanced mismatch negativity (MMN) and P3a ERP components. In addition, the duration change in vowels elicited a larger MMN component than the equivalent change in tones. This result might reflect enhanced processing of duration features in the Finnish language in which phoneme duration plays a critical role.

Superior formation of cortical memory traces for melodic patterns in musicians.

The human central auditory system has a remarkable ability to establish memory traces for invariant features in the acoustic environment despite continual acoustic variations in the sounds heard. By recording the memory-related mismatch negativity (MMN) component of the auditory electric and magnetic brain responses as well as behavioral performance, we investigated how subjects learn to discriminate changes in a melodic pattern presented at several frequency levels. In addition, we explored whether musical expertise facilitates this learning. Our data show that especially musicians who perform music primarily without a score learn easily to detect contour changes in a melodic pattern presented at variable frequency levels. After learning, their auditory cortex detects these changes even when their attention is directed away from the sounds. The present results thus show that, after perceptual learning during attentive listening has taken place, changes in a highly complex auditory pattern can be detected automatically by the human auditory cortex and, further, that this process is facilitated by musical expertise.

The mismatch negativity as an index of temporal processing in audition.

OBJECTIVES: The relation of the mismatch negativity (MMN) elicitation with behavioral stimulus discrimination as well as the replicability of the MMN was evaluated for intervals between paired tones. METHODS: The MMN, obtained in a passive oddball paradigm in two sessions separated by 4-21 days and behavioral responses (button presses to target stimuli) in a separate session were recorded from 10 adult healthy subjects. The standard stimulus (P=0.79) was a tone pair separated by a 120 ms silent inter-stimulus interval (ISI) and the deviant stimuli were tone pairs with an ISI of 100, 60, and 20 ms (P=0.07 for each). RESULTS: The 20 and 60 ms ISI deviant tone pairs elicited a significant MMN during both recording sessions and they were also behaviorally discriminated, whereas neither did the 100 ms ISI deviant pair elicit significant MMN nor was it behaviorally discriminated. Furthermore, there was a significant correlation between the MMN and reaction times to the 20 and 60 ms ISI deviant pairs. The 20 ms ISI deviant stimulus elicited highly replicable MMNs (r=0.75), whereas the less well discriminated 60 ms ISI deviant pair did not (r=0.60). CONCLUSIONS: The MMN reflects discrimination accuracy of temporal sound intervals. Furthermore, when the physical difference between the standard and deviant tone pair in the temporal domain is large, it is elicited with high reliability.

Automatic discriminative sensitivity inside temporal window of sensory memory as a function of time.

Neural representation of preceding sound-patterns stored in the human brain, as reflected by mismatch negativity (MMN) related to the automatic discriminative process, is restricted to a duration of 160-170 ms due to the short form of auditory sensory memory termed the temporal window of integration (TWI). To examine the temporal uniformity of deviation-sensitivity inside TWI of sensory memory, magnetic MMN (MMNm) responses were measured with a dual 37-channel magnetometer for complex sounds of 170 ms duration containing an omitted (silent) segment. Frequent standard stimuli (probability of 80%) consisted of five tone segments. Deviant stimuli were different from standard stimuli in that one of four segments was occasionally (probability of 5%) omitted and replaced by a silent segment. The stimulus duration of 170 ms was intended to correspond to the postulated duration of TWI. When the silent segment occurred later in deviant stimulus, the MMNm peak amplitude was attenuated and MMNm peak latency, measured from the onset of each silent segment, was delayed. Thus, automatic deviation-detection sensitivity declines nonlinearly toward the end of TWI in auditory sensory memory. In the second experiment, two types of deviant stimuli, which differed from each other only in the period after the occurrence of the silent segment, elicited MMNm with the same peak latency but with a different peak amplitude. Thus, mismatch process is triggered at the moment of change but still lasts after the detection of deviation. In other words, both standard and deviant stimuli are treated as a unitary event within a TWI.