Neuroplastic Changes Following Brain Ischemia and their Contribution to Stroke Recovery: Novel Approaches in Neurorehabilitation

Ischemic damage to the brain triggers substantial reorganization of spared areas and pathways, which is associated with limited, spontaneous restoration of function. A better understanding of this plastic remodeling is crucial to develop more effective strategies for stroke rehabilitation. In this review article, we discuss advances in the comprehension of post-stroke network reorganization in patients and animal models. We first focus on rodent studies that have shed light on the mechanisms underlying neuronal remodeling in the perilesional area and contralesional hemisphere after motor cortex infarcts. Analysis of electrophysiological data has demonstrated brain-wide alterations in functional connectivity in both hemispheres, well beyond the infarcted area. We then illustrate the potential use of non-invasive brain stimulation (NIBS) techniques to boost recovery. We finally discuss rehabilitative protocols based on robotic devices as a tool to promote endogenous plasticity and functional restoration

Investigating the long-term stability and neurochemical substrates of TMS and MRS

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

Does Hemispheric Asymmetry Reduction in Older Adults (HAROLD) in motor cortex reflect compensation?

Older adults tend to display greater brain activation in the non-dominant hemisphere during even basic sensorimotor responses. It is debated whether this Hemispheric Asymmetry Reduction in Older Adults (HAROLD) reflects a compensatory mechanism. Across two independent fMRI experiments involving adult-lifespan human samples (N = 586 and N = 81; approximately half female) who performed right hand finger responses, we distinguished between these hypotheses using behavioural and multivariate Bayes (MVB) decoding approaches. Standard univariate analyses replicated a HAROLD pattern in motor cortex, but in- and out-of-scanner behavioural results both demonstrated evidence against a compensatory relationship, in that reaction time measures of task performance in older adults did not relate to ipsilateral motor activity. Likewise, MVB showed that this increased ipsilateral activity in older adults did not carry additional information, and if anything, combining ipsilateral with contralateral activity patterns reduced action decoding in older adults (at least in Experiment 1). These results contradict the hypothesis that HAROLD is compensatory, and instead suggest that the age-related, ipsilateral hyper-activation is non-specific, in line with alternative hypotheses about age-related reductions in neural efficiency/differentiation or inter-hemispheric inhibition.Significance StatementA key goal in the cognitive neuroscience of ageing is to provide a mechanistic explanation of how brain-behaviour relationships change with age. One interpretation of the common finding that task-based hemispheric activity becomes more symmetrical in older adults, is that this shift reflects a compensatory mechanism, with the non-dominant hemisphere needing to "help out" with computations normally performed by the dominant hemisphere. Contrary to this view, our behavioural and brain data indicate that the additional activity in ipsilateral motor cortex in older adults is not reflective of better task performance nor better neural representations of finger actions

The effect of experimental pain on motor training performance and sensorimotor integration

Sensorimotor integration (SMI) is the ability of the central nervous system (CNS) to integrate afferent (incoming) information from different body parts and formulate appropriate motor output to muscles. Effective sensorimotor integration is essential when learning new skills and when performing tasks at home and in the workplace (Rothwell &Rosenkranz, 2005). The overall aim of this thesis is to investigate the effect of acute experimental pain on sensorimotor processing. The primary outcome is the effect of acute experimental pain on somatosensory evoked potential (SEP) peaks. Secondary outcomes include the effect of pain on motor performance and the interactive effect of pain and motor training on SEP peaks. As expected for the placebo condition, no significant differences were found in any of the post-placebo peaks. Contrary to what was expected for the placebo condition, the only peak to be significantly different post-motor learning was the N24 peak. Contrary to what was expected, there were no significant differences for any of the peaks following capsaicin application. One of the secondary outcomes was the interactive effect of pain and motor learning on SEP peaks. The only peak to show any significant differences post-intervention/post-motor learning was the N24 peak. Another secondary outcome was the effect of pain on motor performance. In terms of accuracy, no significant differences were found for either condition following motor learning. However, the data does show a trend towards improved accuracy for the subjects in the intervention group while the subjects in the placebo show a trend towards decreased accuracy. As expected, there was a significant decrease in reaction time for both conditions post-motor learning. However, contrary to what was expected, reaction time decreased to a greater extent in the intervention condition as compared to the placebo condition. It was anticipated that the reaction time would decrease to a greater extent in the placebo condition as it was hypothesized that pain would negatively impact motor performance. It is suspected that the effect of the pain induced by the capsaicin made the motor training task more difficult and participants would have had to focus greater attentional resources to learn the task which lead to the enhanced performance following motor training

Motor learning and neuroplasticity in humans

The central nervous system is plastic, in that the number and strength of synaptic connections changes over time. In the adult the most important driver of such changes is experience, in the form of learning and memory. There are thought to be a number of rules, operating relatively local to each synapse that govern changes in strength and organisation. Some of these such as Hebbian plasticity or plasticity following repeated activation of a connection have been studied in detail in animal preparations. However, recent work with non-invasive methods of transcranial stimulation in human, such as transcranial magnetic stimulation, has opened the opportunity to study similar effects in the conscious human brain. In this thesis I use these methods to explore some of the presumed changes in synaptic connectivity in the motor cortex during different forms of motor learning. The experiments only concern learning in the healthy brain; however it seems likely that the same processes will be relevant to neurorehabilitation and disease of the nervous system. This thesis explores the link between neuroplasticity and motor learning in humans using non-invasive brain stimulation, pharmacological agents and psychomotor testing in 6 related studies. 1) Chapter 3 reports initial pharmacological investigations to confirm the idea that some of the long term effects of TMS are likely to involve LTP-like mechanisms. The study shows that NMDA agonism can affect the response to a repetitive form of TMS known as theta burst stimulation (TBS) 2) Following up on the initial evidence for the role of NMDA receptors in the long term effects of TBS, Chapter 4 explores the possible modulatory effects of dopaminergic drugs on TBS. 3) Chapter 5 takes the investigations to normal behaviours by examining how the NMDA dependent plasticity produced by TBS interacts with learning a simple motor task of rapid thumb abduction. The unexpected results force a careful examination of the possible mechanisms of motor learning in this task. 4) Chapter 6 expands on these effects by employing a battery of TMS methods as well as drug agents to examine the role of different intracortical circuits in ballistic motor learning. 5) Chapter 7 studies the plasticity of intracortical circuits involved in transcallosal inhibition. 6) Chapter 8 studies the interaction between synaptic plasticity invoked by TBS and sequence learning. The studies described in the thesis contribute to understanding of how motor learning and neuroplasticity interact, and possible strategies to enhance these phenomena for clinical application

To Examine the Effects of Exercise & Instructional Based Interventions on Executive Functioning, Motor Learning & Emotional Intelligence Abilities Among Older Adults

Motor skills are a vital part of our life, and there might be situations where we will be required to either learn a new skill or relearn a known one. We examined the effectiveness of two different interventions - eccentric exercise and motivation-based instructions on enhancing the ability of older adults to learn a novel motor skill. Exercise intervention studies have shown that as little as 12 weeks of exercise can lead to improvements in both physical fitness and cognitive function in older adults, particularly executive control. But it is still unclear whether those improvements translate to improvements in other domains that rely on executive control, like motor skill learning and emotional intelligence. Study 1 explored the effect of eccentric exercise on these domains, specifically the ability to handle proactive interference in motor learning. 22 healthy adults (65-85 years of age) were recruited and randomly assigned either to a non-exercise control group, or to an exercise intervention group that performed 12 weeks of low to moderate intensity eccentric leg exercise (Eccentron). Corresponding neurophysiological measures were also recorded using EEG. We found that the control group experienced more proactive interference from baseline learning to post-test compared to the exercise group. The latter also displayed a higher level of emotional processing abilities than controls. They provide preliminary evidence that the cognitive benefits of exercise for older adults can be extended to domains outside of but related to executive control and memory. In study 2, we examined the effectiveness of an intervention based on the OPTIMAL theory of motor learning and performance on skill acquisition in both younger and older adults. We recruited 39 younger adults and 30 older adults and randomly assigned them to either the experimental group or to the control group. The intervention affected the two groups differentially. It was somewhat successful at improving learning in the older adults, but not in the younger adults. In fact, the intervention may have interfered with learning in the latter

Effects of a 12-Week Aerobic Spin Intervention on Resting State Networks in Previously Sedentary Older Adults

Objective: We have previously demonstrated that aerobic exercise improves upper extremity motor function concurrent with changes in motor cortical activity using task-based functional magnetic resonance imaging (fMRI). However, it is currently unknown how a 12-week aerobic exercise intervention affects resting-state functional connectivity (rsFC) in motor networks. Previous work has shown that over a 6-month or 1-year exercise intervention, older individuals show increased resting state connectivity of the default mode network and the sensorimotor network (Voss et al., 2010b; Flodin et al., 2017). However, the effects of shorter-term 12-week exercise interventions on functional connectivity have received less attention.Method: Thirty-seven sedentary right-handed older adults were randomized to either a 12-week aerobic, spin cycling exercise group or a 12-week balance-toning exercise group. Resting state functional magnetic resonance images were acquired in sessions PRE/POST interventions. We applied seed-based correlation analysis to left and right primary motor cortices (L-M1 and R-M1) and anterior default mode network (aDMN) to test changes in rsFC between groups after the intervention. In addition, we performed a regression analysis predicting connectivity changes PRE/POST intervention across all participants as a function of time spent in aerobic training zone regardless of group assignment.Results: Seeding from L-M1, we found that participants in the cycling group had a greater PRE/POST change in rsFC in aDMN as compared to the balance group. When accounting for time in aerobic HR zone, we found increased heart rate workload was positively associated with increased change of rsFC between motor networks and aDMN. Interestingly, L-M1 to aDMN connectivity changes were also related to motor behavior changes in both groups. Respective of M1 laterality, comparisons of all participants from PRE to POST showed a reduction in the extent of bilateral M1 connectivity after the interventions with increased connectivity in dominant M1.Conclusion: A 12-week physical activity intervention can change rsFC between primary motor regions and default mode network areas, which may be associated with improved motor performance. The decrease in connectivity between L-M1 and R-M1 post-intervention may represent a functional consolidation to the dominant M1.Topic Areas: Neuroimaging, Aging