The objectives of my PhD were to identify the spatial and the temporal dynamics of the brain areas involved in tactile change detection as well as the neural mechanisms responsible for the processing of tactile change detection. To that aim, three specific MEG studies were performed; each of them is addressing specific research aims.The first study investigated the spatiotemporal dynamics of the multilevel cortical processing of tactile change detection in human healthy subjects. This study disclosed a hierarchical organization from unimodal early tactile change detection at secondary somatosensory cortex to multi modal complex processing at bilateral temporo-parietal junctions, posterior parietal cortex and supplementary motor areas. The second study aimed at discriminating between debated neural mechanisms responsible for the genesis of the somatosensory mismatch negativity (sMMN). To do so, we manipulated the predictability of the deviant stimuli and the response to omissions in different kind of oddballs, the response to deviant stimuli paired with standards and occurring alone. We found out that mechanisms for early tactile change detection reflected by the sMMN were better explained by the predictive coding theory compared to the adaptation and adjustment theories. Finally we sought to characterize the alterations in early cortical tactile change detection in Friedreich Ataxia (FRDA); a neurological disorder characterized by somatosensory and cerebellar pathways degeneration. The aim of this work was to study the role of the cerebellum in the genesis of sMMN and its potential selectivity for somatosensory change detection compared to auditory. This study demonstrated that, in FRDA, both tactile and auditory pathways are affected at the level of primary sensory neurons and dorsal root/spiral ganglia in a genetically determined. By contrasts, early cortical sensory change detection in FRDA was impaired only in the tactile modality in line with the sMMN impairment described in patients with acquired cerebellar lesions or during cerebellar inhibition by trans cranial magnetic stimulation. These data brought novel empirical evidence supporting the contribution of spinocerebellar tracts in sMMN genesis at cSII cortex.In conclusion, this PhD contributed to identify the network responsible for tactile change detection that involves cuneocerebellar spinocerebellar tract and cSII cortex as somatosensory specific areas and TPJ, SMA & PPC as multimodal brain areas. We further provided evidence that early change detection mechanisms at SII cortex fall under the predictive coding framework and that change detection is hierarchically organized with inputs from low level areas for genesis of an adequate generative model of our environment and conscious representation of our body. / Doctorat en Sciences médicales (Médecine) / info:eu-repo/semantics/nonPublished

This work concerns the investigation of the neuronal mechanisms at the basis of language acquisition and processing, and the complex interactions of language and attention processes in the human brain. In particular, this research was motivated by two sets of existing neurophysiological data which cannot be reconciled on the basis of current psycholinguistic accounts: on the one hand, the N400, a robust index of lexico-semantic processing which emerges at around 400ms after stimulus onset in attention demanding tasks and is larger for senseless materials (meaningless pseudowords) than for matched meaningful stimuli (words); on the other, the more recent results on the Mismatch Negativity (MMN, latency 100-250ms), an early automatic brain response elicited under distraction which is larger to words than to pseudowords. We asked what the mechanisms underlying these differential neurophysiological responses may be, and whether attention and language processes could interact so as to produce the observed brain responses, having opposite magnitude and different latencies. We also asked questions about the functional nature and anatomical characteristics of the cortical representation of linguistic elements. These questions were addressed by combining neurocomputational techniques and neuroimaging (magneto-encephalography, MEG) experimental methods. Firstly, a neurobiologically realistic neural-network model composed of neuron-like elements (graded response units) was implemented, which closely replicates the neuroanatomical and connectivity features of the main areas of the left perisylvian cortex involved in spoken language processing (i.e., the areas controlling speech output – left inferior-prefrontal cortex, including Broca’s area – and the main sensory input – auditory – areas, located in the left superior-temporal lobe, including Wernicke’s area). Secondly, the model was used to simulate early word acquisition processes by means of a Hebbian correlation learning rule (which reflects known synaptic plasticity mechanisms of the neocortex). The network was “taught” to associate pairs of auditory and articulatory activation patterns, simulating activity due to perception and production of the same speech sound: as a result, neuronal word representations distributed over the different cortical areas of the model emerged. Thirdly, the network was stimulated, in its “auditory cortex”, with either one of the words it had learned, or new, unfamiliar pseudoword patterns, while the availability of attentional resources was modulated by changing the level of non-specific, global cortical inhibition. In this way, the model was able to replicate both the MMN and N400 brain responses by means of a single set of neuroscientifically grounded principles, providing the first mechanistic account, at the cortical-circuit level, for these data. Finally, in order to verify the neurophysiological validity of the model, its crucial predictions were tested in a novel MEG experiment investigating how attention processes modulate event-related brain responses to speech stimuli. Neurophysiological responses to the same words and pseudowords were recorded while the same subjects were asked to attend to the spoken input or ignore it. The experimental results confirmed the model’s predictions; in particular, profound variability of magnetic brain responses to pseudowords but relative stability of activation to words as a function of attention emerged. While the results of the simulations demonstrated that distributed cortical representations for words can spontaneously emerge in the cortex as a result of neuroanatomical structure and synaptic plasticity, the experimental results confirm the validity of the model and provide evidence in support of the existence of such memory circuits in the brain. This work is a first step towards a mechanistic account of cognition in which the basic atoms of cognitive processing (e.g., words, objects, faces) are represented in the brain as discrete and distributed action-perception networks that behave as closed, independent systems.

Transcranial direct current stimulation (tDCS) is a non-invasive form of brain stimulation which uses a very weak constant current to temporarily excite or inhibit activity in the brain area of interest via electrodes placed on the scalp, depending on the polarity and strength of the current. Presently, tDCS is being used as a tool to investigate frontal cognition in healthy controls and to improve symptoms in neurological and psychiatric patients. Relatively little research has been conducted with respect to tDCS and the auditory cortex (AC). The primary aim of this thesis was to elucidate the effects of tDCS on auditory sensory discrimination, assessed with the mismatch negativity (MMN) event-related potential (ERP). In the first pilot study, healthy participants were assessed in a randomized, double-blind, sham-controlled design, in which participants received anodal tDCS over the primary AC (2 mA for 20 minutes) in one session and ‘sham’ stimulation (i.e. no stimulation) in the other. Pitch MMN was found to be enhanced after receiving anodal tDCS, with the effects being evidenced in individuals with relatively low (vs. high) baseline amplitudes. No significant effects were seen with sham stimulation. A second study examined the separate and interacting effects of anodal and cathodal tDCS on MMN measures. MMN was assessed pre- and post-tDCS (2 mA, 20 minutes) in 2 separate sessions, one involving sham stimulation, followed by anodal stimulation, and one involving cathodal stimulation, followed by anodal stimulation. Only anodal tDCS over the AC increased pitch MMN in baseline-stratified groups, and while cathodal tDCS decreased MMN, subsequent anodal stimulation did not significantly alter MMNs. As evidence has shown that tDCS lasting effects may be dependent on N-methyl-D-aspartate (NMDA) receptor activity, a pharmacological study investigated the use of dextromethorphan (DMO), an NMDA antagonist, to assess possible modulation of tDCS’ effects on both MMN and working memory (WM) performance. The study involved four test sessions that compared pre- and post-anodal tDCS over the AC and sham stimulation with both DMO (50 mL) and placebo administration. MMN amplitude increases were only seen with anodal tDCS with placebo administration, not with sham stimulation, nor with DMO administration. In the sham condition, DMO decreased MMN amplitudes. Anodal tDCS improved WM performance in the active drug condition. Findings from this study contribute to the understanding of underlying neurobiological mechanisms mediating tDCS-sensory and memory improvements. As cognitive impairment has been proposed to be the core feature of schizophrenia disorder (Sz) and MMN is a putative biomarker of Sz, a pilot study was conducted to assess the effects of pre- and post-tDCS on MMN measures in 12 Sz patients, as well as WM performance. Temporal, frontal and sham tDCS were applied in separate sessions. Results demonstrated a trend for pitch MMNs to increase with anodal temporal tDCS, which was significant in a subgroup of Sz individuals with auditory hallucinations, who had low MMNs at baseline. Anodal frontal tDCS significantly increased WM performance, which was found to positively correlate with MMN-tDCS effects. The findings contribute to our understanding of tDCS effects for MMN-indexed sensory discrimination and WM performance in healthy participants and individuals with Sz disorder and may have implications for treatment of sensory processing deficits in neuropsychiatric illness.

The present thesis employed event-related potentials, the minute responses of the brain, to examine the differences in processing of increases and decreases in auditory intensity. The manner in which intensity was manipulated (i.e., whether it represented physical or psychological change) varied across the studies of the thesis. Study 1 investigated the processing of physical intensity change during wakefulness and natural sleep. An oddball paradigm (80 dB standard, 90 dB increment, 60 dB decrement) was presented to subjects during the waking state and during sleep. The increment elicited a larger deviant-related negativity and P3a than the decrement in the waking state. During sleep, only the increment deviant continued to elicit ERPs related to the detection of change. The waking and sleeping findings support the notion that increases in intensity are more salient to an observer. Studies 2 and 3 of this thesis determined the degree to which this differential salience could be attributed to the fact that intensity increments result in increased activation of the change and transient detection systems while intensity decrements result in greater activation of only the change detection system. In order to address this question, an alternating intensity pattern was employed (HLHLHLHL) with deviants created by the repetition of a tone in the sequence (HLHLHHHL) that violated the expectancy for a higher (psychological decrements) or lower intensity tone (psychological increments). Because deviant stimuli were physically identical to preceding standards, this manipulation should not have led to increased output of the transient detection system (N1 enhancement), permitting isolation of the output of the change detection system (Mismatch Negativity, MMN). The findings of these studies indicated that psychological increments resulted in shorter latency and larger amplitude MMNs than psychological decrements and that these differences could not be explained by the physical differences between deviant stimuli or temporal integration. This thesis provides convincing evidence that stimuli representing increments in intensity result in faster and more robust change detection. Further, the increased salience of increment stimuli cannot be solely explained by the contribution of transient detector activation, as it persists even when deviance-related processing is isolated to the change detection system.

Previous research indicates that humans develop a phonological library in infancy. As humans grow into adulthood, their phonological library becomes well established. Upon encountering phonemes from a new language, humans process these phonemes by comparison to their native phonological library. Event-related potentials (ERP), specifically the mismatch negativity, have been shown to indicate that this process of comparing non-native phonemes to our native phonological library is not improved through learning the new language as an adult. An alternative explanation may be that there is an underlying change in the neural generators as the non-native phonemes are learned, but that this change is not reflected in the ERP. The current study seeks to examine this hypothesis through the simultaneous collection of ERP and blood-oxygen-level-dependent functional MRI (fMRI) data. The findings of the ERP and fMRI data are inconclusive. The study also explores the processing of diphthongs, a category of phonemes rarely tested before, through both behavioral and neuroimaging methods. The study presents behavioral data demonstrating that non-native diphthongs are processed based upon the separate elements of the phonemes, rather than as complete units.

Hearing loss, as a result of old age, has been linked to a decline in speech perception despite the use of additional listening devices. Even though the relationship between hearing loss and decreased speech perception has been well established, research in this area has often focused on the behavioral aspects of language and not on the functionality of the brain itself. In the present study, the mismatch negativity, an event related potential, was examined in order to determine the differences in speech perception between young adult participants, geriatric normal hearing participants, and geriatric hearing-impaired participants. It was hypothesized that a significantly weaker mismatch negativity would occur in the geriatric hearing-impaired participants when compared to the young adult participants and the geriatric normal hearing participants. A passive same/different discrimination task was administered to 10 young adult controls (5 male, 5 female) and eight older adult participants with and without hearing loss (4 male, 4 female). Data from behavioral responses and event related potentials were recorded from 64 electrodes placed across the scalp. Results demonstrated that the mismatch negativity occurred at various amplitudes across all participants tested; however, an increased latency in the presence of the mismatch negativity was noted for the geriatric normal hearing and the geriatric hearing-impaired participants. Dipoles reconstructed from temporal event related potential data were located in the cortical areas known to be instrumental in auditory and language processing for the young adult participants; however, within the geriatric normal hearing and the geriatric hearing-impaired participants, dipoles were seen in multiple locations not directly associated with language and auditory processing. Although not conclusive, it appears that within the geriatric normal hearing and the geriatric hearing-impaired participants there is slower processing of the speech information, as well as some cognitive confusion which leads to fewer available resources for interpretation.

The infrequent occurrence of a transient feature (deviance; e.g., frequency modulation, FM) in one of the regular occurring sinusoidal tones (standards) elicits the deviance related mismatch negativity (MMN) component of the event-related brain potential. Based on a memory-based comparison, MMN reflects the mismatch between the representations of incoming and standard sounds. The present study investigated to what extent the infrequent exclusion of an FM is detected by the MMN system. For that purpose we measured MMN to deviances that either consisted of the exclusion or inclusion of an FM at an early or late position within the sound that was present or absent, respectively, in the standard. According to the information-content hypothesis, deviance detection relies on the difference in informational content of the deviant relative to that of the standard. As this difference between deviants with FM and standards without FM is the same as in the reversed case, comparable MMNs should be elicited to FM inclusions and exclusions. According to the feature-detector hypothesis, however, the deviance detection depends on the increased activation of feature detectors to additional sound features. Thus, rare exclusions of the FM should elicit no or smaller MMN than FM inclusions. In passive listening condition, MMN was obtained only for the early inclusion, but not for the exclusions nor for the late inclusion of an FM. This asymmetry in automatic deviance detection seems to partly reflect the contribution of feature detectors even though it cannot fully account for the missing MMN to late FM inclusions. Importantly, the behavioral deviance detection performance in the active listening condition did not reveal such an asymmetry, suggesting that the intentional detection of the deviants is based on the difference in informational content. On a more general level, the results partly support the “fresh-afferent” account or an extended memory-comparison based account of MMN.

Tinnitus, or the perception of sound in the absence of external acoustic stimuli, is a common condition that impacts approximately 10-15% of the United States population, with similar prevalence rates reported in other countries. Current diagnosis of tinnitus relies on case history and audiometric testing, which depend on responses provided by the patient. To date, there is no objective test that can be used for tinnitus diagnosis, despite the high prevalence and significant financial impacts of this condition. Cortical auditory evoked potentials have shown promise in their ability to assess not only the integrity of the auditory system, but also higher level preattentional and cognitive processing. For this study, the pitch-matched tinnitus frequency was used to evoke an auditory late response. Double oddball paradigms with the tinnitus frequency as the deviant stimuli were also used to evoke a mismatch negativity and P300 to determine where along the auditory pathway biomarkers of tinnitus may exist. The results of this study suggest that when the tinnitus frequency is incorporated into paradigms designed to produce cortical auditory evoked potentials, differences exist between participants with tinnitus and matched controls without tinnitus. Individuals with tinnitus exhibit smaller MMN amplitudes and area under the curve and have a more parietal distribution in their P300 responses on topographic maps compared to non-tinnitus participants. Evaluation of relationships between perceived tinnitus severity and electrophysiological measures also revealed that P2 latency was a significant predictor of tinnitus severity, with longer latencies indicating greater severity. Findings of this study have clinical implications for test paradigms that may be used in an objective tinnitus test battery and for measures that can predict tinnitus severity.

The human auditory system excels at detecting patterns necessary for processing speech and music. This system is adept at detecting changes to the incoming sounds. According to predictive coding theories, the brain generates hypothesis about what the incoming tone should be, and if the incoming tone does not match the hypothesis, a prediction error response is elicited. This process can be estimated in electroencephalography (EEG) by the mismatch negativity and P3a event related potentials (ERPs) in adults or the mismatch response in infants. It remains unclear is how this system responds to unexpected absence of a sound created by silences. In this thesis, we compared ERPs in adults (Chapter 2) elicited by infrequent sound omissions — i.e. unexpected silences or omission deviants — in various sequences of tones to those elicited by regularly occurring omissions — i.e., expected silences or predictable omissions. We found that unexpected silences elicited both the MMN and P3a, although the magnitude of these components was considerably smaller than we would expected from previous research with omission deviants and auditory deviants. We also found that infants (Chapter 3) exhibited a neural response to omission deviants similar to the mismatch response. Unexpectedly this was not influenced by the global predictability of the omission deviants, which typically attenuates the ERPs to a deviant when it is globally predictable. Adults also showed a lack of difference between globally predictable and globally unpredictable omission deviants (Chapter 4). Furthermore, in adults, we did not find the typical deviance detection ERP responses. Overall, we found evidence of robust neural responses to omission deviants in both adults and infants, but the context in which the omission deviants can change the ERP components elicited. This dissertation is the first to investigate the direct effect of global predictability on the neural responses to omission deviants, as well as 6-month-old infants’ response to omission deviants. / Thesis / Candidate in Philosophy / Often when we expect to hear a sound, instead we “hear” silence or an omission of the sound. This thesis investigates how the brain responds to these unexpected omissions in adults and infants. Unexpected silences elicit a response similar to what we would find after an unexpected change to a sound. This seems to be true for adults and infants as young as 6-months old. Typically, predictable sound changes elicit smaller brain responses. Unlike unexpected sound changes, if the silence occurs predictably in the sequence (e.g., occurs after every 4 tones in a sequence) compared to randomly, or unpredictably, no difference is found. This lack of difference seems to be present in infants and adults. These findings further our understanding of how the brain response to unexpected omissions may not follow the same pattern as the response to unexpected changes of a sound.

Neurological evidence indicates that instrumental musicians experience changes in the auditory system following skill acquisition and sensory training; yet, little is known about auditory neural plasticity in formally trained vocal musicians. Furthermore, auditory pitch discrimination and laryngeal control are recognized as essential skills for vocal musicians; however, the relationship between physiological variables, perceptual abilities, and vocal production is unclear. Electrophysiologic and psychoacoustic measures were used to examine pitch production accuracy as well as pre-attentive and active pitch discrimination between nonmusicians and two classes of musicians. Participants included 40 formally trained musicians (19 vocalists/21 instrumentalists) and 21 nonmusician controls. All were right-handed young adult females with normal hearing. Stimuli were harmonic tone complexes approximating the physical characteristics of piano tones and represented the mid-frequency range of the untrained female vocal register extending from C4 to G4 (F0 = 261.63-392 Hz). Vocal pitch recordings were spectrally analyzed to determine pitch production accuracy. Difference limens for frequency (DLFs) were obtained by an adaptive psychophysical paradigm. Pre-attentive auditory discrimination was assessed by auditory evoked potentials (AEPs), including the mismatch negativity (MMN). A standard tone (G4 = 392 Hz) and three deviants differing in frequency (1.5%, 3%, and 6% below) were presented in a multi-deviant paradigm. All musicians demonstrated superior pitch perception and vocal production compared to nonmusicians. Pitch perception and production accuracy did not significantly differ between vocalists and instrumentalists; however, pitch production accuracy was most consistent within the vocalist group. Music training appears to facilitate both auditory perception and vocal production regardless of music specialty. Pitch perception and production were correlated skills only for instrumental musicians. Vocalists demonstrated minimal variability for both skills so that perception and production were not correlated. These two skills may be independent abilities between which a relationship develops with training. AEP analysis revealed an influence of musical expertise on neural responses as early as 50 ms after onset of musically relevant stimuli. MMN responses indicate that vocal musicians as well as instrumental musicians have superior sensory memory representations for acoustic parameters of harmonic stimuli and imply that auditory neural sensitivity is developed by intense music training.