Longitudinal changes in intrinsic motoneuron excitability in amyotrophic lateral sclerosis are dependent on disease progression

Abstract

Increased amplitude of persistent inward currents (PICs) is observed in pre‐symptomatic genetically modified SOD1 mice models of amyotrophic lateral sclerosis (ALS). However, at the symptomatic stage this reverses and there is a large reduction in PIC amplitude. It remains unclear whether these changes in PICs can be observed in humans, with cross‐sectional studies in humans reporting contradictory findings. In people with ALS, we estimated the PIC contribution to self‐sustained firing of motoneurons, using the paired‐motor unit analysis to calculate the Δfrequency (ΔF), to compare the weaker and stronger muscles during the course of disease. We hypothesised that, with disease progression, ΔFs would relatively increase in the stronger muscles; and decline in the weaker muscles. Forty‐three individuals with ALS were assessed in two occasions on average 17 weeks apart. Tibialis anterior high‐density electromyograms were recorded during dorsiflexion (40% of maximal capacity) ramped contractions, followed by clinical tests. ∆F increased from 3.14 (2.57, 3.71) peaks per second (pps) to 3.55 (2.94, 4.17) pps on the stronger muscles (0.41 (0.041, 0.781) pps, standardised difference (d) = 0.287 (0.023, 0.552), P = 0.030). ∆F reduced from 3.38 (95% CI 2.92, 3.84) pps to 2.88 (2.40, 3.36) pps on the weaker muscles (−0.50 (−0.80, −0.21) pps, d = 0.353 (0.138, 0.567), P = 0.001). The ALSFRS‐R score reduced 3.9 (2.3, 5.5) points. These data indicate that the contribution of PICs to motoneuron self‐sustained firing increases over time in early stages of the disease when there is little weakness before decreasing as the disease progresses and muscle weakness exacerbates, in alignment with the findings from studies using SOD1 mice. imageKey points Research on mouse model of amyotrophic lateral sclerosis (ALS) suggests that the amplitude of persistent inward currents (PICs) is increased in early stages before decreasing as the disease progresses. Cross‐sectional studies in humans have reported contradictory findings with both higher and lower PIC contributions to motoneuron self‐sustained firing. In this longitudinal (∼17 weeks) study we tracked changes in PIC contribution to motoneuron self‐sustained firing, using the ΔF calculation (i.e. onset‐offset hysteresis of motor unit pairs), in tibialis anterior muscles with normal strength and with clinical signs of weakness in people with ALS. ΔFs decreased over time in muscles with clinical signs of weakness. The PIC contribution to motoneuron self‐sustained firing increases before the onset of muscle weakness, and subsequently decreases when muscle weakness progresses.

Persistent inward currents: PICking apart the temporal changes in intrinsic motor neuron excitability in amyotrophic lateral sclerosis

“…Trajano et al. (2023) hypothesized that Δ F would: (i) increase in early disease in muscles with preserved function; and (ii) decline with disease progression in weaker muscles, indicating that the contribution of PICs to motor neuron firing in humans with ALS mirror those of pre‐clinical studies conducted by Huh et al. (2021).…”

“…In their recent publication in The Journal of Physiology , Trajano et al. (2023), with a translational perspective in mind, sought to examine longitudinal changes in PIC contribution to self‐sustained firing of motor neurons in humans with ALS.…”

“…Trajano et al. (2023) acknowledge that a limitation of the study is the use of submaximal ramped contractions to 40% of the participants’ maximal EMG amplitudes. Therefore, only motor neurons recruited within this range were assessed.…”

“…The important step forward for the field arising from the work of Trajano et al. (2023), is that it is now established that PIC amplitude varies throughout the course of ALS disease progression in humans. Therefore, there exists the potential for PIC measurements to uncover stage‐specific pathophysiological cascades leading to systemic dysfunction in ALS.…”