Nervous system disorders I: ALS

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting roughly $2$‍ in $100,000$‍ people worldwide. While the causes of ALS are not definitively known, it is understood that the symptoms of the disease are due to the progressive degeneration of motor neurons. Interestingly, sensory afferent neurons are unaffected by the degenerative changes in ALS, while efferent motor neurons are lost both centrally and peripherally. In fact, this global quality of affected motor cells is required for a diagnosis of ALS. That is, a diagnosis requires symptoms of the loss of both upper and lower motor neurons (UMN and LMN, respectively), which may include muscle atrophy, weakness, either increased or decreased muscle tone/spasticity, and exaggerated deep tendon reflexes, for example the knee-jerk or patellar reflex (Figure $1$‍).

Figure 1: Hierarchical organization of somatic motor systems.

Upper motor neurons from the brain synapse onto lower motor neurons in the spinal cord. Lower motor neurons also receive input from sensory afferent fibers, which together mitigate spinal reflexes.

The symptoms of ALS can be understood in terms of the hierarchical organization of motor neurons. UMNs with cell bodies in the precentral gyrus project their axons from the brain to synapse onto LMNs in the ventral horn of the spinal cord. LMNs project from their respective spinal segments onto muscles at neuromuscular junctions to promote muscle contraction. Apart from UMNs, LMNs in the ventral horn also receive input from spinal interneurons, as well as sensory input from type Ia sensory axons.

This organization of neural cells creates a feedback system which serves to modulate the strength of muscle contraction, maintain passive muscle tone, and to mitigate stretch and spinal reflexes. Specialized cells within muscle fibers, known as muscle spindles, sense increased tension on a muscle or tendon. When stretched, type Ia sensory axons fire action potentials, which excite alpha motor neurons in the ventral horn, causing the muscle to contract. This contraction is modulated via feedback from UMNs. Conversely, in a situation wherein a muscle becomes increasingly relaxed, the slackened muscle spindles cease firing, and effectively fall ‘off-line’. A special type of LMN, called a gamma motor neuron, responds to the decreased firing from the muscle spindle, and causes the muscle spindle to contract, thus returning the spindle to ‘on-line’. This gamma loop, as it is known, maintains passive muscle tone.