It’s a question Professor Matthew Kiernan, Bushell Chair of Neurology at the University of Sydney and Co-Director of Discovery and Translation at the Brain and Mind Centre, thinks about often.

“For patients with a motor neuron disease like ALS, it can seem like it comes out of nowhere,” he says. “I’ve seen patients with no other serious health issues develop severe disability over the course of 18 to 24 months. And it’s heartbreaking when they ask, why me?”

Cortical hyperexcitability results from a reduction in, or lack of, short-interval intracortical inhibition (SICI). This lack of inhibition leads to overaction in the upper motor neurons that control human movement. The condition is a known hallmark of ALS,^2-4 but the potential for cortical hyperexcitability, according to Prof. Kiernan, is something we are all born with.

“We know that newborns, in their first few weeks of life, have more excitatory pathways in their brains,” Prof. Kiernan says. “Gradually, within the course of a few months, this changes. The process is not very well understood at a biological level, but the brain switches from an excitatory brain to an inhibitory brain. Subsequently, when ALS manifests, patients experience another switch from inhibitory back to excitatory. The disease seems to be, in some way, reactivating these pathways.”^5,6 Over time, this hyperexcitability becomes permanent, leading to neuron death and loss of muscle function in patients with ALS.^2,4,7

The destruction of upper motor neurons caused by cortical hyperexcitability is thought to be related to the ALS symptom known as “split-hand syndrome.”^2,4

“This is one of the most common presentations of ALS, when the muscle in the first dorsal interossei becomes wasted,”^2,4 says Prof. Kiernan. “We're unusual as humans in that we’re the only mammals with a pincer grip. But for as evolved as we are, one of the vulnerabilities in our highly developed motor system—at least when it comes to ALS manifestation—is its large representation in our hand grip function.” This insight is consistent with Prof. Kiernan’s observation about the natural excitability of the brain: in mapping the development of common ALS hallmarks, the trail leads him back to the evolutionary developments and biological processes we’re all born with.

Traditionally, the theory of cortical hyperexcitability in ALS—or any theory about the origins of neuromuscular diseases that hinged on neurology alone—was controversial.

According to Prof. Kiernan, another hypothesis held that ALS onset was at least somewhat random, and that “upper and the lower motor neurons weren't related. For whatever reason, the disease just kicked off everywhere at once.” This theory never sat well with Prof. Kiernan. “When you think about any biological phenomenon, most of them have an origin. Most things start somewhere.” Prof. Kiernan began trying to pinpoint that “somewhere” by phenotyping patients with genetic ALS.

Prof. Kiernan and his colleagues have spent a long time investigating the connections between cortical hyperexcitability and genetic ALS mutations, and how those connections might affect disease onset.

“We started by studying families where a genetic ALS mutation was present, but whose members had no manifestation of the disease. And what we discovered was that their cortical function was normal. So then we began studying them longitudinally; they would come back every 6 to 12 months and we'd study their brain function. Eventually, a number of them developed hyperexcitability in their brains. This was followed, 6 to 9 months later, by the development of clinical symptoms.”^4,8

Prof. Kiernan and his team saw the pattern: the presence of a genetic ALS mutation is often followed by the development of cortical hyperexcitability, which is generally followed some months later by the onset of ALS symptoms.^4,8 “We've seen that hyperexcitability often predates clinical features by a period of 6 to 12 months. This is only an estimate at this point. With better technology, we'll hopefully be able to develop a much more precise understanding.”

The technology Prof. Kiernan and his team rely on to measure cortical hyperexcitability in their lab is known as transcranial magnetic stimulation (TMS). “TMS is noninvasive. We use it to observe the speed of signals traveling through the brain and the spinal cord.^3,9 The technology, at this point, doesn’t allow us to go down to a molecular level to observe a single cell. What we’re seeing is more likely a group of neurons that innervate a particular muscle. But it is still quite effective to take measurements in this way. Then, in 6 to 9 months, we observe the same area on the same patients and take the measurement again.”

Prof. Kiernan is adamant about the potential cortical hyperexcitability holds as a measure of disease activity. “We need to understand the biology of this disease very intricately,” he says. “Otherwise, everything else is a shot in the dark. If we can monitor patients’ disease course with measures of cortical hyperexcitability, we may develop a better understanding of the process of the disease itself—and that is an important step to developing new ways of managing genetic ALS clinically.”