Le système auditif ascendant est constitué d’étages multiples procédant chacun à un traitement complexe du signal, traitement qui est modulé par un système descendant, formant de multiples boucles corticales et sous-corticales de rétroaction : le système efférent auditif. La boucle la plus longue de ce système serait capable de moduler directement le fonctionnement des cellules sensorielles de l’organe périphérique de l’audition. Le but de ce travail était d’étudier pour la première fois chez le sujet sain, l’effet d’une modulation corticale expérimentale sur le fonctionnement périphérique auditif. Nous avons donc recueilli, dans le cadre d’un protocole en double aveugle contre placebo, chez 34 sujets sains, l’activité des cellules ciliées externes de l’organe de Corti (cellules sensorielles directement en contact avec les fibres nerveuses efférentes), par le recueil d’otoémissions acoustiques (OEAs), avant et après stimulation du cortex auditif par une stimulation magnétique transcrânienne répétitive (SMTr). Une diminution de l’amplitude d’un type d’OEA a été obtenue du côté controlatéral à une stimulation du cortex auditif par SMTr à 10 Hz, effet qui ne peut être expliqué seulement par une action non-spécifique liée au bruit de la SMTr mais qui reste extrêmement variable d’un sujet à un autre. De plus, nous avons montré, du côté ipsilatéral à la SMTr, une diminution de l’amplitude des OEAs immédiatement après la SMTr, et uniquement pour les fortes intensités d’utilisation de la SMTr (donc, pour des niveaux de bruit plus importants), reflétant un effet direct du bruit de la SMTr sur les mécanismes cochléaires actifs, effet présent chez nos sujets même en cas de protections auditives de bonne qualité / The ascending auditory system involves multiples stages where the auditory information is processed and modulated by a top-down influence involving multiple cortico sub-cortical loops: the efferent auditory system. It is hypothesized that the longest loop of this efferent system is able to modulate directly the sensory cells of the peripheral auditory organ. The aim of this work was to study this system, to our knowledge for the first time in healthy humans, and to show a direct cortical influence on the auditory periphery. In a double blind randomized procedure, we recorded, in 34 healthy subjects, the activity of outer hair cells of the organ of Corti (sensory cells, that are in direct synaptic contact with medial efferent fibers), by means of evoked otoacoustic emissions (OAEs), before and after auditory cortex stimulation by repetitive transcranial magnetic stimulation (rTMS). We showed an inhibitory influence of the auditory cortical stimulation by 10 Hz rTMS on OAE amplitudes, predominantly in the ear contralateral to the rTMS, effect that cannot be attributed to a non-specific effect linked to the impulse noise associated with the rTMS technique, but that remains highly variable across subjects. In addition, we showed a decrease in OAE amplitude on the ipsilateral side, immediately after the rTMS session and only for high rTMS intensities (and hence, higher noise levels), that reflect a direct influence of the rTMS noise on the auditory periphery, effect that is present even in well ear-protected subjects

Background: Eating disorders are psychiatric illnesses whose treatment is difficult and usually the classic procedures fail. Recently, the number of researches in neuromodulatory methods has increased. I present an overview of basic stimulation methods, their use in the treatment of anorexia nervosa (AN), bulimia nervosa and binge-eating and the results of our study focused on the treatment of AN by transcranial direct current stimulation (tDCS). Methods: It was a randomized, double-blind, sham-controlled trial. Forty-three inpatients with AN were divided to receive either active (n=22) or sham (n=21) tDCS over the left DLPFC (anode F3/cathode Fp2, 2mA for 30 minutes). All patients filled the Eating Disorder Examination Questionnaire (EDE-Q) and Zung depression scale (ZUNG), we measured them the thermal pain threshold, the objective dissatisfaction with their own body by Anamorfic program and evaluated BMI before the first and after the last tDCS. Follow-up was after 2 and 4 weeks. It was evaluated using ANOVA and OPLS model. Results: Compared to sham tDCS, active tDCS improved self-evaluation based on one's body shape (p < 0,05) and significantly decreased the need of excessive control over calorie intake (p < 0,05) in 4-week follow-up (questions 4 and 23 in EDE-Q). Question 21 in EDE-Q was more...

A full-sine (biphasic) pulse waveform is most commonly used for repetitive transcranial magnetic stimulation (TMS), but little is known about how variations in duration or amplitude of distinct pulse segments influence the effectiveness of a single TMS pulse to elicit a corticomotor response. Using a novel TMS device, we systematically varied the configuration of full-sine pulses to assess the impact of configuration changes on resting motor threshold (RMT) as measure of stimulation effectiveness with single-pulse TMS of the non-dominant motor hand area (M1). In young healthy volunteers, we (i) compared monophasic, half-sine, and full-sine pulses, (ii) applied two-segment pulses consisting of two identical half-sines, and (iii) manipulated amplitude, duration, and current direction of the first or second full-sine pulse half-segments. RMT was significantly higher using half-sine or monophasic pulses compared with full-sine. Pulses combining two half-sines of identical polarity and duration were also characterized by higher RMT than fullsine stimuli resulting. For full-sine stimuli, decreasing the amplitude of the halfsegment inducing posterior-anterior oriented current in M1 resulted in considerably higher RMT, whereas varying the amplitude of the half-segment inducing anterior-posterior current had a smaller effect. These findings provide direct experimental evidence that the pulse segment inducing a posterior anterior directed current in M1 contributes most to corticospinal pathway excitation. Preferential excitation of neuronal target cells in the posterior-anterior segment or targeting of different neuronal structures by the two half-segments can explain this result. Thus, our findings help understanding the mechanisms of neural stimulation by full-sine TMS.

Die transkranielle Magnetstimulation (TMS) ist zu einer essentiellen Untersuchungsmethode der Neurowissenschaften geworden. Sie ermöglicht es, mittels eines kurzen, starken Magnetfeldes, Neuronen im Gehirn anzuregen und kurzfristig deren Aktivität zu modulieren. Diese Effekte sind allerdings nur bei Stimulation des motorischen Kortexes als motorisch evozierte Potentiale (MEP) an peripheren Muskeln direkt messbar. Hier lässt sich auch eine individuelle Reizschwelle (engl. motorthreshold, MT) bestimmen, die sich allerdings von Proband zu Proband stark unterscheidet. Bei Stimulation außerhalb des motorischen Kortexes, bei der durch Änderung der Aktivität einer umschriebenen Neuronengruppe, behaviorale Effekte erzeugt werden sollen, existiert ein solches direktes Maß der neuronalen Erregbarkeit nicht, weshalb häufig die Stimulationsintensität an die individuelle MT angepasst wird. Die vorliegenden Arbeit stellt, diese Anpassung der Intensität in Frage. Hierzu erhielten Probanden vor der Durchführung eines kognitiven Tests über einer mittels funktioneller Magnetresonanztomographie (fMRT) ermittelten Region des präfrontalen Kortex eine Stimulation. Die Intensität wurde hierbei einmal an die MT angepasst und einmal nicht. Erstmals konnte mittels einer Korrelationsanalyse gezeigt werden, dass es einen Zusammenhang zwischen der Sensitivität des präfrontalen Kortexes und der des Motorkortexes gibt. Dieser Zusammenhang kann zur nachträglichen Korrektur der behavioralen Daten genutzt werden, da die MT die zwischen den Probanden bestehenden relativen Unterschiede erklärt.

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Dystonia is a neurological syndrome characterized by the involuntary contraction of opposing muscles, causing twisting movements or abnormal postures (modified by Fahn, 1987). Writer's cramp is the most common form of task-specific focal dystonia. In the first study, patients with writer's cramp were evaluated for differences in cortical activation during movements likely to induce cramps (complex movements) and movements which rarely lead to dystonia (simple movements). Although complex patient movements during fMRI were never associated with dystonic cramps, they exhibited abnormally decreased cortical activity. This was not observed in simple movements and was unrelated to the character of handwriting or the presence/absence of visual feedback. Our results support the theory of dualistic sensorimotor system behavior in writer's cramp. As the somatosensory system is believed to be affected in focal dystonia, we focused on modulation of the primary somatosensory cortex (SI) induced by repetitive transcranial magnetic stimulation (rTMS) in the second study, in order to improve writer's cramp. In conclusion, 1 Hz rTMS of the SI cortex can improve manifestations of writer's cramp while increasing cortical activity in both hemispheres. Handwriting as well as subjective assessment improved in most...

La stimulation magnétique transcrânienne répétée (SMTr) est une technique de neuromodulation utilisée dans le traitement de la dépression majeure. La stimulation thêta-burst intermittente (STBi), une forme spécifique de SMTr, bénéficie d’un temps de stimulation plus court. Ses mécanismes d’action et sa durée optimale de stimulation restent toutefois inconnus. En effet, en clinique, la durée standard de STBi tend à être allongée dans l’espoir d’augmenter les effets thérapeutiques. Cette hypothèse n’a cependant jamais été vérifiée empiriquement. Le présent mémoire vise ainsi à mieux comprendre les mécanismes neuronaux de la STBi du cortex dorsolatéral préfrontal gauche et à déterminer la durée optimale de stimulation parmi les trois durées les plus fréquemment utilisées : 600 (standard), 1200 et 1800 impulsions. La question est explorée chez 14 participants neurotypiques. Chaque participant a pris part aux trois conditions expérimentales lors de trois sessions distinctes. L’activité cérébrale induite a été mesurée par l’utilisation combinée de la stimulation magnétique transcrânienne et l’électroencéphalographie, via les potentiels évoqués par la SMT (PÉS) et les perturbations spectrales liées à l’évènement (PSLE). Ces mesures ont été comparées avant et après chaque condition à l’aide d’un modèle linéaire mixte. Pour l’ensemble des mesures de l’activité corticale, aucune différence significative n’a été obtenue entre les trois durées. Spécifiquement, la STBi a induit une réduction de l’amplitude de la majorité des PÉS et des PSLE de la bande thêta. Ainsi, le protocole STBi standard engendre une modification de l’activité cérébrale comparable aux durées prolongées, dénotant l’importance de répliquer cette étude auprès d’une population clinique. / Repetitive transcranial magnetic stimulation (rTMS) is a neuromodulation technique used as a treatment of major depressive disorder. Intermittent theta burst stimulation (iTBS), a specific kind of rTMS, offers a reduced stimulation duration. Yet, its mechanism of action and optimal duration are still largely unknown. In clinical settings, standard duration is often increased with the expectation of increasing therapeutic effects. However, this hypothesis has never been tested. This master thesis aims to provide better understanding of neuronal mechanism associated with iTBS on the left dorsolateral prefrontal cortex (DLPFC) of healthy participants and to determine the optimal stimulation duration over the three more commonly used durations in clinical practice: 600 (standard), 1,200 and 1,800 pulses. This was explored in 14 neurotypical participants who experienced each of the three conditions during three different sessions. The induced brain activity was measured combining transcranial magnetic stimulation and electroencephalography, via TMS evoked potentials (TEP) and event-related spectral perturbation (ERSP). These measures were compared before and after each condition using a mixed linear model. For the three durations, no significant difference was found in all cortical activity measures. Specifically, after iTBS, the amplitude of most of the TEPs, as well as of the ERSP of theta band, are reduced. Therefore, the iTBS standard protocol induces a modification of cortical activity which is similar to longer durations, showing the importance of replicating this study on a clinical population.

La stimulation magnétique transcrânienne (SMT) et la spectroscopie par résonance magnétique (SRM) sont des techniques non-invasives permettant de quantifier l’activité GABAergique et glutamatergique du cerveau. La SMT et la SRM ont plusieurs applications en clinique et en recherche. En effet, ces outils peuvent être utilisés afin de déterminer l’efficacité d’un traitement ou la progression d’un processus pathologique. Cependant, malgré leur utilisation croissante dans le domaine médical, une certaine incertitude demeure quant aux substrats neurochimiques de ces techniques et à la stabilité à long terme des données acquises par SMT et SRM. Donc, dans un premier temps, la stabilité à long terme de plusieurs mesures prises par SMT et par SRM a été étudiée. En second lieu, afin de mieux comprendre quelles composantes du système GABAergique sont ciblées par ces deux techniques, des mesures de SRM et de SMT ont été obtenues après l’administration d’une benzodiazépine, le lorazépam, selon un devis expérimental randomisé, croisé, à double-aveugle et contrôlé par placébo. Deux articles composent cette thèse. Le premier article fait état d’une étude longitudinale, auprès d’adultes en santé, ayant pour but de déterminer la stabilité à long terme des concentrations de GABA et de Glx (glutamate + glutamine) obtenues par SRM ainsi que la stabilité des mesures d’inhibition et de facilitation corticale obtenues par SMT (rMT : seuil moteur au repos, %MSO : pourcentage d’intensité maximale du stimulateur, SICI : inhibition intra-corticale courte, LICI : inhibition intra-corticale longue, ICF : facilitation intra-corticale). Il a été démontré que les niveaux de GABA et de Glx sont stables au cours d’une période de trois mois. Alors que les mesures SMT de seuil moteur au repos, d’excitabilité corticale et de période corticale silencieuse sont stables à travers le temps, l’inhibition corticale à court intervalle et à long intervalle ainsi que la facilitation corticale sont beaucoup plus variables. Le deuxième article vise à comprendre la dissociation dans la sensibilité des mesures de SMT et SRM à refléter différentes facettes de l’activité GABAergique du cortex moteur. L’article porte sur une étude dans laquelle du lorazépam a été administré à des participants adultes en santé selon un devis randomisé, croisé, à double-aveugle et contrôlé par placébo. Des données SRM (GABA et Glx; cortex sensorimoteur et occipital) ainsi que des mesures SMT (cortex moteur) ont été obtenues suivant l’administration de lorazépam (ou de placébo). Il a été démontré que la prise de lorazépam réduisait les niveaux de GABA occipitaux, augmentait l’inhibition corticale et réduisait l’excitabilité du cortex moteur. La prise de médicament n’avait pas d’effet sur les autres mesures obtenues. De plus, il a été trouvé que l’effet du traitement sur l’inhibition corticale dépendait des concentrations endogènes de GABA dans le cortex sensorimoteur; une plus grande concentration de GABA étant prédictive d’une plus grande inhibition corticale suivant la prise de lorazépam. Dans leur ensemble, les résultats provenant des deux articles présentés dans cette thèse permettent de conclure que les mesures SRM des divers neurométabolites sont stables à long terme dans le cortex moteur et pourraient potentiellement servir de marqueurs dans l’évaluation de l’efficacité d’un traitement ou de l’évolution de processus pathologiques. Par contre, bien que certaines mesures SMT soient stables à long terme (rMT, %MSO, CSP), d’autres sont beaucoup plus variables (SICI, LICI, ICF); ainsi, la prudence est conseillée dans l’interprétation de ces mesures lors d’études cliniques. De plus, les effets différents que produit la prise de lorazépam sur les mesures SRM et SMT supportent la théorie selon laquelle les deux techniques n’ont pas les mêmes substrats neurochimiques. En effet, alors que les mesures TMS d’inhibition corticale refléteraient l’activité phasique des récepteurs GABAA, le signal SRM de GABA serait majoritairement intracellulaire et ne représenterait pas la neurotransmission GABAergique. / Transcranial magnetic stimulation (TMS) and magnetic resonance spectroscopy (MRS) are non-invasive techniques that allow the measurement of GABAergic and glutamatergic activity in the brain. TMS and MRS can be used to assess inhibitory and excitatory mechanisms, treatment response or disease presence and progression in vivo. However, despite their growing use in research and medical settings, ambiguity remains regarding their neurochemical substrates and long-term reproducibility. The goal of the present thesis is twofold. First, the long-term stability and reliability of various MRS and TMS measurements, obtained in the motor cortex, was investigated. Second, to better understand which aspects of the GABAergic network are targeted by the two techniques, TMS and MRS measures reflecting cortical inhibition and excitation were obtained following lorazepam administration using a placebo-controlled, double-blind, randomized, crossover design. Two articles comprise this thesis. The first article is a longitudinal assessment of the stability and reliability of MRS-GABA and Glx (glutamate + glutamine) and TMS measures of cortical inhibition and facilitation in the sensorimotor (SMC) cortex of healthy adults. It was determined that MRS-GABA and MRS-Glx are stable over a three-month interval. TMS measures of resting motor threshold (rMT), cortical excitability (% maximum stimulator output; MSO) and cortical silent period (CSP) were also found to be stable and reliable. However, paired-pulse TMS measures such as short-interval cortical inhibition (SICI), long-interval cortical inhibition (LICI) and intracortical facilitation (ICF) had greater variability. The second article aims to understand the differential sensitivity of TMS and MRS with respect to GABAergic activity in the primary motor cortex. It is based on the results and conclusions of a placebo-controlled, double-blind, randomized, crossover study, where benzodiazepine lorazepam was given to healthy adult volunteers. Magnetic resonance spectroscopy (GABA and Glx) was performed in the sensorimotor cortex and occipital cortex (OC). TMS measurements were acquired in the motor cortex only. MRS and TMS measures of cortical inhibition and excitability (rMT, input/output (I/O) curve, SICI, LICI, ICF, CSP) were obtained following lorazepam or placebo administration. Lorazepam was found to decrease occipital GABA concentration, increase motor cortical inhibition and decrease cortical excitability. Lorazepam administration had no effect on other neurometabolites or TMS measurements. The effect of Lorazepam on short-interval cortical inhibition was found to depend on endogenous GABA levels in the SMC; higher GABA concentrations predicted a greater increase in SICI following drug intake. Taken together, the studies presented in this thesis indicate that MRS neurometabolite levels are stable over time and may thus potentially serve as markers for the monitoring of disease progression and treatment response. However, while some TMS measures have good long-term stability (rMT, %MSO, CSP), others are not as reliable nor stable (SICI, LICI, ICF); care must be taken in clinical settings. Furthermore, the differential effects of lorazepam on MRS and TMS measures support the idea that the two techniques probe different aspects of the GABAergic system. Whereas TMS measures of cortical inhibition reflect phasic GABAA receptor activity, MRS-GABA primarily reflects intracellular, non-neurotransmitter metabolic GABA.

Deep brain stimulation (DBS) of the globus pallidus internus (GPi) is an effective symptomatic treatment for pharmacoresistant dystonic syndromes. The relationship between grey matter volume and intracortical inhibition of the primary motor cortex (MI) in regard to the effectiveness and the state (ON/OFF) of GPi DBS was analysed in the first study. The grey matter of chronically treated patients showed hypertrophy of the supplementary motor area and cerebellar vermis whereas this difference was more significant in patients with a better clinical outcome. The grey matter of the cerebellar hemispheres of the patients showed positive correlation with the improvement of an intracortical inhibition which was generally less effective in patients regardless of the GPi DBS state. Moreover, we showed the same level of SICI in the good responders as in the healthy controls, while in non-responders was the SICI decreased. In the second study, by using paired associative stimulation (PAS) we studied the influence of primary somatosensory cortex (SI) on the MI excitability in dystonia in regards to the effectiveness of GPi DBS. SI PAS decreased the MI excitability in the GPi DBS ON state while switching the stimulation off decreased an inhibitory effect of SI on MI excitability. Non-responders showed a...

Bakgrund: Visuell snö är ett perceptionsstörande neurooftalmologiskt tillstånd karakteriserat av bestående mikroskopiska flimrande prickar som täcker hela det bilaterala synfältet. Det kan liknas vid att titta genom en flimrande tv-skärm, eller Gaussiskt brus. Några etablerade riktlinjer för behandling finns inte för närvarande. Syfte: Denna litteraturstudie syftar till att undersöka tillgänglig litteratur rörande effekten av olika behandlingsalternativ för tillståndet visuell snö.  Metod: En sökning utfördes i sökmotorn PubMed den 20 mars 2023. Söksträngen som användes var “visual snow” OR “visual snow syndrome” AND “treatment”. Fler studier tillkom genom granskning av referenser. Begränsningar i urvalet baserades på relevans rörande behandling, samt en litteraturstudie utförd av Eren &amp; Schankin publicerad 2020. Den här studien tar upp arbeten tillkomna därefter, totalt 8 artiklar utgivna mellan 2020-2022.  Resultat: Vår studie har lyckats identifiera behandlingsalternativ för visuell snö i form av neuro-optometrisk synträning, farmaceutika, kosttillskott, kiropraktik, filterglasögon, antikroppar, mydriatika, synstimuli, samt repetitiv transkraniell magnetstimulering. Samtliga studier utfördes på deltagare med bekräftad och diagnostiserad visuell snö, antingen som isolerat symptom, som del av Visual Snow Syndrome, eller som sekundärt tillstånd. Positiva behandlingssvar med partiell remission förekommer, samt enstaka fall av total remission. Samtliga inkluderade studier har sina begränsningar, en gemensam sådan är svårigheten att kvantifiera symptomen. Med hjälp av enkäter och symptomdagböcker har 7 av 8 studier visat på viss subjektiv effekt av behandling, av okänd magnitud.  Slutsats: Patofysiologin bakom visuell snö är ännu inte klarlagd. I dagsläget finns ingen generellt applicerbar behandling för visuell snö, men enstaka fall av total remission samt ett antal fall av partiell remission förekommer i litteraturen. Vid behandling av patienter med visuell snö bör hänsyn tas till individuella patienters förutsättningar, komorbiditet och tidigare prövad behandling. / Background: Visual snow is a neuro-ophthalmological perception disorder characterized by persistent microscopic flickering dots covering the bilateral field of vision. It can be described as looking through TV static, or Gaussian noise. There are currently no established guidelines regarding treatment. Purpose: This literature survey aimed to investigate available literature regarding the efficacy of different therapeutic approaches for the condition of visual snow.   Method: A search was performed in the PubMed search engine on March 20, 2023. The search string used was “visual snow” OR “visual snow syndrome” AND “treatment”. Further studies were added through references. Restrictions in article selection were based on relevance regarding treatment, as well as a review by Eren &amp; Schankin published in 2020. This study covers subsequent articles, a total of 8 articles published between 2020-2022. Results: Our study has identified therapeutic approaches to visual snow in the form of neuro-optometric rehabilitation therapy, pharmaceuticals, nutraceuticals, chiropractic treatment, filter glasses, antibodies, mydriatics, visual stimuli, and repetitive transcranial magnetic stimulation. All participants had confirmed and diagnosed visual snow either as an isolated symptom, as part of Visual Snow Syndrome, or as a secondary condition. Positive responses with partial remission occur, as well as occasional total remissions. All included studies have some limitations, a common one being the difficulty in quantifying the symptoms. Using questionnaires and symptom diaries, 7 out of 8 studies have shown some subjective effect of treatment of unknown magnitude.  Conclusion: The pathophysiology behind visual snow is not yet fully understood. Currently, there is no generally applicable treatment for visual snow, but occasional cases of total remission and a number of cases of partial remission appear in the literature. When treating patients with visual snow, the individual patient’s conditions, comorbidity and previously tried treatment should be taken into account.