Modulation of human corticospinal excitability by paired associative stimulation

Paired Associative Stimulation (PAS) has come to prominence as a potential therapeutic intervention for the treatment of brain injury/disease, and as an experimental method with which to investigate Hebbian principles of neural plasticity in humans. Prototypically, a single electrical stimulus is directed to a peripheral nerve in advance of transcranial magnetic stimulation (TMS) delivered to the contralateral primary motor cortex (M1). Repeated pairing of the stimuli (i.e., association) over an extended period may increase or decrease the excitability of corticospinal projections from M1, in manner that depends on the interstimulus interval (ISI). It has been suggested that these effects represent a form of associative long-term potentiation (LTP) and depression (LTD) that bears resemblance to spike-timing dependent plasticity (STDP) as it has been elaborated in animal models. With a large body of empirical evidence having emerged since the cardinal features of PAS were first described, and in light of the variations from the original protocols that have been implemented, it is opportune to consider whether the phenomenology of PAS remains consistent with the characteristic features that were initially disclosed. This assessment necessarily has bearing upon interpretation of the effects of PAS in relation to the specific cellular pathways that are putatively engaged, including those that adhere to the rules of STDP. The balance of evidence suggests that the mechanisms that contribute to the LTP- and LTD-type responses to PAS differ depending on the precise nature of the induction protocol that is used. In addition to emphasizing the requirement for additional explanatory models, in the present analysis we highlight the key features of the PAS phenomenology that require interpretation

Have Standard Tests of Cognitive Function Been Misappropriated in the Study of Cognitive Enhancement?

In the past decade, there has emerged a vast research literature dealing with attempts to harness brain plasticity in older adults, with a view to improving cognitive function. Since cognitive training (CT) has shown restricted utility in this regard, attention has increasingly turned to interventions that use adjunct procedures such as motor training or physical activity (PA). As evidence builds that these have some efficacy, it becomes necessary to ensure that the outcome measures being used to infer causal influence upon cognitive function are subjected to appropriate critical appraisal. It has been highlighted previously that the choice of specific tasks used to demonstrate transfer to the cognitive domain is of critical importance. In the context of most intervention studies, standardized tests and batteries of cognitive function are de rigueur. The argument presented here is that the latent constructs to which these tests relate are not usually subject to a sufficient level of analytic scrutiny. We present the historical origins of some exemplar tests, and give particular consideration to the limits on explanatory scope that are implied by their composition and the nature of their deployment. In addition to surveying the validity of these tests when used to appraise intervention-related changes in cognitive function, we also consider their neurophysiological correlates. In particular, we argue that the broadly distributed brain activity associated with the performance of many tests of cognitive function, extending to the classical motor networks, permits the impact of interventions based on motor training or PA to be better understood

Shaping the Effects of Associative Brain Stimulation by Contractions of the Opposite Limb

There has been an explosion of interest in methods that may promote neural plasticity by indirectly stimulating tissue in damaged brains using transient magnetic fields or weak electrical currents. A major limitation of these approaches is that the induced variations in brain activity tend to be diffuse. Thus far it has proved extremely difficult to target pathways from the brain to specific muscles. This is a particular challenge for applications in rehabilitation. Stroke survivors often exhibit abnormal patterns of muscle activation, including diminished specificity and high levels of co-contraction. For the clinical relevance of brain stimulation to be enhanced, it is desirable that the effects can be restricted to pathways controlling muscles that are the specific targets of movement therapy. We have demonstrated previously that increases in the excitability of corticospinal projections to forearm muscles generated by paired associative stimulation (PAS), are modulated by contractions ipsilateral to the site of the cortical stimulus. The current aim was to determine whether in chronic stroke survivors, simultaneous contractions performed by the non-paretic limb increase the muscle specificity of changes in the excitability of projections to the impaired limb induced by PAS. Ten chronic stroke survivors, 13 age-equivalent and 27 younger healthy controls, completed two separate sessions/conditions. In one (PAS+CONT), isometric wrist flexion contractions of the non-impaired limb were made simultaneously with PAS. In the other (PAS), associative stimulation only was applied. In all groups, PAS alone gave rise to large increases in the excitability of projections to a wrist extensor muscle (extensor carpi radialis – ECR) that was not the target of stimulation. In marked contrast, for the stroke survivors, following combined PAS and flexion contractions of the non-impaired limb, there was no corresponding elevation in the excitability of corticospinal projections to the ECR of the paretic limb. A similar effect was present for the healthy young adults, but not expressed clearly for the age-equivalent controls. The implications of these findings with respect to the clinical deployment of non-invasive brain stimulation in movement rehabilitation are discussed

Duration-dependent effects of the BDNF Val66Met polymorphism on anodal tDCS induced motor cortex plasticity in older adults: a group and individual perspective

The brain derived neurotrophic factor (BDNF) Val66Met polymorphism and stimulation duration are thought to play an important role in modulating motor cortex plasticity induced by non-invasive brain stimulation (NBS). In the present study we sought to determine whether these factors interact or exert independent effects in older adults. Fifty-four older adults (mean age = 66.85 years) underwent two counterbalanced sessions of 1.5 mA anodal transcranial direct current stimulation (atDCS), applied over left M1 for either 10 min or 20 min. Single pulse transcranial magnetic stimulation (TMS) was used to assess corticospinal excitability (CSE) before and every 5 min for 30 min following atDCS. On a group level, there was an interaction between stimulation duration and BDNF genotype, with Met carriers (n =13) showing greater post-intervention potentiation of CSE compared to Val66Val homozygotes (n = 37) following 20 min (p = 0.002) but not 10 min (p = 0.219) of stimulation. Moreover, Met carriers, but not Val66Val homozygotes, exhibited larger responses to TMS (p = 0.046) after 20 min atDCS, than following 10 min atDCS. On an individual level, two-step cluster analysis revealed a considerable degree of inter-individual variability, with under half of the total sample (42%) showing the expected potentiation of CSE in response to atDCS across both sessions. Intra-individual variability in response to different durations of atDCS was also apparent, with one-third of the total sample (34%) exhibiting LTP-like effects in one session but LTD-like effects in the other session. Both the inter-individual (p = 0.027) and intra-individual (p = 0.04) variability was associated with BDNF genotype.In older adults, the BDNF Val66Met polymorphism along with stimulation duration appears to play a role in modulating tDCS-induced motor cortex plasticity. The results may have implications for the design of NBS protocols for healthy and diseased aged populations

SMART arm with outcome-triggered electrical stimulation: a pilot randomized clinical trial

Background: The SMART (SensoriMotor Active Rehabilitation Training) Arm is a nonrobotic device designed to allow stroke survivors with severe paresis to practice reaching. It can be used with or without outcome-triggered electrical stimulation (OT-stim) to augment movement. The aim of this study was to evaluate the efficacy of SMART Arm training when used with or without OT-stim, in addition to usual care, as compared with usual care alone during inpatient rehabilitation. Methods: Eight stroke survivors received 20 hours of SMART Arm training over 4 weeks; they were randomly assigned to either (1) SMART Arm training with OT-stim or (2) SMART Arm training alone. Usual therapy was also provided. A historical cohort of 20 stroke survivors formed the control group and received only usual therapy. The primary outcome was Motor Assessment Scale Item 6, Upper Arm Function. Results: Findings for all participants were comparable at baseline. SMART Arm training, with or without OT-stim, led to a significantly greater improvement in upper arm function than usual therapy alone (P=.024). There was no difference in improvement between training with or without OT-stim. Initial motor severity and presence of OT-stim influenced the number of repetitions performed and the progression of SMART Arm training practice conditions. Conclusion: Usual therapy in combination with SMART Arm training, with or without OT-stim, appears to be more effective than usual therapy alone for stroke survivors with severe paresis. These findings warrant further investigation into the benefits of SMART Arm training for stroke survivors with severe paresis undergoing inpatient rehabilitation during the subacute phase of recovery

Artificial Gravity Reveals that Economy of Action Determines the Stability of Sensorimotor Coordination

Background: When we move along in time with a piece of music, we synchronise the downward phase of our gesture with the beat. While it is easy to demonstrate this tendency, there is considerable debate as to its neural origins. It may have a structural basis, whereby the gravitational field acts as an orientation reference that biases the formulation of motor commands. Alternatively, it may be functional, and related to the economy with which motion assisted by gravity can be generated by the motor system

In Vivo Efficacy of a Cocktail of Human Monoclonal Antibodies (CL184) Against Diverse North American Bat Rabies Virus Variants

Following rabies virus (RABV) exposure, a combination of thorough wound washing, multiple-dose vaccine administration and the local infiltration of rabies immune globulin (RIG) are essential components of modern post-exposure prophylaxis (PEP). Although modern cell-culture-based rabies vaccines are increasingly used in many countries, RIG is much less available. The prohibitive cost of polyclonal serum RIG products has prompted a search for alternatives and design of anti-RABV monoclonal antibodies (MAbs) that can be manufactured on a large scale with a consistent potency and lower production costs. Robust in vitro neutralization activity has been demonstrated for the CL184 MAb cocktail, a 1:1 protein mixture of two human anti-RABV MAbs (CR57/CR4098), against a large panel of RABV isolates. In this study, we used a hamster model to evaluate the efficacy of experimental PEP against a lethal challenge. Various doses of CL184 and commercial rabies vaccine were assessed for the ability to protect against lethal infection with representatives of four distinct bat RABV lineages of public health relevance: silver-haired bat (Ln RABV); western canyon bat (Ph RABV); big brown bat (Ef-w1 RABV) and Mexican free-tailed bat RABV (Tb RABV). 42–100% of animals survived bat RABV infection when CL184 (in combination with the vaccine) was administered. A dose-response relationship was observed with decreasing doses of CL184 resulting in increasing mortality. Importantly, CL184 was highly effective in neutralizing and clearing Ph RABV in vivo, even though CR4098 does not neutralize this virus in vitro. By comparison, 19–95% survivorship was observed if human RIG (20 IU/kg) and vaccine were used following challenge with different bat viruses. Based on our results, CL184 represents an efficacious alternative for RIG. Both large-scale and lower cost production could ensure better availability and affordability of this critical life-saving biologic in rabies enzootic countries and as such, significantly contribute to the reduction of human rabies deaths globally

Evaluation of rK39 rapid diagnostic tests for canine visceral leishmaniasis : longitudinal study and meta-analysis

Canine visceral leishmaniasis is a vector-borne disease caused by the intracellular parasite Leishmania infantum. It is an important veterinary disease, and dogs are also the main animal reservoir for human infection. The disease is widespread in the Mediterranean area, and parts of Asia and South and Central America, and is potentially fatal in both dogs and humans unless treated. Diagnosis of canine infections requires serological or molecular tests. Detection of infection in dogs is important prior to treatment, and in epidemiological studies and control programmes, and a sensitive and specific rapid diagnostic test would be very useful. Rapid diagnostic tests (RDTs) have been developed, but their diagnostic performance has been reported to be variable. We evaluated the sensitivity of a RDT based on serological detection of the rK39 antigen in a cohort of naturally infected Brazilian dogs. The sensitivity of the test to detect infection was relatively low, but increased with time since infection and the severity of infection. We then carried out a meta-analysis of published studies of rK39 RDTs, evaluating the sensitivity to detect disease and infection. The results suggest that rK39 RDTs may be useful in a veterinary clinical setting, but the sensitivity to detect infection is too low for operational control programmes