The influence of motor function on processing speed in preterm and term-born children.

This study investigates the relationship between motor function and processing speed in preterm children. Processing speed was compared in 145 adolescents, born 25-41 weeks gestational age, utilizing tasks including differing motor demands. The influence of motor cortex excitability and functional motor skills on task performance was assessed. For tasks with motoric demands, differences in performance between preterm and term-born children were mediated by the relationship between gestational age, corticomotor excitability, and motor function. There were no differences in non-motor processing speed task performance between preterm and term-born children. Measures of processing speed may be confounded by a timed motor component.

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

BACKGROUND/OBJECTIVES: Over the last ten years, an increasing number of authors have used the theta burst stimulation (TBS) protocol to investigate long-term potentiation (LTP) and long-term depression (LTD)-like plasticity non-invasively in the primary motor cortex (M1) in healthy humans and in patients with various types of movement disorders. We here provide a comprehensive review of the LTP/LTD-like plasticity induced by TBS in the human M1. METHODS: A workgroup of researchers expert in this research field review and discuss critically ten years of experimental evidence from TBS studies in humans and in animal models. The review also includes the discussion of studies assessing responses to TBS in patients with movement disorders. MAIN FINDINGS/DISCUSSION: We discuss experimental studies applying TBS over the M1 or in other cortical regions functionally connected to M1 in healthy subjects and in patients with various types of movement disorders. We also review experimental evidence coming from TBS studies in animals. Finally, we clarify the status of TBS as a possible new non-invasive therapy aimed at improving symptoms in various neurological disorders.

Minimum number of trials required for within- and between-session reliability of TMS measures of corticospinal excitability.

Transcranial magnetic stimulation (TMS)-elicited motor-evoked potentials (MEPs) exhibit considerable trial-to-trial variability, potentially reducing the sensitivity and reproducibility of this measure. While increasing the number of trials will improve accuracy, prolonged recording blocks are not always feasible. In this study, we investigated the minimum number of trials required to provide a measure of human corticospinal excitability that is stable both within and between sessions. Single-pulse TMS was applied to the left primary motor cortex, and MEPs were recorded from the right first dorsal interosseous muscle. Approximately 20-30 trials were required to provide a stable measure of MEP amplitude with high within- and between-session reliability. Extending the number of trials beyond 30 provided no additional benefit. Collecting 30 trials may be optimal for reliably estimating corticospinal excitability using TMS. These findings may have significant implications for using TMS to measure corticospinal excitability in both basic and clinical research settings.

The influence of short-interval intracortical facilitation when assessing developmental changes in short-interval intracortical inhibition.

OBJECTIVE: Measures of short-interval intracortical inhibition (SICI) can be contaminated by excitatory influences of short-interval intracortical facilitation (SICF), unless examined at individually-optimized interstimulus intervals (ISIs). We hypothesized that age-related differences in SICF would explain previously reported reduced SICI in children and adolescents compared with adults. METHODS: Fifty-one participants, aged 8-29years, underwent transcranial magnetic stimulation. SICF curves were constructed to determine the ISI at which SICF was minimal (i.e. the first trough). SICI curves were constructed at this individually-determined ISI with conditioning stimulus (S1) intensities of 60-110% of active motor threshold. RESULTS: There was no effect of age on the ISI corresponding with the SICF trough. However, there was a main effect of age on the amplitude of the conditioned motor-evoked potential at the different ISIs, such that children aged 8-12years demonstrated greater SICF than those aged 16-18 and 19-21years. There was no effect of age on SICI, and no interaction between age group and S1 intensity. CONCLUSIONS: Compared with that in older adolescents and young adults, SICF is enhanced in children aged 8-12years. Surprisingly, this enhanced SICF does not appear to reduce the degree of SICI that can be evoked at the first trough in this age group. SIGNIFICANCE: This is the first report of enhanced SICF in young children. It remains possible that enhanced SICF may have confounded earlier reports of reduced SICI in children less than 8years.

Inter- and intra-subject variability of motor cortex plasticity following continuous theta-burst stimulation.

BACKGROUND: The potential of non-invasive brain stimulation (NIBS) for studying, and inducing, functionally relevant neuroplasticity is dependent on protocols that can induce lasting, robust and reliable effects. A current limiting factor is the large inter- and intra-subject variability in NIBS-induced neuroplastic responses. There has been some study of inter-subject response variability and factors that contribute to it; however, intra-subject response variability has, so far, received little investigation. OBJECTIVES: By testing participants on multiple occasions we aimed to (1) compare inter- and intra-subject variability of neuroplastic responses induced by continuous theta-burst stimulation (cTBS); (2) determine whether the transcranial magnetic stimulation (TMS) intensity used to measure cTBS-induced neuroplastic responses contributes to response variability; (3) determine whether assessment of factors known to influence response variability can be used to explain some of the variability in cTBS-induced neuroplastic responses across experimental sessions. METHODS: In three separate experimental sessions, motor-evoked potential (MEP) input-output (IO) curves were obtained before and after cTBS, and questionnaire-based assessments of physical activity and perceived stress were obtained. RESULTS: cTBS-induced MEP suppression was greatest at the upper end of the IO curve (150-180% resting motor threshold; RMT) and most consistent across subjects and across experimental sessions when assessed with a TMS intensity of 150% RMT. The magnitude of cTBS-induced MEP suppression evoked at 150% RMT correlated with self-reported perceived stress, but not with self-reported physical activity. CONCLUSIONS: The most reliable TMS intensity to probe cTBS-induced long-term depression (LTD)-like neuroplastic responses is 150% RMT. This is unlikely to simply be a ceiling effect and, we suggest, may be due to changes in the descending volley evoked at higher stimulus intensities. The perceived stress scale appears to be sufficiently sensitive to measure the influence of subject stress on LTD-like neuroplastic responses.

A new temporal window for inducing depressant associative plasticity in human primary motor cortex.

OBJECTIVE: Spike-timing dependent plasticity (STDP) usually refers to synaptic plasticity induced by near-synchronous activation of neuronal input and neuronal firing. However, some models of STDP predict effects that deviate from this tight temporal synchrony. We aimed to characterise the induction of STDP using paired associative stimulation (PAS) when the pre-synaptic input arrives in primary motor cortex (M1) at (i) intermediate intervals (50-80 ms; PAS(50),..PAS(80)) before the post-synaptic neuron is activated and (ii) long intervals (100-450 ms; PAS(-100),..PAS(-450)) after the post-synaptic neuron is activated. PAS at near-synchronicity (PAS(25)) was applied for comparison. METHODS: To characterise the physiological effects of the different PAS protocols, we examined short- and long-interval intra-cortical inhibition; intra-cortical facilitation and short- and long-latency afferent inhibition, in addition to recording MEPs in 45 healthy individuals. RESULTS: MEP amplitude was reduced at PAS intervals between -250 and -450 ms, increased with PAS(25), and unaltered at the remaining intervals. There was no change in intra-cortical inhibitory or facilitatory circuits following any PAS protocol. CONCLUSIONS: These findings provide evidence of a previously unreported temporal window in which PAS induces a depression of corticospinal excitability in human M1. SIGNIFICANCE: Establishing new temporal rules for STDP broadens its applicability for therapeutic usage in future.

The response to repetitive stimulation of human motor cortex is influenced by the history of synaptic activity.

Non-invasive brain stimulation techniques, such as repetitive transcranial magnetic stimulation (rTMS), can modify cortical excitability in a lasting fashion. The modification can be bi-directional in nature and holds considerable therapeutic promise for a number of neurological conditions. However, the effectiveness of these techniques is currently limited by large intra- and inter-subject variability in the response. A number of factors that contribute to response variability have now been identified, with one of the most important being the history of synaptic activity within the cortical region being targeted by stimulation. In this review we discuss what is currently known about the influence of behaviourally, or experimentally, induced changes in synaptic activity in the cortical (or interconnected) region being targeted by stimulation on the response to rTMS techniques. Understanding such influences is a critical step in the development of effective therapeutic paradigms employing such techniques.

Circadian modulation of neuroplasticity in humans and potential therapeutic implications.

Learning, memory, and recovery from various neurological insults occur by a process known as neuroplasticity. Neuroplastic changes occur by a variety of physiological processes that modify central nervous system structure and function. The ability to non-invasively induce neuroplastic change in humans is developing as an exciting new field in neuroscience and may ultimately improve treatment outcomes for those suffering various neurological conditions reliant on neuroplasticity for recovery of function. The induction of neuroplastic changes is influenced by several factors, and do not occur evenly throughout the day, but appear to be under circadian control. This review will discuss the known mechanisms and techniques used to induce neuroplasticity, circadian modulation of neuroplasticity, and will discuss the potential implications of these findings for human neurorehabilitation.

Determinants of the induction of cortical plasticity by non-invasive brain stimulation in healthy subjects.

The ability to induce cortical plasticity with non-invasive brain stimulation (NBS) techniques has provided novel and exciting opportunities for examining the role of the human cortex during a variety of behaviours. Additionally, and importantly, the induction of lasting changes in cortical excitability can, under some conditions, reversibly modify behaviour and interact with normal learning. Such findings have driven a large number of recent studies examining whether by using such approaches it might be possible to induce functionally significant changes in patients with a large variety of neurological and psychiatric conditions including stroke, Parkinson's disease and depression. However, even in neurologically normal subjects the variability in the neurophysiological and behavioural response to such brain stimulation techniques is high. This variability at present limits the therapeutic usefulness of these techniques. The cause of this variability is multifactorial and to some degree still unknown. However, a number of factors that can influence the induction of plasticity have been identified. This review will summarise what is known about the causes of variability in healthy subjects and propose additional factors that are likely to be important determinants. A greater understanding of these determinants is critical for optimising the therapeutic applications of non-invasive brain stimulation techniques.

Substantia nigra echomorphology and motor cortex excitability.

The aim of our study was to investigate the relation between substantia nigra (SN) echomorphology and indices of motor cortex excitability. Nigral hyperechogenicity in healthy individuals is thought to represent an SN abnormality or predisposition to Parkinson's disease (PD) and its prevalence is greater in the very old. Our study involved 20 old healthy subjects (aged 72-84 years) known to have normal (n=10) or abnormal (n=10) SN echomorphology. All were in good health with no overt neurological signs. SN morphology was assessed with transcranial sonography through the pre-auricular bone window. Motor cortical excitability and intracortical inhibition were assessed with transcranial magnetic stimulation (TMS) over the first dorsal interosseus motor area. Single stimuli were delivered during relaxation and voluntary contraction and paired stimuli were delivered during relaxation. Each cortical hemisphere was analysed separately. The response to single-pulse TMS (in motor cortex ipsilateral to the target SN) did not differ between groups. However, a significant difference between groups was observed in the paired pulse paradigm (conditioning stimulus intensity: 70% resting motor threshold; interstimulus interval: 2 ms). The conditioned motor evoked potential amplitude was significantly larger ipsilateral to the hyperechogenic SN than in controls (P=0.014). Thus, healthy subjects with SN hyperechogenicity exhibit significantly less intracortical inhibition within the motor cortex than subjects with normal echomorphology. Decreased intracortical inhibition is also observed in PD patients. This study provides further evidence that SN hyperechogenicity in healthy individuals is associated with changes characteristic of PD supporting a role for this feature as a vulnerability marker or state marker for subtle nigral dopaminergic dysfunction.

Selective modulation of intracortical inhibition by low-intensity Theta Burst Stimulation.

OBJECTIVE: Theta Burst Stimulation (TBS) is a repetitive transcranial magnetic stimulation paradigm which has effects on both excitatory and inhibitory intracortical pathways when applied at an intensity of 80% of active motor threshold. As intracortical inhibitory pathways have a lower threshold for activation than excitatory pathways, we sought to determine whether it was possible to selectively target cortical inhibitory circuitry by reducing the intensity of TBS to 70% of active motor threshold. METHODS: Motor evoked potentials (MEPs), short latency intracortical facilitation (SICF), intracortical facilitation (ICF) and short interval intracortical inhibition (SICI) were measured at baseline, 5-20 and 20-35 min following continuous (cTBS) and intermittent (iTBS) low-intensity TBS in nine healthy subjects. RESULTS: Low-intensity cTBS significantly reduced SICI 5-20 min following stimulation, whilst having no effect on MEPs, SICF or ICF. Low-intensity iTBS had no effect on SICI, MEPs, SICF or ICF. CONCLUSIONS: It is possible to selectively target intracortical inhibitory networks for modulation by low-intensity TBS, however, responses may critically depend upon the particular paradigm chosen. SIGNIFICANCE: These findings have important implications for the treatment of neurological disorders where abnormal levels of intracortical inhibition are present, such as Parkinson's disease and focal hand dystonia and requires further investigation.

Role of the primary motor and sensory cortex in precision grasping: a transcranial magnetic stimulation study.

Human precision grip requires precise scaling of the grip force to match the weight and frictional conditions of the object. The ability to produce an accurately scaled grip force prior to lifting an object is thought to be the result of an internal feedforward model. However, relatively little is known about the roles of various brain regions in the control of such precision grip-lift synergies. Here we investigate the role of the primary motor (M1) and sensory (S1) cortices during a grip-lift task using inhibitory transcranial magnetic theta-burst stimulation (TBS). Fifteen healthy individuals received 40 s of either (i) M1 TBS, (ii) S1 TBS or (iii) sham stimulation. Following a 5-min rest, subjects lifted a manipulandum five times using a precision grip or completed a simple reaction time task. Following S1 stimulation, the duration of the pre-load phase was significantly longer than following sham stimulation. Following M1 stimulation, the temporal relationship between changes in grip and load force was altered, with changes in grip force coming to lag behind changes in load force. This result contrasts with that seen in the sham condition where changes in grip force preceded changes in load force. No significant difference was observed in the simple reaction task following either M1 or S1 stimulation. These results further quantify the contribution of the M1 to anticipatory grip-force scaling. In addition, they provide the first evidence for the contribution of S1 to object manipulation, suggesting that sensory information is not necessary for optimal functioning of anticipatory control.

The influence of correlated afferent input on motor cortical representations in humans.

Animal models reveal that correlated afferent inputs are a powerful driver of sensorimotor cortex reorganisation. Recently we developed a stimulation paradigm, which evokes convergent afferent input from two hand muscles and induces reorganisation within human motor cortex. Here we investigated whether this reorganisation is characterised by expansion and greater overlap of muscle representation zones, as reported in animal models. Using transcranial magnetic stimulation, we mapped the motor representation of the right first dorsal interosseous (FDI), abductor digiti minimi (ADM) and abductor pollicis brevis (APB) in 24 healthy subjects before and after 1 h of (1) associative stimulation to FDI and ADM motor points, (2) associative stimulation to digits II and V (3) a control condition employing non-correlated stimulation of FDI and ADM motor points. Motor point associative stimulation induced a significant increase in the number of active sites in all three muscles and volume in FDI and ADM. Additionally, the centre of gravity of the FDI and ADM maps shifted closer together. Similar changes were not observed following digital associative stimulation or motor point non-associative stimulation. These novel findings provide evidence that convergent input induces reorganisation of the human motor cortex characterised by expansion and greater overlap of representational zones.

Transient motor evoked potential suppression following a complex sensorimotor task.

OBJECTIVE: To investigate the mechanism involved in the transient suppression of the response to transcranial magnetic stimulation (TMS) following repeated performance of a complex sensorimotor training task (ST). METHODS: A total of 19 healthy subjects participated in 4 experiments, all involving performance of the grooved pegboard test (GPT). The experiments investigated the effect of the ST on corticospinal and intracortical excitability, spinal excitability and maximal pinch grip force. RESULTS: Motor evoked potential amplitude decreased significantly following the ST in both muscles tested and this was associated, but not correlated, with a decrease in the time taken to perform the GPT. There was no change in intracortical inhibition or facilitation (tested at interstimulus intervals of 3 and 10 ms, respectively). M wave amplitude was unchanged, as were F wave amplitude, latency and persistence and there was no evidence of muscle fatigue. CONCLUSIONS: The reduction in corticospinal excitability was short lasting (<10 min) and was not accompanied by changes at the spinal or peripheral level, suggesting that other intracortical circuits may be involved. SIGNIFICANCE: Repeated performance of motor tasks can result in both short- and long-term modulation of motor cortical excitability. However, the relationship between changes in corticospinal excitability and motor performance is complex and critically dependent upon task type and duration.

Induction of plasticity in the dominant and non-dominant motor cortices of humans.

There are clear hemispheric differences in the human motor system. Studies using magnetic resonance morphometry have shown that representation of hand muscles is larger in the dominant hemisphere than the non-dominant hemisphere. There is some limited evidence of electrophysiological differences between hemispheres. For example, it has been reported recently that there is less intracortical inhibition in the dominant hemisphere than the non-dominant hemisphere, and it has been hypothesised that this reduction in inhibition may facilitate use-dependent plasticity in the dominant motor cortex. In the present study we examined this hypothesis in human subjects by examining plasticity induction in both dominant and non-dominant hemispheres using an experimental paradigm known to induce motor cortical plasticity, namely paired associative stimulation (PAS). Additionally, we investigated changes in dominant and non-dominant hand performance on a simple ballistic training task. Short-interval intracortical inhibition (SICI) was also measured for both dominant and non-dominant hands at a range of conditioning intensities. There was significantly less SICI in the dominant motor cortical hand area than in the non-dominant hand area. PAS induced a significant, and similar, increase in motor cortical excitability in both the dominant and non-dominant hemispheres. Motor training resulted in significant performance improvement in both dominant and non-dominant hands. However, there was significantly more improvement in the non-dominant hand. The results from these studies provide some further evidence of electrophysiological differences between the motor cortices of the two hemispheres. Additionally, these findings offer no support for the hypothesis that the dominant hemisphere is positioned more favourably, due to decreased inhibitory tone, than the non-dominant hemisphere for use-dependent plasticity.

Afferent stimulation facilitates performance on a novel motor task.

Training on a motor task results in performance improvements that are accompanied by increases in motor cortex excitability. Moreover, periods of afferent stimulation result in increased motor cortex excitability. There is increasing evidence to suggest that raised motor cortical excitability may facilitate movement and learning. Here we examined whether a period of electrical stimulation of hand afferents ("associative stimulation"), known to increase motor cortex excitability, facilitated the performance of a complex sensorimotor task. Three groups of nine normal subjects participated in these studies. All subjects were trained on the grooved pegboard test (GPT). Training consisted of three blocks, each of five trials, of placing pegs as quickly as possible. The time to complete each block was recorded. One group of subjects had a 1-h period of associative stimulation prior to training on the GPT. A second group received non-associative stimulation (which does not change cortical excitability) of the same hand afferents while a third group received no stimulation prior to training. Motor evoked potentials (MEPs) were recorded from the first dorsal interosseous (FDI) and abductor digiti minimus (ADM) muscles both prior to and following stimulation and performance of the GPT. In contrast to non-associative stimulation, associative stimulation increased motor cortical excitability, as evidenced by an increase in the amplitude of MEPs evoked in the FDI, one of the stimulated muscles, but not the ADM. Training on the GPT resulted in significant improvements in the time taken to complete the task for all three groups. However, in subjects who had preconditioning associative stimulation, performance on the GPT improved more rapidly. Additionally, there was a strong trend for the improvement in the performance of the stimulated group to be greater than that of the control group. The results of the present study suggest that increased motor cortical excitability, induced by associative stimulation, may facilitate the performance of a novel complex sensorimotor task.

Motor cortex excitability after thalamic infarction.

Transcranial magnetic stimulation was used to map hand muscle representations in the motor cortex of a patient in whom infarction of the sensory thalamus deprived the sensorimotor cortex of sensory input. The threshold for activation of the motor cortex on the affected side was higher and the cortical representational maps of individual muscles were less well defined than those on the normal side. It is concluded that electrophysiological changes in cortical organisation can be demonstrated following withdrawal of, or imbalance in sensory afferent activity to the cerebral cortex in humans.

Modulation of intracortical excitability in human hand motor areas. The effect of cutaneous stimulation and its topographical arrangement.

Changes in afferent input can alter the excitability of intracortical inhibitory systems. For example, using paired transcranial magnetic stimulation (TMS), both electrical digital stimulation and muscle vibration have been shown to reduce short-interval intracortical inhibition (SICI). The effects following muscle vibration are confined to the corticospinal projection to the vibrated muscles. The results following digital stimulation are less clear and the relative timing of the cutaneous stimulation and TMS is critical. Here we investigated further whether changes in SICI following digit stimulation exhibit topographic specificity. Eleven normal subjects were investigated (age 28.2+/-7.5 years, mean+/-SD). Electromyographic recordings were made from the right first dorsal interosseous (FDI), abductor digiti minimi (ADM) and abductor pollicis brevis (APB) muscles. SICI was measured, with and without preceding electrical digit II or digit V cutaneous stimulation. The interval between the digital nerve stimulus and test magnetic stimulus was independently set for each subject and established by subtracting the onset latency of the motor evoked potential (MEP) from the latency of the E2 component of the cutaneomuscular reflex. Therefore, measures of intracortical excitability were made at a time at which it is known that cutaneous input is capable of modulating cortical excitability. Single digital nerve stimuli applied to digit II significantly reduced SICI in FDI but not in ADM. Single digital nerve stimuli applied to digit V significantly reduced SICI in ADM but not in FDI or APB. There was a more generalised effect on intracortical facilitation (ICF) with both digit II and digit V stimulation significantly increasing ICF in FDI and ADM. Digital stimulation (either DII or DV) did not significantly affect SICI/ICF in APB. These findings show that appropriately timed cutaneous stimuli are capable of modulating SICI in a topographically specific manner. We suggest that the selective decrease in SICI seen with cutaneous stimulation may be important for focusing of muscle activation during motor tasks.

Modification of the human motor cortex by associative stimulation.

Manipulation of afferent input is capable of inducing reorganisation of the motor cortex. For example, following 1 h of paired electrical stimulation to the motor point of two hand muscles ("associative stimulation") the excitability of the corticospinal projection to the stimulated muscles is increased. Here we investigated the mechanisms responsible for such change using transcranial magnetic stimulation (TMS). Cortical excitability changes were investigated by measuring motor evoked potentials (MEPs), intracortical inhibition (ICI), intracortical facilitation (ICF), and short-interval intracortical facilitation (SICF). Following 1 h of associative stimulation MEP amplitudes in the stimulated muscles significantly increased. Additionally, there was a significant increase in ICF and of SICF at interstimulus intervals in the range of 2.3-3.3 ms. There was no significant change in ICI. These findings confirm previous observations that a 1-h period of associative stimulation can increase the excitability of the cortical projection to stimulated muscles. Additionally, these results suggest that the observed modifications of excitability are due to changes in intracortical excitatory circuits.

Does induction of plastic change in motor cortex improve leg function after stroke?

Combined peripheral nerve and brain stimulation ("dual stimulation") induces changes in the excitability of normal motor cortex. The authors sought to establish whether dual stimulation would also induce motor cortex plasticity and associated functional improvements in nine stroke patients with chronic stable hemiparesis. Following 4 weeks of daily dual stimulation, improvements were seen in some neurophysiological and functional measures. This technique may offer therapeutic opportunities in some stroke patients.