Cortical hyperexcitability has a driving role in ALS

By Lucy Piper, Senior medwireNews Reporter

Cortical hyperexcitability is an intrinsic feature of amyotrophic lateral sclerosis (ALS) symptoms in patients carrying the chromosome 9 open reading frame 72 (c9orf72) gene hexanucleotide repeat expansion, show study findings.

Comparable findings were seen in patients with sporadic ALS, whereas hyperexcitability was not evident in ALS expansion carriers who were asymptomatic, the researchers note.

They say the findings of cortical hyperexcitability in c9orf72 familial ALS are similar to those previously reported with familial ALS due to other genetic mutations and suggest that cortical hyperexcitability may “represent a uniform pathophysiological process in ALS irrespective of underlying genetic status.”

The team suggests in JAMA Neurology: “Cortical hyperexcitability could represent one of the final steps in ALS pathogenesis, perhaps developing just prior to or at the onset of neuronal degeneration, a notion supported by findings of significant correlations between features of cortical hyperexcitability, motor amplitude, and muscle strength.”

Indeed, hypercortical excitability in the 15 c9orf72 familial ALS patients and 73 sporadic ALS patients in their study was most prominent when muscle strength and motor amplitudes were relatively preserved.

Cortical excitability variables, including short-interval intracortical inhibition (SICI), were measured using a threshold-tracking transcranial magnetic stimulation technique.

The patients with c9orf72 familial ALS had significantly reduced SICI, reflected by the increase in the conditioned stimulus intensity needed to produce a constant motor-evoked potential of 0.2 mV for between 1 and 7 milliseconds, at an average of 1.2%. This reduced value was comparable to the 1.6% seen in patients with sporadic ALS and in both cases differed significantly from the 10.2% seen in the 11 asymptomatic c9orf72expansion carriers and the 11.8% for 74 healthy individuals.

This SICI inhibition was followed by a significant increase in intracortical facilitation during interstimulus intervals of between 10 and 30 milliseconds in the ALS patients, compared with asymptomatic carriers and controls. And it was accompanied by significant increases in motor-evoked potential amplitude, resting motor threshold and cortical silent period duration.

Researcher Steve Vucic (Westmead Hospital, Sydney, New South Wales, Australia) and colleagues believe that “[t]he identification and modulation of factors that trigger cortical hyperexcitability may prove therapeutically useful.”

Brian Wainger and Merit Cudkowicz, both from Massachusetts General Hospital in Boston, USA, concur with the researchers in their related editorial and call for efforts into cortical and axonal hyperexcitability testing to advance patient care to be intensified.

“[A]bnormalities in the different excitability measurements may reflect different disease components, each with a unique temporal profile”, they note.

“Pharmacological studies must evaluate how different drugs affect cortical and axonal hyperexcitability in ALS and how modulating excitability does or does not affect clinical or composite outcomes.”

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