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.

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.

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.

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.

"Primitive intelligence" in the auditory cortex.

The everyday auditory environment consists of multiple simultaneously active sources with overlapping temporal and spectral acoustic properties. Despite the seemingly chaotic composite signal impinging on our ears, the resulting perception is of an orderly "auditory scene" that is organized according to sources and auditory events, allowing us to select messages easily, recognize familiar sound patterns, and distinguish deviant or novel ones. Recent data suggest that these perceptual achievements are mainly based on processes of a cognitive nature ("sensory intelligence") in the auditory cortex. Even higher cognitive processes than previously thought, such as those that organize the auditory input, extract the common invariant patterns shared by a number of acoustically varying sounds, or anticipate the auditory events of the immediate future, occur at the level of sensory cortex (even when attention is not directed towards the sensory input).

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.

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.

Musical sound processing in the human brain. Evidence from electric and magnetic recordings.

Recently, our knowledge regarding the brain's ability to represent invariant features of musical information even during the performance of a simultaneous task (unrelated to the sounds) has accumulated rapidly. Recordings of the change-specific mismatch negativity component of event-related brain potentials have shown that temporally and spectrally complex sounds as well as their relations are automatically processed by human auditory cortex. Furthermore, recent magnetoencephalographic and positron emission topographic investigations indicate that this processing differs between phonetic and musical sounds within and between the cerebral hemispheres. These data thus suggest that despite the focus of listeners' conscious attention, relatively complex sound phenomena can be encoded by neural mechanisms that are specialized for musical sounds.

Preattentive periodicity detection in auditory patterns as governed by time and intensity information.

The present study demonstrated that the mismatch negativity (MMN), generated by the brain's preattentive detection of a sound change, is elicited by infrequent reversals of two consecutive tones differing in intensity. When tones were presented in a pairwise manner, the MMN was time-locked to the onset of the intensity reversal. When the tones were continuously presented, the MMN was elicited by an irregular loud tone succeeding a regular loud tone but not by an irregular soft tone following a regular soft tone. Results suggest that the preattentive construction of auditory units is primarily governed by the timing of tone presentation but that it may also utilize intensity information, when no sufficient timing information is available.

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.

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.

Selective tuning of the left and right auditory cortices during spatially directed attention.

Effects of spatially directed auditory attention on human brain activity, as indicated by changes in regional cerebral blood flow (rCBF), were measured with positron emission tomography (PET). Subjects attended to left-ear tones, right-ear tones, or foveal visual stimuli presented at rapid rates in three concurrent stimulus sequences. It was found that attending selectively to the right-ear input activated the auditory cortex predominantly in the left hemisphere and vice versa. This selective tuning of the left and right auditory cortices according to the direction of attention was presumably controlled by executive attention mechanisms of the frontal cortex, where enhanced activation during auditory attention was also observed.

Neural representations of abstract stimulus features in the human brain as reflected by the mismatch negativity.

Neural sensory-memory representations that encode physical properties of incoming stimuli can be probed by recording the change-specific mismatch negativity of the event-related potential (ERP). The present study was aimed at determining whether invariant stimulus features, abstracted from the continuously changing acoustic environment, are encoded in these sensory-memory representations. Regularly descending tone sequences with an occasional ascending tone or tone repetition were presented to reading subjects. A significant MMN was elicited by the ascending tones. When instead of simple tones, Shepard tones creating an illusion of a continuous pitch decrement were used in the same paradigm, the MMN was elicited by both ascending and repeating tones. It was concluded that besides physical stimulus properties, abstract stimulus features are also encoded in the neural representations of sensory memory.

Pre-attentive categorization of sounds by timbre as revealed by event-related potentials.

Infrequent (10%) pure tones were randomly presented among nine different missing-fundamental tones having the same pitch (10% each) to subjects playing a computer game. MMN (an index of pre-attentive change detection) was elicited by timbre-deviant pure tones with 150 and 500 ms stimulus duration. This suggests that the spectral component of timbre is pre-attentively determined from relatively short (150 ms) acoustic samples. Previous research established that resolving the pitch of the same missing-fundamental tones requires longer (> 150 ms) sounds. Consequently, timbre and pitch are probably determined by separate neural processes. The present results also demonstrate pre-attentive categorization of sounds based on timbre as MMN could only be elicited by the pure tones if their timbre was contrasted with the combined group of the nine standard sounds of qualitatively similar rich timbre.

Neural mechanisms of the octave illusion: electrophysiological evidence for central origin.

The octave illusion is experienced when two simultaneous tones, separated by one octave and presented to the opposite ears, are continuously reversed between the two ears. Subjects consistently report a sequence of alternating single tones: the high tone in the right ear and the low in the left. We wished to determine whether such a complex tone sequence is encoded as it is presented or as it is perceived. This was accomplished by making the tone sequence infrequently correspond to how it is perceived, and recording event-related potentials (ERPs) to these perceptually equivalent but physically different events. The illusion-mimicking tones elicited the mismatch negativity (MMN), a change-specific ERP component with origin in the auditory cortex. This indicates that the stimuli giving rise to the octave illusion are encoded according to their physical rather than perceptual properties. Consequently, the generator of the octave illusion is located beyond the level of the auditory cortex.

Superior pre-attentive auditory processing in musicians.

The present study focuses on influences of long-term experience on auditory processing, providing the first evidence for pre-attentively superior auditory processing in musicians. This was revealed by the brain's automatic change-detection response, which is reflected electrically as the mismatch negativity (MMN) and generated by the operation of sensoric (echoic) memory, the earliest cognitive memory system. Major chords and single tones were presented to both professional violinists and non-musicians under ignore and attend conditions. Slightly impure chords, presented among perfect major chords elicited a distinct MMN in professional musicians, but not in non-musicians. This demonstrates that compared to non-musicians, musicians are superior in pre-attentively extracting more information out of musically relevant stimuli. Since effects of long-term experience on pre-attentive auditory processing have so far been reported for language-specific phonemes only, results indicate that sensory memory mechanisms can be modulated by training on a more general level.

Temporal window of integration revealed by MMN to sound omission.

The central auditory system for event perception involves the integrating mechanism of sequential information addressed by the present study. The mismatch negativity (MMN) component of the event-related potentials (ERP) reflects the automatic detection of sound change. ERPs to occasionally omitted stimuli were measured when sequences with constant stimulus onset asynchronies (SOAs) were presented. In separate blocks, the SOA was from 100 to 350 ms. A clear MMN was elicited by a stimulus omission in a sequence of regularly spaced tone pips only when the SOA was shorter than 150 ms, yielding an estimate for the duration of the temporal window of integration used the perceptual segregation of auditory events.

Representation of abstract attributes of auditory stimuli in the human brain.

Representations of abstract attributes of auditory stimuli in the human brain were demonstrated using the mismatch negativity (MMN), an event-related potential component elicited by a change in a repetitive sound. Stimuli were pairs of sinusoidal tones. There were two types of tone pairs in each block, standard (p = 85%) and deviant pairs (p = 15%), delivered in a random order. Standard and deviant tone pairs differed only in the direction of within-pair frequency change. In addition, the frequency levels of both the standard and deviant pairs varied randomly within a wide range in a block; thus the standard pairs shared the direction of the within-pair frequency change but not the absolute frequency level. Correspondingly, the deviant pairs only shared the opposite direction of the within-pair change. Nevertheless, the deviant tone pairs elicited MMN, implying that even the direction of the within-pair frequency change of the standard stimuli, and not just their absolute frequencies, developed a neural representation.

Development of a memory trace for a complex sound in the human brain.

The development of a memory trace for a complex, unfamiliar sound in the human brain was studied by repeatedly presenting reading subjects with this sound ('standard') which was occasionally replaced by a slightly different sound ('deviant'). Deviants did not elicit the mismatch negativity, an index of automatic change detection in auditory cortex, in the beginning but did later during the session. This result reflects a gradual 'sharpening' of sensory information encoded in the memory trace: the representation of the standard stimulus eventually became precise enough to enable the cortical change-detector mechanism to detect a slight different stimulus.