Objectives Amyotrophic lateral sclerosis (ALS) is characterised by focal disease onset with a predominantly contiguous pattern of disease spread. The pathophysiological mechanisms underlying disease progression in ALS have not been elucidated. Given that cortical hyperexcitability has been identified as an important pathogenic mechanism in ALS, the aim of the present study was to determine whether changes in cortical function could mediate disease spread in ALS.
Methods Threshold tracking transcranial magnetic stimulation (TMS) was undertaken in 50 sporadic ALS patients with recording of responses over both abductor pollicis brevis muscles, with results matched to clinical assessments and concurrent neurophysiological interrogation of lower motor neuron function. Subsequently, patients were followed longitudinally to map patterns of clinical disease progression.
Results Cortical dysfunction was evident over both motor cortices, with hyperexcitability more prominent over the dominant motor cortex, contralateral to site of disease onset, with reduction of resting motor threshold (F=3.83, p<0.05), short interval intracortical inhibition (F=15.0, p<0.0001) and cortical silent period duration (F=8.01, p<0.01), along with an increase in motor evoked potential amplitude (F=5.66, p<0.01). In addition, patterns of cortical change were consistent with a contiguous pattern of disease progression.
Conclusions Cortical hyperexcitability appears to be more prominent over the dominant motor cortex, contralateral to the side of symptom onset, and contributes to a contiguous pattern of spread in sporadic ALS.
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