<p dir="ltr">Sensory feedback is a critical component for controlling neuroprosthetic devices and brain-machine interfaces (BMIs). A lack of sensory pathways can result in slow, coarse movements when using either of these technologies and, in addition, the user is unable to fully interact with the environment around them. Spinal cord stimulation (SCS) has shown potential for restoring these pathways, but traditional stimulation patterns with constant parameters fail to reproduce the complex neural firing necessary for conveying sensory information. Recent studies have proposed various biomimetic stimulation patterns as a more effective means of evoking naturalistic neural activity and, in turn, communicating meaningful sensory information to the brain. Unlike conventional patterns, biomimetic waveforms vary in frequency, amplitude, or pulse-width over the duration of the stimulation. To better understand the role of these parameters in sensory perception, this thesis worked to investigate the effects of SCS patterns utilizing stochastic frequency modulation, linear frequency modulation, and linear amplitude modulation. By calculating sensory detection thresholds and just-noticeable differences, the null hypothesis for stochastically-varied frequency and linear amplitude modulation techniques was rejected.</p>

Introdução: Níveis elevados de ansiedade têm sido associados com intensidade e comportamento da dor em pacientes com dores aguda e crônica. Foi observado, em indíviduos com síndrome dolorosa miofascial (SDM), que o estresse e a ansiedade aumentam a predisposição para o desenvolvimento de pontos-gatilhos miofasciais. Adicionalmente a isto, existe a tendência do indivíduo experimentar emoções negativas em situações de estresse (neuroticismo), característica de personalidade associada ao traço de personalidade, que pode influenciar negativamente na experiência de dor. Indivíduos com alta ansiedade-traço são geralmente hipersensíveis a estímulos e psicologicamente mais reativos. É concebível supôr a coexistência de alteração na excitabilidade cortical, entre dor crônica e ansiedade nestes pacientes. Para melhorar a compreensão dos mecanismos centrais relacionados à ansiedade e à dor crônica, avaliou-se os parâmetros de excitabilidade cortical, usando estimulação magnética transcraniana (EMT), pulso único e pareado. Nossa hipótese é que a excitabilidade corticoespinhal seja modulada pela ansiedade favorecendo a perda de influxo inibitório descendente. Objetivos: O presente estudo teve como objetivo responder a três perguntas relacionadas à síndrome dolorosa miofascial (SDM): 1) A excitabilidade do córtex motor está relacionada com a ansiedade-traço? 2) A ansiedade-traço modula alterações da excitabilidade corticoespinhal, após dor evocada pelo Quantitative Sensory Testing (QST)? 3) A ansiedade-traço prevê resposta à dor evocada pelo QST, se receber simultaneamente um estímulo heterotópico [Conditioned Pain Modulation (CPM)]? Pacientes e métodos: Foram incluídas mulheres com SDM (n = 47) e controles saudáveis (n = 11), com idade entre 19 e 65 anos. A excitabilidade do córtex motor foi avaliada pela EMT, e a ansiedade foi avaliada com base no Inventário de Ansiedade Traço-Estado (IDATE). A incapacidade relacionada à dor foi avaliada pelo perfil da escala de dor crônica para a população brasileira (B:PCP:S), e as medidas psicofísicas da dor foram medidas pelo QST e CPM. Resultados: Nas pacientes, a ansiedade-traço foi positivamente correlacionada com a facilitação intracortical (FIC) no baseline e após a dor evocada pelo QST (β = 0,05 e β = 0,04, respectivamente) e negativamente relacionada com o período de silêncio cortical (PSC) no baseline e após a dor evocada pelo QST (β = -1,17 e β = -1,23, respectivamente) (P <0,05 para todas as comparações). Após dor evocada pelo QST, a incapacidade relacionada à dor crônica foi positivamente correlacionada com a FIC (β = 0,02) (P <0,05). Os escores de dor durante o CPM foram positivamente correlacionados com a ansiedadetraço, quando a incapacidade relacionada à dor crônica foi igualmente alta (β = 0,39, P = 0,02). A excitabilidade cortical das controles saudáveis permaneceu inalterada após o QST. Conclusões: Estes resultados sugerem que, na SDM, o desequilíbrio entre os sistemas excitatórios e inibitórios descendentes do trato corticoespinhal está associado concomitantemente a maiores níveis de ansiedade-traço e maiores níveis de incapacidade funcional ocasionados pela dor crônica. / Background: High levels of anxiety have been associated with the intensity and pain behavior in patients with acute and chronic pain. It was observed that in subjects with myofascial pain (SDM), stress and anxiety syndrome increase the predisposition for the development of myofascial trigger points. In addition to this, there is a tendency of individuals to experience negative emotions in stressful situations (neuroticism), personality characteristic associated with trait personality that may negatively influence in the experience of pain. Individuals with higher trait anxiety are usually hypersensitive to stimuli and more psychologically reactive. It is conceivable to assume the co-existence of change in cortical excitability, chronic pain and anxiety, in these patients. To improve the understanding of the central mechanisms related to anxiety and chronic pain, we assessed cortical excitability parameters by single and paired pulse transcranial magnetic stimulation (TMS). We hypothesize that corticospinal excitability is modulated by anxiety favoring loss of descendent inhibitory influx. Objectives: This study aimed to answer three questions related to chronic myofascial pain syndrome (MPS): 1) Is the motor cortex excitability, as assessed by transcranial magnetic stimulation parameters (TMS), related to state-trait anxiety? 2) Does anxiety modulate corticospinal excitability changes after evoked pain by Quantitative Sensory Testing (QST)? 3) Does the state-trait anxiety predict the response to pain evoked by QST if simultaneously receiving a heterotopic stimulus [Conditional Pain Modulation (CPM)]? Patient and methods: We included females with chronic MPS (n=47) and healthy controls (n=11), aged from 19 to 65 years. Motor cortex excitability was assessed by TMS, and anxiety was assessed based on the State-Trait Anxiety Inventory. The disability related to pain (DRP) was assessed by the Profile of Chronic Pain scale for the Brazilian population (B:PCP:S), and the psychophysical pain measurements were measured by the QST and CPM. Results: In patients, trait-anxiety was positively correlated to intracortical facilitation (ICF) at baseline and after QST evoked pain (β= 0.05 and β= 0.04, respectively) and negatively correlated to the cortical silent period (CSP) (β= -1.17 and β= -1.23, respectively) (P <0.05 for all comparisons). After QST evoked pain, the DRP was positively correlated to ICF (β= 0.02) (P<0.05). Pain scores during CPM were positively correlated with trait-anxiety when it was concurrently with high DRP (β= 0.39; P= 0.02). Controls’cortical excitability remained unchanged after QST. Conclusions: These findings suggest that, in chronic MPS, the imbalance between excitatory and inhibitory descending systems of the corticospinal tract is associated with higher trait-anxiety concurrent with higher DRP.

How are neuromodulatory networks organised to adapt sensory discrimination for different contexts? I hypothesised that neurons within a sensory circuit express different neuromodulatory receptors for differential modulation. Here I aimed to use the simple and genetically amenable Drosophila larval Mushroom Body (MB) calyx, a higher order processing area involved in learned odour discrimination, as a model to map octopamine (OA) neuromodulatory circuitry. I first identified olfactory projection neurons (PNs), a GABAergic feedback neuron and cholinergic extrinsic neurons as putative postsynaptic partners to OA neurons in the MB calyx using GFP reconstitution across synaptic partners. Next, I used novel EGFP-tagged OA receptors generated from recombination-mediated cassette exchange with MiMIC insertions in receptor genes to visualise endogenous expression patterns of OA receptors. Most notably, this is the first report of α2-adrenergic-like OA receptor localisation in any insect. For the first time, I showed that the α1-adrenergic-like OAMB localised to PN presynaptic terminals in the calyx; while Octβ1R localised diffusely in the calyx, resembling the innervation pattern of MB neuron dendrites. I detected EGFP-tagged Octα2R and Octβ2R in some PN cell bodies but not in neuron terminals - suggesting that Octα2R and Octβ2R may be expressed in some PNs, provided the misfolded fusion proteins are retained in the cell bodies of the neurons they are normally expressed in. Furthermore, I found that Octα2R and GABAAR fusion proteins localised to OA cell bodies but not to neuronal terminals, suggesting that OA neurons are subjected to inhibition, again given that these are not artefacts of the fusion proteins. To obtain tools to study OA modulation in the larval calyx, I then confirmed the expression patterns of driver lines that more specifically labelled calyx-innervating OA and extrinsic neurons, and tested the efficacy of three OAMB receptor knockdown lines. This initial attempt of mapping OA receptors, while subjected to further verification and development, is consistent with my hypothesis that a single neuromodulatory source can regulate multiple neuronal types in the same circuit through the distribution of different types of neuromodulatory receptors. This provides a new perspective in how the anatomical organisation of neuromodulation within a sensory network may translate to flexible outputs.

Tinnitus continues to challenge patients from all walks of life and clinicians from a variety of disciplines. The lack of an evidence base to support a specific treatment confounds efforts to provide consistent benefit to patients and in many instances creates in the patient the impression that nothing can be done to improve their situation. Part of the problem is that although patients rarely experience complete elimination of a tinnitus signal, they often experience relief when receiving effective counseling, specific coping strategies, and sound therapy. Although in most clinical activities the tinnitus remains (i.e., it is not cured), its influence may wane as the patient learns to manage their environment, activities, and ultimately their response to tinnitus. At the same time, several medical interventions target reduction of the tinnitus sound, an approach more consistent with what patients expect as a cure. Therefore, the majority of clinical activity directed at care for patients with tinnitus typically targets either elimination of the tinnitus sound (tinnitus treatment) or modification of the patient's response to the sound (tinnitus management). This review distinguishes and offers examples of both treatment and management programs employed clinically for patients with tinnitus.

Normal movement execution requires proper coupling of motor and sensory activation. An increasing body of literature supports the idea that incorporation of sensory stimulation into motor rehabilitation practices increases its effectiveness. Paired associative stimulation (PAS) studies, in which afferent and efferent pathways are activated in tandem, have brought attention to the importance of well-timed stimulation rather than non-associative (i.e., open-loop) activation. In patients with tetraplegia resulting from spinal cord injury (SCI), varying degrees of upper limb function may remain and could be harnessed for rehabilitation. Incorporating associative sensory stimulation coupled with self-paced motor training would be a means for supplementing sensory deficits and improving functional outcomes. In a motor rehabilitation setting, it seems plausible that sensory feedback stimulation in response to volitional movement execution (to the extent possible), which is not utilized in most PAS protocols, would produce greater benefits. This capability is developed and tested in the present study by implementing a brain-computer interface (BCI) to apply sensory stimulation synchronized with movement execution through the detection of movement intent in real time from electroencephalography (EEG). The results demonstrate that accurate sensory stimulation application in response to movement intent is feasible in SCI patients with chronic motor deficit and often precedes the onset of movement, which is deemed optimal by PAS investigations that do not involve a volitional movement task.

La question du rôle du cortex dans la modulation des afférences somesthésiques inhérente à l'intégration sensorimotrice et au contrôle moteur reste l'objet de recherches cliniques et fondamentales. Si le cortex moteur primaire (M1) occupe un rôle central dans le contrôle du mouvement en participant activement à l'élaboration du plan moteur et à son exécution, il semble réciproquement influencé par les afférences somesthésiques générées par le mouvement. Il est probable que réciproquement il soit capable de moduler ces afférences somesthésiques. L'objectif principal de ce travail de thèse était d'apporter des arguments en faveur de cette modulation potentielle des afférences somesthésiques par le cortex moteur. Nous nous sommes, dans ce contexte, intéressés à la stimulation électrique chronique du cortex moteur (SCM) utilisée dans la prise en charge de certaines douleurs neuropathiques et dont les mécanismes de l'effet analgésique demeurent mal connus. Afin de mettre en évidence une possible neuromodulation induite par la SCM nous avons étudié son influence sur les rythmes corticaux liés au mouvement, particulièrement la synchronisation du rythme béta suivant le mouvement (SLE β) sachant qu'il existe des arguments en faveur d'une relation entre SLE β et le traitement cortical des afférences somesthésiques liées au mouvement. La première partie du travail a consisté à conforter cette probable influence des afférences somesthésiques corticales sur la SLE β. Nous avons pour ce faire étudié les profils de SLE β en enregistrement électroencéphalographique (EEG) 128 voies chez des patients présentant, dans un contexte de douleurs neuropathiques, une déafférentation sensitive d'origine centrale ou périphérique, documentée par une altération des potentiels évoqués somesthésiques (PES). Nous avons pu constater que la déafférentation sensitive provoquait une destructuration du profil de SLE β en comparaison à une population de volontaires sains. En effet, les patients présentaient une SLE β dont la distribution spatiale était restreinte et volontiers ipsilatérale au mouvement du côté douloureux contrairement à la distribution spatiale physiologique de la SLE β volontiers bilatérale à prédominance controlatérale au mouvement. Nous avons donc conclu au terme de cette première partie que la SLE β pouvait être considérée comme un reflet des afférences somesthésiques au niveau cortical et un bon outil de l'étude de l'intégration sensori-motrice. La deuxième partie du travail a consisté à étudier les effets de la SCM sur les modifications de la SLE β en condition de déafférentation sensitive. Nous avons exploré les profils de SLE β chez des patients éligibles à une SCM pour la prise en charge de leurs douleurs neuropathiques. Ces explorations ont eu lieu avant et durant la réalisation de la SCM. Nous avons pu constater une modulation significative de la SLE β par la SCM avec une restauration d'une distribution spatiale plus physiologique. Compte tenu du rôle du thalamus dans la génèse des oscillations corticales, des connexions réciproques du cortex moteur et du thalamus et de l'influence des afférences somesthésiques sur la SLE β, nous avons supposé que la SCM facilitait les afférences somesthésiques thalamo-corticales liées au mouvement. Dès lors, nous nous sommes intéressés dans une troisième partie aux effets de la SCM sur les PES de ces patients. Nous avons constaté chez certains d'entre eux une augmentation de l'amplitude des potentiels N20/P25, et ce de façon corrélée à l'effet analgésique de la SCM. Notre travail semble apporter des arguments en faveur d'une capacité du cortex moteur à moduler les afférences somesthésiques tout au moins en condition non physiologique d'une stimulation électrique. Ces résultats sont concordants avec des données cliniques et fondamentales antérieurement rapportées dans la littérature.

Ces travaux de thèse portent sur l'étude de nouvelles modalités de guidage de la thérapie transcrânienne par ultrasons focalisés, technique non invasive particulièrement prometteuse pour le traitement de troubles neurologiques tels que le tremblement essentiel ou le tremblement parkinsonien. Une nouvelle technique d'imagerie par résonance magnétique a tout d'abord été utilisée pour imager l'emplacement du faisceau ultrasonore produit par un prototype préclinique : les déplacements induits par les ultrasons dans une cervelle de veau ex vivo ont été imagés sans distorsion à l'aide d'une séquence d'écho de spin accélérée, avec un dépôt d'énergie jusqu'à quatre fois inférieur aux techniques existantes. Nous avons ensuite étudié les effets directs des ultrasons sur l'activité cérébrale par neuromodulation ultrasonore in vivo, de façon similaire à la stimulation magnétique transcrânienne, mais avec les capacités de ciblage millimétriques des ultrasons focalisés. Des expériences ont été tout d'abord menées sur un modèle de rat anesthésié afin d'étudier la pression seuil pouvant induire un effet moteur. Le champ acoustique simulé dans la tête de rat est fortement affectée par des réverbérations, ce qui doit être pris en compte pour l'évaluation in situ des paramètres acoustiques de neurostimulation, en particulier à basse fréquence et pour les petits animaux. Enfin, pour la première fois, nous avons montré que les ultrasons focalisés de faible intensité pouvaient moduler de façon causale le comportement d'un primate non humain éveillé: le temps de latence d'une tâche d'anti-saccade est retardé de façon significative par des ultrasons focalisés dans le champ visuel frontal.

An innovative mathematical architecture for modelling neuronal electrical activity is presented, called the cognitive rhythm generator (CRG), wherein the proposed architecture is a hybrid model comprised of three interconnected stages, namely: (1) a bank of neuronal modes; (2) a ring device (limit-cycle oscillator); and (3) a static output nonlinearity (mapper). Coupled CRG networks are employed to emulate and elucidate the dynamics of biological neural networks, including the recurrent networks in the hippocampus. Several species of ring devices are described and investigated, including the clock, labile clock, hourglass and multistable ring systems, and their applications to neuronal modelling explored. Complexity measures such as the maximum Lyapunov exponent, correlation dimension and detrended fluctuation analysis are applied to compare model and biological records and validate the CRG methodology. The basis of neural coding is also examined in mathematical detail, with particular regard to its description by Volterra-Wiener kernel formalism, from which the neuronal modes are derived. Applications to theta-gamma coding are discussed. Further on in the thesis, a CRG epileptiform network model of spontaneous seizure-like events (SLEs) is developed and used as a platform to test neuromodulation approaches for seizure abatement. (Neuromodulation mentioned here refers to methods involving electrical stimulation of neural tissue for therapeutic benefit). Spontaneous SLE transitions in the epileptiform network are shown to be related to the mechanism of intermittency, as determined by examining the state space dynamics of the model. The onset of SLEs is associated with increased network excitability and decreased stability, consistent with experimental results from the low-magnesium/high-potassium in vitro model of epilepsy. Lastly, a novel strategy for therapeutic neuromodulation is presented wherein a coupled CRG network (called the “therapeutic network”) is interfaced with the epileptiform network model, forming a closed loop for responsive, biomimetic neuromodulation of the epileptiform network. Relevance to clinical applications and future work is discussed.

An innovative mathematical architecture for modelling neuronal electrical activity is presented, called the cognitive rhythm generator (CRG), wherein the proposed architecture is a hybrid model comprised of three interconnected stages, namely: (1) a bank of neuronal modes; (2) a ring device (limit-cycle oscillator); and (3) a static output nonlinearity (mapper). Coupled CRG networks are employed to emulate and elucidate the dynamics of biological neural networks, including the recurrent networks in the hippocampus. Several species of ring devices are described and investigated, including the clock, labile clock, hourglass and multistable ring systems, and their applications to neuronal modelling explored. Complexity measures such as the maximum Lyapunov exponent, correlation dimension and detrended fluctuation analysis are applied to compare model and biological records and validate the CRG methodology. The basis of neural coding is also examined in mathematical detail, with particular regard to its description by Volterra-Wiener kernel formalism, from which the neuronal modes are derived. Applications to theta-gamma coding are discussed. Further on in the thesis, a CRG epileptiform network model of spontaneous seizure-like events (SLEs) is developed and used as a platform to test neuromodulation approaches for seizure abatement. (Neuromodulation mentioned here refers to methods involving electrical stimulation of neural tissue for therapeutic benefit). Spontaneous SLE transitions in the epileptiform network are shown to be related to the mechanism of intermittency, as determined by examining the state space dynamics of the model. The onset of SLEs is associated with increased network excitability and decreased stability, consistent with experimental results from the low-magnesium/high-potassium in vitro model of epilepsy. Lastly, a novel strategy for therapeutic neuromodulation is presented wherein a coupled CRG network (called the “therapeutic network”) is interfaced with the epileptiform network model, forming a closed loop for responsive, biomimetic neuromodulation of the epileptiform network. Relevance to clinical applications and future work is discussed.

Connectomics – the study of neural connectivity – is primarily concerned with the mapping and characterisation of wired synaptic links; however, it is well established that long-distance chemical signalling via extrasynaptic volume transmission is also critical to brain function. As these interactions are not visible in the physical structure of the nervous system, current approaches to connectomics are unable to capture them. This work addresses the problem of missing extrasynaptic interactions by demonstrating for the first time that whole-animal volume transmission networks can be mapped from gene expression and ligand-receptor interaction data, and analysed as part of the connectome. Complete networks are presented for the monoamine systems of Caenorhabditis elegans, along with a representative sample of selected neuropeptide systems. A network analysis of the synaptic (wired) and extrasynaptic (wireless) connectomes is presented which reveals complex topological properties, including extrasynaptic rich-club organisation with interconnected hubs distinct from those in the synaptic and gap junction networks, and highly significant multilink motifs pinpointing locations in the network where aminergic and neuropeptide signalling is likely to modulate synaptic activity. Thus, the neuronal connectome can be modelled as a multiplex network with synaptic, gap junction, and neuromodulatory layers representing inter-neuronal interactions with different dynamics and polarity. This represents a prototype for understanding how extrasynaptic signalling can be integrated into connectomics research, and provides a novel dataset for the development of multilayer network algorithms.