Persistent inward currents in spinal motoneurones: how can we study them in human participants?

Activation of a motoneurone occurs when excitatory synaptic input from descending motor pathways, or sensory projections, is sufficient to bring the membrane potential of the motoneurone above its firing threshold. The input–output gain of motoneurones is enhanced by monoamine neuromodulators released from raphe-spinal neurons (serotonin, 5-HT) and locus coeruleus neurons (noradrenaline, NA). These pathways form monosynaptic connections with the dendrites of motoneurones and have multiple effects on motoneurone excitability. Notably, 5-HT and NA have strong facilitation effects on voltage-gated persistent inward currents (PICs), which amplify synaptic input and promote the self-sustained discharge of motoneurones. In animal preparations with restricted neuromodulator release, intracellular recordings of motoneurones reveal that increasing the magnitude of injected current increases discharge rate linearly. However, in the presence of neuromodulation and PIC activation, the relationship between injected current and discharge rate becomes non-linear. This is reflected in the hysteresis between the magnitude of injected current needed for recruitment and at de-recruitment, one of many PIC-induced non-linearities (e.g. acceleration of firing, firing rate saturation). Compared to recruitment, injected current is lower at de-recruitment as less excitatory input is needed tomaintain ongoingmotoneurone discharge as PICs are active and are generating a strong intrinsic depolarization. Human motoneurones also exhibit hysteresis in the amount of excitatory drive needed to recruit compared to de-recruitment. Instead of injecting current to cause recruitment and de-recruitment, voluntary isometric contractions can be performed to activate motoneurones via synaptic input, and the magnitude of synaptic activation can be inferred from motor unit discharge recorded with electromyography (EMG). Specifically, the discharge rate of a voluntarily recruited lower-threshold ‘control’ unit can be used as an estimate of net synaptic input to the motoneurone pool and a higher-threshold ‘test’ unit. The difference in firing rates for the control unit at the time of recruitment and de-recruitment of the test unit (delta frequency, F) is used to determine the contribution of PICs to test unit activation, with smaller differences indicating a smaller contribution of PICs to motoneurone activation (Gorassini et al., 2002). Animal preparations indicate that the amplitude of PICs in motoneurones is directly proportional to neuromodulatory drive (Heckman et al., 2009), and hence estimating PIC amplitude with the paired motor unit technique provides an opportunity to study the neuromodulatory control of human motoneurones. Neuromodulatory drive to the spinal cord is dynamic, whereby the amount of monoamine release depends on certain behaviours. 5-HT release is coupled with the intensity of motor activity, where higher-intensity motor activities result in more release. NA release to the spinal cord probably corresponds with high levels of stress/anxiety. Regardless of the behaviour that facilitates neuromodulatory drive, monoaminergic projections in the spinal cord are diffuse, with axons branching at multiple spinal levels. This diffuse release can be problematic for the targeted activation of motoneurone pools, as it can increase the gain of multiple pools simultaneously, sometimes with opposing effects on joint movement (i.e. facilitation of agonist and antagonist pools can cause co-contraction). To mitigate the effects of diffuse neuromodulatory drive, and improve the specificity of motoneurone recruitment, intraspinal interneurones may act to inhibit motoneurones that are not needed for a given motor task. For example, with passive movements of the ankle that lengthen the opposing ankle flexors, Ia reciprocal inhibition markedly reduces PIC amplitude in cat ankle extensor motoneurones (Hyngstrom et al., 2007). This potentially represents a strategy to suppress PICs in motoneurones when excitability across multiple motoneurone pools is high. Although the amplitude of PICs can be estimated for human motoneurones, and inhibition and neuromodulation have strong effects on PIC amplitude in animal motoneurones, there are few human studies linking reciprocal inhibition and/or neuromodulatory drive to PIC activity.