•PAS induces LTP/LTD-like plasticity non-invasively in the human motor cortex.•PAS discloses abnormal plasticity in several neurological disorders.•Evidence from “modified PAS” protocols promotes ...future applications in neuromorphic circuits.
The original protocol of Paired Associative Stimulation (PAS) in humans implies repetitive cortical and peripheral nerve stimuli, delivered at specific inter-stimulus intervals, able to elicit non-invasively long-term potentiation (LTP)- and long-term depression (LTD)-like plasticity in the human motor cortex. PAS has been designed to drive cortical LTP/LTD according to the Hebbian rule of associative plasticity. Over the last two decades, a growing number of researchers have increasingly used the PAS technique to assess cortical associative plasticity in healthy humans and in patients with movement disorders and other neuropsychiatric diseases. The present review covers the physiology, pharmacology, pathology and motor effects of PAS. Further sections of the review focus on new protocols of “modified PAS” and possible future application of PAS in neuromorphic circuits designed for brain-computer interface.
Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain-stimulation procedure noted for its effects on emotional, cognitive, sensory, and motor functions in patients with ...neuropsychiatric diseases. Despite the large use of rTMS in different neuroscience fields the precise mechanism of this technique remain poorly understood. It is likely that rTMS induces long-term potentiation (LTP) or depression, which, in turn, produce lasting changes on neocortical excitability and synaptic connections. In recent years, brain-derived neurotrophic factor (BDNF) and its cognate receptor tyrosine receptor kinase B (TrkB), a member of the neurotrophin receptor tyrosine kinase family, have emerged as important upstream regulators of LTP in brain regions, including hippocampus and neocortex (Minichiello, 2009; Fritsch et al., 2010). In keeping with these findings we have recently reported that daily 5 Hz rTMS for 5 d improves BDNF–TrkB signaling in rats by increasing the affinity of BDNF for TrkB, which results in higher tyrosine-phosphorylated TrkB, increased recruitment of PLC- γ 1 and shc/N-shc to TrkB, and heightened downstream ERK2 and PI-3K activities in prefrontal cortex and in lymphocytes. The elevated BDNF–TrkB signaling is accompanied by an increased association between the activated TrkB and NMDA receptor (NMDAR). In normal human subjects, 5 d rTMS to motor cortex decreased resting motor threshold, which correlates with heightened BDNF-TrkB signaling and intensified TrkB–NMDAR association in lymphocytes. These findings suggest that rTMS to cortex facilitates BDNF–TrkB–NMDAR functioning in both cortex and lymphocytes. We propose TMS as a non invasive tool to test the NMDA receptor machinery at a molecular level.
In March 2020, WHO declared Covid-19 outbreak pandemic. There has been increasing evidence that frail, old, multi-pathological patients are at greater risk of developing severe Covid-19 infection ...than younger, healthy ones. Covid-19’s impact on Parkinson’s Disease (PD) patients could be analysed through both the influence on PD patients’ health and their risk of developing severe Covid-19, and the consequences of lockdown and restrictive measures on mental and cognitive health on both patients and caregivers. Moreover, there are critical issues to be considered about patients’ care and management through an unprecedented time like this. One important issue to consider is physiotherapy, as most patients cannot keep exercising because of restrictive measures which has profoundly impacted on their health. Lastly, the relationship between PD and Sars-Cov2 may be even more complicated than it seems as some studies have hypothesized a possible Covid-19-induced parkinsonism. Hereby, we review the state of the art about the relationship between Covid-19 and Parkinson’s Disease, focusing on each of these five points.
Highlights ► This guideline paper provides an up-date on the clinical use of transcranial magnetic stimulation (TMS). ► The clinically relevant technical and physiological principles of TMS are ...outlined. ► A detailed description how to examine corticomotor conduction to the hand, leg, trunk and facial muscles is presented.
Abstract
Movement is accompanied by beta power changes over frontal and sensorimotor regions: a decrease during movement (event-related desynchronization, ERD), followed by an increase (event-related ...synchronization, ERS) after the movement end. We previously found that enhancements of beta modulation (from ERD to ERS) during a reaching test (
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) occur over frontal and left sensorimotor regions after practice in a visuo-motor adaptation task (ROT) but not after visual learning practice. Thus, these enhancements may reflect local cumulative effects of motor learning. Here we verified whether they are triggered by the learning component inherent in ROT or simply by motor practice in a reaching task without such learning (MOT). We found that beta modulation during
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increased over frontal and left areas after three-hour practice of either ROT or MOT. However, the frontal increase was greater after ROT, while the increase over the left area was similar after the two tasks. These findings confirm that motor practice leaves local traces in beta power during a subsequent motor test. As they occur after motor tasks with and without learning, these traces likely express the cost of processes necessary for both usage and engagement of long-term potentiation mechanisms necessary for the learning required by ROT.
Repetitive transcranial magnetic stimulation (rTMS) induces neuronal long-term potentiation or depression. Although brain-derived neurotrophic factor (BDNF) and its cognate tyrosine receptor kinase B ...(TrkB) contribute to the effects of rTMS, their precise role and underlying mechanism remain poorly understood. Here we show that daily 5 Hz rTMS for 5 d improves BDNF-TrkB signaling in rats by increasing the affinity of BDNF for TrkB, which results in higher tyrosine-phosphorylated TrkB, increased recruitment of PLC-γ1 and shc/N-shc to TrkB, and heightened downstream ERK2 and PI-3K activities in prefrontal cortex and in lymphocytes. The elevated BDNF-TrkB signaling is accompanied by an increased association between the activated TrkB and NMDA receptor (NMDAR). In normal human subjects, 5 d rTMS to motor cortex decreased resting motor threshold, which correlates with heightened BDNF-TrkB signaling and intensified TrkB-NMDAR association in lymphocytes. These findings suggest that rTMS to cortex facilitates BDNF-TrkB-NMDAR functioning in both cortex and lymphocytes.
•5-Hz rPAS25ms produces a long-lasting increase in corticospinal excitability.•5-Hz rPAS15ms effectively suppresses corticospinal excitability.•5-Hz rPAS induces spike-timing dependent ...plasticity-like bidirectional plasticity.
Sub-motor threshold 5 Hz repetitive paired associative stimulation (5 Hz-rPAS25ms) produces a long-lasting increase in corticospinal excitability. Assuming a spike-timing dependent plasticity-like (STDP-like) mechanism, we hypothesized that 5 Hz-rPAS at a shorter inter-stimulus interval (ISI) of 15 ms (5 Hz-rPAS15ms) would exert a lasting inhibitory effect on corticospinal excitability.
20 healthy volunteers received two minutes of 5 Hz-rPAS15ms. Transcranial magnetic stimulation (TMS) was applied over the motor hotspot of the right abductor pollicis brevis muscle at 90% active motor threshold. Sub-motor threshold peripheral electrical stimulation was given to the left median nerve 15 ms before each TMS pulse. We assessed changes in mean amplitude of the unconditioned motor evoked potential (MEP), short-latency intracortical inhibition (SICI), intracortical facilitation (ICF), short-latency afferent inhibition (SAI), long-latency afferent inhibition (LAI), and cortical silent period (CSP) before and for 60 minutes after 5-Hz rPAS15ms.
Subthreshold 5-Hz rPAS15ms produced a 20–40% decrease in mean MEP amplitude along with an attenuation in SAI, lasting at least 60 minutes. A follow-up experiment revealed that MEP facilitation was spatially restricted to the target muscle.
Subthreshold 5-Hz rPAS15ms effectively suppresses corticospinal excitability. Together with the facilitatory effects of subthreshold 5-Hz rPAS25ms (Quartarone et al., J Physiol 2006;575:657–670), the results show that sub-motor threshold 5-Hz rPAS induces STDP-like bidirectional plasticity in the motor cortex.
The results of the present study provide a new short-time paradigm of long term depression (LTD) induction in human sensory-motor cortex.
Low‐frequency median nerve stimulation, paired with suprathreshold transcranial magnetic stimulation (TMS) over the optimal site for activation of the abductor pollicis brevis (APB) muscle induces a ...long‐lasting increase in the excitability of corticospinal output neurons, if median nerve stimulation is given 25 ms before TMS. Here we employed this protocol of stimulation to assess associative plasticity of the primary motor hand area in 10 patients with writer’s cramp and 10 age‐matched controls. Motor evoked potentials (MEPs) were recorded from right APB muscle and right first dorsal interosseus (FDI) muscle. Resting and active motor threshold, mean MEP amplitude at rest, short‐latency intracortical inhibition (SICI) at an interstimulus interval of 2 ms and the duration of the cortical silent period (CSP) were assessed immediately before and after associative stimulation. In both groups, associative stimulation led to an increase in resting MEP amplitudes which was more pronounced in the right APB muscle. Compared with healthy controls, stimulation‐induced facilitation of MEP amplitudes was stronger in patients with writer’s cramp. In addition, only patients showed a slight decrease of resting and active motor thresholds after conditioning stimulation. In both groups, associative stimulation induced a prolongation of CSP in the APB and FDI muscles, which was significant only in the APB muscle in healthy controls. Associative stimulation had no effects on SICI in patients and healthy controls. Taken together, in patients with writer’s cramp, the motor system exhibited an abnormal increase in corticospinal excitability and an attenuated reinforcement of intracortical inhibitory circuits that generate the CSP in response to associative stimulation. This altered pattern of sensorimotor plasticity may favour maladaptive plasticity during repetitive skilled hand movements and, thus, may be of relevance for the pathophysiology of writer’s cramp and other task‐specific dystonias.
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