Lara Boyd

While studies have investigated the effect of exercise on corticospinal, intracortical, and interhemispheric processes in young adults, few studies have focused on older adults. Current evidence supports the hypothesis that there is a shift from predominantly inhibitory to excitatory interhemispheric interactions as we age. Other work suggests that changes observed in transcallosal inhibition (TCI) with age (i.e., reduced ipsilateral silent period (iSP) duration and area) may be mitigated by physical activity. Therefore, the main purpose of this experiment was to advance understanding of how an acute bout of high intensity exercise alters patterns of corticospinal and interhemispheric excitability in the healthy older adult population. 41 healthy older adults participated in this study. Participants were randomized into the exercise (n=21) or the rest (n=20) group. Participants in the exercise group completed an acute bout of high intensity exercise on a recumbent bike lasting 23 minutes. Participants in the rest group sat for the same duration of time while their attention was controlled by watching a nature documentary. Corticospinal excitability and TCI of the upper limbs was assessed via transcranial magnetic stimulation before (baseline), immediately (Post 1), and 30 minutes (Post 2) following high intensity exercise or rest. Results indicated that there was an increase in corticospinal excitability immediately and 30 minutes post exercise in the dominant hemisphere. There was also an interaction effect between timepoint and hemisphere in transcallosal inhibition. The current study showed following an acute bout of high intensity exercise, there was an increase in corticospinal excitability in the dominant hemisphere and a hemispheric difference in TCI in older adults. The present research provides insight on how exercise could be used to mitigate age related changes in the brain and informs how exercise therapies could be employed in association with rehabilitation in clinical populations.

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Cross-education (CE) of strength occurs when a muscle is trained unilaterally and bilateral improvements in strength are noted. Unilateral resistance exercise can therefore be advantageous for clinical populations, including individuals with stroke, as a means to improve strength bilaterally when only the less affected side of the body can be trained. Yet we do not understand the mechanism through which CE is mediated in the brain, nor do we know if the cortical effects of CE are localized and spatially confined to homologous muscles. The main purpose of the current thesis was to determine the impact of bilateral and unilateral lower extremity (LE) resistance exercise on corticospinal excitability in the unexercised upper extremity (UE). Twelve healthy participants were recruited to participate in two sessions on separate days. During each session, transcranial magnetic stimulation (TMS) and peripheral nerve stimulation were used to quantify baseline corticospinal excitability in the unexercised UE in the abductor pollicus brevis muscle (APB). This was followed by an acute bout of either a bilateral or unilateral leg extension exercise condition. All participants completed both conditions; the order of the conditions was randomized. Immediately following the acute exercise bout, measures of corticospinal excitability were repeated in the same manner as at baseline. Strength improved in both legs post-exercise in the bilateral (p= 0.042) and unilateral (p=0.005) condition. There was a decrease in intracortical inhibition after bilateral leg extensions were performed in both hemispheres (p=0.05). There were no changes in corticospinal excitability after the unilateral exercise. There were no changes in spinal excitability in either condition in the unexercised UE after LE resistance exercise.These data suggest that unilateral resistance exercise can improve strength bilaterally. In addition, an acute bout of bilateral LE resistance exercise can influence cortical areas beyond the cortical representation of the exercised limbs. However, acute unilateral resistance exercise bouts may not be able to produce these wide-spread cortical changes to the same extent as bilateral exercise. This current research contributes to the current CE literature, helping to explain the limits of this phenomenon which in turn will facilitate the assimilation of CE into clinical practice.

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The acquisition of complex motor skills shapes our behavior and ability to adapt in everyday life. The underlying biological processes are complex, involving multiple neuroanatomic pathways and efficient communication within functional brain networks. Understanding the neural underpinnings of motor learning and adaptation within the context of health and disease is fundamental, and particularly relevant to brain injury, recovery, and rehabilitation. Following middle cerebral artery (MCA) stroke, individuals often experience upper limb motor impairment that continues into the chronic phase. Motor recovery is influenced by the reorganization of brain networks compensating for tissue damage and by well-designed motor rehabilitation programs that promote use of the remaining motor output. However, predicting the outcome of rehabilitation has been difficult and recovery is often incomplete. Impairments in cortical-cerebellar pathways may underlie motor deficits and influence motor function, yet, to date, little work has examined the influence of cortical-cerebellar relationships in relation to motor adaptation in chronic MCA stroke. The overall objective of the present thesis was to investigate the impact of MCA stroke on cortical-cerebellar neurophysiology and motor adaptation using transcranial magnetic stimulation (TMS). TMS was employed to investigate cortical-cerebellar excitability at baseline, and then during a sensorimotor adaptation task in a group of chronic MCA stroke and a group healthy older controls. Both groups had similar cortical-cerebellar excitability before and during the adaptation task. However, individuals with MCA stroke are impaired compared to healthy age matched controls in sensorimotor adaptation. This suggests that adaptation deficits after MCA stroke may be influenced by motor network substrates beyond the cerebellum. The present thesis contributes new knowledge towards understanding the impact of chronic MCA stroke on cortical-cerebellar pathways and sensorimotor adaptation. The finding of sufficient cortical-cerebellar connectivity suggests that it may be a candidate pathway for TMS stimulation to modulate motor related networks for stroke rehabilitation.

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Aging is associated with a reduced ability to perform motor tasks, as well as a decreased capacity for neuroplastic change and motor skill learning. Evidence in young healthy adults suggests a single session of aerobic exercise can facilitate motor learning and changes in movement-related neurophysiological circuits. However, we do not know whether these effects extend to healthy older adults. The objectives of the present thesis were to examine whether a single session of moderate-intensity aerobic exercise 1) facilitates motor skill acquisition and consolidation, and 2) modulates motor cortical and intracortical circuitry, in healthy older adults. Twenty-two participants (55-75 years old) completed a maximal exercise stress test at least two days prior to all other sessions. Next, participants practiced a motor sequence task after 20-minutes of moderate-intensity cycling or 20-minutes of seated rest, on separate occasions. To assess motor learning, participants performed the motor task 24 hours later at a no-exercise retention test. On a separate day, neurophysiological measures using transcranial magnetic stimulation were obtained at two time-points prior to and two time-points following an acute bout of moderate-intensity cycling. Performing aerobic exercise immediately prior to task practice did not yield any statistically significant differences in measures of motor skill acquisition or consolidation. However, we observed a non-significant trend towards improvements in motor memory consolidation, such that under the exercise condition there were greater improvements in repeated sequences compared to rest. Additionally, we found that after exercise there was an increase in long-interval intracortical inhibition (LICI), which returned to near baseline levels within 30 minutes post-exercise. Overall, these findings suggest that a single bout of moderate-intensity aerobic exercise transiently modulates GABA-B mediated intracortical inhibition in healthy older adults, however, these exercise-induced neurophysiological effects may not necessarily translate to changes in motor behaviour.This work is the first to investigate the efficacy of an acute bout of aerobic exercise in facilitating motor performance and learning, as well as modulating motor cortical and intracortical circuits, in healthy older adults. Further understanding of how exercise influences motor learning and neurophysiology in the aging brain will be critical for the development of potential rehabilitation strategies. 

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Individuals with type-2 diabetes have an increased incidence of ischemic stroke, and experience higher rates of disability after stroke than non-diabetics. Recent research suggests that type-2 diabetes has adverse effects on neuronal integrity and function, however, to date very little work has examined the interactions of diabetes with chronic stroke recovery. The goal of the present thesis is to address this gap in the literature by employing multimodal magnetic resonance imaging (MRI) techniques to examine the impact of type-2 diabetes on the integrity of surviving sensorimotor neural tissue in individuals with chronic hemiparesis as a result of ischemic stroke. We employ volumetric MRI, diffusion tractography, and magnetic resonance spectroscopy (MRS) to explore the structure of motor and sensory cortex grey matter and white matter projections. We found individuals with chronic stroke and diabetes had lower regional cortical thickness in primary somatosensory cortex, and primary and secondary motor cortices. Contralesional primary and secondary motor cortex thicknesses were negatively related to motor outcomes of the paretic upper-limb in the diabetes group. MRS revealed stroke survivors with diabetes had bilaterally reduced creatine levels in sensorimotor cortex. Diabetes status did not impact gross cortical volumes, white matter volumes, or white matter microstructure in projections from the primary motor and sensory cortex. These results suggest that type-2 diabetes alters cerebral metabolic function, which may result in thinning to sensorimotor grey matter. This work provides preliminary evidence for differential profiles of cerebral recovery from stroke in individuals with diabetes. Given the worldwide increase in the prevalence of diabetes it is critical that we examine the mechanisms of increased post-stroke disability in type-2 diabetes to inform targeted therapies for this population.

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Unilateral strength training of the less affected (LA) limb has been shown to improve strength bilaterally. This improved strength is referred to as cross-education in the literature. This intervention has the potential to be beneficial for individuals who cannot train both sides of the body due to post-stroke hemiparesis. To date only one group has researched cross-education in the upper limb in stroke, with varied results. The main purpose of our work was to determine if strength training of the LA forearm would change patterns of cortical excitability bilaterally after stroke, and additionally affect changes in strength and function bilaterally. Twenty-four participants with chronic (> 6 months) stroke-related hemiparesis engaged in three baseline sessions separated by 4-7 days. During these sessions individuals’ forearm strength, motor function, and motor impairment were tested, along with a TMS based assessment of corticospinal excitability and intracortical circuits. On a fourth visit participants completed their first training session using the LA arm, then were given the same wrist extension strength-training device to take home. Participants completed three 25-minute training sessions, weekly; one in the laboratory and the remaining two at home. After 5 weeks of training, participants returned to the laboratory for post-intervention retention tests. Cross-education increased strength in the LA wrist extensors (p = 0.026) and the untrained, more-affected (MA) wrist extensors (p = 0.05) in participants with chronic stroke, at the 1-week retention test. Further, LA arm strength remained increased at 5-week retention test (p = 0.023) despite there being no further training. There were strength improvements in the majority of participants in both their trained (17 of 24) and untrained (12 of 24) wrist extensors. There was a decrease in corticospinal inhibition in the LA hemisphere, and a release of interhemispheric inhibition (IHI) bilaterally. A significant increases in motor function and a decrease in motor impairment was seen, respectively. Results indicate that cross-education could be a valuable tool for increasing strength in chronic stroke. Cross-education training of the LA upper limb may allow individuals who do not have adequate function in their MA limb prior to training engage in rehabilitative interventions post-training.

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Aerobic exercise has been promoted as a possible adjunct therapy to neurorehabilitation practice, given its positive effects on brain health. In healthy young adults, acute high-intensity cycling can enhance motor performance and learning of a complex motor task, and promote neuroplasticity in the motor system. However, clinical populations may not be able to participate in high-intensity exercise. To date there is inconsistent evidence for the efficacy of moderate-intensity aerobic exercise to alter motor learning and neuroplasticity in healthy young adults. Using two experiments, we aimed to determine how acute moderate-intensity cycling affects motor behavior and neuroplasticity in healthy young individuals. First, 16 participants practiced a complex motor skill after 30 minutes of moderate-intensity cycling or seated rest, on separate occasions. Motor performance was assessed at baseline, immediately after, and 5 minutes after exercise or rest. Twenty-four hours later, we assessed motor learning at a no-exercise retention test. Under the exercise condition, participants maintained performance over time, whereas, performance diminished over time under the rest condition, and became worse than post-exercise performance. Conditions did not differ at retention. Second, another group of 16 participants underwent paired associative stimulation (PAS) a transcranial magnetic stimulation (TMS) protocol known to induce neuroplasticity in the motor system. Effects of PAS were separately compared after a 30-minute bout of moderate-intensity cycling versus seated rest. At baseline, immediately after PAS, and 30 minutes post-PAS, we measured corticomotoneuronal excitability and excitability of intracortical neural circuits using TMS. We found that PAS increased corticomotoneuronal excitability when performed after exercise, but not rest. Exercise and PAS modulated activity in specific neural circuits post-intervention, without similar results under the rest condition. Moderate-intensity aerobic exercise can promote neuroplasticity in the motor system, but in this study similar effects did not transfer to behavioral measures of motor learning. In order to evaluate the clinical feasibility of this pairing moderate intensity exercise with skilled motor practice, we must first elucidate the dose-response effects of exercise on motor behavior, explore timing effects of exercise on motor learning, and examine how long-term pairing of exercise with practice impacts motor learning.

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Stroke is the leading cause of chronic adult disability, and standard post-stroke therapiesmay not be sufficient for individuals to reach their full recovery potential. When paired withskilled motor practice, non-invasive brain stimulation techniques such as repetitive transcranialmagnetic stimulation (rTMS) may enhance motor recovery by transiently modulating corticalexcitability, effectively priming the brain to facilitate mechanisms of motor learning. Dependingon the pulse frequency, rTMS may be used to increase cortical excitability in the damagedhemisphere, or decrease it in the undamaged hemisphere, with the goal of re-establishing anormal interhemispheric balance. While theoretically promising, the majority of studiesconsidering the effects of rTMS over the primary motor cortex (M1) have shown relatively smalleffect sizes and high inter-individual variability. Improved effect sizes may be produced by 1)finding the optimal cortical target for stimulation, rather than defaulting to M1, and 2) choosingan appropriate sample that will optimally benefit from the intervention. In the following thesis,we will explore the potential of the primary sensory cortex (S1) as an alternative target for rTMSintervention, and the anatomical and physiological variables that may help to identify who maybest benefit from this intervention. First, we describe a randomized, single blind experimentcomparing the impact of active versus sham rTMS over S1 paired with practice of a skilledvisuomotor reaching task in individuals with chronic stroke. Second, we describe a retrospectiveanalysis of the participants from the first experiment, to determine whether individual differencesin morphology of the underlying sensory cortex might be predictive of rTMS responsiveness.Third, we describe an exploratory study using a paired median nerve somatosensory evokedpotential paradigm using electroencephalography in healthy individuals, to elucidate theneurophysiological mechanism of interhemispheric inhibition between S1s. We conclude that S1should be considered as a viable target for future rTMS trials as an adjunct therapy torehabilitation after stroke.

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Chronic upper extremity hemiparesis is common after stroke (Jørgensen et al., 1995). This chronic impairment has a direct impact on functional independence and the ability to perform daily activities (Lloyd-Jones et al., 2010). Given the high levels of functional losses after stroke, investigation into treatments for chronic impairments should be considered. The purpose of the current study was to examine the effects of short-term bimanual coordination training on the modulation of sensorimotor cortical activity and motor performance. Thirty healthy participants were randomized to one of three training groups: 1) physical practice, 2) observational practice, and 3) no practice (control condition). Movement-related potentials (MRPs) and somatosensory evoked potentials (SEPs) were collected before and after training to examine the effects of training on cortical activity. Motor performance on the bimanual coordination task was also compared between groups. The results showed that: (1) there was no significant difference in MRP or SEP measures between groups, (2) the physical practice group performed significantly better (as indexed by greater accuracy following practice) than the control group on the bimanual coordination task, (3) although the observational practice group did not perform as well as the physical practice group, there was a trend for greater accuracy following observation as compared to the control group. These results suggest that both short-term physical and observational practice of a bimanual coordination task can result in improved motor performance and provide support for the use of observational practice in motor learning.

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Movement-related gating is influenced by task-relevancy manipulations, such that increased sensory information ascends to the cortex when information is relevant, but does not when it is irrelevant (1). Regardless of relevancy, during movement smaller cortical somatosensory responses are produced as compared to those evoked by similar stimulation at rest (1). These task-relevancy effects have specifically been documented during movement of the lower limb (1). Task-relevancy effects have been hypothesized to be controlled by the prefrontal cortex (PFC) based on this region's known role in selective attention, as well as filtering of distracting information at later stages of somatosensory processing (2). The purpose of the current study was first to verify task-relevancy influences on movement-related gating in the upper limb, and second to test the contribution of the PFC to these relevancy effects. Eleven healthy participants received median nerve stimulation at the left wrist during three conditions: rest, task-irrelevant movement, and task-relevant movement. The cortical responses to these median nerve stimulations were measured in the form of somatosensory evoked potentials (SEPs). Each of these three conditions was collected on a baseline day and on two separate days following either continuous theta burst (cTBS), which has a net inhibitory effect on cortical excitability, over the contralateral primary somatosensory cortex (S1) or the right dorsolateral prefrontal cortex (DLPFC). Results demonstrated a significant interaction effect between the stimulation site and the condition, with post-hoc tests revealing that following cTBS over S1 or DLPFC, relevancy based modulation of SEP amplitude was abolished. These results indicate that both S1 and DLPFC are integral to individual ability to facilitate relevant sensory information in order to complete a motor task.

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Hemiparesis is one of the most prevalent chronic disabilities after stroke, particularly in subcortical stroke. Neuroimaging has provided important morphological insight in to the mechanisms associated with hemiparesis in individuals with stroke. Assessing morphological changes within the primary motor cortex may provide valuable information of the neural events that underlie upper-extremity (UE) hemiparesis in chronic stroke. The purposes of this study were to 1) evaluate anatomical and metabolic changes in the motor cortex, and 2) examine the relationship between anatomical and metabolic changes and hemiparetic arm use in individuals in the chronic stage of stroke recovery. Seventeen individuals with chronic (>6 months) subcortical ischemic stroke and eleven neurologically healthy controls were recruited. Single voxel proton magnetic resonance spectroscopy (H1MRS) was performed to measure metabolite concentrations of total N-acetylaspartate (tNAA) and glutamate+glutamine (Glx). FreeSurfer software package (http://surfer.nmr.mgh.havard.edu) was used to quantify cortical thickness of the precentral gyrus. Upper-extremity motor performance was assessed using the Wolf Motor Function Test (WMFT) and the Motor Activity Log Quality of Movement scale (MAL-QOM) and upper-extremity motor activity was assessed using activity counts from wrist-mounted accelerometers. Results demonstrated a significant decrease in tNAA and Glx concentration in the hand area of the primary motor cortex in the stroke group, particularly within the ipsilesional hemisphere. Precentral gyrus cortical thickness was also decreased in the ipsilesional hemisphere of the stroke group. Parametric correlation analysis revealed a significant positive correlation between precentral gyrus thickness and tNAA concentration bilaterally. Multivariable regression analyses revealed that, after accounting for age and post-stroke duration, the combination of ipsilesional metabolite concentration (tNAA and Glx) and ipsilesional cortical thickness was associated with hemiparetic UE motor performance, but not UE motor activity in individuals in the chronic stage of stroke recovery. The observed link between structural and neurochemical changes in the stroke-affected brain and hemiparetic UE motor performance during the chronic phase of recovery may improve the understanding of the underlying neural mechanisms that support motor impairment after stroke.

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After stroke, cortical excitability is decreased in the ipsilesional primary motor cortex andincreased in the contralesional primary motor cortex. This abnormal pattern of excitabilitydetrimentally affects performance with the hemiparetic arm. Short lasting improvements inmotor performance occur following repetitive transcranial magnetic stimulation (rTMS) over thecontralesional hemisphere after stroke; however, no work has considered the impact of pairingrTMS with skilled motor practice over multiple days on motor learning, hemiparetic armfunction, or electroneurophysiology in the brain. The aim of this thesis was to determine theimpact of 3 days of continuous theta burst stimulation (cTBS) over contralesional primary motorcortex paired with skilled motor practice on 1) learning of a novel motor task and hemipareticarm motor function and 2) levels of intracortical inhibition, intracortical facilitation, andtranscallosal inhibition following stroke. In a cross-over design, participants with chronic strokewere randomized to first receive either active or sham cTBS over the contralesional primarymotor cortex. Functional measures, motor task performance, and electroneurophysiology wereassessed at baseline. 3 days of cTBS paired with skilled motor practice were completed;functional measures, motor learning, and electroneurophysiology were re-evaluated at posttesting.After a 2-week washout period participants underwent the second half of the study withthe other form of cTBS. Participants showed larger motor learning related change followingactive cTBS than sham cTBS. The magnitude of this improvement correlated with enhancedperformance on standardized measures of arm function after stroke. Active cTBS also decreasedlevels of facilitation in the contralesional hemisphere and decreased the amount of inhibitionbeing sent from the contralesional hemisphere to the ipsilesional hemisphere. No adverse effectswere reported. Results of this thesis suggest that cTBS over the contralesional motor cortexiiipaired with skilled motor practice facilitates both improved hemiparetic arm function and motorlearning beyond that seen with skilled motor practice alone. The results of this thesis contributeto research relevant to rehabilitation of individuals with stroke and may facilitate thedevelopment of new rehabilitation strategies to improve functional recovery after stroke.

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Walking in a novel environment, such as with resistance, has been associated with changes in muscle activity (Lam, Anderschitz & Dietz, 2006), limb position (Lam et al., 2006; 2008) and cortical spinal activity (Capaday, Lavoie, Barbeau, Schneider & Bonnard, 1999; Bonnard, Camus, Coyle & Pailhous, 2002) compared to baseline walking measurements. Previous literature on locomotor adaptation, suggests that the nervous system has the ability to adapt to task demands. The location and mechanisms of these physiological and kinematic changes are still unknown. The purpose of the current study was to verify that corticospinal (CS) excitability is altered by resisted walking. Second, we explored whether CS changes are modulated by attention and lastly whether changes in excitability are muscle specific. Locomotor adaptations were induced in 40 healthy participants using a robotic gait-assisted treadmill (Lokomat). Velocity-dependent resistance was applied against hip and knee movements during walking. CS excitability was assessed by quantifying motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation immediately before and after adaptation to both resisted and nonresisted walking. Recruitment curves were collected by stimulating at increments of 5% from 105-145%AMT. To determine whether adaptation is muscle specific, MEPs were measured through random assignment of either the biceps femoris (BF) or rectus femoris (RF). To evaluate the impact of attention on adaptive walking, half the participants attended to their walking pattern via a visual feedback tracking task (post_cog). The other half watched a controlled visual stimulus (post_nocog). Results demonstrated a significant increase in MEP amplitude in the BF and not the RF following resisted walking. The post_cog condition adaptations did not reveal an increase in MEP amplitude compared the post_nocog condition. Results suggest that locomotor adaptations result in an increase in CS excitability that is muscle specific. Focused attention to motor adaptation may not be an important modulator of movement and motor learning as has been reported in past work. The current study is the first to consider both the role of the CS system in adaptations during walking and the impact of attention on CS excitability and parallels previous findings on muscle specific locomotor adaptations.

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