Efficacy and safety of bilateral continuous theta burst stimulation (cTBS) for the treatment of chronic tinnitus: design of a three-armed randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Tinnitus, the perception of sound and noise in absence of an auditory stimulus, has been shown to be associated with maladaptive neuronal reorganization and increased activity of the temporoparietal cortex. Transient modulation of tinnitus by repetitive transcranial magnetic stimulation (rTMS) indicated that these areas are critically involved in the pathophysiology of tinnitus and suggested new treatment strategies. However, the therapeutic efficacy of rTMS in tinnitus is still unclear, individual response is variable, and the optimal stimulation area disputable. Recently, continuous theta burst stimulation (cTBS) has been put forward as an effective rTMS protocol for the reduction of pathologically enhanced cortical excitability.</p> <p>Methods</p> <p>48 patients with chronic subjective tinnitus will be included in this randomized, placebo controlled, three-arm trial. The treatment consists of two trains of cTBS applied bilaterally to the secondary auditory cortex, the temporoparietal associaction cortex, or to the lower occiput (sham condition) every working day for four weeks. Primary outcome measure is the change of tinnitus distress as quantified by the Tinnitus Questionnaire (TQ). Secondary outcome measures are tinnitus loudness and annoyance as well as tinnitus change during and after treatment. Audiologic and speech audiometric measurements will be performed to assess potential side effects. The aim of the present trail is to investigate effectiveness and safety of a four weeks cTBS treatment on chronic tinnitus and to compare two areas of stimulation. The results will contribute to clarify the therapeutic capacity of rTMS in tinnitus.</p> <p>Trial registration</p> <p>The trial was registered with the clinical trials register of <url>http://www.clinicaltrials.gov</url> (NCT00518024).</p

Neuronale Korrelate visuomotorischer Integration: Modulation von oszillatorischer Aktivität durch kortikale Stimulation und Alter

Previous findings showed that the network for visuo-motor integration comprises mainly precentral and occipito-parietal regions. The binding theory assumes that the integration of spatially distributed information into a coherent percept is based on transiently formed functional networks. Based on that it is hypothesized that the integration of multimodal sensory input and motor control is achieved by linking the various involved brain areas by phaselocked oscillatory activity. It also widely known that the morphology and neurophysiology of the brain changes along the course of aging. The present thesis aimed (1.) to further elucidate the neuronal mechanisms underlying visuo-motor integration, (2.) to investigate which alterations occur depending on aging and (3.) to explore whether it is possible to modulate cortico-cortical coupling using repetitive Transcranial Magnetic Stimulation (rTMS) applied simultaneously to two cortical sides. Therefore, two studies were designed. The first study of this thesis aimed to investigate mechanisms contributing to visuo-motor integration and changes occuring during healthy aging. Four different age groups (25 years, 40 years, 60 years, and 80 years) were recruited and combined Magnetoencephalography (MEG)/ Electroencephalography (EEG) was recorded while subjects performed a continuous visuo-motor (VM), visual (V), motor (M), or visual plus motor (V+M) (without feedback) task. Using Synthetic Aperture Magnetometry (SAM), a beamformer technique for MEG source localization, and performing a group level analysis of the localized sources, the regions contributing to the network for visuo-motor integration were identified. In a second step, the power spectra and coherence, a measure for cortico-cortical coupling, were computed for MEG and EEG data. We could replicate former results stating that the network for visuo-motor integration comprises occipito-parietal and precentral cortices. We found the formerly described shift of brain activity to more prefrontal areas in the elderly subjects. The elderly showed an overall higher neuronal activity, yet more pronounced in the beta frequency, compared to young adults. We found a tendency in an increased activity of the parietal cortex in the elderly. We found a tendency towards previous reports that aging is accompanied by progressing impairment of motor performance which also corresponds to previous findings. And we could not replicate previously reported results on cortico-cortical coupling between the areas involved in visuo-motor integration, nor could we confirm the decrease of coherence in the VM task when comparing young and elderly subjects. The second study that aimed to extend the findings that rTMS applied simultaneously to two distinct brain regions increases cortico-cortical coupling as measureed with EEG coherence. Four conditions of bifocally applied rTMS were designed. A synchronous stimulation, and three asynchronous stimulation, i. e. there was a short delay between the two pulses given to Primary Visual Cortex (V1) and Primary Motor Cortex (M1): either 3 ms, 7 ms or a random delay between 0 ms and 7 ms. The synchronous stimulation proved to be the one to increase the coherence between M1 and V1 immediately after stimulation. This effect vanished after 15 minutes. The findings suggest that source localization of MEG data using a beamformer technique is a reliable tool to identify cortical networks involved in multimodal integration and to identify aging related alterations. Further analysis of the time course of these identified regions would give an inside on the temporal scale of integrative neuronal processing. To date, there are several approaches to analyze cortico-cortical coupling, but further methodological developments are necessary to improve analysis strategies for extracting the synchronized activities.Frühere Ergebnisse zeigten, dass das Netzwerk für visuomotorische Integration hauptsächlich aus präzentralen und occipito-parietalen Arealen besteht. Die „Binding“ Theorie vermutet, dass die Integration von räumlich verteilter Information in eine kohärente Wahrnehmung auf die Bildung vorübergehender funktioneller Netzwerke basiert. Basierend darauf wird hypothetisiert, dass die Integration von multimodalen sensorischen Eingängen und motorischer Kontrolle erreicht wird, indem die verschiedenen darin involvierten Hirnareale durch phase locking miteinander gekoppelt werden. Es ist ebenfalls weithin bekannt, dass sich die Morphologie und Neurophysiologie des Gehirns im Verlauf des Alterns verändern. Das Ziel der hier vorliegenden Dissertation war (1.) die neuronalen Mechanismen, die der visuomotorischen Integration unterliegen, weiter zu beleuchten, (2.) zu untersuchen, welche altersabhängigen Veränderungen auftreten und (3.) zu erforschen, ob es möglich ist, kortiko-kortikale Kopplung durch repetitive transkranielle Magnetstimulation (rTMS) simultan appliziert auf zwei kortikale Areale zu modulieren. Dafür wurden zwei Studien entworfen. Das Ziel der ersten Studie dieser Arbeit war es, die Mechanismen, die zur visuomotorischen Integration beitragen und altersbedingte Veränderungen zu untersuchen. Vier verschiedene Altersgruppen (25 Jahre, 40 Jahre, 60 Jahre und 80 Jahre) wurden rekrutiert und kombiniert Magnetoenzephalographie (MEG)/ Elektroenzephalographie (EEG) aufgezeichnet, während die Probanden eine visuomotorische (VM), rein visuelle (V), rein motorische oder eine visuell + motor (V+M) Aufgabe (ohne Feedback) ausführten. Mit Hilfe von Synthetic Aperture Magnetometry (SAM), einer Beamformertechnik für die MEG Quellenlokalisation, und einer Gruppenanalyse der lokalisierten Quellen wurden die Regionen, die zum Netzwerk der visuomotorischen Integration gehören, identifiziert. In einem zweiten Schritt wurden Powerspektrum und Kohärenz, ein Maß für kortiko-kortikale Kopplung, für die MEG- und die EEG-Daten berechnet. Wir konnten frühere Ergebnisse replizieren, die besagen, dass das Netzwerk für visuomotrische Integration occipito-parietale und präzentrale Regionen beinhaltet. Wir fanden die früher beschriebene Verschiebung der Hirnaktivität zu mehr präfrontale Arealen in den älteren Probanden. Die Älteren zeigten eine insgesamt höhere neuronale Aktivität, ausgeprägter im Betafrequenzbereich, verglichen mit den jungen Probanden. Wir fanden einen Trend für eine erhöhte Aktivität des Parietalkortex bei den älteren Probanden. Wir fanden eine Tendenz in Richtung früherer Berichte, dass das Altern einhergeht mit der fortschreitenden Beeinträchtigung motorischer Leistung, die ebenfalls mit früheren Ergebnissen korrespondiert. Und wir konnten frühere Ergebnisse über kortiko-kortikale Kopplung zwischen den Arealen, die in visuomotorische Integration involviert sind, nicht replizieren und wir konnten auch eine Abnahme der Kohärenz während dem Ausführen der visuomotorischen Aufgabe bei einem Vergleich der jungen und alten Probanden nicht bestätigen. Das Ziel der zweiten Studie war es, die Ergebnisse zu erweitern, dass rTMS simultan appliziert auf zwei unterschiedliche Hirnregionen, kortiko-kortikale Kopplung gemessen mit EEG-Kohärenz erhöht. Dafür wurden vier Bedingungen von bifokal angewendeter rTMS entworfen. Eine synchrone Stimulation, und drei asynchrone Stimulationen, d. h. es war eine kurze zeitliche Verzögerung zwischen den beidenen abgegebenen Pulsen über V1 (primärer visueller Kortex) und M1 (primärer motorischer Kortex): entweder 3 ms, 7 ms oder eine zufällige Verzögerung zwischen 0 ms und 7 ms. Die synchrone Stimulation erwies sich als diejenige, die die Kohärenz zwischen M1 und V1 unmittelbar nach der Stimulation erhöhte. Dieser Effekt verschwand nach 15 Minuten. Die Ergebnisse lassen darauf schließen, dass Quellenlokalisation mit MEG-Daten unter Verwendung einer Beamformertechnik eine zuverlässige Methode darstellt, um kortikale Netzwerke, die in multimodale Integration involviert sind sowie altersbedingte Veränderungen zu identifizieren. Weiterführende Analysen des zeitlichen Verlaufes der Aktivität in diesen identifizierten Regionen würden Einblick in die Zeitskala integrativer neuronaler Prozesse geben. Bisher gibt es unterschiedliche Ansätze um kortiko-kortikale Kopplung zu analysieren, aber weiterführende methodische Entwicklungen sind notwendig, um diese Analysestrategien zum extrahieren der synchronisierten Aktivitäten zu verbessern

Whole-brain haemodynamic after-effects of 1-Hz magnetic stimulation of the posterior superior temporal cortex during action observation.

The posterior superior temporal sulcus (pSTS) is active when observing biological motion. We investigated the functional connections of the pSTS node within the action observation network by measuring the after-effect of focal repetitive transcranial magnetic stimulation (rTMS) with whole-brain functional magnetic resonance imaging (fMRI). Participants received 1-Hz rTMS over the pSTS region for 10 min and underwent fMRI immediately after. While scanned, they were shown short video clips of a hand grasping an object (grasp clips) or moving next to it (control clips). rTMS\u2013fMRI was repeated for four consecutive blocks. In two blocks we stimulated the left pSTS region and in the other two the right pSTS region. For each side TMS was applied with an effective intensity (95 % of motor threshold) or with ineffective intensity (50 % of motor threshold). Brain regions showing interactive effects of (clip type) 7 (TMS intensity) were identified in the lateral temporo-occipital cortex, in the anterior intraparietal region and in the ventral premotor cortex. Remote effects of rTMS were mostly limited to the stimulated hemisphere and consisted in an increase of blood oxygen level-dependent responses to grasp clips compared to control clips. We show that the pSTS occupies a pivotal relay position during observation of goal-directed actions

Multivariate EEG spectral analysis evidences the functional link between motor and visual cortex during integrative sensorimotor tasks

The identification of the networks connecting brain areas and the understanding of their role in executing complex tasks is a crucial issue in cognitive neuroscience. In this study, specific visuomotor tasks were devised to reveal the functional network underlying the cooperation process between visual and motor regions. Electroencephalography (EEG) data were recorded from twelve healthy subjects during a combined visuomotor task, which integrated precise grip motor commands with sensory visual feedback (VM). This condition was compared with control tasks involving pure motor action (M), pure visual perception (V) and visuomotor performance without feedback (V + M). Multivariate parametric cross-spectral analysis was applied to ten EEG derivations in each subject to assess changes in the oscillatory activity of the involved cortical regions and quantify their coupling. Spectral decomposition was applied to precisely and objectively determine the power associated with each oscillatory component of the spectrum, while surrogate data analysis was performed to assess the statistical significance of estimated coherence values. A significant decrease of the alpha and/or beta power in EEG spectra with respect to rest values was assumed as indicative of specific cortical area activation during task execution. Indeed alpha band coherence increased in proximity of task-involved areas, while it was suppressed or remained unchanged in other regions, suggesting the activation of a specific network for each task. According to our coherence analysis, a direct link between visual and motor areas was activated during V + M and VM tasks. The effect of visual feedback was evident in the beta band, where the increase of coherence was observed only during the VM task. Multivariate analysis suggested the presence of a functional link between motor and visual cortex subserving sensorimotor integration. Furthermore, network activation was related to the sum of single task (M and V) local effects in the alpha band, and to the presence of visual feedback in the beta band

Inferior frontal gyrus links visual and motor cortices during a visuomotor precision grip force task

Coordination between vision and action relies on a fronto-parietal network that receives visual and proprioceptive sensory input in order to compute motor control signals. Here, we investigated with magnetoencephalography (MEG) which cortical areas are functionally coupled on the basis of synchronization during visuomotor integration. MEG signals were recorded from twelve healthy adults while performing a unimanual visuomotor (VM) task and control conditions. The VM task required the integration of pinch motor commands with visual sensory feedback. By using a beamformer, we localized the neural activity in the frequency range of 1-30Hz during the VM compared to rest. Virtual sensors were estimated at the active locations. A multivariate autoregressive model was used to estimate the power and coherence of estimated activity at the virtual sensors. Event-related desynchronisation (ERD) during VM was observed in early visual areas, the rostral part of the left inferior frontal gyrus (IFG), the right IFG, the superior parietal lobules, and the left hand motor cortex (M1). Functional coupling in the alpha frequency band bridged the regional activities observed in motor and visual cortices (the start and the end points in the visuomotor loop) through the left or right IFG. Coherence between the left IFG and left M1 correlated inversely with the task performance. Our results indicate that an occipital-prefrontal-motor functional network facilitates the modulation of instructed motor responses to visual cues. This network may supplement the mechanism for guiding actions that is fully incorporated into the dorsal visual stream

One’s motor performance predictably modulates the understanding of others’ actions through adaptation of premotor visuo-motor neurons

Neurons firing both during self and other’s motor behavior (mirror neurons) have been described in the brain of vertebrates including humans. The activation of somatic motor programs driven by perceived behavior has been taken as evidence for mirror neurons’ contribution to cognition. The inverse relation, that is the influence of motor behavior on perception, is needed for demonstrating the long-hypothesized causal role of mirror neurons in action understanding. We provide here conclusive behavioral and neurophysiological evidence for that causal role by means of cross-modal adaptation coupled with a novel transcranial magnetic stimulation (TMS)-adaptation paradigm. Blindfolded repeated motor performance of an object-directed action (push or pull) induced in healthy participants a strong visual after-effect when categorizing others’ actions, as a result of motor-to-visual adaptation of visuo-motor neurons. TMS over the ventral premotor cortex, but not over the primary motor cortex, suppressed the after-effect, thus localizing the population of adapted visuo-motor neurons in the premotor cortex. These data are exquisitely consistent in humans with the existence of premotor mirror neurons that have access to the action meaning. We also show that controlled manipulation of the firing properties of this neural population produces strong predictable changes in the way we categorize others’ actions

Enhancement of long-range EEG coherence by synchronous bifocal transcranial magnetic stimulation

Interregional coupling of distant brain regions can be measured by electroencephalographic (EEG) coherence reflecting the spatial-temporal correlation between two oscillatory signals. It has been suggested that this coherence in activity is a signature of functional integration of multimodal neuronal networks. Repetitive transcranial magnetic stimulation (rTMS) is a well-established technique for non-invasive cortical stimulation. Its modulating effects outlast the train of stimulation and affect behavior. In the present study, we tested the hypothesis that cortico-cortical coherence between distant brain areas can be selectively enhanced by synchronous bifocal rTMS. Cortico-cortical coherence was assessed in 16 healthy human subjects before and after three trains of synchronous high-frequency (10 Hz) rTMS to the left primary motor cortex and the visual cortex at the occipital pole simultaneously. Stimulation of the left M1 alone served as the control condition. Coherence and spectral power were measured between these areas on the stimulated and the homologue contralateral side. Synchronous bifocal rTMS induced an increase of interregional coupling in the alpha and lower beta band on the stimulated side without effects on spectral power. These data indicate that synchronous bifocal rTMS is a feasible technique for selective modulation of interregional EEG coherence. Furthermore, they raise the hypothesis that interventional enhancement of long-range coherence may effectively modulate interregional integration with behavioral consequences