Transcranial magnetic stimulation (TMS) is a non-invasive technique that can be used to assess the integrity neuronal circuits in the motor cortex, both at the intrahemispheric and interhemispheric level. In the present study, TMS was used to examine age-related modulation of corticospinal function. Participants underwent hand function testing to examine possible links between TMS measures and manual ability. Participants consisted of healthy young (n=13) and senior (n=17) right-handed individuals. Hand function testing consisted of a battery of tests administered bilaterally to assess each participant’s dexterity, strength, movement speed and reaction time. The following TMS measures were assessed bilaterally: resting motor threshold, recruitment curve and silent periods of the contralateral and ipsilateral hand. Both young and senior subjects showed significant intermanual differences in most behavioral measures, favoring their dominant right hand. There was an age-related difference in TMS measures indicating a decline in intrahemispheric excitability and interhemispheric inhibition. A general trend linking specific TMS measures in the active state with age-related changes in hand function on the dominant hand was found. Our results suggest that TMS markers of corticospinal excitability can be used to predict declining hand function with age and thus could provide an early diagnosis of pathological aging.

The human shoulder complex relies on the sensorimotor system to maintain stability. The sensorimotor system includes sensory feedback, control of the central nervous system and motor output. Exercise is considered an important part of shoulder rehabilitation and sports training to help improve control of the sensorimotor system. However, few studies have investigated the effect of exercise on the sensorimotor system. The first study of this dissertation explored the central control of the deltoid and rotator cuff (infraspinatus). Although both the deltoid and infraspinatus contribute to shoulder abduction, the results from this study showed that the modulation of their corticospinal excitability was affected differently by elevation angle. This could be explained by the fact that they play different roles at the shoulder: the deltoid is a prime mover while the infraspinatus is a stabilizer. The second study of this dissertation investigated scapular proprioception, which has not been assessed in previous studies. The findings of this study demonstrated that joint position sense errors of the overall shoulder joint mainly came from the glenohumeral joint. Scapular proprioception may need to be tested separately in addition to overall shoulder proprioception. In the third study, the effect of the exercise on shoulder sensorimotor system was investigated by measuring shoulder kinematics, shoulder joint position sense and cortical excitability before and after a four-week exercise training program. This protocol included strengthening and neuromuscular exercises targeting rotator cuff and scapular muscles. After the training protocol, although strength increased overall, the only observed sensorimotor adaptations were a decrease in upper trapezius activation and a decrease in the corticospinal excitability of the supraspinatus. There were no changes in other key parameters. Exercises focusing on specific muscles, combined with low-intensity closed-chain exercises, were not found to improve shoulder joint position sense or scapular kinematics. Combined with the findings of the decrease in corticospinal excitability of the supraspinatus and no change in muscle activity of the rotator cuff, it appears that while the exercises increased rotator cuff strength, these gains did not transfer to an increase in muscle activation during motion. This dissertation includes previously published co-authored material.

Transcranial magnetic stimulation (TMS) is a non-invasive technique that can be used to assess the integrity neuronal circuits in the motor cortex, both at the intrahemispheric and interhemispheric level. In the present study, TMS was used to examine age-related modulation of corticospinal function. Participants underwent hand function testing to examine possible links between TMS measures and manual ability. Participants consisted of healthy young (n=13) and senior (n=17) right-handed individuals. Hand function testing consisted of a battery of tests administered bilaterally to assess each participant’s dexterity, strength, movement speed and reaction time. The following TMS measures were assessed bilaterally: resting motor threshold, recruitment curve and silent periods of the contralateral and ipsilateral hand. Both young and senior subjects showed significant intermanual differences in most behavioral measures, favoring their dominant right hand. There was an age-related difference in TMS measures indicating a decline in intrahemispheric excitability and interhemispheric inhibition. A general trend linking specific TMS measures in the active state with age-related changes in hand function on the dominant hand was found. Our results suggest that TMS markers of corticospinal excitability can be used to predict declining hand function with age and thus could provide an early diagnosis of pathological aging.

Chez les personnes post-AVC (Accident Vasculaire Cérébral), spasticité, faiblesse et toute autre coactivation anormale proviennent de limitations dans la régulation de la gamme des seuils des réflexes d'étirement. Nous avons voulu savoir si les déficits dans les influences corticospinales résiduelles contribuaient à la limitation de la gamme des seuils et au développement de la spasticité chez les patients post-AVC. La stimulation magnétique transcranienne (SMT) a été appliquée à un site du cortex moteur où se trouvent les motoneurones agissant sur les fléchisseurs et extenseurs du coude. Des potentiels évoqués moteurs (PEM) ont été enregistrés en position de flexion et d'extension du coude. Afin d'exclure l'influence provenant de l'excitabilité motoneuronale sur l'évaluation des influences corticospinales, les PEM ont été suscités lors de la période silencieuse des signaux électromyographiques (EMG) correspondant à un bref raccourcissement musculaire juste avant l'enclenchement de la SMT. Chez les sujets contrôles, il y avait un patron réciproque d'influences corticospinales (PEM supérieurs en position d'extension dans les extenseurs et vice-versa pour les fléchisseurs). Quant à la plupart des sujets post-AVC ayant un niveau clinique élevé de spasticité, la facilitation corticospinale dans les motoneurones des fléchisseurs et extenseurs était supérieure en position de flexion (patron de co-facilitation). Les résultats démontrent que la spasticité est associée à des changements substantiels des influences corticospinales sur les motoneurones des fléchisseurs et des extenseurs du coude. / In post-stroke patients, spasticity, weakness and abnormal coactivation result from limitations in the range of regulation of stretch reflex thresholds. We investigated whether the deficits in residual corticospinal influences contribute to the limitation in the regulation of those thresholds and as a result to spasticity in post-stroke subjects. A single-pulse transcranial magnetic stimulation (TMS) was applied to the site of the motor cortex projecting to motoneurons of elbow flexors and extensors. Responses to TMS (motor evoked potentials or MEPs) were recorded at a flexion and an extension position of the elbow joint. To exclude the influence of background motoneuronal excitability on the evaluation of corticospinal influences, MEPs were elicited during the electromyographic (EMG) silent period produced by brief muscle shortening prior to TMS. In control subjects, corticospinal facilitation of flexor motoneurons was usually larger whereas that of extensor motoneurons was smaller during actively maintained flexion than when the extension position was maintained (reciprocal pattern of position-related changes in flexor and extensor MEPs). In most post-stroke subjects with high clinical spasticity scores, corticospinal facilitation of both flexor and extensor motoneurons was greater at the actively established flexion position (co-facilitation pattern). Results show that spasticity is associated with substantial changes in the corticospinal influences on flexor and extensor motoneurons. Corticospinal co-facilitation of the two groups of motoneurons may be related to the necessity to overcome resistance of spastic muscles during active changes in the elbow joint angle.

The corticospinal tract (CST), which carries commands from the cerebral cortex to the spinal cord, is vital to fine motor control. Spinal cord injury (SCI) often damages CST axons, causing loss of motor function, most notably in the hands and legs. Our preliminary work in rats suggests that CST circuitry is complex: neurons whose axons project to the lower cervical spinal cord, which directly controls hand function, also send axon collaterals to other locations in the nervous system and may engage parallel motor systems. To inform research into repair of SCI, we therefore aimed to map the entire projection pattern, or “connectome,” of such cervically-projecting CST axons. In this study, we mapped the corticospinal connectome of the Rhesus macaque - an animal model more similar to humans, and therefore more clinically relevant for examining SCI. Comparison of the Rhesus macaque and rat CST connectome, and extrapolation to the human CST connectome, may improve targeting of treatments and rehabilitation after human SCI. To selectively trace cervically-projecting CST motor axons, a virus encoding a Cre-recombinase-dependent tracer (AAV-DIO-gCOMET) was injected into the hand motor cortex, and a virus encoding Cre-recombinase (AAV-Cre) was injected into the C8 level of the spinal cord. In this intersectional approach, the gCOMET virus infects many neurons in the cortex, but gCOMET expression is not turned on unless the nucleus also contains Cre-recombinase, which must be retrogradely transported from axon terminals in the C8 spinal cord. Thus, gCOMET is only expressed in neurons that project to the C8 spinal cord, and it proceeds to fill the entire neuron, including all axon collaterals. Any gCOMET-labeled axon segments observed in other regions of the nervous system are therefore collaterals of cervically-projecting axons. gCOMET-positive axons were immunohistochemically labeled, and axon density was quantified using a fluorescence microscope and Fiji/ImageJ software. Specific regions of interest were chosen for analysis because of their known relevance in motor function in humans, and for comparison to results of a similar study in rats. Results in the first monkey have revealed both similarities and differences between the monkey and rodent CST connectome. Analyses of additional monkeys are ongoing. The final results will provide detailed information about differences between rodent and primate CST, will serve as a baseline for examining changes in the CST connectome after SCI, and will provide guidance for studies targeting treatment and functional recovery after SCI.

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This thesis describes experiments designed to investigate the effects of neuromuscular electrical stimulation (NMES) on corticospinal (CS) excitability in humans. NMES delivered at 100 Hz was more effective for increasing CS excitability than 10-, 50-, or 200-Hz NMES. CS excitability increases occurred after 24 min of 100-Hz NMES, were strongest in the stimulated muscle, and were mediated primarily at a supraspinal level. NMES of the common peroneal nerve of the leg increased CS excitability in multiple leg muscles, whereas NMES of the median nerve of the hand increased CS excitability in only the muscle innervated by that nerve. Additionally, CS excitability for the hand increased after 40 min of relatively high intensity and frequency NMES but not after 2 h of lower intensity and frequency NMES. These results have implications for identifying optimal NMES parameters to augment CS excitability for rehabilitation after central nervous system injury.

The series of experiments comprising this thesis investigate how neural inputs arising from higher motor centres (e.g., the motor cortex) and the periphery are translated into a variety of activation patterns of alpha motoneurones during the performance of various muscle contraction types. The thesis consists of six chapters, with the first chapter providing an introduction to the research program, and the final chapter giving a summary of the main research findings. Chapter 2 to 5 each represent stand-alone scientific works. The study presented in Chapter 2 examined whether the soleus (SOL) H-reflex is modulated during shortening contractions in a manner that has been observed for isometric contractions. It was revealed that no significant correlation was found between the SOL H-reflex and increasing plantar flexion torque during shortening contractions (ρ = −0.07, P = 0.15), while a strong positive correlation was observed for the isometric conditions (ρ = 0.99, P < 0.01). Furthermore, no modulation in the H-reflexes via paired stimuli in voluntary shortening contractions suggested that the level of homosynaptic post-activation depression (HPAD) did not change in response to the varying levels of activation in voluntary shortening contractions. Therefore, Ia-excitatory input is likely to be reduced during shortening contractions at increasing intensities, possibly due to a centrally regulated increase in presynaptic inhibition. The study described in Chapter 3 investigated corticospinal-evoked responses in triceps surae muscles during voluntary contractions at varying strengths. Motor-evoked potentials (MEPs) and cervicomedullary motor-evoked potentials (CMEPs) were elicited in the SOL and medial gastrocnemius (MG) muscles using magnetic stimulation over the motor cortex and cervicomedullary junction during voluntary plantar flexions with the torque ranging from 0 to 100% of a maximal voluntary contraction (MVC). In both SOL and MG, MEP and CMEP amplitudes [normalized to maximal M wave (Mmax)] showed an increase, followed by a plateau, over the greater part of the contraction range with responses increasing from 0.2 to 6% of Mmax for SOL and from 0.3 to 10% of Mmax for MG. It was suggested that increases in the evoked responses from the triceps surae muscle over a greater range of contraction strengths than for upper limb muscles, probably stems from differences in the pattern of motor unit recruitment and rate coding for these muscles, and the strength of the corticospinal input. In Chapter 4, in an attempt to investigate how the recruitment and rate coding of motor unit organisation can affect the responsiveness of gross evoked potentials to artificial excitatory stimuli, a computer simulation was performed based upon a physiologically plausible model of the motoneurone. The simulation revealed that the force level where the evoked response commences to decline corresponds approximately to the upper limit of recruitment of motor units. This observation was consistent no matter whether firing rates for low-threshold units exceed those for high-threshold units. Since the simulated results were consistent with previous observations in both individual (single motor unit) and population (motoneurone pool) terms, the proposed model is physiologically plausible and can be useful to predict the evoked EMG response via artificial stimulation protocols, thereby inferring the underlying neural mechanisms occurring at the motoneurone pool during voluntary movements. The study presented in Chapter 5 determined the recruitment range and discharge behaviours in the SOL motor units, and examined the possible influence of persistent inward currents (PICs) on SOL motor unit recruitment and discharge rates. Forty-two clearly identified motor units from five subjects revealed that soleus motor units are recruited progressively from rest to contraction strengths close to 95% of MVC, with low-threshold motor units discharging action potentials slower at their recruitment and with a lower peak rate than later recruited high-threshold units. This observation is in contrast to the ‘onion skin phenomenon’ often reported for the upper limb muscles. Based on positive correlations of the peak discharge rates, initial rates and recruitment order of the units with the magnitude of the onset-offset hysteresis (i.e., a difference in discharge rate between recruitment and de-recruitment) and not PIC contribution, we conclude that discharge behaviours among motor units appear to be related to a variation in an intrinsic property other than PICs.

The process of movement execution can be separated into two sections; the foreperiod and the response time. The foreperiod represents the time between the warning signal (WS) and the presentation of the imperative “go” signal, and the response time incorporates both the reaction time (RT) and the movement time (Schmidt & Lee, 2011). Transcranial magnetic stimulation (TMS) was used to probe corticospinal excitability (CE) which has been measured in a variety of RT tasks during both the foreperiod and the response time periods. The purpose of the two studies in this thesis was to measure when and at what rate changes in CE occur in both simple and complex tasks. The results of the first experiment indicated that CE levels quickly increased from baseline with the presentation of the WS. This was followed by a holding period in which CE was held constant until a decline in CE occurred prior to the presentation of the IS. This decline was followed by a rapid increase in CE as the movement was initiated and released. Importantly, even though levels of CE were decreasing relative to the start of the decline, participants were still in a heightened state as they prepared to release their movements. Furthermore, it is suggested that selective inhibitory control mechanisms were at least partly responsible for the decline prior to the IS. The results of the second experiment indicated that MEP amplitudes in a simple task were significantly larger compared to those in a complex task relative to both the IS and the onset of electromyography. These findings suggest that simple and complex tasks achieve differing levels of corticospinal excitability, and it is suggested that the complex requires the use of the cerebellum, which suppresses excitatory projections to the thalamus, and consequently to the motor cortex.