Motor training modulates intracortical inhibitory dynamics in motor cortex during movement preparation.

BACKGROUND: The primary motor cortex (M1) has a vital role to play in the learning of novel motor skills. However, the physiological changes underpinning this learning, particularly in terms of dynamic changes during movement preparation, are incompletely understood. In particular, a substantial decrease in resting gamma-amino butyric acid (GABA) activity, i.e. a release of resting inhibition, is seen within M1 as a subject prepares to move. Although there is evidence that a decrease in resting inhibition occurs within M1 during motor learning it is not known whether the pre-movement "release" of GABAergic inhibition is modulated during skill acquisition. OBJECTIVE: Here, we investigated changes in pre-movement GABAergic inhibitory "release" during training on a motor skill task. METHODS: We studied GABAA activity using paired-pulse TMS (Short-Interval Intracortical Inhibition (SICI)) during training on a ballistic thumb abduction task, both at rest and at two time-points during movement preparation. RESULTS: Improvement in task performance was related to a later, steeper, release of inhibition during the movement preparation phase. Specifically, subjects who showed greater improvement in the task in the early stages of training showed a reduced level of GABAergic release immediately prior to movement compared with those who improved less. Later in training, subjects who performed better showed a reduction in GABAergic release early in movement preparation. CONCLUSIONS: These findings suggest that motor training is associated with maintained inhibition in motor cortex during movement preparation.

Selective alteration of human value decisions with medial frontal tDCS is predicted by changes in attractor dynamics.

During value-based decision making, ventromedial prefrontal cortex (vmPFC) is thought to support choices by tracking the expected gain from different outcomes via a competition-based process. Using a computational neurostimulation approach we asked how perturbing this region might alter this competition and resulting value decisions. We simulated a perturbation of neural dynamics in a biophysically informed model of decision-making through in silico depolarization at the level of neuronal ensembles. Simulated depolarization increased baseline firing rates of pyramidal neurons, which altered their susceptibility to background noise, and thereby increased choice stochasticity. These behavioural predictions were compared to choice behaviour in healthy participants performing similar value decisions during transcranial direct current stimulation (tDCS), a non-invasive brain stimulation technique. We placed the soma depolarizing electrode over medial frontal PFC. In line with model predictions, this intervention resulted in more random choices. By contrast, no such effect was observed when placing the depolarizing electrode over lateral PFC. Using a causal manipulation of ventromedial and lateral prefrontal function, these results provide support for competition-based choice dynamics in human vmPFC, and introduce computational neurostimulation as a mechanistic assay for neurostimulation studies of cognition.

Binding space and time through action.

Space and time are intimately coupled dimensions in the human brain. Several lines of evidence suggest that space and time are processed by a shared analogue magnitude system. It has been proposed that actions are instrumental in establishing this shared magnitude system. Here we provide evidence in support of this hypothesis, by showing that the interaction between space and time is enhanced when magnitude information is acquired through action. Participants observed increases or decreases in the height of a visual bar (spatial magnitude) while judging whether a simultaneously presented sequence of acoustic tones had accelerated or decelerated (temporal magnitude). In one condition (Action), participants directly controlled the changes in bar height with a hand grip device, whereas in the other (No Action), changes in bar height were externally controlled but matched the spatial/temporal profile of the Action condition. The sign of changes in bar height biased the perceived rate of the tone sequences, where increases in bar height produced apparent increases in tone rate. This effect was amplified when the visual bar was actively controlled in the Action condition, and the strength of the interaction was scaled by the magnitude of the action. Subsequent experiments ruled out that this was simply explained by attentional factors, and additionally showed that a monotonic mapping is also required between grip force and bar height in order to bias the perception of the tones. These data provide support for an instrumental role of action in interfacing spatial and temporal quantities in the brain.

Relationship between physiological measures of excitability and levels of glutamate and GABA in the human motor cortex.

Magnetic resonance spectroscopy (MRS) allows measurement of neurotransmitter concentrations within a region of interest in the brain. Inter-individual variation in MRS-measured GABA levels have been related to variation in task performance in a number of regions. However, it is not clear how MRS-assessed measures of GABA relate to cortical excitability or GABAergic synaptic activity. We therefore performed two studies investigating the relationship between neurotransmitter levels as assessed by MRS and transcranial magnetic stimulation (TMS) measures of cortical excitability and GABA synaptic activity in the primary motor cortex. We present uncorrected correlations, where the P value should therefore be considered with caution. We demonstrated a correlation between cortical excitability, as assessed by the slope of the TMS input-output curve and MRS-assessed glutamate levels (r = 0.803, P = 0.015) but no clear relationship between MRS-assessed GABA levels and TMS-assessed synaptic GABA(A) activity (2.5 ms inter-stimulus interval (ISI) short-interval intracortical inhibition (SICI); Experiment 1: r = 0.33, P = 0.31; Experiment 2: r = -0.23, P = 0.46) or GABA(B) activity (long-interval intracortical inhibition (LICI); Experiment 1: r = -0.47, P = 0.51; Experiment 2: r = 0.23, P = 0.47). We demonstrated a significant correlation between MRS-assessed GABA levels and an inhibitory TMS protocol (1 ms ISI SICI) with distinct physiological underpinnings from the 2.5 ms ISI SICI (r = -0.79, P = 0.018). Interpretation of this finding is challenging as the mechanisms of 1 ms ISI SICI are not well understood, but we speculate that our results support the possibility that 1 ms ISI SICI reflects a distinct GABAergic inhibitory process, possibly that of extrasynaptic GABA tone.

Studying plasticity of sensory function: insight from pregnancy.

Plasticity of sensory function has become an object of study because of its proposed role in the recovery of function after central nervous system damage. Normal pregnancy may provide a useful in vivo model to study the effects of progressive reduction in the abdominal skin receptor density. As such changes are confined to abdominal skin, other parts of the body are only moderately affected by pregnancy and therefore can provide a control for other changes during pregnancy. The two-point discrimination test (TPDT) of the skin is a simple test of the sensory function. We conducted the TPDT in a pregnant population longitudinally studied at different pregnancy stages and in different skin regions. In this pregnant population, we found a reduction in sensory sensibility that was not skin region specific. In particular, the increase in abdominal circumference did not produce different effects of TPDT on the belly compared to the dorsum or the hand. This suggests that the sensory system is able to compensate for the reduction in peripheral information flow through central nervous system plasticity.

Bayesian model selection maps for group studies.

This technical note describes the construction of posterior probability maps (PPMs) for Bayesian model selection (BMS) at the group level. This technique allows neuroimagers to make inferences about regionally specific effects using imaging data from a group of subjects. These effects are characterised using Bayesian model comparisons that are analogous to the F-tests used in statistical parametric mapping, with the advantage that the models to be compared do not need to be nested. Additionally, an arbitrary number of models can be compared together. This note describes the integration of the Bayesian mapping approach with a random effects analysis model for BMS using group data. We illustrate the method using fMRI data from a group of subjects performing a target detection task.

Neurochemical effects of theta burst stimulation as assessed by magnetic resonance spectroscopy.

Continuous theta burst stimulation (cTBS) is a novel transcranial stimulation technique that causes significant inhibition of synaptic transmission for

Cortical correlates of TMS-induced phantom hand movements revealed with concurrent TMS-fMRI.

We studied an amputee patient who experiences a conscious sense of movement (SoM) in her phantom hand, without significant activity in remaining muscles, when transcranial magnetic stimulation (TMS) is applied at appropriate intensity over the corresponding sector of contralateral motor cortex. We used the novel methodological combination of TMS during fMRI to reveal the neural correlates of her phantom SoM. A critical contrast concerned trials at intermediate TMS intensities: low enough not to produce overt activity in remaining muscles; but high enough to produce a phantom SoM on approximately half such trials. Comparing trials with versus without a phantom SoM reported phenomenally, for the same intermediate TMS intensities, factored out any non-specific TMS effects on brain activity to reveal neural correlates of the phantom SoM itself. Areas activated included primary motor cortex, dorsal premotor cortex, anterior intraparietal sulcus, and caudal supplementary motor area, regions that are also involved in some hand movement illusions and motor imagery in normals. This adds support to proposals that a conscious sense of movement for the hand can be conveyed by activity within corresponding motor-related cortical structures.

Inhibitory interactions between pairs of subthreshold conditioning stimuli in the human motor cortex.

OBJECTIVE: These experiments examined short interval paired-pulse paradigms for intracortical inhibition (ICI) and facilitation (ICF). We tested whether pairs of subthreshold conditioning stimuli interact, and whether they showed rapid periodicity similar to that observed in subthreshold I-wave interaction. METHODS: Transcranial magnetic stimulation (TMS) was given over left M1 to evoke a motor-evoked potential (MEP) of approximately 1 mV peak-to-peak amplitude in the contralateral first dorsal interosseous (FDI) muscle. Each test shock (TS) was preceded by single or paired subthreshold conditioning stimuli (CS(1) and CS(2)) at short interstimulus intervals (ISIs 1-15 ms). Intensities of CS were set just below thresholds for intracortical inhibition (ICI) or intracortical facilitation (ICF). RESULTS: Each CS(single) alone had no effect on the test MEP, but with two CS, clear inhibition was elicited at certain intervals. With a CS(2)-TS interval of 2 ms, maximum suppression occurred if CS(1) was applied 1-2.5 ms before CS(2). This inhibitory effect tapered off gradually as the CS(2)-CS(1) interval was increased up to 13 ms. When facilitation was present with a CS(single)-TS interval of 10 ms, a small but non-significant extra-facilitation occurred at ISIs between CS(2) and CS(1) of 6-15 ms. CONCLUSIONS: Two subthreshold conditioning stimuli facilitate inhibition that lacks the rapid periodicity typical of I-wave interaction. The data would be compatible with a model in which synaptic inputs converge on a common inhibitory interneurone.

Parietal magnetic stimulation delays visuomotor mental rotation at increased processing demands.

Visuomotor rotation (VMR) is a variant of the classic mental rotation paradigm. Subjects perform a center-out arm reaching movement, with the instruction to point clockwise or anticlockwise away from the direction of a reaction signal by a prespecified amount. Like classic mental rotation (MR) tasks, there is a linear relationship between reaction time (RT) and required angle of rotation (angular disparity). Although functional imaging studies have consistently demonstrated parietal activations centered around the intraparietal sulcus during MR tasks, the involvement of parietal cortex in VMR has not been investigated. The aim of the present experiments was to test in human subjects whether VMR also involves activity in parietal areas. We used short trains of transcranial magnetic stimulation (TMS) to produce a temporary "virtual lesion" of the posterior parietal cortex (PPC) around the intraparietal sulcus during the reaction period of a VMR task. Four pulses of 20-Hz rTMS were applied to the left PPC, right PPC, or vertex (control condition) 100 ms after the presentation of an instruction cue. Reaction times (RTs) were evenly prolonged by right or left parietal TMS compared with vertex stimulation, but only for large angles of rotation, and without affecting the spatial accuracy of the final response. A control experiment showed that parietal rTMS did not impair visual perception or the ability to judge the size of visual angles. The data thus provide evidence for bilateral involvement of the PPC in VMR that increases with processing demands.

rTMS over the cerebellum can increase corticospinal excitability through a spinal mechanism involving activation of peripheral nerve fibres.

OBJECTIVES: Single-pulse transcranial magnetic stimulation (TMS) over the cerebellum affects corticospinal excitability by a cerebellar and a peripheral mechanism. We have investigated whether any of the long-lasting effects of repetitive TMS (rTMS) over cerebellum can also be attributed to peripheral effects. METHODS: Five hundred conditioning stimuli at 1 Hz were given over either the right cerebellum using a double-cone coil, or over the right posterior neck using a figure-8-coil. Corticospinal excitability was assessed by measuring the amplitude of motor evoked potentials (MEPs) evoked in the right and left hand and forearm muscles. Hoffman reflexes (H-reflex) were also obtained in the right flexor carpi radialis muscle. RESULTS: rTMS over either the right cerebellum or the right posterior neck significantly facilitated MEPs in hand and forearm muscles in the right but not in the left arm (n=8) for up to 30 min after the end of the train. rTMS (1 Hz) of the right neck area increased the amplitude of the H-reflex (n=5). CONCLUSIONS: Much of the persisting effects of rTMS over the cerebellum on corticospinal excitability appear to be mediated through stimulation of peripheral rather than central structures. Moreover, the results show that rTMS over peripheral areas can cause long-lasting changes in spinal reflexes.

Two phases of intracortical inhibition revealed by transcranial magnetic threshold tracking.

Intracortical inhibition was investigated in normal human volunteers by paired-pulse transcranial magnetic stimulation, using a new, computer-assisted threshold-tracking method. Motor threshold was defined as the stimulus amplitude required to evoke a motor evoked potential of 0.2 mV (peak-to-peak) in abductor pollicis brevis, and inhibition was measured as the percentage increase in threshold, when the test stimulus was preceded by a subthreshold conditioning stimulus. This method was used to investigate the dependence of intracortical inhibition on conditioning stimulus parameters and on voluntary activity. Interstimulus interval (ISI) was first stepped from 1 to 4.5 ms, as inhibition was measured using conditioning stimuli of fixed amplitude (50-90% resting motor threshold). Maximal inhibition was produced at ISIs of 1 and 2.5 ms. The effect of conditioning stimulus intensity was then assessed at these ISIs. Inhibition occurred at significantly lower conditioning stimulus intensities with ISI=1 ms than with ISI=2.5 ms. Voluntary activity reduced inhibition at both ISIs, but had a much greater effect on inhibition at ISI=2.5 ms. Inhibition during voluntary activity was also examined for single motor units in first dorsal interosseous by generating poststimulus time histograms. Inhibition, indicated by a reduction in the later peaks of increased firing, was observed with ISI=1 ms, but not with ISI=2.5 ms. We conclude that there are two distinct phases of inhibition, occurring at ISI=1 ms and ISI=2.5 ms, differing both in thresholds and susceptibility to voluntary activity.

Functional MRI of cortical activations induced by transcranial magnetic stimulation (TMS).

The effects of repetitive transcranial magnetic stimulation (rTMS) on human brain activity and associated hemodynamics were investigated by blood-oxygenation-level-dependent (BOLD) MRI using echo-planar imaging at 2.0 T. Apart from bilateral activation of the auditory cortex by the audible rTMS discharges (23 bursts, 1 s duration, 10 Hz, 10-20 s interstimulus intervals), BOLD responses were restricted to cortical representations of actual finger movements performed either voluntarily or evoked by suprathreshold rTMS of the motor cortex. Neither subthreshold rTMS of the motor cortex nor suprathreshold rTMS of the lateral premotor cortex induced a detectable BOLD response. These findings suggest that neuronal depolarization as induced by rTMS modulates the spiking output of a brain area but does not automatically alter cerebral blood flow and oxygenation. The observation of BOLD MRI activations probably reflects the afferent intracortical processing of real movements.

Motor cortex excitability following short trains of repetitive magnetic stimuli.

Trains of repetitive transcranial magnetic stimuli (rTMS) appear to have effects on corticospinal excitability that outlast the duration of the train. In order to investigate the mechanism of this effect in more detail we applied short periods of rTMS consisting of up to 20 stimuli at 5 Hz, 10 Hz or 20 Hz (rTMS) to the motor cortex at an intensity equal to resting threshold in 11 healthy, relaxed subjects. Spinal excitability, as judged by effects on the H-reflex or on transcranial anodal facilitation of the H-reflex, was not affected by the rTMS. However, cortical excitability, as judged by the effect on the size of EMG responses evoked by a suprathreshold TMS pulse, was decreased for up to 1 s after the end of rTMS. Post-train suppression was more powerful following longer trains or higher frequencies of rTMS. The predominant suppression contrasts with previous reports of facilitation, particularly after high-frequency rTMS. A second set of experiments, however, showed that this could be converted into facilitation if the intensity of rTMS was increased. We conclude that the after-effects of rTMS depend on its frequency, intensity and duration. The results are consistent with a model in which inhibition and facilitation build up gradually during the course of a conditioning train. Inhibition reaches its maximum effect after only a small number of stimuli, whereas facilitation takes longer. The threshold for evoking inhibition is lower than that for facilitation. Thus if moderate intensities of conditioning train are applied, inhibition is predominant after short trains, whereas facilitation dominates after long trains.

Predictive control of muscle responses to arm perturbations in cerebellar patients.

OBJECTIVES: To examine changes in predictive control of early antagonist responses to limb perturbations in patients with defined lesions of the cerebellum. METHODS: Eight cerebellar patients and eight sex and age matched control subjects participated. Subjects held a handle that was rotated around the elbow joint. They were instructed to hold the forearm at 90 degrees flexion against a mechanical perturbation. Extensor torque (5 Nm) was applied for 140 ms (pulse), or for 1400 ms (step) through an external motor. Motor responses were tested under two different conditions of anticipatory information. In the expected condition, subjects anticipated and received a pulse. Under the unexpected condition, subjects expected steps, but received unexpected pulses. Biceps and triceps EMG as well as angular kinematics were compared between expected and unexpected pulse perturbations to quantify possible effects of prediction. RESULTS: In all healthy subjects, the degree of overshoot in the return flexion movement was significantly less in expected pulse perturbations compared with unexpected trials. The degree of amplitude reduction was significantly smaller in the patient group than in the control group (22.8% v 40.0%). During the expected trials, latency of peak triceps activity was on average 20% shorter in the control group, but 4% larger in the cerebellar patients. CONCLUSIONS: In the expected condition, controls achieved a significant reduction in angular amplitude by generating triceps activity earlier, whereas the ability to use prediction for adjusting early antagonist responses after limb perturbation was impaired in cerebellar patients.