Post-training load-related changes of auditory working memory: An EEG study

Working memory (WM) refers to the temporary retention and manipulation of information, and its capacity is highly susceptible to training. Yet, the neural mechanisms that allow for increased performance under demanding conditions are not fully understood. We expected that post-training efficiency in WM performance modulates neural processing during high load tasks. We tested this hypothesis, using electroencephalography (EEG) (N = 39), by comparing source space spectral power of healthy adults performing low and high load auditory WM tasks. Prior to the assessment, participants either underwent a modality-specific auditory WM training, or a modality-irrelevant tactile WM training, or were not trained (active control). After a modality-specific training participants showed higher behavioral performance, compared to the control. EEG data analysis revealed general effects of WM load, across all training groups, in the theta-, alpha-, and beta-frequency bands. With increased load theta-band power increased over frontal, and decreased over parietal areas. Centro-parietal alpha-band power and central beta-band power decreased with load. Interestingly, in the high load condition a tendency toward reduced beta-band power in the right medial temporal lobe was observed in the modality-specific WM training group compared to the modality-irrelevant and active control groups. Our finding that WM processing during the high load condition changed after modality-specific WM training, showing reduced beta-band activity in voice-selective regions, possibly indicates a more efficient maintenance of task-relevant stimuli. The general load effects suggest that WM performance at high load demands involves complementary mechanisms, combining a strengthening of task-relevant and a suppression of task-irrelevant processing

Cortical Plasticity following Adult-Onset Hearing Loss

The consequences of hearing loss are not confined to how the central auditory system processes sound; crossmodal plasticity also occurs, which is characterized by an increased responsiveness of neurons in auditory areas to visual and/or tactile stimuli. In the primary auditory cortex, partial hearing loss causes a decrease in the number of auditory-responsive neurons, as well as an increase in multisensory neurons. However, it was relatively unknown how adult-onset hearing loss affected cortical areas that are already capable of integrating multisensory information, such as the lateral extrastriate visual cortex (V2L). Using a combination of in vivo electrophysiology, neuropharmacology and behavioural testing, this thesis investigated the nature and extent that crossmodal plasticity occurs within higher-order sensory cortices, and its perceptual consequences. At the level of single neurons, hearing loss increased the proportion of visually-responsive neurons, and decreased the number of neurons activated by both auditory and visual stimuli in V2L; findings inconsistent with the plasticity observed in the neighbouring dorsal auditory cortex (AuD), where the proportion of multisensory neurons nearly doubled. Subsequent analyses of the microcircuits within these higher-order cortices, revealed a layer-specific enhancement of auditory input (i.e., central gain enhancement) within the granular layer of AuD. In contrast, crossmodal plasticity was evident across multiple cortical layers within V2L, and also manifested in AuD. Despite the extensive plasticity in the higher-order sensory cortices, hearing loss lead to behavioural changes in audiovisual perception, characterized by a rapid recalibration of temporal sensitivity to the audiovisual stimuli. Next, a neurophysiological assessment revealed that adult-onset hearing loss did not cause a loss of temporally-precise audiovisual processing, but rather a shift in the cortical region displaying the capacity for temporal sensitivity. Lastly, using pharmacological manipulations, hearing loss was found to cause a layer-specific enhancement of visual-evoked input within the granular layer of the V2L cortex, indicative of thalamocortical plasticity. Overall, this work demonstrates that adult-onset hearing loss induces plasticity at the level of single neurons, local cortical microcircuits and sensory perception, all of which are associated with a complex assortment of crossmodal and intramodal changes across the layers of higher-order sensory cortices

Cognitive and Neurophysiological Models of Brain Asymmetry

Asymmetry is an inherent characteristic of brain organization in both humans and other vertebrate species, and is evident at the behavioral, neurophysiological, and structural levels. Brain asymmetry underlies the organization of several cognitive systems, such as emotion, communication, and spatial processing. Despite this ubiquity of asymmetries in the vertebrate brain, we are only beginning to understand the complex neuronal mechanisms underlying the interaction between hemispheric asymmetries and cognitive systems. Unfortunately, despite the vast number of empirical studies on brain asymmetries, theoretical models that aim to provide mechanistic explanations of hemispheric asymmetries are sparse in the field. Therefore, this Special Issue aims to highlight empirically based mechanistic models of brain asymmetry. Overall, six theoretical and four empirical articles were published in the Special Issue, covering a wide range of topics, from human handedness to auditory laterality in bats. Two key challenges for theoretical models of brain asymmetry are the integration of increasingly complex molecular data into testable models, and the creation of theoretical models that are robust and testable across different species

The cognition of non-verbal sound in dementia

A growing body of functional imaging studies provides considerable insight into cortical networks for non-verbal auditory processing. However, determination of the essential cognitive and anatomical components of these networks depends upon the study of damaged brains, and yet, auditory neuropsychology is little studied and poorly understood. Whilst naturally occurring lesions that selectively disrupt auditory processes are rare, increasing evidence suggests that degenerative diseases target functional networks implicated in non-verbal auditory processing. Furthermore, a small but significant auditory neuropsychological literature shows that dementia can lead to impairments of non-verbal sound processing. This thesis comprises a series of studies designed to reveal deficits of non-verbal auditory processing in four distinct dementia syndromes: three variants of primary progressive aphasia (semantic dementia, SD; progressive non-fluent aphasia, PNFA; logopenic aphasia, LPA), and typical Alzheimer’s disease (AD). The first two studies (Chapters 2 and 3) involve the development of two novel non-verbal auditory neuropsychological batteries, including tests to examine perceptual property, apperceptive, and semantic stages of processing; the subsequent use of these batteries reveals syndrome-specific profiles of non-verbal auditory impairment. Next, a detailed psychoacoustic assessment of two single cases (Chapter 4) provides evidence for specific disorders of auditory property and object processing. A further study (Chapter 5) comprises the examination of non-verbal auditory object processing in SD using functional magnetic resonance imaging (fMRI); results suggest that auditory object recognition depends upon a distributed temporo-parietal network involving closely associated mechanisms of perceptual and semantic processing. Finally, novel neuropsychological assessments are used to reveal the selective impairment of auditory scene analysis in AD (Chapter 6). Together, these neuropsychological findings provide novel insights into the organisation of cortical networks for non-verbal auditory cognition

The efficacy of a TrkB monoclonal antibody agonist in preserving the auditory nerve in deafened guinea pigs

The auditory nerve typically degenerates following loss of cochlear hair cells or synapses. In the case of hair cell loss neural degeneration hinders restoration of hearing through a cochlear implant, and in the case of synaptopathy suprathreshold hearing is affected, potentially degrading speech perception in noise. It has been established that neurotrophins such as brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) can mitigate auditory nerve degeneration. Several potential BDNF mimetics have also been investigated for neurotrophic effects in the cochlea. A recent in vitro study showed favorable effects of M3, a TrkB monoclonal antibody agonist, when compared with BDNF. In the present study we set out to examine the effect of M3 on auditory nerve preservation in vivo. Thirty-one guinea pigs were bilaterally deafened, and unilaterally treated with a single 3-µl dose of 7 mg/ml, 0.7 mg/ml M3 or vehicle-only by means of a small gelatin sponge two weeks later. During the experiment and analyses the experimenters were blinded to the three treatment groups. Four weeks after treatment, we assessed the treatment effect (1) histologically, by quantifying survival of SGCs and their peripheral processes (PPs); and (2) electrophysiologically, with two different paradigms of electrically evoked compound action potential (eCAP) recordings shown to be indicative of neural health: single-pulse stimulation with varying inter-phase gap (IPG), and pulse-train stimulation with varying inter-pulse interval. We observed a consistent and significant preservative effect of M3 on SGC survival in the lower basal turn (approximately 40% more survival than in the untreated contralateral cochlea), but also in the upper middle and lower apical turn of the cochlea. This effect was similar for the two treatment groups. Survival of PPs showed a trend similar to that of the SGCs, but was only significantly higher for the highest dose of M3. The protective effect of M3 on SGCs was not reflected in any of the eCAP measures: no statistically significant differences were observed between groups in IPG effect nor between the M3 treatment groups and the control group using the pulse-train stimulation paradigm. In short, while a clear effect of M3 was observed on SGC survival, this was not clearly translated into functional preservation

Tinnitus, biomarkers and quality of life in an older population

Tinnitus is a symptom involving the perception of sound in the ears or head, without a corresponding external acoustic stimulus. It is related to many different conditions and has a major impact on quality of life of the affected person. Currently, its diagnosis and monitoring are based on subjective audiometric and psychometric measures. There are no objective methods for tinnitus identification. In addition, the pathophysiological mechanisms underlying tinnitus remains unknown. The purpose of this thesis was to study the mechanisms underlying tinnitus and their relationship to hearing loss, being that hearing loss is the comorbidity most frequently associated with tinnitus. It also aimed to evaluate the contribution of genetic, audiological and immunological factors to the etiology of tinnitus. For this purpose, systematic reviews (SR) were performed, in order to account the state of art, the perspectives of the patient and their relatives, and previous clinical trials of tinnitus treatments. SRs contributed to the identification of a pool of tinnitus-related complaint domains used by COMIT’ID (Core outcome measures in tinnitus international Delphi) in a 3-round internet-based Delphi survey to identifying core outcome sets (COS), i.e., which complaints related to tinnitus are essential for evaluation in clinical trials. These recommendations are specific to the three main therapeutic modalities: sound, psychological, and pharmacological. In order to contribute to the standardization of tinnitus clinical evaluation and treatment, TINNET, a European network for scientific tinnitus research, was created. Among the different activities carried out in were a systematic review of existing national clinical practice guidelines for the diagnosis and treatment of tinnitus. This review contributed to the development of a multidisciplinary European guideline for tinnitus: diagnosis, evaluation and treatment. This guideline was presented at TINNET final meeting and it is being disseminated widely. Another aim of the present thesis was to review work on somatosensory tinnitus (pathophysiology, diagnosis, treatment and the participation in an international Delphi consensus group on the diagnosis of this subtype of tinnitus), to contribute to a better understanding of this subtype of tinnitus. In order to achieve the objectives of this PhD study, 114 participants aged 55 to 75 years were recruited from the Portuguese population. Participants were divided into four groups according to the presence/absence of tinnitus and hearing loss. The completion of the study protocol gave rise to four original research articles, including a demographic characterization, relevant psychological and quality of life aspects comparing the studied population and the published literature, audiologic markers of tinnitus, and immunological profile of population and biomarkers of presbycusis and tinnitus. The results point to hearing loss as a risk factor for the development of tinnitus and psychological complaints as a risk factor for more severe tinnitus and consequently less quality of life in patients with this symptom. In characterizing audiological markers, the presence of previous noise exposure and the hearing loss increased the probability of developing tinnitus. Also, participants with an abrupt onset of tinnitus and who had a negative effect or rebound on residual inhibition were more likely to develop severe or catastrophic tinnitus. For the population with tinnitus, a reduction in amplitude of auditory evoked potentials wave I and a higher values in the 'Ratio of Waves V/I for both ears' were associated with a greater probability of developing severe or catastrophic tinnitus. The inflammatory profile of the study population showed significant differences in IL10 levels between the group with and without tinnitus. IL1α was significantly higher in patients with tonal tinnitus, while IL2 was higher in participants who reported negative or rebound effect on residual inhibition of tinnitus. A negative correlation was also found between IL10 and tinnitus duration, and between HSP70 and tinnitus intensity. Biomarkers were explored in this thesis. A systematic review was performed to synthesize evidence for the existence and clinical usefulness of biomarkers. GRM7 and NAT2 were evaluated in the thesis population. The results indicate a higher prevalence of the T allele in the GRM7 gene (60.3% T/T and 33.3% A/T). Participants with a T/T genotype appeared to be at a higher risk for ARHL development, and 33% have a lower risk of developing tinnitus compared to participants with A/A and A/T genotype. Regarding the NAT2 phenotype, the slow acetylator (53%) was most common, followed by the intermediate acetylator (35.9%). These results suggest that the AT allele of GRM7 and the slow acetylating phenotype of Nat2 are potential biomarkers of tinnitus severity. The results in this thesis are very interesting and original, showing us the need for future research in larger samples, and employing rigorous methodological design in order to control for confounding variables. On the other hand, translational studies may be the key to clarifying the pathophysiologic dilemmas of tinnitus.O acufeno é um sintoma referente à perceção de um som nos ouvidos ou na cabeça, sem que exista um estímulo acústico externo correspondente. Está presente em diferentes patologias (otológicas ou não) e tem um impacto importante na qualidade de vida da pessoa afetada. Atualmente, o seu diagnóstico e monitorização são baseados em medidas subjetivas audiométricas e psicométricas, sendo que não existem métodos objetivos para a identificação do acufeno. Além disso, os mecanismos fisiopatológicos subjacentes ao acufeno subjectivo permanecem desconhecidos. O objetivo da presente tese é estudar os mecanismos subjacentes ao acufeno subjectivo e a sua relação com a surdez, visto que a surdez é a co-morbilidade mais frequentemente associada ao acufeno. Pretende-se também avaliar a contribuição dos fatores genéticos, audiológicos e imunológicos na etiologia do acufeno. Para isso, foram realizadas revisões sistemáticas (RS) sobre esta temática de forma a conhecer o estado de arte, primeiramente em relação à forma como os pacientes e os familiares percecionam o acufeno e também sobre os ensaios clínicos existentes acerca da eficácia do tratamento do acufeno. Ambas as RS contribuíram para a identificação de um conjunto de domínios relacionados com o acufeno, usado pelo COMIT’ID (Core outcome measures in tinnitus international Delphi), num método de consensos Delphi, baseado na Internet, com o objetivo de identificar um ‘Core Outcome Set’ (ou seja definir quais as queixas relacionadas com o acufeno que são imprescindíveis para a sua avaliação) recomendado para ensaios clínicos de eficácia terapêutica para o acufeno assim como para o seu diagnóstico. Estas recomendações são específicas para as três modalidades terapêuticas principais: sonora, psicológica e farmacológica uma vez que cada modalidade tem fundamentos específicos e por isso visam avaliar diferentes aspetos do acufeno. Com o objetivo de contribuir para a padronização da avaliação e do tratamento clínico do acufeno, foi constituída a TINNET, uma rede europeia para a investigação científica do acufeno. Considerando o objetivo do presente estudo e a hipótese de integrar esta rede europeia, foram desenvolvidas um conjunto de atividades que em muito contribuíram para o conhecimento sobre o acufenos. Entre as diferentes atividades realizadas com o apoio da TINNET destaca-se a realização de uma revisão sistemática sobre as ‘guidelines’ clínicas existentes para o diagnóstico e tratamento do acufeno. Esta revisão foi uma das bases que conduziu ao desenvolvimento das ‘guidelines’ europeias multidisciplinares para o acufeno: diagnóstico, avaliação e tratamento. Estas ‘guidelines’ foram apresentadas na conferência final do TINNET e estão atualmente em fase de disseminação. Outro foco de interesse da presente tese foi a realização de trabalhos de revisão sobre o acufeno somatosensorial (nomeadamente sobre a fisiopatologia, diagnóstico e tratamento), bem como a participação num grupo de consenso internacional sobre o diagnóstico deste subtipo do acufeno, de forma a contribuir para uma melhor compreensão deste subtipo do acufeno. Também estas atividades contribuíram para o desenvolvimento de competências cientificas essenciais ao desenvolvimento do presente estudo, dado que permitiram uma melhor compreensão deste subtipo do acufeno, demonstrando-se a heterogeneidade e diversidade do acufeno. De forma a alcançar os objetivos deste estudo de doutoramento, recrutaram-se 114 voluntários da população portuguesa com idade dos 55 aos 75 anos. Os indivíduos desta amostra permitiam a realização de diferentes estudos nomeadamente os laboratoriais, tendo a analise dos resultados envolvido a amostra dividida em quatro grupos consoante a presença/ausência do acufeno e de surdez. Dos resultados desta tese fazem parte quatro artigos originais que e incluem uma caracterização demográfica, aspetos relevantes a nível psicológico e de qualidade de vida, marcadores audiológicos do acufeno, perfil imunológico da população e biomarcadores da presbiacusia e do acufeno. Os resultados obtidos sugerem a perda auditiva como fator de risco para o desenvolvimento do acufeno e as queixas a nível psicológico como fator de risco para o acufeno mais grave e consequentemente associado a menor qualidade de vida nos pacientes com este sintoma. A nível da caracterização dos marcadores audiológicos, verificou-se que a presença de antecedentes de exposição ao ruído e a perda auditiva aumentam a probabilidade de desenvolver acufeno. Também, os participantes com um início abrupto do acufeno e que apresentam um efeito negativo ou ‘rebound’ na inibição residual têm maior probabilidade de desenvolver acufeno grave ou catastrófico. Encontrou-se nos Potenciais Evocados Auditivos, uma redução da amplitude na onda I em pacientes com acufeno, bem como valores maiores no ‘Ratio de amplitude das ondas V e I de ambos ouvidos’ estando associados a maiores probabilidades de desenvolver acufeno severo ou catastrófico. O perfil inflamatório da nossa população mostra diferenças significativas entre o grupo com e sem acufeno quando comparados para a IL10. Quanto à relação entre os parâmetros imunológicos e a acufenometria, verificou-se uma correlação entre o aumento da IL1α e acufeno tonal, bem como entre o aumento da IL2 e a inibição residual do acufeno. Foi também encontrada uma correlação negativa para a IL10 e a duração do acufeno e para o HSP70 e a intensidade do acufeno. Estes resultados são muito originais e suscitam a necessidade de estudos futuros que permitam esclarecer os mecanismos subjacentes às correlações encontradas. Em relação aos biomarcadores, foi efetuada uma revisão sistemática com a finalidade de sintetizar evidências para a existência e utilidade clínica dos biomarcadores para o desenvolvimento ou gravidade do acufeno. Foi também realizado um estudo acerca do papel do GRM7 e do NAT2 na nossa amostra. Os resultados apontam para uma maior prevalência do alelo T no gene GRM7 (60,3% T/T e 33,3% A/T). Os participantes com um genótipo T/T parecem ter um maior risco para o desenvolvimento de ARHL e 33% apresentam menor risco para o desenvolvimento do acufeno, em comparação com indivíduos com A/A e genótipo A/T. Em relação ao fenótipo NAT2, o acetilador lento (53%) foi o mais comum seguido pelo intermediário acetilador (35,9%). Os nossos resultados sugerem que o genótipo A/T de GRM7 e o fenótipo acetilador lento de NAT2 como potenciais biomarcadores da severidade do acufeno. Os resultados obtidos são originais e no seu conjunto são muito interessantes, apontando para a necessidade de estudos futuros em larga escala de forma a aprofundar as conclusões aqui obtidas. Por outro lado, os estudos translacionais poderão ser a chave para esclarecer os dilemas da fisiopatologia do acufeno

Nature of crossmodal plasticity in the blind brain and interplay with sight restoration

Thèse réalisée en cotutelle avec l'Université catholique de Louvain.Ce travail de thèse s’est intéressé à la plasticité cérébrale associée à la privation/restauration visuelle. A travers deux études transversales utilisant l’imagerie par résonance magnétique fonctionnelle auprès d’un groupe de participants présentant une cécité congénitale ou précoce (ainsi qu’auprès d’un groupe contrôle de participants voyants), nous avons tenté de caractériser la manière dont le cortex occipital - typiquement dédié au traitement de l’information visuelle - se réorganise afin de traiter différents stimuli auditifs. Nous démontrons qu’en cas de cécité précoce, différentes régions du cortex occipital présentent une préférence fonctionnelle pour certains types de stimuli non-visuels, avec une spécialisation fonctionnelle qui respecte celle de régions typiquement impliquées dans le traitement d’informations similaires en vision. Ces découvertes constituent une avancée conceptuelle concernant le rôle joué par les contraintes intrinsèques d’une part, et par l’expérience d’autre part, dans l’émergence de réponses sensorielles et fonctionnelles du cortex occipital. D’une part, l’observation de réponses occipitales à la stimulation auditive chez le non-voyant précoce (réorganisation transmodale) rend compte de la capacité du cortex occipital à réorienter sa modalité sensorielle préférentielle en fonction de l’expérience. D’autre part, l’existence de modules cognitifs spécialisés dans le cortex occipital du non-voyant précoce, semblables à ceux du cerveau voyant, démontre les contraintes intrinsèques imposées à une telle plasticité. Dans une étude de cas longitudinale, nous avons également exploré comment les changements plastiques associés à la cécité interagissent avec une récupération visuelle partielle à l’âge adulte. Nous avons réalisé des mesures pré et post-opératoires auprès d’un patient ayant récupéré la vision, en combinant les techniques comportementales ainsi que de neuroimagerie fonctionnelle et structurelle afin d’investiguer conjointement l’évolution de la réorganisation transmodale et de la récupération des fonctions visuelles à travers le temps. Nous démontrons que les changements structurels et fonctionnels caractérisant le cortex occipital du non-voyant sont partiellement réversibles suite à une récupération visuelle à l’âge adulte. De manière générale, ces recherches témoignent de l’importante adaptabilité du cortex occipital aux prises avec des changements drastiques dans l’expérience visuelle.The present Ph.D. work was dedicated to the study of experience-dependent brain plasticity associated with visual deprivation/restoration. In two cross-sectional studies involving the use of functional magnetic resonance imaging in a group of participants with congenital or early blindness (and in a control group of sighted participants), we attempted to characterize the way the occipital cortex - typically devoted to vision – reorganizes itself in order to process different auditory stimuli. We demonstrate that in case of early visual deprivation, distinct regions of the occipital cortex display a functional preference for specific non-visual attributes, maintaining a functional specialization similar to the one that characterizes the sighted brain. Such studies have shed new light on the role played by intrinsic constraints on the one side, and experience on the other, in shaping the modality- and functional tuning of the occipital cortex. On the one hand, the observation of occipital responses to auditory stimulation (crossmodal plasticity) highlights the ability of the occipital cortex to reorient its preferential tuning towards the preserved sensory modalities as a function of experience. On the other hand, the observation of specialized cognitive modules in the occipital cortex, similar to those observed in the sighted, highlights the intrinsic constraints imposed to such plasticity. In a longitudinal single-case study, we further explored how the neuroplastic changes associated with blindness may interact with the newly reacquired visual inputs following partial visual restoration in adulthood. We performed both pre- and post-surgery measurements in a sight-recovery patient combining behavioral, neurostructural and neurofunctional methods in order to jointly investigate the evolution of crossmodal reorganization and visual recovery across time. We demonstrate that functional and structural changes evidenced in the visually-deprived occipital cortex can only partially reverse following sight restoration in adulthood. Altogether, our findings demonstrate the striking adaptability of the occipital cortex facing drastic changes in visual experience

Terapias auditivas para acúfenos (tinnitus)

Un acúfeno (tinnitus) es la percepción de un sonido en ausencia de estimulación acústica externa, es decir, la experiencia consciente de un sonido que se origina en la propia cabeza del paciente. En colaboración con el departamento de acústica (CAEND) del Consejo Superior de Investigaciones Científicas (CSIC), se pretende revertir (de forma paliativa) las molestias, con ayuda de terapias sonoras que estimulan el sistema auditivo. Primero, se analizan los tratamientos existentes que se utilizan para atender a los pacientes diagnosticados. Por último, se diseñan dos aplicaciones informáticas referentes a las terapias: Auditory Discrimination Training (ADT) y Enriched Acoustic Environment (EAE). Abstract Tinnitus is the perception of sound in the absence of external acoustic stimulation, in addition, the conscious experience a sound originating from the patient’s own head. In collaboration with the department of acoustic (CAEND) of the Consejo Superior de Investigaciones Científicas (CSIC), is to reverse (for palliation) discomfort, using sound therapies that stimulate the auditory system. First, we analyze the existing treatments are used to treat patients diagnosed. Finally, two applications are designed regarding therapies: Auditory Discrimination Training (ADT) and Enriched Acoustic Environment (EAE)