One central oscillatory drive is compatible with experimental motor unit behaviour in essential and Parkinsonian tremor

Pathological tremors are symptomatic to several neurological disorders that are difficult to differentiate and the way by which central oscillatory networks entrain tremorogenic contractions is unknown. We considered the alternative hypotheses that tremor arises from one oscillator (at the tremor frequency) or, as suggested by recent findings from the superimposition of two separate inputs (at the tremor frequency and twice that frequency). Approach. Assuming one central oscillatory network we estimated analytically the relative amplitude of the harmonics of the tremor frequency in the motor neuron output for different temporal behaviors of the oscillator. Next, we analyzed the bias in the relative harmonics amplitude introduced by superimposing oscillations at twice the tremor frequency. These findings were validated using experimental measurements of wrist angular velocity and surface electromyography (EMG) from 22 patients (11 essential tremor, 11 Parkinson’s disease). The ensemble motor unit action potential trains identified from the EMG represented the neural drive to the muscles. Main results. The analytical results showed that the relative power of the tremor harmonics in the analytical models of the neural drive was determined by the variability and duration of the tremor bursts and the presence of the second oscillator biased this power towards higher values. The experimental findings accurately matched the analytical model assuming one oscillator, indicating a negligible functional role of secondary oscillatory inputs. Furthermore, a significant difference in the relative power of harmonics in the neural drive was found across the patient groups, suggesting a diagnostic value of this measure (classification accuracy: 86%). This diagnostic power decreased substantially when estimated from limb acceleration or the EMG. Signficance. The results indicate that the neural drive in pathological tremor is compatible with one central network providing neural oscillations at the tremor frequency. Moreover, the regularity of this neural oscillation varies across tremor pathologies, making the relative amplitude of tremor harmonics a potential biomarker for diagnostic use

Utilisation de l’intelligence artificielle pour identifier les marqueurs de la démence dans le trouble comportemental en sommeil paradoxal

La démence à corps de Lewy (DCL) et la maladie de Parkinson (MP) sont des maladies neurodégénératives touchant des milliers de Canadiens et leur prévalence croît avec l’âge. La MP et la DCL partagent la même pathophysiologie, mais se distinguent par l’ordre de manifestation des symptômes : la DCL se caractérise d’abord par l’apparition d’un trouble neurocognitif majeur (démence), tandis que la MP se manifeste initialement par un parkinsonisme. De plus, jusqu’à 80% des patients avec la MP développeront une démence (MPD). Il est désormais établi que le trouble comportemental en sommeil paradoxal idiopathique (TCSPi) constitue un puissant prédicteur de la DCL et la MP. En effet, cette parasomnie, marquée par des comportements indésirables durant le sommeil, est considérée comme un stade prodromal des synucléinopathies, telles que la MP, la DCL et l'atrophie multisystémique (AMS). Ainsi, la majorité des patients atteints d’un TCSPi développeront une synucléinopathie. Malgré les avancées scientifiques, les causes du TCSPi, de la MP et de la DCL demeurent inconnues et aucun traitement ne parvient à freiner ou à arrêter la neurodégénérescence. De plus, ces pathologies présentent une grande hétérogénéité dans l’apparition et la progression des divers symptômes. Face à ces défis, la recherche vise à mieux cerner les phases précoces/initiales et les trajectoires évolutives de ces maladies neurodégénératives afin d’intervenir le plus précocement possible dans leur développement. C’est pourquoi le TCSPi suscite un intérêt majeur en tant que fenêtre d'opportunités pour tester l’efficacité des thérapies neuroprotectrices contre les synucléinopathies, permettant d'agir avant que la perte neuronale ne devienne irréversible. Le TCSPi offre ainsi une occasion unique d'améliorer la détection de la démence et le suivi des individus à haut risque de déclin cognitif. D'où l'importance cruciale de pouvoir généraliser les résultats issus de la recherche sur de petites cohortes à l'ensemble de la population. Sur le plan de la cognition, les études longitudinales sur le TCSPi ont montré que les atteintes des fonctions exécutives, de la mémoire verbale et de l'attention sont les plus discriminantes pour différencier les individus qui développeront une démence de ceux qui resteront idiopathiques. De plus, un grand nombre de patients TCSPi souffrent d’un trouble neurocognitif mineur ou trouble cognitif léger (TCL), généralement considéré comme un stade précurseur de la démence. Les recherches actuelles sur les données cognitives chez cette population offrent des perspectives prometteuses, mais reposent sur des approches statistiques classiques qui limitent leur validation et généralisation. Bien qu'elles offrent une précision élevée (80 à 85%) pour détecter les patients à risque de déclin cognitif, une amélioration est nécessaire pour étendre l'utilisation de ces marqueurs à une plus large échelle. Depuis les années 2000, l'accroissement de la puissance de calcul et l'accès à davantage de ressources de mémoire ont suscité un intérêt accru pour les algorithmes d'apprentissage machine (AM). Ces derniers visent à généraliser les résultats à une population plus vaste en entraînant des modèles sur une partie des données et en les testant sur une autre, validant ainsi leur application clinique. Jusqu'à présent, aucune étude n'a évalué les apports de l'AM pour la prédiction de l'évolution des synucléinopathies en se penchant sur le potentiel de généralisation, et donc d'application clinique, à travers l'usage d'outils non invasifs et accessibles ainsi que de techniques de validation de modèles (model validation). De plus, aucune étude n'a exploré l'utilisation de l'AM associée à des méthodes de généralisation sur des données neuropsychologiques longitudinales pour élaborer un modèle prédictif de la progression des déficits cognitifs dans le TCSPi. L’objectif général de cette thèse est d’étudier l’apport de l’AM pour analyser l’évolution du profil cognitif de patients atteints d’un TCSPi. Le premier chapitre de cette thèse présente le cadre théorique qui a guidé l’élaboration des objectifs et hypothèses de recherche. Le deuxième chapitre est à deux volets (articles). Le premier vise à fournir une vue d'ensemble de la littérature des études ayant utilisé l'AM (avec des méthodes de généralisation) pour prédire l'évolution des synucléinopathies vers une démence, ainsi que les lacunes à combler. Le deuxième volet vise à explorer et utiliser pour la première fois l'AM sur des données cliniques et cognitifs pour prédire la progression vers la démence dans le TCSPi, dans un devis longitudinal. Enfin, le dernier chapitre de la thèse présente une discussion et une conclusion générale, comprenant un résumé des deux articles, ainsi que les implications théoriques, les forces, les limites et les orientations futures.Lewy body dementia (LBD) and Parkinson's disease (PD) are neurodegenerative diseases affecting thousands of Canadians, and their prevalence increases with age. PD and DLB share the same pathophysiology, but differ in the order of symptom manifestation: DLB is characterized first by the onset of a major neurocognitive disorder (dementia), whereas PD initially manifests as parkinsonism. Moreover, up to 80% of PD patients will go on to develop dementia (PDD). It is established that idiopathic REM sleep behavior disorder (iRBD) is a powerful predictor of DLB and PD. Indeed, this parasomnia, marked by undesirable behaviors during sleep, is considered a prodromal stage of synucleinopathies, such as PD, DLB and multisystem atrophy (MSA). Therefore, the majority of patients with iRBD will develop synucleinopathy. Despite scientific advancements, the causes of iRBD, PD, and DLB remain unknown and no treatment has been able to slow or halt neurodegeneration. Furthermore, these pathologies display great heterogeneity in the onset and progression of various symptoms. Faced with these challenges, research aims to better understand the early/initial stages and the progressive trajectories of these neurodegenerative diseases in order to intervene as early as possible in their development. This is why iRBD garners major interest as a window of opportunities to test the effectiveness of neuroprotective therapies against synucleinopathies, enabling action to be taken before neuronal loss becomes irreversible. iRBD thus provides a unique opportunity to improve dementia detection and monitoring of individuals at high risk of cognitive decline. Hence the crucial importance of being able to generalize results of research on small cohorts to the entire population. In terms of cognition, longitudinal studies on iRBD have shown that impairments in executive functions, verbal memory, and attention are the most discriminating in differencing between individuals who will develop dementia from those who will remain idiopathic. In addition, many iRBD patients suffer from a mild neurocognitive disorder or mild cognitive impairment (MCI), generally considered as a precursor stage of dementia. Current research on cognitive data in this population offers promising prospects, but relies on traditional statistical approaches that limit their validation and generalizability. While they provide high accuracy (80 to 85%) for detecting patients at risk of cognitive decline, improvement is needed to extend the use of these markers to a larger scale. Since the 2000s, increased computational power and access to more memory resources have sparked growing interest in machine learning (ML) algorithms. These aim to generalize results to a broader population by training models on a subset of data and testing them on another, thus validating their clinical application. To date, no study has assessed the contributions of ML for predicting the progression of synucleinopathies, focusing on the potential for generalization, and hence clinical application, through the use of non-invasive, accessible tools and model validation techniques. Moreover, no study has explored the use of ML in conjunction with generalization methods on longitudinal neuropsychological data to develop a predictive model of cognitive deficit progression in iRBD. The general objective of this thesis is to study the contribution of ML in analyzing the evolution of the cognitive profile of patients with iRBD. The first chapter of this thesis presents the theoretical framework that guided the formulation of the research objectives and hypotheses. The second chapter is in two parts (articles). The first aims to provide an overview of the literature of studies that have used ML (with generalization methods) to predict the progression of synucleinopathies to dementia, as well as the gaps that need to be filled. The second part aims to explore and use for the first time ML on clinical and cognitive data to predict progression to dementia in iRBD, in a longitudinal design. Finally, the last chapter of the thesis presents a discussion and a general conclusion, including a summary of the two articles, as well as theoretical implications, strengths, limitations, and future directions

Low-frequency repetitive transcranial magnetic stimulation modulates evoked-gamma power, event-related potentials, and behavior in autism spectrum disorders.

Evidence suggests that cortical minicolumns are reduced in size and increased in number in individuals with autism spectrum disorder (ASD), especially in the dorsolateral prefrontal cortex (DLPFC). More specifically minicolumns in individuals with ASD are narrower and contain less peripheral, neuropil space; this may cause an increase in the ratio of cortical excitation to inhibition and adversely affect the functional distinctiveness of minicolumnar activation. A lack of cortical inhibition may cause signal/sensory amplification which can impair functioning, raise physiological stress, and adversely affect social interaction in patients with ASD. Additionally, the DLPFC forms a circuit interconnected with many areas of cortex (e.g., anterior cingulate, orbitofrontal) and is involved in selecting a possible range of responses while suppressing inappropriate ones. Low-frequency (:\u27SlHz) repetitive transcranial magnetic stimulation (rTMS) has been shown to increase inhibition of stimulated cortex by the activation of inhibitory circuits. The baseline hypothesis was that individuals with ASD would show electroencephalopgrahic (EEG) and event-related potential (ERP) evidence of amplified cortical activity at early and late stages of visual processing as well as impaired indices of selective attention. The second hypothesis was that low-frequency rTMS would reduce augmented cortical responses at early stage and late stages of visual processing and improve selective attention and behavior in ASD. The baseline findings indicate both ERP and evoked gamma activity are amplified and indiscriminative in ASD at early stages of visual processing which may reflect decreased \u27signal to noise\u27 due to decreased cortical inhibitory processing. Additionally, individuals with ASD showed evidence of compromised selective attention, and had a significantly higher rate of motor response errors. After low-frequency rTMS individuals with ASD showed significant reductions in augmented ERP responses at very early stages of visual processing and showed significant improvement in discriminatory EEG gamma activity. There was also evidence of improved ERP indices of selective attention and significant reductions in irritability and repetitive behavior. TMS has the potential to become an important therapeutic tool in ASD treatment and has shown significant benefits in treating core symptoms of ASD with few, if any side effects

Sleep homeostasis in the European jackdaw (<i>Coloeus monedula</i>):Sleep deprivation increases NREM sleep time and EEG power while reducing hemispheric asymmetry

Introduction: Sleep is a wide-spread phenomenon that is thought to occur in all animals. Yet, the function of it remains an enigma. Conducting sleep experiments in different species may shed light on the evolution and functions of sleep. Therefore, we studied sleep architecture and sleep homeostatic responses to sleep deprivation in the European jackdaw (Coloeus monedula).Methods: A total of nine young adult birds were implanted with epidural electrodes and equipped with miniature data loggers for recording movement activity (accelerometery) and electroencephalogram (EEG). Individually-housed jackdaws were recorded under controlled conditions with a 12:12-h light-dark cycle.Results: During baseline, the birds spent on average 48.5% of the time asleep (39.8% non-rapid eye movement (NREM) sleep and 8.7% rapid eye movement (REM) sleep). Most of the sleep occurred during the dark phase (dark phase: 75.3% NREM sleep and 17.2% REM sleep; light phase 4.3% NREM sleep and 0.1% REM sleep). After sleep deprivation of 4 and 8 h starting at lights off, the birds showed a dose-dependent increase in NREM sleep time. Also, NREM sleep EEG power in the 1.5–3 Hz frequency range, which is considered to be a marker of sleep homeostasis in mammals, was significantly increased for 1-2 h after both 4SD and 8SD. While there was little true unihemispheric sleep in the Jackdaws, there was a certain degree of hemispheric asymmetry in NREM sleep EEG power during baseline, which reduced after sleep deprivation in a dose-dependent manner.Conclusion: In conclusion, jackdaws display homeostatic regulation of NREM sleep and sleep pressure promotes coherence in EEG power

Sensorimotor Modulations by Cognitive Processes During Accurate Speech Discrimination: An EEG Investigation of Dorsal Stream Processing

Internal models mediate the transmission of information between anterior and posterior regions of the dorsal stream in support of speech perception, though it remains unclear how this mechanism responds to cognitive processes in service of task demands. The purpose of the current study was to identify the influences of attention and working memory on sensorimotor activity across the dorsal stream during speech discrimination, with set size and signal clarity employed to modulate stimulus predictability and the time course of increased task demands, respectively. Independent Component Analysis of 64–channel EEG data identified bilateral sensorimotor mu and auditory alpha components from a cohort of 42 participants, indexing activity from anterior (mu) and posterior (auditory) aspects of the dorsal stream. Time frequency (ERSP) analysis evaluated task-related changes in focal activation patterns with phase coherence measures employed to track patterns of information flow across the dorsal stream. ERSP decomposition of mu clusters revealed event-related desynchronization (ERD) in beta and alpha bands, which were interpreted as evidence of forward (beta) and inverse (alpha) internal modeling across the time course of perception events. Stronger pre-stimulus mu alpha ERD in small set discrimination tasks was interpreted as more efficient attentional allocation due to the reduced sensory search space enabled by predictable stimuli. Mu-alpha and mu-beta ERD in peri- and post-stimulus periods were interpreted within the framework of Analysis by Synthesis as evidence of working memory activity for stimulus processing and maintenance, with weaker activity in degraded conditions suggesting that covert rehearsal mechanisms are sensitive to the quality of the stimulus being retained in working memory. Similar ERSP patterns across conditions despite the differences in stimulus predictability and clarity, suggest that subjects may have adapted to tasks. In light of this, future studies of sensorimotor processing should consider the ecological validity of the tasks employed, as well as the larger cognitive environment in which tasks are performed. The absence of interpretable patterns of mu-auditory coherence modulation across the time course of speech discrimination highlights the need for more sensitive analyses to probe dorsal stream connectivity

Models and Analysis of Vocal Emissions for Biomedical Applications

The International Workshop on Models and Analysis of Vocal Emissions for Biomedical Applications (MAVEBA) came into being in 1999 from the particularly felt need of sharing know-how, objectives and results between areas that until then seemed quite distinct such as bioengineering, medicine and singing. MAVEBA deals with all aspects concerning the study of the human voice with applications ranging from the neonate to the adult and elderly. Over the years the initial issues have grown and spread also in other aspects of research such as occupational voice disorders, neurology, rehabilitation, image and video analysis. MAVEBA takes place every two years always in Firenze, Italy. This edition celebrates twenty years of uninterrupted and succesfully research in the field of voice analysis

Activation of the pro-resolving receptor Fpr2 attenuates inflammatory microglial activation

Poster number: P-T099 Theme: Neurodegenerative disorders & ageing Activation of the pro-resolving receptor Fpr2 reverses inflammatory microglial activation Authors: Edward S Wickstead - Life Science & Technology University of Westminster/Queen Mary University of London Inflammation is a major contributor to many neurodegenerative disease (Heneka et al. 2015). Microglia, as the resident immune cells of the brain and spinal cord, provide the first line of immunological defence, but can become deleterious when chronically activated, triggering extensive neuronal damage (Cunningham, 2013). Dampening or even reversing this activation may provide neuronal protection against chronic inflammatory damage. The aim of this study was to determine whether lipopolysaccharide (LPS)-induced inflammation could be abrogated through activation of the receptor Fpr2, known to play an important role in peripheral inflammatory resolution. Immortalised murine microglia (BV2 cell line) were stimulated with LPS (50ng/ml) for 1 hour prior to the treatment with one of two Fpr2 ligands, either Cpd43 or Quin-C1 (both 100nM), and production of nitric oxide (NO), tumour necrosis factor alpha (TNFα) and interleukin-10 (IL-10) were monitored after 24h and 48h. Treatment with either Fpr2 ligand significantly suppressed LPS-induced production of NO or TNFα after both 24h and 48h exposure, moreover Fpr2 ligand treatment significantly enhanced production of IL-10 48h post-LPS treatment. As we have previously shown Fpr2 to be coupled to a number of intracellular signaling pathways (Cooray et al. 2013), we investigated potential signaling responses. Western blot analysis revealed no activation of ERK1/2, but identified a rapid and potent activation of p38 MAP kinase in BV2 microglia following stimulation with Fpr2 ligands. Together, these data indicate the possibility of exploiting immunomodulatory strategies for the treatment of neurological diseases, and highlight in particular the important potential of resolution mechanisms as novel therapeutic targets in neuroinflammation. References Cooray SN et al. (2013). Proc Natl Acad Sci U S A 110: 18232-7. Cunningham C (2013). Glia 61: 71-90. Heneka MT et al. (2015). Lancet Neurol 14: 388-40

Student Research Colloquium Proceedings 2013

2013 Student Research Colloquium proceedings include the following: a schedule of the day\u27s events, acknowledgement of research sponsors, conference presentation abstracts, formal paper competition participants; poster presentation competition participants; student presenter index, research sponsor index, poster and paper presentation judges, sponsors, and donors, map of Atwood Memorial Center

Intelligent technologies for real-time monitoring and decision support systems

MPhilAutomation of data processing and control of operations involving intelligent technologies that is considered the next generation technology requires error-free data capture systems in both clinical research and healthcare. The presented research constitutes a step in the development of intelligent technologies in healthcare. The proposed improvement is by automation that includes the elements of intelligence and prediction. In particular automatic data acquisition systems for several devices are developed including pervasive computing technologies for mobility. The key feature of the system is the minimisation/near eradication of erroneous data input along with a number of other security measures ensuring completeness, accuracy and reliability of the patients‟ data. The development is based on utilising existing devices to keep the cost of Data Acquisition Systems down. However, with existing technology and devices one can be limited to features required to perform more refined analysis. Research of existing and development of a new device for assessment of neurological diseases, such as MS (Multiple Sclerosis) using Stroop test is performed. The software can also be customized for use in other diseases affecting Central Nervous System such as Parkinson‟s disease. The introduction of intelligent functions into the majority of operations enables quality checks and provides on-line user assistance. It could become a key tool in the first step of patient diagnosis before referring to more advanced tests for further investigation. Although the software cannot fully ensure the diagnosis of MS or PD but can make significant contribution in the process of diagnosis and monitorin