MODELLING THE EMERGENCE OF ASYMMETRIC MOTOR DEFICITS IN AMYOTROPHIC LATERAL SCLEROSIS USING A BILATERAL SPINAL CENTRAL PATTERN GENERATOR

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease marked by progressive loss of motor neurons and interneurons in the brainstem and spinal cord. Early symptoms typically emerge asymmetrically, with weakness often appearing first in the dominant limb before spreading contralaterally. Although this lateralised onset is well documented in patients and SOD1 mouse models, its circuit-level origins remain poorly understood.
In this project, we develop a computational modelling framework to investigate how asymmetric degeneration within spinal locomotor circuits gives rise to lateralised motor dysfunction. We construct a bilateral mammalian spinal central pattern generator comprising reciprocally coupled flexor–extensor rhythm generators, ipsilateral interneuron populations (V1, V2a, V2b, V0c, Renshaw, and Ia pathways), and commissural interneurons (V0d, V0v, and V3 subtypes) that coordinate left–right activity. The model is informed by established experimental and computational literature and implemented in the NEST simulation environment to generate rhythmic spinal network activity. Network output is quantified using oscillation frequency, burst duration, firing rates, and phase relationships between flexor–extensor and left–right populations to characterise the emergence and progression of asymmetry.
We predict that unilateral degeneration of inhibitory interneuron populations, particularly V1 and V2b subtypes, is sufficient to drive lateralised motor deficits by disrupting flexor–extensor timing and weakening interlimb coupling. This degeneration produces altered burst timing, reduced rhythmic stability, and left–right phase shifts that recapitulate early-stage ALS.
Overall, this work provides a mechanistic framework linking circuit-level asymmetry to early ALS pathology and offers insight into therapeutic strategies aimed at preserving spinal network stability.