Maladaptation of cortical circuits underlies fatigue and weakness in ALS.

Although fatigue is frequently reported in amyotrophic lateral sclerosis (ALS), the underlying mechanisms remain to be elucidated. Cortical excitability studies were utilized to determine the contribution of central mechanisms to development of fatigue and weakness in ALS. Threshold-tracking transcranial magnetic stimulation (TMS) studies were undertaken in 16 ALS patients and 22 normal controls using a 90-mm circular coil. TMS studies were performed at baseline, immediately after a voluntary contraction (VC) period of 120 s duration (three VC periods), and at 5, 10 and 20 min after last VC. At baseline, there was a significant reduction of short-interval intracortical inhibition (SICI) at interstimulus interval of 1 ms (ALS 2.3 ± 2.3%; controls 9.5 ± 2.5%, p < 0.01) and 3 ms (ALS5.1 ± 3.4%; controls 16.8 ± 1.7%, p < 0.01) in ALS patients. Although there was a significant reduction of SICI post-VC in controls at ISI 1 ms (p < 0.05) and ISI 3 ms (p < 0.05), there was no significant change in ALS patients at ISI 1 ms (p = 0.15) or 3 ms (p = 0.31). The changes in cortical excitability correlated with fatigue (R = 0.59, p < 0.05). In conclusion, maladaptation of cortical processes related to degeneration of inhibitory GABAergic intracortical circuits, is a feature of ALS that significantly correlates with development of fatigue and weakness.