Amyotrophic lateral sclerosis · Grey Matter

Amyotrophic lateral sclerosis (ALS) is a degenerative disease that kills the motor neurons of the cortex, brainstem and spinal cord, so that the voluntary muscles weaken until a person cannot move, speak, swallow or breathe unaided, and it is the disease of most participants in trials of speech implants.

Amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis (ALS) is a degenerative disease that kills the motor neurons of the cortex, brainstem and spinal cord, so that the voluntary muscles weaken until a person cannot move, speak, swallow or breathe unaided, and it is the disease of most participants in trials of speech implants.

It strikes both ends of the motor pathway. The upper motor neurons of the motor cortex send their axons down the corticospinal tract, and the lower motor neurons of the brainstem and spinal cord drive the muscles; ALS loses both, so stiffness and brisk reflexes appear together with wasting and twitching. It usually begins in one limb or in the muscles of speech and swallowing and spreads. Sensation is spared, and so, in most people, is thought, although some develop changes in behaviour or language and a minority frontotemporal dementia. In 97 % of cases the dying neurons carry clumps of the protein TDP-43.

About one case in ten is familial. Repeat expansions in the gene C9orf72 are the most common cause, and mutations in SOD1 another; tofersen, which lowers SOD1, received accelerated approval in the United States in April 2023 for that form only.

It is why implants are tested in it. The cortex that plans speech keeps working while the muscles fail, and late in the disease some people are locked in with no reliable way to communicate; see speech neuroprosthesis.

It also limits them. A woman with ALS used an implant over her sensorimotor cortex at home for almost seven years, signalling with attempted hand movements; after about six years the signal shrank and imaging showed the brain atrophying, while the hardware still worked.

ALS takes away the body's outputs one by one while the person who would use them remains.

That is what makes it the first use for implants that read intention, and its slow advance into the cortex is what bounds how long they keep working.

Questions: Is glutamate to blame for the death of motor neurons in ALS? Partly, at most. Excess glutamate signalling can overload neurons with calcium and kill them, and that idea led to riluzole, a drug that dampens glutamate release and was the first treatment for ALS. Its effect is modest: in the trials it raised median survival by about two to three months, from 11.8 to 14.8 months. That suggests excitotoxicity contributes without being the whole story, and the clumps of TDP-43 protein found in almost every case point to a deeper failure inside the neurons. Why does ALS make muscles both stiff and wasted at the same time? Because it kills two kinds of motor neuron at once. The lower motor neurons in the spinal cord and brainstem connect directly to the muscles, and when they die the muscle loses its nerve supply, twitches and wastes away. The upper motor neurons in the cortex control those spinal neurons from above and hold back the spinal reflexes, so when they die the reflexes become brisk and the limbs stiff. Finding both kinds of sign in the same person is what points a neurologist to ALS. Why did a brain implant that worked for six years in a woman with ALS stop working? Because the disease reached the cortex under it. Electrode strips placed on the surface of her sensorimotor cortex in 2015 let her signal her carers with attempted hand movements, and by 2020 it had become her only way to call them, even at night. After about six years the signals shrank and her use of it fell, until it ended in 2023; scans taken eight years apart showed her brain tissue wasting, while the hardware had no fault. A device that reads the cortex lasts only as long as the cortex it reads.