INTRODUÇÃO: Evidências relevantes acerca dos benefícios da hipotermia terapêutica provieram da utilização de técnicas de resfriamento sistêmico. Essas técnicas, no entanto, podem causar complicações graves que poderiam ser evitadas com métodos de hipotermia encefálica seletiva. O presente estudo objetiva: 1) verificar a viabilidade da hipotermia encefálica exclusiva através de um sistema de resfriamento nasofaríngeo concomitante ao de preservação da temperatura corpórea em suínos e 2) investigar os efeitos da hipotermia encefálica exclusiva nas variáveis fisiológicas sistêmicas e encefálicas. MÉTODOS: Dez suínos híbridos foram submetidos a resfriamento nasofaríngeo durante 60 minutos e subsequente reaquecimento espontâneo. Foram obtidos dados referentes a: pressão arterial média, débito cardíaco, temperatura encefálica, pressão parcial de oxigênio do tecido encefálico (PbtO2, do inglês, pressure of brain tissue O2), velocidade do fluxo sanguíneo nas artérias encefálicas, índice de resistência e índice de pulsatilidade. RESULTADOS: O resfriamento nasofaríngeo associou-se à um decréscimo gradual da temperatura encefálica, que foi mais marcante no hemisfério cerebral esquerdo (p < 0,01). Neste hemisfério, houve redução de 1,47 ± 0,86°C nos primeiros 5 minutos (p < 0,01), 2,45 ± 1,03°C aos 10 minutos e 4,45 ± 1,36°C após 1 hora (p < 0,01). A diferença entre as temperaturas cerebral sistêmica foi 4,57 ± 0,87°C (p < 0,01). As temperaturas centrais (retal, esofágica e da artéria pulmonar), assim como a hemodinâmica encefálica e sistêmica, mantiveram-se estáveis durante o procedimento. Houve diminuição significativa da PbtO2, concomitantemente ao decréscimo da temperatura encefálica. CONCLUSÕES: A indução de hipotermia encefálica exclusiva é possível através de resfriamento nasofaríngeo associado a medidas de preservação da temperatura sistêmica. O resfriamento encefálico exclusivo não influencia as funções hemodinâmicas sistêmicas e encefálicas, contudo reduz significativamente a PbtO2 / INTRODUCTION: Relevant evidences for the use of therapeutic hypothermia derive from studies using whole body cooling methods. These methods can lead to serious complications. To avoid such complications, selective brain cooling methods were developed. The objective of this study was: 1) to verify the feasibility of exclusive brain hypothermia by means of nasopharyngeal cooling along with measures of systemic temperature preservation in an experimental swine model, and 2) to investigate the influence of the exclusive brain cooling on cerebral and systemic hemodynamics as well as on cerebral oxygenation. METHODS: Ten hybrid swine underwent nasopharyngeal cooling for 60 minutes, followed by spontaneous rewarming. A number of physiological variables were monitored: arterial blood pressure, cardiac output, temperature in the right and left cerebral hemispheres, pressure of brain tissue O2, cerebral blood flow velocities, resistance index, and pulsatility index. RESULTS: Nasopharyngeal cooling was associated with decrease in brain temperature, which was more significant in the left cerebral hemisphere (p < 0,01). There was a reduction of 1.47 ± 0.86°C in the first 5 minutes (p < 0.01), 2.45 ± 1.03°C within 10 min, and 4.45 ± 1.36°C after 1 hour (p < 0.01). The brain-core gradient was 4.57 ± 0.87°C (p < 0,001). Rectal, esophageal, and pulmonary artery temperatures, as well as brain and systemic hemodynamics, remained stable during the procedure. PbtO2 values significantly decreased following the brain cooling. CONCLUSION: Achievement of exclusive brain hypothermia is feasible by means of nasopharyngeal cooling associated with measures of systemic temperature preservation. Selective brain cooling does not influence both systemic and cerebral hemodynamics, except PbtO2, which decreased significantly

Recentes evidências sugerem que a dor lombar crônica está associada a alterações plásticas no cérebro, que podem ser modificadas por estratégias de neuromodulação. Neste ensaio clínico investigamos a eficácia analgésica de 12 sessões não consecutivas de estimulação transcraniana por corrente contínua (ETCC), estimulação elétrica periférica (EEP), ETCC+EEP e estimulação simulada (sham) em 92 pacientes com dor lombar crônica inespecífica. A intensidade, aspecto sensorial e afetivo da dor, incapacidade e percepção global de recuperação foram avaliadas antes do tratamento e quatro semanas, três e seis meses pós-randomização. Efeitos adversos, satisfação do paciente com o tratamento e fatores de confusão como ansiedade e depressão também foram avaliados. Os resultados demonstraram efeitos analgésicos clinicamente importantes da ETCC+EEP (MD = -2,6 IC95% = -4,4 a -0,9) e EEP isolada (MD = -2,2 IC95% = -3,9 a -0,4) comparada ao grupo sham, mas não da ETCC isolada (MD = -1,7 IC95% = -3,4 a -0,0). Além da manutenção do efeito analgésico por até três meses a ETCC+EEP obteve maior proporção de respondedores em diferentes pontos de corte. Os resultados sugerem que tanto a ETCC+EEP quanto EEP isolada são eficazes em curto prazo para o alívio da dor lombar crônica inespecífica. No entanto o efeito analgésico mais duradouro aliado a maior proporção de respondedores indicam um possível efeito aditivo e sinérgico da ETCC+EEP no alívio da dor em pacientes com dor lombar crônica não específica. Os nossos resultados não apoiam o uso da ETCC no regime de tratamento utilizado / Recent evidence suggests that chronic low back pain is associated with plastic changes in the brain that can be modified by neuromodulation strategies. In this clinical trial we have investigated the analgesic efficacy of 12 non-consecutive sessions of transcranial direct current stimulation (tDCS), peripheral electrical stimulation (PES), tDCS+PES and sham stimulation in 92 patients with chronic nonspecific low back pain. Intensity, the sensory and affective aspect of pain, disability, and overall perception of recovery were assessed before treatment and four weeks, three and six months post-randomization. Adverse effects, patient satisfaction with treatment and confounding factors such as anxiety and depression were also evaluated. The results showed clinically significant analgesic effects of tDCS+PES (Mean Reduction (MR) = -2.6; CI95% = -4.4 to - 0.9) and PES alone (MD = -2.2, CI95% = -3.9 to -0.4) compared to sham group, but not tDCS alone (MD = -1.7, CI95% = -3.4 to -0.0). In addition to maintaining the analgesic effect for up to three months, tDCS+PES treatment had a higher proportion of responders in different cutoff points. The results suggest that both tDCS+PES and PES alone are effective in relieving chronic nonspecific low back pain in the short term. However the most lasting analgesic effect, combined with a higher proportion of responders, indicates a possible additive and synergistic effect of tDCS+PES in relieving low back pain. Our findings do not support the use of tDCS alone in this condition

Introdução: O presente estudo tem como objetivo avaliar a eficácia da estimulação magnética transcraniana de repetição (EMTr) em freqüência excitatória, aplicada ao córtex pré-frontal dorsolateral direito (CPFDLd), quando adicionada ao tratamento vigente de pacientes com transtorno obsessivocompulsivo (TOC) resistente. Método: 30 pacientes com TOC resistente ao tratamento foram alocados aleatoriamente para receber EMTr ativa ou placebo, sendo que a condição de tratamento permaneceu oculta para pacientes e avaliador. O tratamento vigente permaneceu estável por ao menos 8 semanas. A EMTr foi realizada com uma bobina em formato de oito à freqüência de 10Hz, com 110% do limiar motor em 30 sessões diárias de 40 séries de 5 segundos com 25 segundos de intervalo. A gravidade dos sintomas foi avaliada inicialmente, após 2 e 6 semanas de tratamento e 2 e 6 semanas de seguimento com a escala de Yale-Brown para avaliação de sintomas obsessivo-compulsivos (Y-BOCS), Escala de Impressão Clínica Global (CGI), Escala de Hamilton para ansiedade (HAM-A), Escala de Hamilton para depressão com 17 itens (HAM-D17), e inventário SF-36 de qualidade de vida. A medida primária de eficácia foi definida como redução de 30% ou mais nos escores da Y-BOCS e avaliação melhor ou muito melhor na sub-escala de melhora clínica da CGI ao término do seguimento. Resultados: A análise da medida primária de eficácia revelou que apenas um paciente em cada grupo preencheu critérios de resposta para o tratamento com EMTr (P=1.00). A análise de medidas repetidas dos escores de Y-BOCS mostrou um efeito significativo do tempo (F=7.33, P=0.002). Entretanto, não foi observada diferença entre os grupos ou interação grupo/tempo. A análise de medidas repetidas da CGI (gravidade), HAM-D17 e HAM-A também mostrou efeito significativo do tempo (P<0.001, =0.001 e <0.001 respectivamente), novamente sem diferença significativa entre os grupos ou interação. Conclusão: EMTr excitatória aplicada ao CPFDLd de pacientes com TOC resistente ao tratamento não foi diferente de placebo na redução de sintomas obsessivo-compulsivos ou melhora da impressão clínica global. Entretanto, ocorreu uma resposta placebo significativa / Introduction: The present study aims to evaluate the efficacy of added excitatory repetitive transcranial magnetic stimulation (rTMS), applied to the right dorsolateral prefrontal cortex in patients with treatment resistant obsessive-compulsive disorder (OCD). Methods: 30 treatment resistant OCD outpatients were randomized to receive either active or sham rTMS, remaining both patients and rater blind to treatment condition. Baseline treatment was kept stable for at least 8 weeks, and rTMS was performed with a figure-of-eight coil at 10Hz, 110% of motor threshold at 30 daily sessions of 40 trains of 5 seconds with 25 seconds interval. Symptom severity was determined at baseline and after 2 and 6 weeks of treatment and further 2 and 6 weeks of follow-up, using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), Clinical Global Impression Scale (CGI), Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Rating Scale (HAM-D17) and SF-36 quality of life inventory. The primary outcome measure was defined as 30% or more improvement in Y-BOCS scores and a much improved or improved score at the CGIimprovement subscale by the end of follow up. Results: The analysis of primary outcome measure revealed that only one patient on each group met response criteria for treatment with rTMS (P=1.00). Repeated-measures analysis of Y-BOCS scores showed a significant effect of time (F=7.33, P=0.002). However, no significant group effect or group by time interaction was observed. Repeated measures analysis of CGI (severity), HAM-D17 and HAM-A also showed a significant effect of time (P<0.001, =0.001 and <0.001 respectively) with no significant group effect or group by time interaction. Conclusion: Excitatory rTMS delivered to the rDLPFC of treatment resistant OCD patients was not different from placebo in reducing obsessive-compulsive symptoms or improving clinical global impression. However, a significant placebo response occurred

La faiblesse des muscles périphériques, définie par une diminution de la force maximale volontaire en dehors de tout état de fatigue neuromusculaire, est une complication fréquente de la broncho-pneumopathie chronique obstructive (BPCO). La force maximale volontaire dépend à la fois des propriétés musculaires périphériques (i.e. volume et architecture musculaire, qualités contractiles) et de la capacité du système nerveux à activer le muscle maximalement. Dans la BPCO, plusieurs travaux ont souligné l'existence paradoxale d'une perte de force maximale volontaire sans altérations musculaires périphériques et sans qu'un déficit d'activation volontaire n'ait clairement été identifié. Pourtant, les patients atteints de BPCO présentent de nombreuses altérations du système nerveux, compatibles avec une capacité d'activation volontaire altérée.L'objectif de ce travail de thèse était donc de tester l'implication du système nerveux dans la faiblesse musculaire de la BPCO et d'en déterminer les mécanismes sous-jacents. Au cours de nos travaux, nous avons mis en évidence une activité corticale diminuée dans la BPCO lors de contractions maximales et sous-maximales volontaires. Nous avons par ailleurs rapporté une perte d'excitabilité du cortex moteur et un déficit d'activation volontaire spécifique aux patients atteints de faiblesse musculaire. Ces résultats sont en accord avec une implication des altérations cérébrales dans la faiblesse musculaire périphérique de la BPCO. Nous sommes ensuite parvenus à identifier une origine potentielle des altérations cérébrales : les désaturations en O2 au cours du sommeil avec mouvements non-rapides des yeux (NREM). Cette hypothèse a été corroborée par l'observation d'un niveau d'activation volontaire réduit chez les patients désatureurs en sommeil NREM. En revanche, aucune répercussion significative n'a pu être observée sur la force maximale volontaire de ces patients, suggérant l'existence d'un mécanisme compensatoire. In fine, nos résultats constituent une avancée importante dans la compréhension du phénomène de faiblesse musculaire, classiquement attribué à la seule perte de masse musculaire. L'implication du système nerveux central dans la faiblesse musculaire ouvre notamment la voie à de nouvelles modalités de prise en charge par des approches spécifiques, dans l'optique de lutter contre la faiblesse musculaire et ses multiples répercussions négatives dans la vie du patient atteint de BPCO. / Peripheral muscle weakness, as defined by a reduced voluntary strength outside any state of neuromuscular fatigue, is a common complication of chronic obstructive pulmonary disease (COPD). Maximal voluntary strength is determined by both peripheral muscle properties (i.e. muscle volume and architecture, contractile quality) and the nervous system's ability to activate the muscle maximally. In COPD, many studies highlighted the paradoxical existence of maximal voluntary strength loss without any peripheral muscle impairment, and without a clearly identified voluntary activation deficit. However, patients with COPD exhibited several nervous system alterations compatible with a reduced maximal voluntary activation capacity. The aim of this thesis was to test the nervous system implication in COPD muscle weakness and to determine the involved mechanisms. As major results, we found a reduced cortical activity in COPD during maximal and sub-maximal voluntary contractions. Furthermore, we reported reduced motor cortex excitability and voluntary activation deficit, specifically in patients with muscle weakness. These results are in accordance with an involvement of cortical alterations in COPD muscle weakness. Then, we indentified a potential origin for cortical alterations: O2 desaturation during non-rapid eye movement (NREM) sleep. This hypothesis has been corroborated by the observation of a reduced voluntary activation in patients with NREM sleep desaturation. However, no significant repercussion could have been observed on maximal voluntary strength in these patients, suggesting a compensatory mechanism.Our results are an important step forward in understanding the COPD muscle weakness that was classically attributed to loss of muscle mass only. The involvement of the central nervous system in COPD muscle weakness also brings about new patient care opportunities via tailored approaches, in order to fight against muscle weakness and its deleterious consequences on a patient's life.

Estimulação Magnética Transcraniana profunda (EMTp) modula estruturas corticais mais profundas, como a Ínsula Posterior Superior (IPS) e o Córtex Cingulado Anterior (CCA) e tem sido usada para tratar condições não anteriormente sensíveis à EMT superficial. No entanto, até o momento, nenhum estudo avaliou os efeitos da EMTp na cognição após várias sessões de estimulação de maneira abrangente, especialmente em pacientes com disfunção cognitiva basal devido a lesões estruturais da SNC. Apresentamos resultados secundários de um estudo randomizado paralelo de três braços sobre os efeitos da EMTp ativa de 10Hz para o CCA ou IPS contra EMTp simulada na avaliação neuropsicológica de 98 pacientes com dor neuropática central submetidos a um curso de 12 semanas (16 sessões) de tratamento. Vários canais cognitivos foram avaliados em um desenho cego (atenção, controle inibitório, velocidade de processamento, flexibilidade mental, fluência verbal-fonêmica e semântica, memória operacional e episódica, cognição global e percepção visual) no início e após o último dia de estimulação. Nós observamos que não há efeitos do córtex Insular Posterior Superior (IPS) ou do Cíngulado Anterior (CCA) comparado com EMTp simulada na dor clínica, apesar do achado antinociceptivo significativo nos limiares térmicos após EMTp- IPS e um efeito ansiolítico significativo de EMTp- CCA comparado com estimulação simulada. Não encontramos efeitos significativos da estimulação ativa para o IPS ou para o CCA em comparação com a estimulação simulada em qualquer um dos domínios cognitivos. Os autores concluíram que a EMTp CCA/IPS de alta frequência e repetidas sessões de longa duração é segura em pacientes com lesões do SNC que apresentam lesões cerebrais estruturais e comprometimento cognitivo significantes / Deep-TMS (dTMS) modulates deeper cortical structures such as the posterior superior insular (PSI) and the anterior cingulate cortices (ACC) and has been used to treat conditions not previously responsive to superficial-TMS. However, to date no study has assessed the effects of dTMS on cognition after several sessions of stimulation in a comprehensive manner, especially in patients with baseline cognitive dysfunction due to SNC structural lesions. We present secondary outcome results form a three-arm parallel randomized trial on the effects of active10Hz dTMS to either the ACC or PSI against sham dTMS on neuropsychological assessment of 98 central neuropathic pain patients undergoing a 12-week (16 sessions) course of treatment. Several cognitive channels were assessed in a blinded design (attention, inhibitory control, processing speed, mental flexibility, verbal fluency-phonemic and semantic, working and episodic memory, global cognition and visual perception) at baseline and after the last day of stimulation. We observed that there were no effects of either posterior insular (PSI) or anterior cingulate cortex (ACC) compared to sham dTMS on clinical pain, despite the finding of a significant anti-nociceptive on thermal thresholds after PSI d- TMS and a significant anxiolytic effect of ACC d-TMS compared to sham stimulation. We found no significant effects of active stimulation to either the PSI or to the ACC compared to sham stimulation in any of the cognitive domains. Long-term repetitive-session high frequency ACC/PSI- dTMS is safe in patients with structural SNC lesions who have baseline significant structural brain lesions and cognitive impairment

Mes travaux de thèse portent sur l’application de l’imagerie fUS (functional ultrasound imaging) à l’imagerie cérébrale préclinique chez le petit animal. Le but était de transformer cette technique d’imagerie cérébrale récente en un véritable outil de quantification de l’état cérébral. Les objectifs principaux ont été de démontrer la faisabilité de l’imagerie fUS chez le petit animal non anesthésié ainsi que de passer du modèle rat au modèle souris - modèle de choix en imagerie préclinique en neurosciences - de surcroît de façon non invasive. J’ai tout d’abord mis au point une nouvelle séquence d’imagerie ultrasonore ultrarapide (Multiplane Wave imaging), permettant d’améliorer le rapport signal-à-bruit des images grâce à l’augmentation virtuelle de l’amplitude du signal émis, sans diminuer la cadence ultrarapide d’acquisition. Dans un deuxième temps j’ai démontré la possibilité d’imager le cerveau de la souris et du jeune rat anesthésiés par échographie Doppler ultrarapide, de manière transcrânienne et complètement non invasive, sans chirurgie ni injection d’agents de contraste. J’ai ensuite mis au point un montage expérimental, une séquence ultrasonore et un protocole expérimental permettant de réaliser de l’imagerie fUS de manière minimalement invasive chez des souris éveillées et libres de leurs mouvements. Enfin, j’ai démontré la possibilité d’utiliser le fUS pour étudier la connectivité fonctionnelle du cerveau au repos (sans stimulus) chez des souris éveillées ou sédatées. L’imagerie fUS et la combinaison « modèle souris » + « minimalement invasif » + « animal éveillé » + « connectivité fonctionnelle » constituent un outil précieux pour la communauté des neuroscientifiques travaillant sur des modèles animaux pathologiques ou de nouvelles molécules pharmacologiques / My work focuses on the application of fUS (functional ultrasound) imaging to preclinical brain imaging in small animals. The goal of my thesis was to turn this recent vascular brain imaging technique into a quantifying tool for cerebral state. The main objectives were to demonstrate the feasibility of fUS imaging in the non-anaesthetized small rodents and to move from rat model imaging to mouse model imaging –most used model for preclinical studies in neuroscience-, while developing the least invasive imaging protocols. First, I have developed a new ultrafast ultrasonic imaging sequence (Multiplane Wave imaging), improving the image signal-to-noise ratio by virtually increasing emitted signal amplitude, without reducing the ultrafast framerate. Then, I have demonstrated the possibility to use ultrafast Doppler ultrasound imaging to image both the mouse brain and the young rat brain, non-invasively and through the intact skull, without surgery or contrast agents injection. Next, I have developed an experimental setup, an ultrasound sequence and an experimental protocol to perform minimally invasive fUS imaging in awake and freely-moving mice. Finally, I have demonstrated the possibility to use fUS imaging to study the functional connectivity of the brain in a resting state in awake or sedated mice, still in a transcranial and minimally invasive way. fUS imaging and the combination of "mouse model" + "minimally invasive" + "awake animal" + "functional connectivity" represent a very promising tool for the neuroscientist community working on pathological animal models or new pharmacological molecules

La schizophrénie (SZ) est une pathologie psychiatrique chronique et invalidante dont les conséquences fonctionnelles sont principalement liées à des déficits cognitifs. Ceux-ci sont étroitement associés à des déficits de perception auditive précoce d’informations de bas niveaux telle que la hauteur sonore. La perception auditive précoce peut s’évaluer avec un paradigme comportemental simple appelé « tone-matching » (appariement tonal AT), dans le lequel les sujets doivent discriminer activement entre deux sons courts (300-ms) d’une même paire séparés par un intervalle bref (500-ms). Les performances d’AT reflètent un processus cognitif de comparaison préattentionnelle se déroulant au sein du système auditif central (SAC). Le SAC est constitué du noyau géniculé médian du thalamus (MGN), de l’aire corticale auditive précoce (EA) et de l’aire corticale auditive associative (AA). Cependant, les dysfonctionnements du SAC sous-tendant les déficits d’AT dans la SZ restent mal connus. De plus, ces déficits sont élevés mais hétérogènes selon les cohortes. Ce travail de thèse propose de caractériser le fonctionnement du SAC associé aux performances d’AT chez les sujets SZ afin de mieux comprendre la physiopathologie du trouble et de développer des traitements ciblés. L’hypothèse guidant les 4 études expérimentales de ce travail est que des altérations psychophysiques et neurophysiologiques spécifiques du SAC sont impliquées dans les déficits d’AT dans la SZ. Nos études psychophysiques utilisant différents paradigmes de « tone-matching » ont montré 1) un déficit d’AT de magnitude croissante pour l’intensité, la hauteur et la longueur des stimuli auditifs chez les sujets SZ (n=29), 2) un déficit d’appariement de trios de sons médiant une corrélation entre les déficits d’appariement de paires de sons (AT proprement dit) et l’identification de phrases émotionnelles (n=27). Ces résultats démontrent que les sujets SZ présentent différents niveaux de déficits d’AT selon le type de caractéristique acoustique, ainsi que des niveaux de déficits hiérarchiquement organisés entre les types de complexité des stimuli auditifs perçus. 3) Nos approches neurophysiologiques ont montré une distribution bimodale des performances d’AT chez les sujets atteints de SZ (n=310) avec un 1er groupe présentant une réduction significative de ces performances associée à une réduction de la connectivité fonctionnelle de repos à l’IRM entre les différentes régions du SAC (MGN-EA, MGN-AA et EA-AA impliquant particulièrement des sous-régions AA adjacentes à l’EA) et un 2nd ne présentant pas de déficits d’AT mais une réduction plus modérée de la connectivité uniquement entre EA-AA. Ces résultats démontrent que les performances d’AT permettent de séparer deux sous-types de SZ présentant des patterns topographiques spécifiques de dysconnectivité fonctionnelle de repos au sein du SAC. 4) Les résultats préliminaires de l’étude de l’effet d’une procédure de stimulation électrique transcrânienne non invasive (tES) ciblant le SAC gauche (2mA, 10x20min) montrent une modulation significative des performances d’AT après la procédure de stimulation chez les sujets SZ (n=2). Cela suggère que les déficits d’AT pourraient être dépendants de mécanismes d’excitabilité et de plasticité des neurones du SAC modulables par tES. Pris ensembles, ces résultats confirment l’influence d’altérations mécanistiques du SAC sur les déficits d’AT dans la SZ, dont les spécificités anatomo-fonctionnelles seront à confirmer par des études de validation et des explorations neurophysiologiques « temps réel » du SAC en situation d’AT. En perspective, comme les paradigmes de « tone-matching » peuvent être implémentés facilement en pratique clinique, ces nouvelles donnés pourront permettre de différencier facilement des sous-types physiopathologiques de patients, et de développer des approches thérapeutiques ciblées sur le SAC à la fois en tES et en entraînement cognitif sensoriel / Schizophrenia (SZ) is a chronic brain disorder with outcome primarily driven by deficits in cognition. These have been related to impaired discrimination of basic auditory information such as pitch, as assessed in tone-matching behavioral paradigms in which subjects are asked to actively discriminate between two short pure tones (300-ms) following a brief delay (500-ms). More specifically, tone-matching indexes early, pre-attentive comparison mechanisms occurring in the central auditory system (CAS, divided into thalamic medial geniculate nucleus (MGN), early auditory (EA) and association auditory (AA) cortical areas). Therefore, characterisations of the CAS functioning associated with tone-matching abilities in SZ individuals may be useful drivers for pathophysiology understanding and therapeutic development. First, we aimed at exploring tone-matching abilities in SZ across major acoustic features (length, pitch, intensity) and different levels of complexity (2-tones, 3-tones, emotional sentences) using psychophysical testing. We predicted that patients would display differential deficits across acoustic features, and present a mediated relationship between tone-matching levels of complexity. Second, we investigated the CAS functioning associated with tone-matching at a neurophysiological level, using resting-state functional connectivity MRI (rsFC-MRI) and CAS-targeted transcranial electrical stimulation (left fronto-temporal tES, 2mA, random noise current, ten 20-min twice-daily sessions). We predicted that functional dysconnectivity within the CAS would be associated with tone-matching impairments, and that tES would significantly modulate these impairments in patients. As complementary, we reviewed historical aspects of basic auditory explorations in SZ and studies investigating basic auditory-training approaches as a potential remediative treatment. Psychophysical studies demonstrated more prominent deficits for length than pitch and, in turn, than intensity (n=29), and showed that 3-tones discrimination mediates the correlation between 2-tones and auditory emotion recognition deficits (n=27). Neurophysiological approaches showed that tone-matching performances are bimodally distributed across SZ subjects (n=310), with one group (SZ-) showing significant reductions in both tone-matching and rsFC-MRI in regions of the bilateral CAS (i.e., between MGN and both EA and AA, as well as reductions between EA and AA, particularly involving parcels which are immediately adjacent to EA), and one group (SZ+) showing intact tone-matching and significant reductions only in EA-AA connectivity. The investigation of CAS-targeted tES impact on tone-matching abilities in patients is still ongoing, but preliminary results demonstrated significant modulations of tone-matching scores after the tES procedure (n=2). Our results demonstrate that SZ individuals present with different patterns of tone-matching deficits across acoustic features, but similar yet hierarchical levels of impairments for processing of simple vs. more complex auditory stimuli. Nevertheless, both feature- and complexity- dependant tone-matching deficits might be associated with different types of anatomo-functional underpinnings in the CAS. In addition, we showed that tone-matching measure segregates between discrete SZ subgroups presenting distinct topographic patterns of functional dysconnectivity in the CAS. Finally, tone-matching deficits might be related to neuronal excitability and plasticity mechanisms in the SAC that are modulated by tES. As tone-matching paradigms can be readily implemented within routine clinical settings, these experimental results may be useful to permit differentiation of discrete subtypes of SZ and to develop both non-invasive brain stimulation and remediative approaches

Diss. (sammanfattning) Umeå : Umeå universitet, 2009. / Härtill 3 uppsatser. Även tryckt utgåva.

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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