Canadian epilepsy priority-setting partnership: Toward a new national research agenda.

BACKGROUND: Health research agendas are often set by researchers or by industry and may not reflect the needs and priorities of end users. This priority-setting partnership (PSP) for epilepsy was undertaken to identify the most pressing unanswered questions about epilepsy and seizures from the perspective of people with epilepsy (PWE) and their care providers. METHODS: Using the methodology developed by the James Lind Alliance (JLA), evidence uncertainties were gathered via online surveys from stakeholders across Canada. Submissions were formed into summary questions and checked against existing evidence to determine if they were true uncertainties. Verified uncertainties were then ranked by patients, caregivers, and healthcare providers and a final workshop was held to reach a consensus on the top 10 priorities. RESULTS: The final top 10 list reflects the priority areas of focus for research as identified by the Canadian epilepsy community, including genetic markers for diagnosis and treatment, concerns about living with the long-term effects of epilepsy, and addressing knowledge gaps in etiology and treatment approaches. CONCLUSION: This project represents the first systematic evidence of patient- and clinician-centered research priorities for epilepsy. The results of this priority-setting exercise provide an opportunity for researchers and funding agencies to align their agendas with the values and needs of the epilepsy community in order to improve clinical outcomes and quality of life (QOL) for PWE.

Acute exercise enhances the response to paired associative stimulation-induced plasticity in the primary motor cortex.

There is evidence that a single session of aerobic exercise can modulate intracortical inhibition. While decreases in inhibition appear to be a necessary precursor to the induction of long-term potentiation (LTP)-like plasticity, it is not known whether aerobic exercise can enhance the response to LTP induction. We investigated whether the addition of a preceding bout of exercise would modulate the response to paired associative stimulation (PAS) of the upper limb. It was hypothesized that exercise would enhance motor cortical (M1) excitability following PAS compared to a session of PAS alone. Ten healthy individuals underwent a control session involving PAS alone and an exercise session where PAS was preceded by 20 min of moderate-intensity stationary biking. PAS involved 180 pairs of stimuli (right median nerve, left M1) delivered at 0.1 Hz to the right abductor pollicis brevis representation. Excitability changes were measured by the area under a stimulus-response curve, and intracortical circuits were probed by testing short-interval intracortical inhibition (SICI), long-interval intracortical inhibition and intracortical facilitation. Two-way ANOVAs were conducted to compare excitability changes between sessions. PAS-induced increases in M1 excitability were enhanced in the exercise session (p < 0.026). In addition, SICI was differentially modulated between the two sessions, with greater decreases in SICI observed immediately after PAS when it was preceded by the exercise session (p < 0.03). Aerobic exercise enhances the effectiveness of PAS and may be a useful adjunct to traditional therapies and interventions that aim to promote neuroplasticity in cortical networks.

Aerobic exercise abolishes cTBS-induced suppression of motor cortical excitability.

A preceding bout of acute aerobic exercise can enhance the induction of early long-term potentiation (LTP) in the primary motor cortex (M1). However, the influence of exercise when performed after the induction of plasticity has not been investigated. In addition, it is unclear whether the same effects are seen with techniques that induce long-term depression (LTD). We used continuous theta-burst stimulation (cTBS) to temporarily suppress cortical excitability and investigate whether moderate-intensity cycling exercise would alter the duration or intensity of cTBS after-effects in a nonexercised upper limb muscle. We observed that cTBS effects were abolished when followed by exercise, with no corresponding changes in intracortical network activity. We hypothesize that the induction of LTD may be suppressed by exercise-linked neurotransmitters that interact with glutamate receptors. Exercise appears to shift the neural balance towards facilitation and may work to counteract the effects of LTD-like processes.

Aerobic exercise enhances neural correlates of motor skill learning.

INTRODUCTION: Repetitive, in-phase bimanual motor training tasks can expand the excitable cortical area of the trained muscles. Recent evidence suggests that an acute bout of moderate-intensity aerobic exercise can enhance the induction of rapid motor plasticity at the motor hotspot. However, these changes have not been investigated throughout the entire cortical representation. Furthermore, it is unclear how exercise-induced changes in excitability may relate to motor performance. We investigated whether aerobic exercise could enhance the neural correlates of motor learning. We hypothesized that the combination of exercise and training would increase the excitable cortical area to a greater extent than either exercise or training alone, and that the addition of exercise would enhance performance on a motor training task. METHODS: 25 young, healthy, right-handed individuals were recruited and divided into two groups and three experimental conditions. The exercise group performed exercise alone (EX) and exercise followed by training (EXTR) while the training group performed training alone (TR). RESULTS: The combination of exercise and training increased excitability within the cortical map of the trained muscle to a greater extent than training alone. However, there was no difference in performance between the two groups. These results indicate that exercise may enhance the cortical adaptations to motor skill learning.

The effects of acute aerobic exercise on the primary motor cortex.

The effect of aerobic exercise on primary motor cortical excitability is a relevant area of interest for both motor learning and motor rehabilitation. Transient excitability changes that may follow an exercise session are a necessary precursor to more lasting neuroplastic changes. While the number of studies is limited, research suggests that a session of aerobic exercise can create an ideal environment for the early induction of plasticity. Potential mechanisms include the upregulation of neurotransmitter activity, altered cerebral metabolism and cortisol levels, and increases in brain-derived neurotrophic factor. While there is considerable evidence that chronic physical activity positively impacts brain health and function, studies examining cortical excitability changes and motor performance after a single session of exercise are lacking. Further research is required to determine the clinical utility and feasibility of aerobic exercise.

Bilateral primary motor cortex circuitry is modulated due to theta burst stimulation to left dorsal premotor cortex and bimanual training.

Motor preparatory and execution activity is enhanced after a single session of bimanual visuomotor training (BMT). Recently, we have shown that increased primary motor cortex (M1) excitability occurs when BMT involves simultaneous activation of homologous muscles and these effects are enhanced when BMT is preceded by intermittent theta burst stimulation (iTBS) to the left dorsal premotor cortex (lPMd). The neural mechanisms underlying these modulations are unclear, but may include interhemispheric interactions between homologous M1s and connectivity with premotor regions. The purpose of this study was to investigate the possible intracortical and interhemispheric modulations of the extensor carpi radials (ECR) representation in M1 bilaterally due to: (1) BMT, (2) iTBS to lPMd, and (3) iTBS to lPMd followed by BMT. This study tests three related hypotheses: (1) BMT will enhance excitability within and between M1 bilaterally, (2) iTBS to lPMd will primarily enhance left M1 (lM1) excitability, and (3) the combination of these interventions will cause a greater enhancement of bilateral M1 excitability. We used single and paired-pulse transcranial magnetic stimulation (TMS) to quantify M1 circuitry bilaterally. The results demonstrate the neural mechanisms underlying the early markers of rapid functional plasticity associated with BMT and iTBS to lPMd primarily relate to modulations of long-interval inhibitory (i.e. GABAB-mediated) circuitry within and between M1s. This work provides novel insight into the underlying neural mechanisms involved in M1 excitability changes associated with BMT and iTBS to lPMd. Critically, this work may inform rehabilitation training and stimulation techniques that modulate cortical plasticity after brain injury.

Modulation of left primary motor cortex excitability after bimanual training and intermittent theta burst stimulation to left dorsal premotor cortex.

Bimanual visuomotor movement training (BMT) enhances the excitability of human preparatory premotor and primary motor (M1) cortices compared to unimanual movement. This occurs when BMT involves mirror symmetrical movements of both upper-limbs (in-phase) but not with non-symmetrical movements (anti-phase). The neural mechanisms mediating the effect of BMT is unclear, but may involve interhemispheric connections between homologous M1 representations as well as the dorsal premotor cortices (PMd). The purpose of this study is to assess how intermittent theta burst stimulation (iTBS) of the left PMd affects left M1 excitability, and the possible combined effects of iTBS to left PMd applied before a single session of BMT. Left M1 excitability was quantified using transcranial magnetic stimulation (TMS) in terms of both the amplitudes and spatial extent of motor evoked potentials (MEPs) for the extensor carpi radialis (ECR) before and multiple time points following (1) BMT, (2) iTBS to left PMd or (3) iTBS to left PMd and BMT. Although there was not a greater increase in either specific measure of M1 excitability due to the combination of the interventions, iTBS applied before BMT showed that both the spatial extent and global MEP amplitude for the ECR became larger in parallel, whereas the spatial extent was enhanced with BMT alone and global MEP amplitude was enhanced with iTBS to left PMd alone. These results suggest that the modulation of rapid functional M1 excitability associated with BMT and iTBS of the left PMd could operate under related early markers of neuro-plastic mechanisms, which may be expressed in concurrent and distinct patterns of M1 excitability. Critically, this work may guide rehabilitation training and stimulation techniques that modulate cortical excitability after brain injury.

Selective modulation of left primary motor cortex excitability after continuous theta burst stimulation to right primary motor cortex and bimanual training.

Bimanual movement training (BMT) enhances the excitability of human preparatory premotor and primary motor (M1) cortices. We have shown that activity in M1 is enhanced after BMT involving simultaneous activation of homologous muscles (in-phase). Potential neural mechanisms underlying this effect could be input from premotor areas (i.e. dorsal premotor cortex (PMd)) and/or the homologous M1 representation. Recently, we showed that increasing PMd activity using theta burst stimulation (TBS) followed by BMT enhanced the corticospinal excitability of M1 compared to BMT alone. The purpose of this study was to investigate the effects of continuous TBS (cTBS) to right hemisphere M1 (rM1) on the homologous wrist extensor representation in left M1 (lM1), and its potential combined effects when followed by BMT. We used transcranial magnetic stimulation (TMS) to measure cortical excitability of extensor carpi radialis (ECR) representation at multiple time points in three conditions: (1) BMT, (2) cTBS to rM1 or (3) cTBS to rM1 and BMT. The combination of cTBS to rM1 and BMT resulted in an increased shift in the centre of gravity (CoG) compared to either intervention alone, along with an increased muscle topographical representation up to 60 min when cTBS to rM1 was combined with BMT compared to cTBS to rM1 alone. These results suggest that modulation of M1 may reduce ongoing interhemispheric inhibition (or increase facilitation indirectly) to the opposite homologous M1 region in healthy individuals via transcallosal or subcortical connections. Critically, this work may guide rehabilitation training and stimulation techniques that modulate cortical plasticity after brain injury.

Aerobic exercise modulates intracortical inhibition and facilitation in a nonexercised upper limb muscle.

BACKGROUND: Despite growing interest in the relationship between exercise and short-term neural plasticity, the effects of exercise on motor cortical (M1) excitability are not well studied. Acute, lower-limb aerobic exercise may potentially modulate M1 excitability in working muscles, but the effects on muscles not involved in the exercise are unknown. Here we examined the excitability changes in an upper limb muscle representation following a single session of lower body aerobic exercise. Investigating the response to exercise in a non-exercised muscle may help to determine the clinical usefulness of lower-body exercise interventions for upper limb neurorehabilitation. METHODS: In this study, transcranial magnetic stimulation was used to assess input-output curves, short-interval intracortical inhibition (SICI), long-interval intracortical inhibition (LICI) and intracortical facilitation (ICF) in the extensor carpi radialis muscle in twelve healthy individuals following a single session of moderate stationary biking. Additionally, we examined whether the presence of a common polymorphism of the brain-derived neurotrophic factor (BDNF) gene would affect the response of these measures to exercise. RESULTS: We observed significant increases in ICF and decreases in SICI following exercise. No changes in LICI were detected, and no differences were observed in input-output curves following exercise, or between BDNF groups. CONCLUSIONS: The current results demonstrate that the modulation of intracortical excitability following aerobic exercise is not limited to those muscles involved in the exercise, and that while exercise does not directly modulate the excitability of motor neurons, it may facilitate the induction of experience-dependent plasticity via a decrease in intracortical inhibition and increase in intracortical facilitation. These findings indicate that exercise may create favourable conditions for adaptive plasticity in M1 and may be an effective adjunct to traditional training or rehabilitation methods.