Neural Preparation For Step Initiation In Unpredictable Conditions With Age And Parkinson\u27s Disease

Mobility is essential for the independent lifestyle. However, as the US population ages, challenges to mobility start to arise, among them just the aging itself which leads to decreased postural stability, falls and the second most common neurodegenerative disease, that is Parkinson’s disease (PD). We decided to investigate step initiation as it is crucial to mobility: walking is not possible without the first step. Step initiation is impaired in PD. However, the impact of PD on the neural mechanisms of step initiation when some of the step parameters are unpredictable remains unexplored. Cortical preparation for step initiation can be assessed by beta event-related desynchronization (ERD) derived from electroencephalography (EEG) recordings. We hypothesized that subjects with PD would exhibit less cortical modulation between conditions of forward step initiation with and without prior knowledge of limb choice. Further, we hypothesized that decreased cortical modulation in PD would associate with a higher impairment of motor performance. Results identified that the group with PD exhibited decreased beta ERD amplitudes that were similar regardless of condition, whereas control subjects modulated beta ERD amplitudes between conditions, particularly in early stages of pre-movement processing in areas overlying sensory cortex. Subjects with PD presented with delayed and reduced postural preparation with increased step target error across both conditions and exhibited a greater incidence of multiple anticipatory postural adjustments (APAs) in the predictable relative to the unpredictable condition. Delayed postural preparation significantly correlated with lower amplitudes of beta ERD. We concluded that diminished early pre-movement processing over sensory cortex was concomitant with poor pre-selection of the stepping limb in predictable conditions and that a generally diminished amplitude of cortical pre-movement processing relates to delayed step initiation in people with PD. Furthermore, impaired mobility accompanies healthy aging, but there is a need for deeper understanding of how aging changes central control of motor behavior. Using previous study’s method, we compared cortical preparation for step initiation using beta ERD in young and older healthy subjects performing forward steps with and without prior knowledge of limb choice. Our results show that older subjects exhibited increased beta ERD amplitudes before the step regardless of whether they were informed of limb choice or not. Moreover, older subjects exhibited early increases in beta ERD in the “sensory” cluster of electrodes, but only when full limb-choice information was available. Behaviorally, the older subjects also exhibited shortened and increased anticipatory postural adjustments which led to earlier step initiation and similar swing-foot velocities but was also accompanied by greater target step placement errors and decreased postural stability. For the older group, condition-related increases in beta ERD amplitudes and stability correlated with condition-related prolongation of APA durations. We conclude that older subjects exhibited a spectrum across two strategies: (1) a “fast” strategy associated with decreased neural preparation that trades shortened step preparation and higher swing-foot velocity for target step errors and lowered postural stability; and (2) an “accurate” strategy associated with greater neural preparation, longer step-preparation time, and higher stability during step execution. In conclusion, this thesis provides more support for beta ERD as a useful tool for studying cortical preparation non-invasively. We have also established the importance of the signals recorded by “sensory” clusters: in subjects with PD the absence of beta ERD similar to the control group was associated with impaired motor behavior even when conditions were predictable. Similarly, a part of the older group seemed to pre-potentiate its cortex lying beneath the cluster of “sensory” electrodes which was associated with more safe and accurate steps. Further investigations should focus on the importance of sensorimotor integration and its’ changes due to PD or healthy aging and beta ERD may be an excellent tool for this task

Practice changes beta power at rest and its modulation during movement in healthy subjects but not in patients with Parkinson\u27s disease

Abstract Background PD (Parkinson\u27s disease) is characterized by impairments in cortical plasticity, in beta frequency at rest and in beta power modulation during movement (i.e., event‐related ERS [synchronization] and ERD [desynchronization]). Recent results with experimental protocols inducing long‐term potentiation in healthy subjects suggest that cortical plasticity phenomena might be reflected by changes of beta power recorded with EEG during rest. Here, we determined whether motor practice produces changes in beta power at rest and during movements in both healthy subjects and patients with PD. We hypothesized that such changes would be reduced in PD. Methods We thus recorded EEG in patients with PD and age‐matched controls before, during and after a 40‐minute reaching task. We determined posttask changes of beta power at rest and assessed the progressive changes of beta ERD and ERS during the task over frontal and sensorimotor regions. Results We found that beta ERS and ERD changed significantly with practice in controls but not in PD. In PD compared to controls, beta power at rest was greater over frontal sensors but posttask changes, like those during movements, were far less evident. In both groups, kinematic characteristics improved with practice; however, there was no correlation between such improvements and the changes in beta power. Conclusions We conclude that prolonged practice in a motor task produces use‐dependent modifications that are reflected in changes of beta power at rest and during movement. In PD, such changes are significantly reduced; such a reduction might represent, at least partially, impairment of cortical plasticity

Abnormal reactivity of resting-state EEG alpha rhythms during eyes open in patients with Alzheimer's and Lewy body diseases

Previous studies suggest that resting-state electroencephalographic (rsEEG) rhythms recorded in old patients with dementia due to different neurodegenerative diseases have a significant heuristic and clinical potential in identifying peculiar abnormalities of the ascending activating systems and reciprocal thalamocortical circuits in which oscillatory (de)synchronizing signals dynamically underpin cortical arousal in the regulation of quiet vigilance. In the present PhD program, a new methodological approach based on rsEEG cortical source estimation and individually-based frequency bands was used to test the hypothesis of significant abnormalities in the neurophysiological oscillatory mechanisms underlying the regulation of the quiet vigilance during the transition from an eyes-closed to an eyes-open condition in patients with the most prevalent neurodegenerative dementing disorders such as Alzheimer’s disease and Lewy Body and Parkinson’s diseases and initial abnormalities in the prodromal stage of ADD, characterized by mild cognitive impairment. Three rsEEG studies were performed for that purpose. In the first study, we tested if the reactivity of posterior rsEEG alpha rhythms from the eye- closed to the eyes-open condition may differ in patients with dementia due to Lewy Bodies (DLB) and Alzheimer’s disease (ADD) as a functional probe of the dominant neural synchronization mechanisms regulating the vigilance in posterior visual systems. We used clinical, demographical, and rsEEG datasets in 28 healthy elderly (Healthy) seniors, 42 DLB, and 48 ADD participants. The eLORETA freeware estimated rsEEG cortical sources at individual delta, theta, and alpha frequencies. Results showed a substantial (> -10%) reduction in the posterior alpha activities during the eyes-open condition in 24 Healthy, 26 ADD, and 22 DLB subjects. There were lower reductions in the posterior alpha activities in the ADD and DLB groups than in the Healthy group. The reduction in the occipital region was lower in the DLB than in the ADD group. These results suggest that DLB patients may suffer a greater alteration in the neural synchronization mechanisms regulating vigilance in occipital cortical systems compared to ADD patients. In the second study, we hypothesized that the vigilance dysregulation seen in PDD patients might be reflected by altered reactivity of posterior rsEEG alpha rhythms during the vigilance transition from an eyes-closed to an eyes-open condition. We used clinical, demographical, and rsEEG datasets in 28 healthy elderly (Healthy), 73 PDD, and 35 ADD participants. We have applied the same methodology used for the first study. Results showed substantial (> -10%) reduction (reactivity) in the posterior alpha source activities from the eyes-closed to the eyes-open condition in 88% of the Healthy seniors, 57% of the ADD patients, and only 35% of the PDD patients. In these alpha-reactive participants, there was lower reactivity in the parietal alpha source activities in the PDD group than in the Healthy and the ADD groups. These results suggest that PDD is characterized by poor reactivity of mechanisms desynchronizing posterior rsEEG alpha rhythms in response to visual inputs. This finding could be an interesting biomarker of impaired vigilance regulation in quiet wakefulness in PDD patients. Indeed, such biomarkers may provide endpoints for pharmacological intervention and brain electromagnetic stimulations to improve the PDD patients’ general ability to regulate vigilance and primary visual consciousness in the activities of daily living. In the third study, we tested the exploratory hypothesis that rsEEG alpha rhythms may predict and be sensitive to mild cognitive impairment due to AD (ADMCI) progression at a 6-month follow- up (a relevant feature for intervention clinical trials). Clinical, neuroimaging, and rsEEG datasets in 52 ADMCI and 60 Healthy seniors were used. We applied the same methodology used for the first and the second studies. Results showed a substantial (> -10%) reduction in the posterior alpha source activities during the eyes-open condition in about 90% and 70% of the Healthy and ADMCI participants, respectively. In the younger ADMCI patients (mean age of 64.3±1.1) with “reactive” rsEEG alpha source activities, posterior alpha source activities during the eyes closed condition predicted the global cognitive status at the 6-month follow-up. In all ADMCI participants with “reactive” rsEEG alpha source activities, posterior alpha source activities during the eyes-closed condition reduced in magnitude at that follow-up. These effects could not be explained by neuroimaging and neuropsychological biomarkers of AD. These results suggest that in ADMCI patients, the true (“reactive”) posterior rsEEG alpha rhythms, when present, predict (in relation to younger age) and are quite sensitive to the effects of the disease progression on neurophysiological mechanisms underpinning vigilance regulation. The results of the three studies unveiled the significant extent to which the well-known impairments in the cholinergic and dopaminergic neuromodulatory ascending systems could affect the brain neurophysiological oscillatory mechanisms underpinning the reactivity of rsEEG alpha rhythms during eyes open and, then, the regulation of quiet vigilance in ADD, PDD, and DLB patients, thus enriching the neurophysiological model underlying their known difficulties to remain awake in quiet environmental conditions during daytime

The role of oscillatory synchrony in motor control.

Synchronized oscillations are manifest in various regions in the motor system. Their variable nature has increased the interest in the functional significance. Subcortical and cortical activity in the beta band is pathologically increased in Parkinson's disease (PD) - a state dominated by bradykinesia and rigidity. After the administration of the drug levodopa, beta activity and motor impairment are substantially decreased, while activity in the gamma band is increased. The function of beta bursts within the healthy motor system remains unknown. Recent evidence suggests that beta activity may promote the existing motor set and posture. In this thesis, with the use of positional hold tasks the role of beta activity on performance will be examined. It will be demonstrated that during bursts of beta synchrony in the corticomuscular system of healthy subjects there is an improvement, in the performance of these tasks. The findings will argue that physiological fluctuations in the beta band in the motor system may be of behavioural advantage during fine postural tasks involving the hand. The present work will also examine the role of population oscillations in the parkinsonian basal ganglia. It will demonstrate that under levodopa treatment the pattern of movement-related reactivity in the subthalamic nucleus (STN) and the pedunculopontine nucleus (PPN) as well as the background activity in the PPN change significantly. It will be shown that levodopa suppresses movement-related beta activity around the time of self-paced movements and promotes the increase of movement-related gamma activity contralateral to the movement side, following the same pattern as in the non dopamine-depleted brain. This suggests that dopaminergic therapy restores a more physiological pattern of reactivity in the STN. In the untreated state, beta activity in the STN will be shown to be modulated during repetitive self-paced movements, reflecting a role in ongoing performance, but only when motor performance is maximal and not when bradykinesia occurs. Finally, it will be demonstrated that levodopa promotes alpha band activity in the PPN at rest and before movement suggesting a possible physiological role of this activity in this nucleus. These observations provide further insight in the function of neuronal synchronization in the motor system in health and disease

Copper in the Suprachiasmatic Nucleus: Copper Signaling, Homeostasis, and Circadian Rhythms and Trace Metals in the Master Clock

we present data supporting a role for copper (Cu) and Cu homeostasis in the suprachiasmatic nucleus (SCN), the location of the mammalian circadian pacemaker. Although many studies have investigated the function and effects of Cu in synaptic function and receptor signaling in the brain and other tissues, these results are the first to directly link Cu with the SCN master clock and circadian neuronal activity rhythms. Previous work using extracellular recordings of SCN neurons in ex vivo hypothalamic slices has demonstrated that resetting the circadian clock, e.g. by glutamate (Glu) treatment during the night, induces shifts in the phase of SCN neuronal activity rhythms that correspond to phase shifts in circadian behavioral activity (Albers et al., 2017; Golombek and Rosenstein, 2010; Herzog et al., 2017; Lindsay et al., 2014; Prosser, 1998). Here we first have demonstrated that both Cu chelation and Cu application are able to induce night-time phase shifts in neuronal activity rhythms in vitro. Second, we have shown that these two treatments affect N-methyl-D-aspartate receptor (NMDAR) and Glu neurotransmission differently. Since Glu phase-shifts the SCN clock through NMDAR-mediated, calcium-dependent signaling pathways and activation of other pathways, we pharmacologically tested several of these pathways to investigate how application of Cu or the Cu chelator, tetrathiomolybdate (TTM), induces NMDAR-independent and dependent phase shifts, respectively. Our results demonstrate that Cu induces mitogen-activated protein kinase (MAPK)-dependent phase shifts in the absence of NMDAR-mediated calcium influx. On the other hand, the specific extra- and intracellular mechanisms by which Cu removal induces phase shifts remain unclear. Lastly, we have preliminary results indicating that concentrations of Cu in the SCN are comparable to other brain regions, and show day-night expression of two Cu transporters, copper transporter 1 (CTR1) and ATPase-7A (ATP7A) in the SCN. We discuss these findings in light of the existing literature and current models of SCN circadian oscillator mechanisms. Our results together with published findings suggest that Cu homeostasis is tightly regulated in the SCN, and that changes in Cu levels serves as a time cue for the circadian clock. Future research can elucidate how Cu (dys)regulation interacts with oscillations in SCN neuronal firing and signaling activity and whether Cu or other trace elements influence SCN metabolic and redox activity

Oscillatory activity in the basal ganglia - is it relevant to movement disorders therapy?

Chronic high frequency stimulation of the basal ganglia can be a highly effective intervention for movement disorders in patients. In the past decade, therapeutic benefits have been seen with stimulation of the subthalamic nucleus and globus pallidus interna for Parkinson's disease (PD) and dystonia, respectively. These procedures have allowed direct recording of basal ganglia activity and have suggested that abnormal synchronisation of neurons in these nuclei may contribute to motor impairment. This thesis explores the possible correlation between synchronised activity in the basal ganglia, as evidenced by oscillations in local field potentials, and movement disorders. In Chapter 3, we demonstrate the correlation between synchronization at frequencies under 10 Hz in the globus pallidus interna and dystonic EMG. This low frequency activity is shown to be locked to neuronal activity within GPi in patients with dystonia (Chapter 4). Deep brain stimulation is thought to suppress spontaneous pathological activity in the basal ganglia. Equally, however, it must also suppress any residual physiological activity in these nuclei. In Chapter 5, we demonstrate that the basal ganglia are involved in the processing of simple limb movements in the human, by separating the effects of deep brain stimulation on pathological and physiological activities based on baseline task performance. An impairment of motor performance was seen during high frequency stimulation in those patients with the best task performance at baseline. This deleterious effect, however, should be distinguished from the effect of direct stimulation at 20 Hz in Parkinson's disease. Oscillatory activity at around 20 Hz is thought to be a core feature in Parkinson's disease. In Chapter 6, we demonstrate that the excessive synchronization imposed by stimulation of the subthalamic nucleus at 20 Hz slows movement, in those patients with the best task performance at baseline. This supports the notion that synchronization around 20 Hz may be causally linked to bradykinesia. Last, the therapeutic effectiveness of DBS therapy for patients with PD partially relies on the accurate localisation of the motor region of the subthalamic nucleus. In Chapter 7, we propose an alternative method for the localization of this region using the spontaneous pathological 20 Hz activity to be found in this nucleus. The findings of these studies provide evidence that basal ganglia oscillatory activities of differing frequencies contribute to movement disorders

Cortical activations underlying human bipedal balance control

Human bipedal balance is a complex sensorimotor task controlled by the central nervous system. Balance impairments, caused by aging or neuromuscular diseases, often lead to falls which are one of the leading causes of injury and subsequent increases in health care costs. Hence, understanding the mechanisms underlying human bipedal balance control has many functional and clinical implications. Traditionally, it was believed that balance control is mediated by subcortical structures. However, evidence from research in the past few decades has shown that the cerebral cortex plays a major role in bipedal balance control. Nevertheless, the cortical contributions in balance control are still unclear. Hence, the purpose of this thesis was to extend the understanding of cortical involvement in human bipedal balance control. Specifically, the two overarching goals of this thesis were to examine evidence of a cortical network involvement and its generalizability across reactive and predictive balance control. These two overarching goals were addressed through four different studies. Study 1 explored the frequency characteristics and mechanisms underlying the generation of perturbation-evoked potentials. Study 2 investigated cortical activity linked to ‘automatic’ balance reactions that occur continuously while standing still and its dependence on the amplitude of these balance reactions. Study 3 examined the cortical activations related to the preparation and execution of anticipatory postural adjustments that precede a step and whether the activations are dependent on the context of control. Study 4 was designed to examine the functional connectivity in balance control and whether similar networks underlie reactive and predictive balance control. Studies were conducted on young healthy adults and cortical activations were acquired using electroencephalography during feet-in-place balance reactions, standing still, and voluntary stepping. Overall, the findings of these studies provided direct and indirect evidence for the involvement of a cortical network in balance control and its generalizability across different classes of balance control. This work reinforces the view that cortical networks likely play an important role in the control of stability. It is proposed that the synchronized activation of neural assemblies distributed across the cortex might have contributed to the balance-related cortical activations. The findings of this thesis extend the understanding of cortical control of human bipedal balance that may help to inform future, more precise models of the cortical contributions to balance control. This, in turn, can inform future diagnostic and therapeutic approaches to improve mobility among those with balance impairments

L’influence de l'anticipation sur les modulations de puissance dans la bande de fréquence bêta durant la préparation du mouvement et L'effet de la variance dans les rétroactions sensorielles sur la rétention à court terme

La production du mouvement est un aspect primordial de la vie qui permet aux organismes vivants d'interagir avec l'environnement. En ce sens, pour être efficaces, tous les mouvements doivent être planifiés et mis à jour en fonction de la complexité et de la variabilité de l'environnement. Des chercheurs du domaine du contrôle moteur ont étudié de manière approfondie les processus de planification et d’adaptation motrice. Puisque les processus de planification et d'adaptation motrice sont influencés par la variabilité de l'environnement, le présent mémoire cherche à fournir une compréhension plus profonde de ces deux processus moteurs à cet égard. La première contribution scientifique présentée ici tire parti du fait que les temps de réaction (TR) sont réduits lorsqu'il est possible d'anticiper l’objectif moteur, afin de déterminer si les modulations de TR associées à l'anticipation spatiale et temporelle sont sous-tendues par une activité préparatoire similaire. Cela a été fait en utilisant l'électroencéphalographie (EEG) de surface pour analyser l'activité oscillatoire dans la bande de fréquence bêta (13 - 30 Hz) au cours de la période de planification du mouvement. Les résultats ont révélé que l'anticipation temporelle était associée à la désynchronisation de la bande bêta au-dessus des régions sensorimotrices controlatérales à la main effectrice, en particulier autour du moment prévu de l'apparition de la cible. L’ampleur de ces modulations était corrélée aux modulations de TR à travers les participants. En revanche, l'anticipation spatiale a augmenté de manière sélective la puissance de la bande bêta au-dessus des régions pariéto-occipitales bilatérales pendant toute la période de planification. Ces résultats suggèrent des états de préparation distinct en fonction de l’anticipation temporelle et spatiale. D’un autre côté, le deuxième projet traite de la façon dont la variabilité de la rétroaction sensorielle interfère avec la rétention à court terme dans l’étude de l’adaptation motrice. Plus précisément, une tâche d'adaptation visuomotrice a été utilisée au cours de laquelle la variance des rotations a été manipulée de manière paramétrique à travers trois groupes, et ce, tout au long de la période d’acquisition. Par la suite, la rétention de cette nouvelle relation visuomotrice a été évaluée. Les résultats ont révélé que, même si le processus d'adaptation était robuste à la manipulation de la variance, la rétention à court terme était altérée par des plus hauts niveaux de variance. Finalement, la discussion a d'abord cherché à intégrer ces deux contributions en revisitant l'interprétation des résultats sous un angle centré sur l'incertitude et en fournissant un aperçu des potentielles représentations internes de l'incertitude susceptibles de sous-tendre les résultats expérimentaux observés. Par la suite, une partie de la discussion a été réservée à la manière dont le champ du contrôle moteur migre de plus en plus vers l’utilisation de tâches et d’approches expérimentales plus complexes, mais écologiques aux dépends des tâches simples, mais quelque peu dénaturées que l’on retrouve dans les laboratoires du domaine. La discussion a été couronnée par une brève proposition allant dans ce sens.Abstract: Motor behavior is a paramount aspect of life that enables the living to interact with the environment through the production of movement. In order to be efficient, movements need to be planned and updated according to the complexity and the ever-changing nature of the environment. Motor control experts have extensively investigated the planning and adaptation processes. Since both motor planning and motor adaptation processes are influenced by variability in the environment, the present thesis seeks to provide a deeper understanding of both these motor processes in this regard. More specifically, the first scientific contribution presented herein leverages the fact that reaction times (RTs) are reduced when the anticipation of the motor goal is possible to elucidate whether the RT modulations associated with temporal and spatial anticipation are subtended by similar preparatory activity. This was done by using scalp electroencephalography (EEG) to analyze the oscillatory activity in the beta frequency band (13 – 30 Hz) during the planning period. Results revealed that temporal anticipation was associated with beta-band desynchronization over contralateral sensorimotor regions, specifically around the expected moment of target onset, the magnitude of which was correlated with RT modulations across participants. In contrast, spatial anticipation selectively increased beta-band power over bilateral parieto-occipital regions during the entire planning period, suggesting that distinct states of preparation are incurred by temporal and spatial anticipation. Additionally, the second project addressed how variance in the sensory feedback interferes with short-term retention of motor adaptation. Specifically, a visuomotor adaptation task was used during which the variance of exposed rotation was parametrically manipulated across three groups, and retention of the adapted visuomotor relationship was assessed. Results revealed that, although the adaptation process was robust to the manipulation of variance, the short-term retention was impaired. The discussion first sought to integrate these two projects by revisiting the interpretation of both projects under the scope of uncertainty and by providing an overview of the internal representation of uncertainty that might subtend the experimental results. Subsequently, a part of the discussion was reserved to allude how the motor control field is transitioning from laboratory-based tasks to more naturalistic paradigms by using approaches to move motor control research toward real-world conditions. The discussion culminates with a brief scientific proposal along those lines

Alpha-synuclein post-translational modifications and abnormal network oscillations in Lewy body dementias

Ph. D. Thesis.Lewy body dementias (LBDs) are age related neurodegenerative diseases characterized by the presence of abnormal alpha-synuclein (αSyn) inclusions termed Lewy Bodies (LBs) and Lewy Neurites (LNs) and represent the second most common form of neurodegenerative dementia after Alzheimer’s disease. LBDs are progressive pathologic conditions with variable clinical signs and symptoms including dementia and abnormal neuronal network oscillations, with no currently available treatment. The interaction between αSyn post-translational modifications (PTMs) and neuronal dysfunction is a core concept in LBDs. Accumulating evidence shows that, αSyn PTMs, such as, phosphorylation, ubiquitination and nitration, are events that occur in the context of synucleinopathies. I hypothesised that these PTMs lead to the formation of toxic/aggregated forms of αSyn that causes neuronal dysfunctions/death and impair neuronal network oscillations. The aim of this thesis was to Identify the PTMs of αSyn, analyse their distribution in LBDs, correlate them with the distribution of parvalbumin expressing interneurons in in post-mortem brain tissues of LBD patients, and analyse its links with mitochondrial dysfunction and neuronal network impairments. Using, electrophysiological and immunohistochemical protocols in selected cases that fulfilled the neuropathological criteria for LBDs and control cases, sourced from Newcastle Brain Tissue Resource (NBTR), and Transgenic A30P and control C57BL6 mice from comparative biology centre (CBC), I found that aged A30P mice had greater sensitivity to the mitochondrial inhibition by reducing the area power of the gamma frequency oscillations. In addition, parvalbumin expressing cells are significantly altered in humans, specifically in areas associated with the development of prodromal stages of LBDs, these same areas correlated with regions that presented higher Burden of αSyn phosphorylation. In conclusion, this thesis demonstrates that, reduction in density of parvalbumin cells depicts the impairments in gamma frequency oscillations and correlates with an increase in αSyn PTMs in some regions of LBD patients