The purpose of the present study was to examine the ability of musicians to preattentively process musical and phonemic information, as assessed by event-related potentials (ERPs), compared with nonmusicians. Participants were musicians (N=22; at least 10 years of formal training) and nonmusicians (N=22; no musical training) from the Virginia Tech community. Participants focused on a video and were instructed to ignore auditory stimuli. Simultaneous to the video presentation, auditory stimuli (60dB) in an oddball paradigm (80% standard, 20% deviant) were presented in 4 conditions (500 stimuli each): chord, phoneme, chord interval, and tone interval. EEG was recorded during each condition. The mismatch negativity (MMN) was identified by subtracting ERPs to standard auditory stimuli from ERPs to deviant auditory stimuli for each of the four qualitatively different conditions. Superior preattentive auditory processing in musicians was found most obviously during the presentation of chords, with no evidence of such superiority during phonemic processing and interval processing. As predicted, during the tone interval condition, musicians had a greater MMN peak amplitude in the central region, and had a greater MMN mean amplitude in the anterior frontal, frontal, frontocentral, and central regions. Contrary to the hypothesis, this did not emerge in the chord, phoneme, or chord interval conditions. As predicted, the MMN latency was shorter for musicians than nonmusicians in the frontocentral region during the phoneme condition. Contrary to the hypothesis, this did not emerge in the chord, chord interval, or tone interval conditions. Differential hemisphere effects were found between groups for MMN latency in the phoneme condition but not the others. Contrary to the hypotheses, no differences were found for MMN amplitude. As predicted, and consistent with Koelsch et al. (1999), musicians were more likely to exhibit an MMN than nonmusicians in the chord condition. Finally, there was the expected stronger preattentive processing in the right hemisphere MMN for the musical stimuli. Contrary to the literature, there was an unexpected stronger right hemisphere bias for phonemic stimuli. / Master of Science

Machine Learning for Analysis of Brain Signals / Event-Related Potential (ERP) measures derived from the electroencephalogram (EEG) have been widely used in outcome prediction of brain disorders. Recently, the ERPs that are transient (EEG) responses to auditory, visual, or tactile stimuli, have been introduced as useful predictors of a positive coma outcome (i.e. emergence from coma). In this study, machine learning techniques were applied for detecting the Mismatch Negativity (MMN) component, which is a transient EEG response to auditory stimuli, and its existence has a high correlation with coma awakening, through analyzing ERPs signals recorded from healthy control brain signals. To this end, two different dimensionality reduction methods, Localized Feature Selection (LFS) and minimum-redundancy maximum-relevance (mRMR) were employed, where a localized classifier and the support vector machine (SVM) with radial basis function (RBF) kernel are used as classifiers. We trained both LFS and mRMR algorithms using signals of healthy brains and evaluated their performance for MMN detection on both healthy subjects and coma patients. The evaluation on healthy subjects, using leave-one-subject-out cross-validation technique, shows the detection accuracy performance of 86.6% (using LFS) and 86.5% (using mRMR). In addition to analyzing brain signals for MMN detection, we also implemented a machine learning algorithm for discriminating healthy subjects from those who have experienced TBI. The EEG signals used in the TBI study were recorded using an ERP paradigm. However, we treated the recorded signals as resting state signals. To this end, we used the mRMR feature selection method and fed the selected features into the SVM classifier that outputs the estimated class labels. This method gives us a poor performance compared to the methods that directly used ERP components (without considering them as resting signals.). We conclude that our hypothesis of treating ERP data as resting data is not valid for TBI detection. / Thesis / Master of Applied Science (MASc)

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Tyrimo metu Sukeltųjų potencialų metodu buvo ištirti 8 šizofrenija sergantys asmenys bei 8 sveiki kontroliniai asmenys. Dažnio ir trukmės nesutapimo negatyvumo (MMN) potencialai pacientams buvo registruoti prieš, 2 savaitės po, ir 4 savaitės po Kvetiapino vartojimo. Rezultatai neparodė statistiškai reikšmingo MMN skirtumo nei MMN amplitudėje nei latensijoje. Taip pat, neaptikta statistiškai reikšmingų koreliacijų tarp PANSS skalės rezultatų pokyčių bei MMN pokyčių. Vidutinėse MMN amplitudziu vertėse, bei individualiuose bandymuose, galima įžvelgti tendenciją: MMN amplitudės deficitas dar labiau padidėja po 2 savaičių Kvetiapino vartojimo, ir pradeda kilti bei viršija baseline, po 4 savaičių. Tai gali būti adaptacinio periodo indikatorius. Šio tyrimo rezultatai sutampa su anksesniais tyrimais, kurie teigia jog atipiniai antipsichotikai neveikia MMN parametrų. Tačiau, turint omenyje stebimas tendencijas, būtų tikslinga tyrimą pakartoti su didesniu stebėjimo periodu bei tiriamųjų apimtimi. / 8 Shizophrenic patients and 8 healthy controls patients were inspected by evoked potential method in order to evaluate Quetiapine effects to MMN potential. Patients were examined before, 2 weeks and 4 weeks after Quetiapine treatment. MMN frequency and duration potentials were registered and analised. The results shows no significant MMN difference neither in MMN amplitude nor in latency. Foremore, no significant corellations between PANSS scale results and MMN differences were found. One could observe tendency of MMN amplitude's deficit to increase after two weeks of treatments, and reduce after 4 weeks, in most electrodes surpassing baseline values. This tendency occures at grand averange MMN's as well as at single trials. The decrease in amplitude after 2 weeks could be the indication of antipsychotic treatment adaptation period, after this period amplitude starts to increase. In conclusion, reseach results goes inline with previously observed atypic antipsychotic effects on MMN. Concidering the tendencties observed, it is reccomended to repeat the experiment with longer period of Quetiapine treatment.

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Le sommeil est défini comme un état comportemental de repos où nous perdons conscience de notre environnement et notre réactivité aux stimuli extérieurs est drastiquement réduite. Pourtant, lorsque nous dormons, l’appel par notre prénom ou à la sonnerie du réveil peuvent encore nous réveiller, suggérant qu’un certain degré de traitement des stimuli reste possible. Dans ce travail, nous soulevons la question de la profondeur du traitement de l’information extérieure pendant le sommeil. Nous avons enregistré simultanément l’activité cérébrale de sujets sains adultes en électro- et magnéto-encéphalographie (EEG et MEG) en réponse à des stimulations auditives, avant, pendant, et après une courte période de sommeil. Afin de tester la profondeur du traitement de l’information à travers la hiérarchie corticale, nous nous sommes concentrés sur les capacités de codage prédictif hiérarchique, qui permettent au cerveau d’anticiper les évènements futurs à partir d’une connaissance passée. Les prédictions sont faites à de nombreuses si ce n’est toutes les étapes de la hiérarchie corticale. Tester les différents niveaux de prédiction nous permet donc d’évaluer précisément à quel niveau l’intégration de l’information est interrompue. Nous avons d’abord testé les capacités du cerveau à détecter la nouveauté auditive. Nous avons présenté aux sujets des séquences de sons comprenant des régularités temporelles à courte (locale) ou à longue (globale) échelle de temps, et analysé les réponses cérébrales à des sons violant ces régularités. Les réponses cérébrales à ces violations locales ou globales se traduisent respectivement en EEG à l’éveil par l’émergence de deux signaux d’erreur de prédiction : la négativité de mismatch (MMN) et la P300. Notre analyse révèle que la MMN et la P300 disparaissent toutes deux dans le sommeil avec la perte des activations des aires associatives préfrontales et pariétales. Au cours de l’endormissement, la MMN diminue progressivement, tandis que la P300 disparait brutalement avec la perte de conscience des stimuli. Ce comportement tout-ou-rien renforce l’hypothèse que la P300 est un marqueur de la conscience. Malgré tout, nous avons montré que le cerveau détecte toujours les nouveaux sons et peut s’y habituer, mais seulement dans un contexte limité d’adaptation sensorielle de bas niveau. Après avoir démontré la perte des capacités de codage prédictif dans le sommeil dans le cadre de régularités statistiques arbitraires et nouvellement acquises, dans une deuxième série d’expériences nous avons testé la capacité du cerveau endormi à établir des prédictions sur les sons à venir dans le cadre de connaissances sémantiques connues déjà stockées en mémoire à long terme. Nous avons présenté à des sujets endormis des opérations arithmétiques simples, comme “deux plus deux égal neuf”, et nous avons enregistré les réponses cérébrales aux résultats corrects et aux résultats faux. Nous avons découvert que le cerveau était toujours capable de détecter les violations arithmétiques dans le sommeil, avec des activations en partie similaires à celles de l’éveil. Nous suggérons que, bien que le sommeil prévienne tout calcul explicite, il y a conservation des signaux d’erreur de prédiction pour les opérations arithmétiques simple déjà mémorisées. Ce travail clarifie à quel niveau l’intégration de l’information auditive est interrompue pendant le sommeil, et quelles fonctions cognitives persistent ou s’altèrent. La persistance de l’adaptation sensorielle et des capacités de prédiction à partir de connaissances déjà mémorisées sont probablement responsables de la réactivité résiduelle qui peut être observée pendant le sommeil alors que les sujets sont inconscients. Finalement, ces résultats aident aussi à mieux comprendre pourquoi un stimulus donné sera traité ou non dans le sommeil. (...) / Sleep can be defined as a behavioral state of rest in which consciousness of external stimuli vanishes and responsiveness to the environment is drastically reduced. When we sleep, however, we may still react and wake up to our name or to the alarm clock, suggesting that some processing of external stimuli remains. We address in the present work the question of how deeply external information is processed during sleep. We recorded brain activity in adult human subjects simultaneously in electro and magnetoencephalography (EEG and MEG) in response to auditory stimulation, before, during and after a short period of sleep. In order to test information integration through the brain hierarchy, we focused on hierarchical predictive coding capabilities, which enable the brain to anticipate the future from previous knowledge. Predictions occur at many if not all steps of the cortical hierarchy. Testing different levels of predictions enables us to assess the steps at which information integration is disrupted during sleep. We first tested the capacity of the sleeping brain to detect auditory novelty. We analyzed brain responses to violations of local and global temporal regularities, which are respectively reflected in EEG during wakefulness by two successive prediction error signals, the mismatch negativity (MMN) and the P300. Our analysis revealed that both the MMN and the P300 vanish during sleep, along with the loss of activations in prefrontal and parietal associative areas. The MMN gradually decreased in the descent to sleep, whereas the P300 vanished abruptly with the loss of awareness during N1 sleep. This all-or-none behavior strongly reinforces the hypothesis that the P300 is a marker of consciousness. Even so, we showed that sounds still activate sensory cortices, and that the brain remains able to detect new sounds and to habituate to them, but only in the limited context of sensory adaptation. Having demonstrated the disruption of predictive coding for arbitrary and newly acquired statistical regularities, in a second set of experiments we tested the capacity of the sleeping brain to develop predictions of future auditory stimuli for over-learned semantic knowledge stored in long-term memory. We presented sleeping subjects with simple arithmetic facts such as “two plus two is nine” and recorded brain responses to correct or incorrect results. We discovered that the sleeping brain was still able to detect arithmetic violations, with activations in part similar to wakefulness. We suggest that, although sleep disrupts explicit arithmetic computations, there is a preservation of prediction error signals for arithmetic facts stored in long-term memory. The present work clarifies the steps at which auditory information integration is disrupted during sleep, and which cognitive functions remain or vanish. The preservation of low-level sensory adaptation and of predictions from long term memory may account for the residual responsiveness that can be observed during sleep, while subjects are unconscious. Finally, these results also help to better understand why a given stimulus may or may not be processed during sleep. The depth of information integration is function of the ongoing spontaneous oscillations of the sleeping brain, but also of the nature of the stimulus, i.e. its salience, its knowledge, and its relevance.

Research Doctorate - Doctor of Philosophy / It is well established that there are changes in cognition and in peripheral sensory mechanisms that occur with age. However, there is much less known about the cause of either change or indeed the relationship between age-related change in sensory processing and age-associated cognitive decline. Understanding these mechanisms could improve our capacity to devise strategies which could assist older adults in aging successfully. In this thesis, I aim to bridge a gap in our knowledge concerning the relationship between age-related change in sensory processing and age-associated cognitive decline by studying the effect of age on what can be considered an intermediary process, sensory memory (in the auditory modality). I continue this line of research by examining the relationship between auditory sensory memory and other types of memory for auditory information in young and older adults. To address these goals, I adopted a cognitive neuroscience approach, relating electrophysiological data to data derived from behavioural memory assessments. In the following thesis, I present a literature review, four studies, and a general discussion of results. Several waveforms of the auditory event-related potential (ERP), including N1, P2, repetition positivity (RP), and mismatch negativity (MMN) were studied. More specifically, in study 1, we looked at the effect of age on N1 and P2 amplitude. In study 2, we examined the conditions eliciting two repetition effects, RP and the MMN memory trace effect, in the auditory ERP of young adults. Studies 3 and 4 concerned the effect of age on RP and the relationship between RP and implicit memory for contextual information as well as explicit memory for auditory information. We concluded that i) age affects auditory sensory memory, ii) the potential relationship between auditory sensory memory and implicit memory for auditory information requires re-investigation, and iii) there is a relationship between auditory sensory memory and explicit memory for auditory information that is altered with age. That is, we concluded that RP occurring in the N1/P2 and MMN latency period indicates memory trace formation and that age affects RP amplitude (restricted to an anterior RP generator). In addition, we showed that RP may be related to implicit memory (priming) in both young and older adults. Across two studies, we found a positive correlation between the response to repetition in the ERP (due to RP activity) and explicit auditory verbal memory in young adults but a negative correlation in older adults. Therefore, although age-related change in RP could reflect the capacity of older adults to encode the context of auditory stimulation, this is potentially due to compensatory activity. We argue it is possible that implicit memory changes with age as a result of age-related change in explicit episodic memory. As a result of well established changes that occur in episodic memory with age, older adults may begin to rely on implicit memory as a source of memory more so than young adults. Our data shows that the implicit memory system may, as a result, favour content over contextual information. An important theme outlined in the discussion of results involves the idea that age-related changes in cognition that are commonly interpreted as cognitive deficits may in fact be beneficial in certain circumstances. We review our results in relation to cognitive theories of aging and find that several theories are applicable to the data, including the frontal hypothesis (incorporating the inhibitory deficit hypothesis), the information degradation hypothesis, and the speed of processing hypothesis. Future research in this area could focus on exploring whether top-down or bottom-up or influences primarily contribute to the age effect on auditory sensory memory and RP, as well as evaluating our hypothesis that the age-related change in RP may be beneficial for explicit item memory but detrimental for implicit contextual memory in older adults (i.e. compensatory mechanisms). While the studies presented in this thesis have provided the foundations guiding our understanding of these issues, researchers in the field of cognitive neuroscience are well equipped to resolve such questions in the future.

Traditional antidepressants, which act on the serotonin, dopamine, and norepinephrine systems, require many weeks to produce a therapeutic effect and are not effective for every patient. A sub-anesthetic dose of the anesthetic agent ketamine, a glutamate N-methyl-D-aspartate receptor antagonist, has been shown to produce a rapid and robust antidepressant effect in treatment-resistant major depressive disorder (MDD). As depressive symptoms typically return after one week following a single infusion, recent work has begun to focus on methods for prolonging the effects. Repeated infusions on a specific dosing schedule are being explored, however, the early identification of treatment responders and non-responders would be beneficial for optimized treatment selection within this population. The mechanisms underlying ketamine’s rapid effects conceivably involve the regulation of altered glutamatergic signaling in MDD, though this is not yet completely understood. Understanding of the central mechanisms mediating ketamine’s rapid antidepressant effects may be increased through the use of non-invasive electroencephalographic measures, including resting electroencephalography (EEG) and the mismatch negativity (MMN) event-related potential. These measures have been shown to be altered in depressed individuals and are sensitive to ketamine administration. The primary objectives of this study were to 1) examine acute changes in EEG- and MMN-derived indices, immediately post- and two hours postinfusion, with a sub-anesthetic ketamine dose in comparison to an active placebo (midazolam), and 2) to examine their relationships with early and sustained antidepressant treatment response to ketamine within an eight week clinical trial involving three study phases. Ketamine decreased measures of scalp-level alpha and theta resting activity, immediately postinfusion, and increased gamma immediately and two hours postinfusion. An increase in source-localized anterior cingulate activity two hours postinfusion was also observed. Regarding the MMN, ketamine reduced frontal amplitudes as well as theta event-related oscillations and source-localized peak frontal generator activity. Measures of resting theta and change in gamma, as well as left frontal MMN amplitude, theta event-related oscillations, baseline left phase locking factor, and baseline right inferior temporal lobe activity were predictive of decreases in depressive symptoms at both early and sustained treatment time points. Alpha power was predictive of decrease in suicidal ideation, though the relationship with baseline and early change in symptoms was stronger. These findings contribute to our understanding of the role of baseline and ketamine-induced changes in both resting and task-evoked electrophysiological measures, and may have the potential to act as non-invasive biomarkers of antidepressant response prediction to glutamatergic agents.

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Timing, and ergo rhythm, are intrinsic features of language that help facilitate real-time speech comprehension. However, work exploring how variable timing is processed in speech is limited. This dissertation addresses this gap in literature by exploring the tenets of how temporal variability is cognitively processed, particularly in the context of real-time stimulus processing. This research is one of the first works to examine temporal variations in linguistic and other acoustically complex contexts. Using electroencephalography (EEG) and behavioural methods, participants were tested on their perception of temporal variations within a continuous stream of either simple tones, complex waves, or syllables. Two timing deviants were presented that occurred early or late compared to other stimuli in the sequence. Event-related potentials (ERPs) were recorded for each stimulus type across three experiments. A fourth experiment tested participant recognition memory for syllable order. Results showed differential processing between the two timing deviants. Unexpectedly earlier tokens elicited larger pre-attentive responses compared to late, suggesting a saliency for the earlier tokens that was not present for the delayed ones. This pattern was observed across all three levels of acoustic and linguistic complexity. Compared to sequences with no timing deviants or an early timing deviant, unexpectedly late tokens were more detrimental to memory, suggesting a negative impact of delays on verbal recognition. Thus, not only were early and late timing variations processed differently, but delays in continuous sequences were also more cognitively taxing for working memory. The results reported in this dissertation contribute to existing knowledge by enriching our understanding of the fundamentals of how aspects of prosodic timing may affect attention and memory. Additionally, it provides new insights into how speech synthesis can be used in neurolinguistic research by tracking how neurophysiological responses change with increasing acoustic complexity and linguistic familiarity. / Dissertation / Doctor of Philosophy (PhD) / This thesis examines how unexpectedly shorter or longer pauses in speech may affect speech comprehension. Specifically, the research reported here examined how stimuli that are presented unexpectedly early or unexpectedly late in a steady-rate sequence impact a listener’s attention and memory. Although the speed at which we speak has been studied previously, work on unexpected changes in its timing has been limited. This research begins to explore this aspect of speech processing. It contributes to our understanding of how speech timing is processed in two important ways. First, we found that unexpected delays in both non-linguistic sounds and syllables were less noticeable than unexpectedly early presentations, when participants were not required to pay attention to them. Second, we found that unexpected delays made recognition memory for stimulus order worse. Overall, the results of these studies indicate that unexpected delays in the rhythm of speech make it more difficult to understand.