Top-down and bottom-up neurodynamic evidence in patients with tinnitus

AbstractAlthough a peripheral auditory (bottom-up) deficit is an essential prerequisite for the generation of tinnitus, central cognitive (top-down) impairment has also been shown to be an inherent neuropathological mechanism. Using an auditory oddball paradigm (for top-down analyses) and a passive listening paradigm (for bottom-up analyses) while recording electroencephalograms (EEGs), we investigated whether top-down or bottom-up components were more critical in the neuropathology of tinnitus, independent of peripheral hearing loss. We observed significantly reduced P300 amplitudes (reflecting fundamental cognitive processes such as attention) and evoked theta power (reflecting top-down regulation in memory systems) for target stimuli at the tinnitus frequency of patients with tinnitus but without hearing loss. The contingent negative variation (reflecting top-down expectation of a subsequent event prior to stimulation) and N100 (reflecting auditory bottom-up selective attention) were different between the healthy and patient groups. Interestingly, when tinnitus patients were divided into two subgroups based on their P300 amplitudes, their P170 and N200 components, and annoyance and distress indices to their tinnitus sound were different. EEG theta-band power and its Granger causal neurodynamic results consistently support a double dissociation of these two groups in both top-down and bottom-up tasks. Directed cortical connectivity corroborates that the tinnitus network involves the anterior cingulate and the parahippocampal areas, where higher-order top-down control is generated. Together, our observations provide neurophysiological and neurodynamic evidence revealing a differential engagement of top-down impairment along with deficits in bottom-up processing in patients with tinnitus but without hearing loss

Epidemiological and Evolutionary study of Vestibular Schwannoma after different types of treatment

Over the last couple of decades, the increased availability of magnetic resonance imaging dramatically influenced to the therapeutic approach of vestibular schwannomas (VSs). However, there are few reports about the course of VS patients following conservative management (CM) compared with gamma knife radiosurgery (GKR). In the current study, we present data of 106 unilateral and one bilateral (due to NF2) VS patient controlled CM (67), GKRS (27) and conventional neurosurgery (13). Objectives The main aim of our study was to compare CM and/or the natural course of VS growth with the effects following GKR along with additional treatment and symptom development during the follow-up. We also aimed to evaluate the utility of diagnostic tests and efficiency of CM in case of small VSs

The utility of the auditory brainstem response in children with atypical saccadic eye movements

Full version unavailable due to 3rd party copyright restrictionsLesions in the brainstem result in widespread damage to a number of sensorimotor systems including oculomotor and auditory neural circuits. Although these systems are spatially separate and highly specialised, they are also co-located. This thesis, investigates whether lesions in the oculomotor system will also cause co-morbid dysfunction in the auditory pathways. Specifically, we investigated the usefulness of the Auditory Brainstem Response (ABR) in two oculomotor conditions: slow saccades in Gaucher disease (GD) and opsoclonus in Dancing Eye Syndrome (DES). We present four empirical studies. In our first study we systematically investigated the ABR in GD. We found that multimodal testing can better delineate underlying neurological deficits in neuronopathic GD (nGD) and distinguish between phenotypes. In the second study we examined the ABR's utility as a longitudinal, objective marker of disease burden and in a randomised clinical control trial. ABRs continued to deteriorate regardless of treatment. In our third study we assessed audiological function in DES. We found that at least 43% of DES patients have hyperacusis. We also found subtle abnormalities in the auditory brainstem, as shown by the ABR. Our final study explored the onset-offset response in the ABR and assessed its utility as a clinical marker. Overall, this thesis provides new evidence that auditory pathways are also affected in diseases which are traditionally assumed to be ‘oculomotor’ in nature. We believe that there is sufficient evidence to warrant the inclusion of audiological testing, such as the ABR, as part of the standard assessment of newly diagnosed GD patients and that they undergo these tests prior to commencing treatment. These tests may also have a wider application as longitudinal outcome measures for use in clinical trials or as markers of neurological burden in GD and we believe may be useful in other metabolic diseases; we found that current therapies for GD have low efficacy. Understanding the underlying neurological deficits in these debilitating illnesses can only help to improve treatments and the long-term outlook for these patients

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

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)

Verbal comprehension after brain damage :a psycholinguistic investigation with special reference to cerebro-vascular accident

PhD ThesisA review of theory and practice in the examination of verbal comprehension in brain-dairiaged adults leads to the conclusion that this underdeveloped area of study can benefit from the application of theories from linguistics. An experimental investigation of (principally) adults who had suffered cerebro -vascular accident applied, amoxigst other linguistic theories, the division of language into phonological, syntactic and semantic levels of organization. The main findings were: a) Semantic abilities in speech and comprehension corresponded; syntactic abilities in speech corresponded with those in reading comprehension, but not aural comprehension; comprehension of phonemic distinctions corresponded with phonetic articulatory abilities, but not with degree of phonemic paraphasia. Tests of verbal comprehension which required simple manipulations of-objects or tokens were contaminated by gesture dyspraxia. Functional comprehension was not a reliable predictor of results on linguistic tests. b) Piphasic adults with left-brain damage experienced significantly more difficulties in comprehension when sequence was critical to the meaning of a word or sentence. At the syntactic level this occurred with reading as well as with aural input, indicating a central difficulty rather than one which is modality-specific. in aural comprehension, unlike all types of control subjects including children, aphasic adults found sentences with reversible elements in surface structure harder than sentences in which reversible deep relations are not made explicit in surface structure sequence. Sequencing appears to be a significant influence on verbal comprehension after left-brain damage. c) Right-brain-damaged adults who were not aphasic in speech, and who were familial right-handers, were selectively impaired in semantic comprehension. Semantic comprehension may be bilaterally represented in the brain, although comprehension at syntactic and phonological levels may depend principally on mechanisms lateralized to the left hemisphere.Ridley Fellowship, Newcastle University

The relationship between tinnitus, cognitive performance and demands on the individual

This Thesis attempted to first replicate the work of Andersson et al. (2000) to identify possible cognitive decrements in tinnitus sufferers. In addition, a number of trait variables were measured in comparison to a matched control group. It was discovered that the tinnitus population did not differ in terms of any trait, yet still performed worse on a number of cognitive tasks - performing as accurately, but significantly more slowly. It was thus concluded that the presence of the tinnitus interfered with cognition by consuming valuable and finite attentional resources.A second study attempted to narrow this down further, identifying specific tasks and specific circumstances in which tinnitus sufferers performed less effectively than their non-tinnitus counterparts.From these results, it was postulated that the relationship between tinnitus severity and cognitive performance is moderated by demand and as such, a longitudinal diary study (six weeks) was undertaken to measure (self-rated) effectiveness under a wide range of demands in real life. Moderated hierarchical regression techniques were thus able to identify situations in which mental demand levels drive the relationship between tinnitus and performance, thus supporting the hypothesis