Biology subjects

Rothwell, J. C.

Publications and source records attributed to Rothwell, J. C..

12 recordsLinked to original sources

bioRxiv2025

Distinct impacts of sodium channel blockers on the strength-duration properties of human motor cortex neurones

Voltage-gated sodium channels (VGSCs) are essential for regulating axonal excitability in the human brain. While sodium channel blockers are known to modulate neuronal excitability, their in vivo effects on the human cortex remain poorly understood. Here, we employed novel transcranial magnetic stimulation (TMS) measures to investigate the effects of sodium channel blockers, carbamazepine and lacosamide, on the strength-duration behaviour of human cortical neurones, serving as an index of sodium channel function. Our data showed that single doses of both medications elevated resting motor thresholds compared to placebo, indicating reduced excitability; however, their impacts varied according to TMS pulse width. Carbamazepine raised thresholds proportionally across all pulse widths, whereas lacosamide disproportionately influenced thresholds for long-duration pulses. Crucially, lacosamide reduced the strength-duration time constant and increased rheobase, while carbamazepine had minimal effects on both. These results reveal subtle and unexpected differences in cortical neurone behaviour following VGSC-blocking medication administration. Lacosamides response aligns with the proposed mechanism of sodium conductance blockade, while carbamazepines effects suggest distinct VGSC interactions or potential off-target effects. Our findings advance the understanding of VGSC-blocking medication interactions in the human cortex and underscore the importance of employing specific TMS measures to gain deeper insights into medication mechanisms of action in vivo. Such measures could serve as valuable adjuncts in medication development and patient monitoring, enhancing understanding of medication action in clinical settings.

neuroscience↗

bioRxiv2023

From Inhibition to Excitation and Why: The Role of Temporal Urgency in Modulating Corticospinal Activity

Previous research on movement preparation identified a period of corticospinal suppression about 200 ms prior to movement initiation. This phenomenon has been observed for different types of motor tasks typically used to investigate movement preparation (e.g., reaction time, self-initiated, and anticipatory actions). However, we recently discovered that this phenomenon is not observed when actions must be initiated under time pressure. In the present study, we investigated urgency effects on corticospinal suppression throughout the time course of an anticipatory timing task. Participants were required to perform timing actions under two urgency scenarios, high and low, and we applied single-pulse transcranial magnetic stimulation at different times during the time course of preparation. We analysed the time course of excitability under high and low scenarios in relation to expected and actual movement onset times. Our results confirmed our earlier findings that corticospinal suppression is not observed when participants perform actions under high urgency scenarios. In addition, we found no evidence that this preparatory suppression could be shifted in time to occur later under high urgency scenarios. Moreover, we found evidence that responses prepared under high urgency are more likely to be disrupted by external events (e.g., TMS pulses). These results suggest that preparatory suppression might be a strategy employed by the central nervous system to shield motor actions from interference of external events (e.g., loud sounds) when time allows. Given these data, we propose conceptual models that could account for the absence of preparatory suppression under time pressure to act.

neuroscience↗

bioRxiv2022

Transcranial alternating current stimulation does not modulate corticospinal activity in humans

Transcranial alternating current stimulation (TACS) is commonly used to synchronise the output of a cortical area to other parts of the nervous system, but evidence for this based on brain recordings in humans is challenging. The brain transmits beta oscillations (~21Hz) to tonically contracted limb muscles linearly and through the fastest corticospinal pathways. Therefore, muscle activity may be used as a proxy measure for the level of beta entrainment in the corticospinal tract due to TACS over motor cortex. Here, we assessed if TACS is able to modulate the neural inputs to muscles, which would provide an indirect evidence for TACS-driven neural entrainment. In the first part of this study, we ran a series of simulations of motor neuron (MN) pools receiving inputs from corticospinal neurons with different levels of beta entrainment. Results indicated that MNs should be highly sensitive to changes in corticospinal beta activity. Then, we ran experiments on healthy human subjects (N=10) in which TACS (at 1mA) was delivered over the motor cortex at 21Hz (beta stimulation), or at 7Hz or 40Hz (control conditions) while the abductor digiti minimi (ADM) or the tibialis anterior muscle (TA) were tonically contracted. Muscle activity was measured using high-density electromyography, which allowed us to decompose the spiking activity of pools of motor units innervating the studied muscles. By analysing motor unit pool activity, we observed that none of the tested TACS conditions could consistently alter the spectral characteristics of the common neural inputs received by the muscles. These results suggest that 1mA-TACS over motor cortex given at frequencies in the beta band does not affect corticospinal beta entrainment. Highlights- TACS is commonly used to entrain the communication between brain regions - It is challenging to find direct evidence supporting TACS-driven neural entrainment - Simulations show that motor neurons are sensitive to corticospinal beta entrainment - Motor unit activity from human muscles does not support TACS-driven entrainment

neuroscience↗

bioRxiv2021

Detection of Motor-Evoked Potentials Below the Noise Floor: Rethinking the Motor Threshold

BackgroundMotor-evoked potentials (MEP) are one of the most prominent responses to brain stimulation, such as supra-threshold transcranial magnetic stimulation (TMS) and electrical stimulation. Understanding of the neurophysiology and the determination of the lowest stimulation strength that evokes responses requires the detection of even smaller responses, e.g., from single motor units. However, available detection and quantization methods suffer from a large noise floor. ObjectiveThis paper develops a detection method that extracts MEPs hidden below the noise floor. With this method, we aim to estimate excitatory activations of the corticospinal pathways well below the conventional detection level. MethodsThe presented MEP detection method presents a self-learning matched-filter approach for improved robustness against noise. The filter is adaptively generated per subject through iterative learning. For responses that are reliably detected by conventional detection, the new approach is fully compatible with established peak-to-peak readings and provides the same results but extends the dynamic range below the conventional noise floor. ResultsIn contrast to the conventional peak-to-peak measure, the proposed method increases the signal-to-noise ratio by more than a factor of 5. The first detectable responses appear to be substantially lower than the conventional threshold definition of 50 V median peak-to-peak amplitude. ConclusionThe proposed method shows that stimuli well below the conventional 50 V threshold definition can consistently and repeatably evoke muscular responses and thus activate excitable neuron populations in the brain. As a consequence, the IO curve is extended at the lower end, and the noise cut-off is shifted. Importantly, the IO curve extends so far that the 50 V point turns out to be closer to the center of the logarithmic sigmoid curve rather than close to the first detectable responses. The underlying method is applicable to a wide range of evoked potentials and other biosignals, such as in electroencephalography.

neuroscience↗

bioRxiv2021

Rise-to-threshold and dynamical systems views of proactive inhibition

Successful models of movement should encompass the flexibility of the human motor system to execute movements under different contexts. One such context-dependent modulation is proactive inhibition, a type of behavioural inhibition concerned with responding with restraint. Whilst movement has classically been modelled as a rise-to-threshold process, there exists a lack of empirical evidence for this in limb movements. Alternatively, the dynamical systems view conceptualises activity during motor preparation as setting the initial state of a dynamical system, that evolves into the movement upon receipt of a trigger. We tested these models by measuring how proactive inhibition influenced movement preparation and execution in humans. We changed the orientation (PA: postero-anterior and AP: antero-posterior flowing currents) and pulse width (120 s and 30 s) of motor cortex transcranial magnetic stimulation to probe different corticospinal interneuron circuits. PA and AP interneuron circuits represent the dimensions of a state space upon which motor cortex activity unfolds during motor preparation and execution. AP30 inputs were inhibited at the go cue, regardless of proactive inhibition, whereas PA120 inputs scaled inversely with the probability of successful inhibition. When viewed through a rise-to-threshold model, proactive inhibition was implemented by delaying the trigger to move, suggesting that motor preparation and execution are independent. A dynamical systems perspective showed that proactive inhibition was marked by a shift in the distribution of interneuron networks (trajectories) during movement execution, despite normalisation for reaction time. Viewing data through the rise-to-threshold and dynamical systems models reveal complimentary mechanisms by which proactive inhibition is implemented. Key pointsO_LIWe view proactive inhibition through the rise-to-threshold and dynamical systems models. C_LIO_LIWe change the orientation (PA: postero-anterior and AP: antero-posterior flowing currents) and pulse width (120 s and 30 s) of transcranial magnetic stimulation to probe interneuron networks in motor cortex during behavioural tasks employing proactive inhibition. C_LIO_LIWhen viewed through a rise-to-threshold model, proactive inhibition was implemented by delaying the trigger to move, suggesting that motor preparation and execution are independent. C_LIO_LIA dynamical systems perspective showed that despite normalisation for reaction time, the trajectory/balance between PA120 and AP30 interneuron inputs during movement execution depended on proactive inhibition. C_LIO_LIViewing data through the rise-to-threshold and dynamical systems models reveal complimentary mechanisms by which proactive inhibition is implemented. C_LI

neuroscience↗

bioRxiv2020

Only the fastest corticospinal fibers contribute to beta corticomuscular coherence

A common way to study human corticospinal transmission is with transcranial magnetic stimulation. However, this is biased to activity in the fastest conducting axons. It is unclear whether conclusions obtained in this context are representative of volitional activity in mild-to-moderate contractions. A possible alternative to overcome this limitation is to study the corticospinal transmission of endogenously generated brain activity. Here we study the transmission speeds of cortical beta rhythms travelling to the muscles during steady contractions. To do this, we introduce new methods to improve delay estimates in the corticomuscular transmission of beta rhythms, and which we validate both in simulations and experimentally. Applying these approaches to experimental data from humans, we show that corticomuscular beta transmission delays are only 1-2ms longer than expected from the fastest corticospinal pathway. Simulations using realistic distributions of the conduction velocities for descending axons projecting to lower motoneurons suggest two scenarios that can explain these results: either a very small fraction of only the fastest corticospinal axons selectively transmit beta activity, or else the entire pool does. The implications that these two scenarios have for our understanding of corticomuscular interactions are discussed in the final part of this manuscript. SIGNIFICANCEWe present and validate an improved methodology to measure the delay in the transmission of cortical beta activity to tonically active muscles. The estimated corticomuscular beta transmission delays which this yields are remarkably similar to those expected from transmission in the fastest corticospinal axons. A simulation of beta transmission along a pool of corticospinal axons using a realistic distribution of fiber diameters suggests two possible mechanisms by which fast corticomuscular transmission is achieved: either a very small fraction of descending axons transmits beta activity to the muscles or, alternatively, the entire population does and natural cancellation of slow channels occurs due to the distribution of axon diameters in the corticospinal tract.

neuroscience↗

bioRxiv2020

Ropinirole, a dopamine agonist with high D3 affinity, reduces proactive inhibition: a double-blind, placebo-controlled study in healthy adults

Response inhibition describes the cognitive processes mediating the suppression of unwanted actions. A network involving the basal ganglia mediates two forms of response inhibition: reactive and proactive inhibition. Reactive inhibition serves to abruptly stop motor activity, whereas proactive inhibition is goal-orientated and results in slowing of motor activity in anticipation of stopping. Due to its impairment in several psychiatric disorders, the neurochemistry of response inhibition has become of recent interest. Dopamine has been posed as a candidate mediator of response inhibition due to its role in functioning of the basal ganglia and the observation that patients with Parkinsons disease on dopamine agonists develop impulse control disorders. Although the effects of dopamine on reactive inhibition have been studied, substantial literature on the role of dopamine on proactive inhibition is lacking. To fill this gap, we devised a double-blind, placebo-controlled study of 1 mg ropinirole (a dopamine agonist) on response inhibition in healthy volunteers. We found that whilst reactive inhibition was unchanged, proactive inhibition was impaired when participants were on ropinirole relative to when on placebo. To investigate how ropinirole mediated this effect on proactive inhibition, we used hierarchical drift-diffusion modelling. We found that ropinirole impaired the ability to raise the decision threshold when proactive inhibition was called upon. Our results provide novel evidence that an acute dose of ropinirole selectively reduces proactive inhibition in healthy participants. These results may help explain how ropinirole induces impulse control disorders in susceptible patients with Parkinsons disease.

neuroscience↗

bioRxiv2020

Comparison between conventional electrodes and ultrasound monitoring to measure TMS evoked muscle contraction

BackgroundTranscranial Magnetic stimulation (TMS) is a non-invasive cortical stimulation method that has been widely employed to explore cortical physiology in health and a range of diseases. At the core of many TMS protocols is the measurement of evoked muscle contractions using surface electromyography (sEMG). While sEMG is appropriate for many superficial muscles such as abductor pollicis brevis (ABP) and first dorsal interosseous (FDI), there are situations where the study of less accessible muscles may be of interest. Peripheral ultrasound is a non-invasive method that could provide a solution. We explore the relationship between TMS evoked sMEP and TMS evoked muscle contractions measured with muscle ultrasound. We hypothesise that in a healthy population, we expect a positive correlation between EMG and ultrasound measures. MethodsIn 10 participants we performed a standard TMS recruitment curve and simultaneously measured MEP and peripheral muscle ultrasound (pUS). We targeted the following muscles: biceps (BI), first dorsal interosseous (FDI), tibialis anterior (TA) and the tongue (TO). ResultsWe report a very close relationship between the MEP and pUS contraction. Resting motor threshold (RMT) measurements and recruitment curves are consistent in sEMG and pUS. A key aspect of this work is the ability to examine clinically relevant muscles that are difficult to probe using surface EMG electrodes, such as the tongue. ConclusionWe find that TMS muscle contractions can be measured with muscle ultrasound in superficial and deep muscles, enable additional, previously hard to study muscles, to be investigated. This could be valuable for allowing TMS to be used to explore a new range of muscles in disorders such as ALS. In muscles less accessible by sEMG, such as the tongue, it may be possible to use pUS as an alternative output. This may be useful in conditions such as ALS and stroke that can differentially affect the tongue.

neuroscience↗

bioRxiv2019

Short interval intracortical inhibition as measured by TMS-EEG

The diagnosis of amyotrophic lateral sclerosis (ALS) relies on involvement of both upper (UMN) lower motor neurons (LMN). Yet, there remains no objective marker of UMN involvement, limiting early diagnosis of ALS. This study establishes whether TMS combined with EEG can be used to measure short-interval intracortical inhibition (SICI) via TMS evoked potentials (TEP) in healthy volunteers - an essential first step in developing an independent marker of UMN involvement in ALS.\n\nWe hypothesised that a SICI paradigm would result in characteristic changes in the TMS-evoked EEG potentials that directly mirror the changes in MEP.\n\nTMS was delivered to the left motor cortex using single-pulse and three inhibitory stimulation paradigms. SICI was present in all three conditions. TEP peaks were reduced predominantly under the SICI 70 protocol but less so for SICI 80 and not at all for SICI 90. There was a significant negative correlation between MEPs and N45 TEP peak for SICI 70 (rho = -0.54, p = 0.04). In other words, as MEPs becomes inhibited the N45 increases. The same trend was maintained across SICI 80 and 90 (SICI 80, rho = -0.5, p = 0.06; SICI 90, rho = -0.48, p = 0.07). Additional experiments suggest these results cannot be explained by artefact.\n\nWe establish that motor cortical inhibition can be measured during a SICI 70 protocol expanding on previous work. We have carefully considered the role of artefact in TEPs and have taken a number of steps to show that artefact cannot explain these results and we suggesting the differences are cortical in origin. TMS-EEG has potential to aid early diagnosis and to further understand central and peripheral pathophysiology in MND.

neuroscience↗

bioRxiv2018

Excitability changes in the motor cortex in preparation for self-paced and cue-guided movements: a transcranial magnetic stimulation study

In a warned reaction time (RT) task, corticospinal excitability (CSE) decreases in task-related muscles at the time of the imperative signal (preparatory inhibition). Because RT tasks emphasise speed of response, it is impossible to distinguish whether preparatory inhibition reflects a mechanism preventing premature reactions, or whether it is an inherent part of movement preparation. We used transcranial magnetic stimulation (TMS) to study CSE changes preceding RT movements and movements that were either self-paced (SP) or performed at predictable times to coincide with an external event (PT). Results show that CSE changes over a similar temporal profile in all cases, suggesting that preparatory inhibition is a necessary state in planned movements allowing the transition between rest and movement. Additionally, TMS given shortly before the times to move speeded the onset of movements in both RT and SP contexts, suggesting that their initiation depends on a form of trigger that can be conditioned by external signals. On the contrary, PT movements do not show this effect, suggesting the use of a mechanistically different triggering strategy. This relative immunity of PT tasks to be biased by external events may reflect a mechanism that ensures priority of internal predictive signals to trigger movement onset.

neuroscience↗

bioRxiv2017

Reward and punishment enhance motor adaptation in stroke

The effects of motor learning, such as motor adaptation, in stroke rehabilitation are often transient, thus mandating approaches that enhance the amount of learning and retention. Previously, we showed in young individuals that reward-and punishment-feedback have dissociable effects on motor adaptation, with punishment improving adaptation and reward enhancing retention. If these findings were able to generalise to stroke patients, they would provide a way to optimize motor learning in these patients. Therefore, we tested this in 45 chronic stroke patients allocated in three groups. Patients performed reaching movements with their paretic arm with a robotic manipulandum. After training (day 1), day 2 involved adapting to a novel force-field. During this adaptation phase, patients received performance-based feedback according to the group they were allocated: reward, punishment or no feedback (neutral). On day 3, patients readapted to the force-field but all groups now received neutral feedback. All patients adapted, with reward and punishment groups displaying greater adaptation and readaptation than the neutral group, irrespective of demographic, cognitive or functional differences. Remarkably, the reward and punishment groups adapted to similar degree as healthy controls. Finally, the reward group showed greater retention. This study provides, for the first time, evidence that reward and punishment can enhance motor adaptation in stroke patients. Further research on reinforcement-based motor learning regimes is warranted to translate these promising results into clinical practice and improve motor rehabilitation outcomes in stroke patients.

neuroscience↗

bioRxiv2016

The effect of subthreshold transcranial magnetic stimulation on the excitation of corticospinal volleys with different conduction times

Previous studies in humans interested in inhibitory synaptic activity at the level of the primary motor cortex (M1) have frequently used an electrophysiological technique call short intracortical inhibition (SICI). This technique consists of two subsequent pulses with transcranial magnetic stimulation (TMS), of which the first pulse (S1) has been argued to target local inhibitory connections, reducing corticospinal output generated by the second pulse (S2). However, the reduction of corticospinal output is not seen in every tested subject, sometimes S1 even increased corticospinal output. Thus there seems to be more occurring than just the targeting of local inhibitory connections by S1, indicating that the mechanisms of SICI are not fully understood. In the present study, in 18 healthy young subjects we applied a method allowing to segregate corticospinal volleys with different conduction times and investigated the effect of S1 on the excitation of these volleys. Our results revealed three major findings, which can be summarized as follows: i) S1 acted not only locally at the level of M1, but produced corticospinal activity which may influence corticospinal output by S2 at the spinal level; ii) there was not only reduced excitation of corticospinal volleys by S1, but also an increased excitation of corticospinal volleys with longer conduction times; iii) at the level of M1, S1 indeed targeted preferentially inhibitory synaptic connections, and these reduced corticospinal excitation of the fastest conduction corticospinal volleys.\n\nOur results indicate that underlying mechanisms in studies applying SICI should be interpreted with caution.

neuroscience↗