Synaptic dysfunction is a key pathophysiological hallmark in several neurodegenerative disorders. In this Review, Lu and colleagues consider a 'synaptic repair'-based therapy for neurodegenerative diseases that targets pathophysiology rather than pathogenesis and discuss BDNF as a potential synaptic repair molecule.

BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases

Safety and recommendations for TMS use in healthy subjects and patient populations, with updates on training, ethical and regulatory issues: Expert Guidelines

Ten Years of Theta Burst Stimulation in Humans: Established Knowledge, Unknowns and Prospects

Recovery of motor function after stroke involves relearning motor skills and is mediated by neuroplasticity. Recent research has focused on developing rehabilitation strategies that facilitate such neuroplasticity to maximize functional outcome poststroke. Although many molecular signaling pathways are involved, brain-derived neurotrophic factor (BDNF) has emerged as a key facilitator of neuroplasticity involved in motor learning and rehabilitation after stroke. Thus, rehabilitation strategies that optimize BDNF effects on neuroplasticity may be especially effective for improving motor function poststroke. Two potential poststroke rehabilitation strategies that consider the importance of BDNF are the use of aerobic exercise to enhance brain function and the incorporation of genetic information to individualize therapy. Converging evidence demonstrates that aerobic exercise increases BDNF production and consequently enhances learning and memory processes. Nevertheless, a common genetic variant reduces activity-dependent secretion of the BDNF protein. Thus, BDNF gene variation may affect response to motor rehabilitation training and potentially modulate the effects of aerobic exercise on neuroplasticity. This perspective article discusses evidence that aerobic exercise promotes neuroplasticity by increasing BDNF production and considers how aerobic exercise may facilitate the acquisition and retention of motor skills for poststroke rehabilitation. Next, the impact of the BDNF gene val66met polymorphism on motor learning and response to rehabilitation is explored. It is concluded that the effects of aerobic exercise on BDNF and motor learning may be better exploited if aerobic exercise is paired more closely in time with motor training. Additionally, information about BDNF genotype could provide insight into the type and magnitude of effects that aerobic exercise may have across individuals and potentially help guide an individualized prescription of aerobic exercise to enhance motor rehabilitation poststroke.

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Promoting Neuroplasticity for Motor Rehabilitation After Stroke: Considering the Effects of Aerobic Exercise and Genetic Variation on Brain-Derived Neurotrophic Factor

Plasticity induced by non-invasive transcranial brain stimulation: A position paper.

There is good evidence that synaptic plasticity in human motor cortex is involved in behavioural motor learning; in addition, it is now possible to probe mechanisms of synaptic plasticity using a variety of transcranial brain-stimulation protocols. Interactions between these protocols suggest that they both utilise common mechanisms. The aim of the present experiments was to test how well responsiveness to brain-stimulation protocols and behavioural motor learning correlate with each other in a sample of 21 healthy volunteers. We also examined whether any of these measures were influenced by the presence of a Val66Met polymorphism in the BDNF gene since this is another factor that has been suggested to be able to predict response to tests of synaptic plasticity. In 3 different experimental sessions, volunteers underwent 5-Hz rTMS, intermittent theta-burst stimulation (iTBS) and a motor learning task. Blood samples were collected from each subject for BDNF genotyping. As expected, both 5-Hz rTMS and iTBS significantly facilitated MEPs. Similarly, as expected, kinematic variables of finger movement significantly improved during the motor learning task. Although there was a significant correlation between the effect of iTBS and 5-Hz rTMS, there was no relationship in each subject between the amount of TMS-induced plasticity and the increase in kinematic variables during motor learning. Val66Val and Val66Met carriers did not differ in their response to any of the protocols. The present results emphasise that although some TMS measures of cortical plasticity may correlate with each other, they may not always relate directly to measures of behavioural learning. Similarly, presence of the Val66Met BDNF polymorphism also does not reliably predict responsiveness in small groups of individuals. Individual success in behavioural learning is unlikely to be closely related to any single measure of synaptic plasticity.

Correlation between cortical plasticity, motor learning and BDNF genotype in healthy subjects.

Background and purpose

Somatosensory temporal discrimination threshold (STDT) is defined as the threshold at which two tactile stimuli applied to the skin are perceived as clearly distinct.



The aim of the study was to investigate whether the extent of STDT alterations differs between patients with parkinsonian type multiple system atrophy (MSA-P) and patients with Parkinson's disease (PD). Possible differences between the two groups may help to differentiate MSA-P from PD.



Methods

STDT was investigated in 20 patients with MSA-P, 21 patients with PD and 18 age-matched healthy subjects. The clinical evaluation included the Mini-Mental State Examination, Hoehn and Yahr Scale, Frontal Assessment Battery, Unified Multiple System Atrophy Rating Scale for patients with MSA-P, and Unified Parkinson's Disease Rating Scale for patients with PD. STDT was investigated by delivering paired electrical stimuli starting with an inter-stimulus interval (ISI) of 0 ms (simultaneous pair), and progressively increasing the ISIs in 10-ms steps.



Results

Between-group anova showed that STDT statistically differed in MSA-P versus patients with PD and healthy subjects. Post hoc showed that STDT values in patients with MSA-P were significantly higher than those in patients with PD and healthy subjects. Receiver operating characteristic curve analysis showed that STDT testing yielded high diagnostic specificity and sensitivity.



Conclusions

STDT is abnormal in patients with MSA-P and PD. The degree of STDT abnormalities is higher in patients with MSA-P than in patients with PD.

Somatosensory temporal discrimination threshold may help to differentiate patients with multiple system atrophy from patients with Parkinson's disease

To investigate whether visuomotor integration processes induce long-term potentiation (LTP) and depression (LTD)-like plasticity in the primary motor cortex (M1), we designed a new paired associative stimulation (PAS) protocol coupling left primary visual area (V1) activation achieved by hemifield visual evoked potentials (VEPs) and transcranial magnetic stimulation (TMS) over the left M1, at specific interstimulus intervals (ISIs), delivered at 1 Hz (V-PAS). Before and after V-PAS, we measured motor evoked potentials (MEPs). To clarify the mechanisms underlying V-PAS, we tested the effect of 1-Hz repetitive TMS (rTMS), 0.25-Hz V-PAS and rTMS, and a shorter 0.25-Hz V-PAS protocol. To examine V-PAS with contralateral V1 activation, we delivered V-PAS activating the right V1. To clarify whether V-PAS increases V1 activity or parieto- and premotor-to-M1 connectivity, before and after V-PAS, we examined VEPs and MEPs evoked by paired-pulse techniques. V-PAS increased, decreased, or left MEPs unchanged according to the ISI used. After 1-Hz rTMS MEPs decreased. Although 0.25-Hz rTMS elicited no aftereffect, 0.25-Hz V-PAS modulated MEPs according to the ISI used. The short 0.25-Hz V-PAS protocol left MEPs unchanged. Contralateral V-PAS inhibited MEPs. After V-PAS, VEPs remained unchanged and the premotor-to-M1 inhibitory connections decreased. V-PAS induces M1 LTP/LTD-like plasticity by activating premotor-to-motor connections.

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P. Li Voti

Papers

Correlation between cortical plasticity, motor learning and BDNF genotype in healthy subjects.

Somatosensory temporal discrimination threshold may help to differentiate patients with multiple system atrophy from patients with Parkinson's disease

Early Visuomotor Integration Processes Induce LTP/LTD-Like Plasticity in the Human Motor Cortex

The Photoparoxysmal Response Reflects Abnormal Early Visuomotor Integration in the Human Motor Cortex.

Somatosensory temporal discrimination threshold is impaired in patients with multiple sclerosis