In the theoretical part of our study, we provide a systematic review of contemporary methods (pharmacological and non-pharmacological) of ECT augmentation, as scored by three factors - manipulation of the seizure threshold, length of therapeutic seizures and the effect on ECT efficacy measured by the total number of ECT sessions and the rate/quantity of change on used objective/subjective scales. We also provide a summary of possible side effects and risks associated with the use of respective ECT augmentation methods. In the research part of our study, we explore the effect of high frequency transcranial magnetic stimulation on the respective ECT parameters, in a double blinded, placebo controlled, randomised study on a sample of 46 patients treated for a major depressive episode. During ECT titration, we registered a significantly lower seizure threshold in the experimental group, an average decrease in charge by 34.55%, from 34.23mC to 22.4mC, p< 0.001 (Wilcox test). We have not observed a significant effect of HF rTMS on the length of seizure or ECT efficacy. Our study confirms the hypothesis, that the application of HF rTMS briefly before an ECT session reduces the seizure threshold, which might be useful in certain types of patients.

Subjektiver Tinnitus ist eine akustische Phantomwahrnehmung, d.h. ohne das Vorhandensein einer externen oder internen Geräuschquelle. Diese oft sehr belastende Störung steht aktuellen Studien zufolge in einem Zusammenhang mit pathologisch gesteigerter Aktivität und Erregbarkeit zentral-nervöser auditorischer Strukturen. Derartige Hyperaktivitäten und –exzitabilitäten konnten bereits experimentell durch eine repetitive transkranielle Magnetstimulation (rTMS) reduziert werden. Die vorliegende randomisierte, Placebo-kontrollierte Studie ging zwei Fragestellungen nach. Erstens sollte geprüft werden, ob sich das Aktivierungsmuster auf akustische Stimulation im auditorischen Kortex bei Tinnituspatienten von dem gesunder Kontrollpersonen unterscheidet. Zweitens sollte untersucht werden, ob durch eine rTMS eine Tinnitussymptomatik verbessert werden kann und dies in Form einer reduzierten kortikalen Hyperaktivität auch mit der Nah-Infrarot Spektroskopie (NIRS) nachweisbar ist. In der Verum-Gruppe wurden an 10 aufeinanderfolgenden Werktagen täglich je 2000 Stimuli mit einer Frequenz von 1 Hz über dem linken auditorischen Kortex appliziert. Die Tinnitussymptomatik wurde mit dem Tinnitusfragebogen nach Göbel & Hiller (TFB), dem Tinnitus-Handicap-Inventory-Score (THI) und dem Tinnitus-Schweregrad-Fragebogen (TSG) erfasst. Die NIRS-Messungen erfolgten vor und direkt nach der letzten Stimulation mit zwei verschiedenen akustischen Paradigmen und einer motorischen Kontrollaufgabe. Es konnten deutliche Unterschiede bezüglich des Aktivierungsmusters auf akustische Stimulation im auditorischen Kortex zwischen den Tinnituspatienten und gesunden Kontrollpersonen gefunden werden. Die Tinnituspatienten zeigten signifikant stärkere Aktivierungen als die gesunden Kontrollpersonen. Diese Ergebnisse unterstützen die „Hyperexzitabilitätstheorie“ von Melcher et al. (2009). Ferner konnte, wie in der Studie von Melcher et al. (2009), kein Zusammenhang zwischen der Tinnituslateralisation und dem Aktivierungsmuster gefunden werden. Bezüglich der Effektivität der rTMS gegenüber einer Placebo-Stimulation ließ sich kein eindeutiger Therapieerfolg nachweisen. Es konnte zwar anhand von NIRS-Messungen gezeigt werden, dass die rTMS eine kortikale Hyperexzitabilität stärker reduzierte als die Placebo-Stimulation. Es ließ sich jedoch kein Zusammenhang zwischen der geringeren Hyperexzitabilität und einer verbesserten Tinnitussymptomatik finden. Da jedoch die Fallzahlen dieser Studie klein waren, sollten diese Ergebnisse mit Vorsicht interpretiert werden. Außerdem deuten die Ergebnisse darauf hin, dass die NIRS eine erfolgversprechende Methode für den objektiven Nachweis Tinnitus-assoziierter zentral-nervöser Veränderungen und möglicherweise auch von Therapieeffekten ist. Sie bietet zahlreiche Vorteile gegenüber anderen bildgebenden Methoden: sie ist einfach in der Handhabung, wiederholt anwendbar, risikoarm, preisgünstig und nicht invasiv. Um die NIRS jedoch als etablierte Nachweismethode in der Klinik einsetzen zu können, sollten weitere Studien mit größeren Fallzahlen generiert werden. Auch sollten optimierte, allgemeingültige akustische Stimulationsparadigmen gefunden werden, um die Ergebnisse künftiger Studien besser miteinander vergleichen zu können. / Subjective Tinnitus is an acoustic phantom perception, i.e. without an external or internal source. According to the latest studies this mostly distressing complex of symptoms is related to a pathologically enhanced activity and excitability in central structures of the auditory system which could have been reduced by repetitive transcranial magnetic stimulation (rTMS) in clinical trials. This randomized, placebo-controlled study followed two questions. Firstly, the activity of the auditory cortex after acoustic stimulation in patients with chronic tinnitus was compared with the activity measured in healthy volunteers. Secondly, the study tried to evaluate, if a tinnitus could be reduced by rTMS and if this effect could be shown as a reduced cortical activity using NIRS. In the verum group 2000 pulses with a frequency of 1Hz were daily applied over the left auditory cortex on 10 consecutive weekdays. The severity of tinnitus was categorized by questionaires, such as Tinnitus-Fragebogen nach Goebel & Hiller (TFB), Tinnitus-Handicap-Inventory-Score (THI) and Tinnitus-Schweregrad-Fragebogen (TSG). The NIRS measurements proceeded before and immediately after the last rTMS during the presentation of two different acoustic stimulation patterns and one motoric task. This study could show considerable differences comparing the activation of the auditory cortex after acoustic stimulation in patients with chronic tinnitus and healthy volunteers. The activation in patients with chronic tinnitus was significantly higher compared to the healthy volunteers. These results support the “Theory of Hyperexcitability” invented by Melcher et al. (2009). Additionally, like Melcher et al. (2009), this study could not show a dependence of the cortical activation on the tinnitus lateralisation. This study could not show a significant benefit of the rTMS compared to the placebo stimulation. Though the NIRS measurements showed a reduced cortical hyperexcitability after the verum stimulation, this effect could not be related to a reduced tinnitus. However, these results should be interpreted carefully as the numbers of treated patients was very little. Furthermore this studie’s results suggest that NIRS is a promising, objective proof procedure for tinnitus related changes in central auditory structures and potentially even for therapeutical effects. Its’ benefits are: simple handling, repeatability, low-risk, low running costs and non-invasiveness. In order to use NIRS as an established method in clinical settings more studies including numerous patients should be generated. Furthermore optimized, universally valid acoustic stimulation patterns should be created and broadly used to be able to compare the different studies’ results.

Swallowing is an important physiological function leading to nourishment of the organism, controlled by complicated interactions between the muscles, the cranial nerves and multiple brain structures. Swallowing impairments, also called dysphagia, are a major health burden for patients with neurological diseases such as stroke, Parkinson’s disease as well as community dwelling elderly individuals. It has been shown that activation of undamaged swallowing motor cortex compensates for the initial lost swallowing function in stroke patients. Non-invasive brain stimulation provides a tool to explore excitability within the areas of the motor cortex responsible for swallowing muscles. Repetitive transcranial magnetic stimulation (rTMS) is one such technique, with defined frequency parameters, however the underlying reasons for the heterogeneity is responses to low (1Hz) and high (5Hz) frequencies is unclear. These physiological interactions affecting the neurological control of swallowing may be influenced by multiple genes and proteins. Insights into the molecular basis of swallowing through genetic interactions could provide a source of information which can be further used in understanding and treating swallowing impairments. Existing evidence is limited in terms of candidate proteins, genes and pathways which might drive the neural control of swallowing. The aim of my doctoral research was to explore genes which might be involved in swallowing neurophysiology and pathophysiology. My hypothesis is that swallowing due to its complicated physiology is most likely affected by multiple genes and interactions between genes and proteins. To study this hypothesis I used two experimentally distinct study designs. Firstly I explored a number of single nucleotide polymorphisms (SNPs) and potential candidate genes presented in the existing literature. Then, I performed a SNP- and gene-based Genome-Wide Association Study (GWAS) of self-reported swallowing impairments compared with over 500,000 single nucleotide changes. For GWAS I used a group of 555 community dwelling individuals from the Dyne Steel Cohort from the areas of Manchester and Newcastle. Further research involved replication of selected genes and SNPs from literature screening and GWAS using two rTMS paradigms on the largest to date cohort of healthy young volunteers. Forty one volunteers (were assessed for corticobulbar excitability after single-pulse TMS. Repeated measurements of motor evoked potentials from the pharynx and the hand were recorded after the interventions of 1Hz and 5Hz rTMS. The subjects’ individual responses were grouped according to multiple criteria and then associated with factors such as gender, ethnicity, time of day of the stimulation and individual genetic information. GWAS analysis for association with swallowing impairment identified one SNP rs17601696 which achieved genome-wide significance (P-value=5×10(-8)) within a non-coding region of chromosome 10. Gene-based analysis did not result in any genome-wide significant association. In replication of these findings and following a priori selected genes from the literature (BDNF, COMT, TRKB, APOE, DRD2, GRIN2B and GRIN1) from neurophysiological studies applying TMS, two main conclusions were formed. Firstly, rTMS paradigms showed high variability in responses which made the phenotype more complicated. Secondly the result from GWAS could not be confirmed. By contrast, SNP rs6269 from the COMT gene was associated with responsiveness of the pharyngeal MEPs after delivering 1Hz paradigm and rs1800497 from the DRD2 gene with responsiveness after 5Hz rTMS.Lack of replication of the findings between two experiments might be caused by high variability in responsiveness with complex molecular networks of swallowing control where multiple genes with small genetic effects are involved. Although our findings support the hypothesis that molecular markers can be associated with swallowing, more studies are needed to understand the individual factors that determine responsiveness and effectiveness of treatment therapies of swallowing impairments.

Background: Gamma oscillations (30-80 Hz) in the dorsolateral prefrontal cortex (DLPFC) are associated with working memory; a process involving the maintenance and manipulation of information on line (Baddeley, 1986). Gamma oscillations are supported by gamma-aminobutyric acid (GABA) inhibitory interneurons in the DLPFC. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive method in which to stimulate the cortex that has been shown to modify oscillations, cognition and GABAergic mechanisms. Patients with schizophrenia have severe deficits in working memory that may be related to impairments in GABAergic inhibitory neurotransmission underlying gamma oscillations in the DLPFC. Objective: First, to evaluate gamma oscillatory activity in patients with schizophrenia during working memory compared to healthy subjects. Second, to examine the effect of rTMS applied over the DLPFC on gamma oscillations generated during working memory in healthy subjects. Third, to examine the effect of rTMS applied to the DLPFC on gamma oscillations in patients with schizophrenia compared to healthy subjects. Hypotheses: First, it was hypothesized that patients with schizophrenia would exhibit an alteration in gamma oscillatory activity. Second, it was hypothesized that rTMS would be effective in enhancing gamma oscillations in healthy subjects. Third, it was hypothesized that rTMS would be effective in inhibiting gamma oscillations in patients with schizophrenia. Results: The first study found that patients with schizophrenia generate excessive gamma oscillations during working memory compared to healthy subjects. The second experiment found that rTMS over the DLPFC resulted in the potentiation of gamma oscillations in healthy subjects during working memory. The third experiment demonstrated that rTMS inhibited excessive gamma oscillations in patients with schizophrenia while an opposite effect was found in healthy subjects. Conclusions: rTMS applied over the DLPFC modulates frontal gamma oscillatory in healthy subjects and in patients with schizophrenia depending on baseline levels of activity, a finding that may ultimately translate into a better understanding of the mechanisms leading to cognitive improvement in this disorder.

Background: Gamma oscillations (30-80 Hz) in the dorsolateral prefrontal cortex (DLPFC) are associated with working memory; a process involving the maintenance and manipulation of information on line (Baddeley, 1986). Gamma oscillations are supported by gamma-aminobutyric acid (GABA) inhibitory interneurons in the DLPFC. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive method in which to stimulate the cortex that has been shown to modify oscillations, cognition and GABAergic mechanisms. Patients with schizophrenia have severe deficits in working memory that may be related to impairments in GABAergic inhibitory neurotransmission underlying gamma oscillations in the DLPFC. Objective: First, to evaluate gamma oscillatory activity in patients with schizophrenia during working memory compared to healthy subjects. Second, to examine the effect of rTMS applied over the DLPFC on gamma oscillations generated during working memory in healthy subjects. Third, to examine the effect of rTMS applied to the DLPFC on gamma oscillations in patients with schizophrenia compared to healthy subjects. Hypotheses: First, it was hypothesized that patients with schizophrenia would exhibit an alteration in gamma oscillatory activity. Second, it was hypothesized that rTMS would be effective in enhancing gamma oscillations in healthy subjects. Third, it was hypothesized that rTMS would be effective in inhibiting gamma oscillations in patients with schizophrenia. Results: The first study found that patients with schizophrenia generate excessive gamma oscillations during working memory compared to healthy subjects. The second experiment found that rTMS over the DLPFC resulted in the potentiation of gamma oscillations in healthy subjects during working memory. The third experiment demonstrated that rTMS inhibited excessive gamma oscillations in patients with schizophrenia while an opposite effect was found in healthy subjects. Conclusions: rTMS applied over the DLPFC modulates frontal gamma oscillatory in healthy subjects and in patients with schizophrenia depending on baseline levels of activity, a finding that may ultimately translate into a better understanding of the mechanisms leading to cognitive improvement in this disorder.

Swallowing is a complex neurophysiological process involving the activation of several components of the central nervous system with bilateral but asymmetric representations of swallowing musculature in the motor cortex. Difficulty in swallowing (dysphagia) in stroke patients has been reported by up to 50% of victims, and can increase morbidity and mortality in this population due to the development of aspiration pneumonia and malnutrition. One of the common factors that predispose patients to dysphagia after a stroke is believed to be the reduced sensory awareness in the oropharyngeal area, which affects the swallowing process. The uses of diet modification to reduce thin liquid aspiration have gained interest but are often unpalatable or have limited success. Carbonated liquid have shown some beneficial effects in swallowing behaviour. However, there is very little evidence to support this intervention. Therefore, the aim of this thesis is to investigate the neurophysiological and behavioural effects of carbonated liquids on swallowing in healthy volunteers.The effects of carbonated solutions on swallowing performance compared to non-carbonated solutions (still water) was investigated in a pilot study and (still water and citric acid) in the main study using reaction time task (chapter 2). Carbonation appears to alter swallowing performance compared to other liquids by improving complex tasks. In addition, beneficial neurophysiological effects of carbonated liquids were evident after 10 minutes of carbonated liquid swallowing compared to still water and citric acid solution in healthy volunteers (chapter 3).In chapter 4, the response of the healthy swallowing motor cortex to carbonated liquids following application of a virtual lesion compared to still water and saliva swallowing, was investigated. Carbonated liquids were able to reverse the inhibitory effect induced by 1 Hz rTMS to the dominant pharyngeal motor representation. Moreover, the beneficial effects of carbonated liquids on swallowing performance, measured with a swallowing reaction times task after application of a virtual lesion was observed in a pilot investigation in healthy volunteers (chapter 5). These data demonstrate that carbonated liquids have beneficial neurophysiological and swallowing performance effects and support notion that the chemical properties of carbonated liquids may provide the required peripheral sensory information that alter the brain swallowing function, which leads to an improvement in the swallowing performance of stroke dysphagic patients. These data lay the foundation for considering the use of carbonation as facilitating stimuli in dysphagic patients.

Over the past decade, efforts have been made to assess the positive therapeutic effects of transcranial magnetic stimulation (TMS) by altering the excitability of the brain. We conducted a double-blind, placebo-controlled study to assess the efficacy of right prefrontal slow repetitive TMS in patients with treatment refractory major depression. This pilot study supports the therapeutic potential of rTMS in the low-frequency range of 1 Hz on right prefrontal cortex for the treatment of refractory major depression. Additional studies will be necessary to assess the efficacy of rTMS with different indices (frequency, intensity, and stimulation site) for major depression and other psychiatric diseases.

No description available.

La stimulation magnétique transcranienne (SMT) est une technique non invasive qui permet de stimuler le cerveau. Les SMT répétitives (SMTr), c'est-à-dire l'application de nombreuses impulsions magnétiques, sont capable d'induire des modifications de longue durée de l'excitabilité neuronale. La SMT s'est développée dans un but thérapeutique et scientifique. Les effets après la SMTr sur le cortex moteur sont bien documentés chez les individus sains, mais on en sait moins sur la stimulation du cortex préfrontal dorso-latéral (DLPFC).L'objectif de cette thèse était de comparer différents protocoles SMTr sur des sujets sains et de trouver des marqueurs électroencéphalograpiques (EEG) de la réponse ou pas à la thérapie SMTr dans la dépression majeure et bipolaire. La principale originalité de la méthode présentée est la comparaison intra-sujet d'effets entre-protocoles et le développement de techniques de localisation de sources.Nous avons étudié chez 20 sujets sains comment les oscillations corticales sont modulées suite à quatre protocoles SMTr actifs différents, et à un protocole sham utilisé comme contrôle, du DLPFC gauche et en comparant la puissance spectrale d'EEG avant et après SMTr de durée de 15 minutes. Le spectre EEG a été estimé grâce à la transformée de Fourier rapide (FFT) et partitionné en bandes de fréquence selon la classification commune.Nous avons trouvé pour chaque protocole actif une diminution significative de puissance delta et theta sur les électrodes préfrontales gauches, principalement localisées dans le DLPFC gauche. Dans des bandes de fréquences plus hautes, la diminution de puissance dans le DLPFC a été de plus observée dans le DLFPC controlatéral et dépend du protocole de stimulation. Parce que les activités delta et theta sont généralement associées à l'inhibition corticale, ces résultats suggérent que la SMTr du DLPFC diminue transitoirement l'inhibition corticale locale. Aussi, les oscillations d'EEG rapides sont associées à l'excitabilité corticale et on peut conclure que des diminutions observées non spécifiques dans l'activité rapide localisée dans le DLPFC suggérent également une réduction de l'excitabilité corticale.Dans la deuxième expérience, nous avons travaillé sur groupe de patients, souffrant de trouble dépressif majeur (MDD) et de trouble bipolaire (BP). Dans cette étude ouverte, nous avons cherché à déterminer s'il existe des différences d'EEG de repos dans l'activité cérébrale entre patients BP et MDD, et entre les répondeurs et non-répondeurs à la SMTr à 10 Hz en étudiant des biomarqueurs d'EEG. Le protocole SMTr à 10 Hz étaient le même entre patients MDD et BP. Les propriétés EEG dans les deux troubles dépressifs ont été étudiées, en comparant la puissance spectrale des enregistrements pré- et post-SMTr EEG au cours des sessions thérapeutiques chez les patients répondeurs et non-répondeurs.La conclusion est qu'il est possible de distinguer les répondeurs des non-répondeurs au traitement SMTr. Les répondeurs avaient une puissance en basse fréquence plus importante. Une augmentation de puissance alpha a aussi été observée au niveau du cortex cingulaire ventral dans les deux groupes. La comparaison des MDD et BP a révélé une activité significativement plus élevée dans la puissance des bandes thêta et bêta chez les patients BP, principalement localisée dans le cortex préfrontal. / Transcranial magnetic stimulation (TMS) is a non-invasive technique for stimulating the brain. A brief electric current passing through a magnetic coil produces a brief, high-intensity magnetic field which stimulates the brain. Repetitive TMS, application of many magnetic pulses, is able to induce relatively long-lasting excitability changes and nowadays is being developed for various therapeutic and scientific purposes. The after-effects of rTMS over motor cortex are well documented in healthy individuals, however less is known about the stimulation of dorso-lateral prefrontal cortex (DLPFC). The aim of this PhD thesis was to compare different rTMS protocols in healthy subjects and to find neurophysiological EEG biomarkers characteristic for response or not to rTMS therapy in major and bipolar depression. The main originality of presented method is within-subject comparison of between-protocols effects. Additionally, source localisation was performed in both analyses. Here, we studied in 20 healthy subjects how cortical oscillations are modulated by four different active rTMS protocols (1 Hz, 10 Hz, cTBS and iTBS) of the left DLPFC, and by a sham-1Hz protocol used as a control condition, by comparing the spectral power of pre- and post-rTMS electroencephalographic (EEG) recordings of 15 minutes duration. EEG spectrum was estimated with the Fast Fourier transform (FFT) and partitioned using the common physiological frequency. We found for every active protocol a significant decrease of delta and theta power on left prefrontal electrodes, mainly localised in the left DLPFC. In higher frequency bands (beta and gamma), the decrease of power in the DLPFC was also observed additionally in the contralateral DLFPC and depended on the stimulation protocol. Because large delta and theta activity is usually associated with cortical inhibition, these results suggest that rTMS of DLPFC transiently decreases local cortical inhibition. Furthermore, fast EEG oscillations are associated to cortical excitability and it can be concluded that observed decreases in fast activity, unspecific to protocol, localised in the DLPFC also suggest reduced cortical excitability, which accompanies a decrease in cortical inhibition. In the second experiment we worked on two subgroups of patients, with major depressive disorder (MDD) and bipolar disorder (BP). In this open study we aimed to examine whether there are EEG differences in resting brain activity between BP and MADD patients, and between responders and non-responders to 10 Hz repetitive transcranial magnetic stimulation (rTMS) by studying EEG biomarkers. Eight MDD (6 females) and 10 BP patients (6 females) were included. The 10 Hz rTMS protocol was the same for MDD and BP. The different patterns of EEG activity in both depressive disorders were studied, by comparing spectral power of pre- and post-rTMS EEG recordings throughout the therapeutic sessions in responders and non-responders.The most important finding is that it is possible to distinguish responders from non-responders to the rTMS treatment. Responders showed significantly higher power of low frequencies. Therefore, an increase of alpha power was observed in ventral cingulate cortex in both groups. The comparison of MDD and BP disorders revealed significantly higher activity in theta and beta bands power in BP patients, mainly localised in prefrontal cortex.

No description available.