Background

The brain’s ability to change in response to experience, known as plasticity, is crucial for learning, memory, and recovery from injury. Most research focuses on synaptic plasticity: changes at the connections between neurons. However, the brain also adapts through intrinsic plasticity, in which changes occur to the excitability of axons thereby regulating action potential firing^1,2. Intrinsic plasticity is poorly understood in humans due to a lack of specific, non-invasive measurement tools. Controllable pulse transcranial magnetic stimulation (cTMS) allows for the systematic variation of pulse shape to directly measure changes in axonal excitability³ thereby dissociating synaptic and intrinsic effects. We sought to determine if motor skill learning in humans is accompanied by changes to the strength-duration time constant (SDTC), a biophysical property reflecting voltage-gated sodium channel activity in the axonal membrane⁴, supporting a role for intrinsic plasticity in the human motor cortex.

Methods

11 healthy adults completed a ballistic thumb abduction task known to drive plasticity⁵. Task performance kinematics were recorded by accelerometery. Motor-evoked potentials (MEPs) were recorded by electromyography (EMG) in response to cTMS stimulation across a range of pulse widths (30, 60, 90, 120 µs) and intensities (90–120%RMT) to derive input-output curves and SDTC before and after practice (5-min, 30-min, 60-min) from the trained APB and a control muscle (ADM). Procedures adhered to the Declaration of Helsinki and were approved by the King’s College London Research Ethics Committee (HR-24/25-39903). All participants were free from neurological or psychiatric disorders and not taking neuroactive medications.

Results

Our interim results (n=11) confirm that motor practice leads to performance gains measured as increased acceleration during thumb abduction (main effect of time: F_(4,40)=16.4, p<0.0001, η²=0.62; baseline vs 1-hr retention:  14.2±2.8 vs 35.5±5.5 m/s²; t₁₀=5.3, p_holm=0.002). We find MEP amplitudes for the APB are increased following motor practice with a clear trend towards a sustained elevation up to 60 min (5-min: t₁₀=2.4, p_holm=0.07, d=0.73; 30-min: t₁₀=2.7, p_holm=0.06, d=0.83; 60-min: t₁₀=1.8, p_holm=0.10, d=0.53). Crucially, we observe a pattern of transient increase in SDTC for the APB (5-min: 9±2%; 30-min: 7±2%) that appears to return to baseline levels over the same period (60-min: -3±1%) and is not apparent in the ADM (5-min: -2±2%). Whilst these trends do not reach statistical significance (muscle x time interaction effect: F_(4,40)=1.47, p=0.22) a power analysis indicates that n=26 will be sufficient to detect a significant muscle x time interaction (α=0.05, 1−β=0.8) which we will target with ongoing data collection.

Conclusions

Whilst preliminary, these findings hint towards a dissociation between synaptic and intrinsic effects: MEPs increase after training and remain elevated, whereas SDTC rises immediately but returns to baseline within 60 min. This pattern raises the possibility for interactions between the two mechanisms, where transient intrinsic changes facilitate (metaplasticity) or maintain balance (homeostasis) after synaptic facilitation; interactions not previously demonstrated in humans. Irrespective of the outcome, these findings will establish a role for intrinsic plasticity in the human motor cortex during motor skill learning, with clinical relevance to the development of neurorehabilitation strategies for patients recovering from stroke, brain injury, or other neurological conditions.