Cortical Dysfunction Underlies the Development of the Split-Hand in Amyotrophic Lateral Sclerosis

Abstract

The split-hand phenomenon, a specific feature of amyotrophic lateral sclerosis (ALS), refers to preferential wasting of abductor pollicis brevis (APB) and first dorsal interosseous (FDI) with relative preservation of abductor digiti minimi (ADM). The pathophysiological mechanisms underlying the split-hand phenomenon remain elusive and resolution of this issue would provide unique insights into ALS pathophysiology. Consequently, the present study dissected out the relative contribution of cortical and peripheral processes in development of the split-hand phenomenon in ALS. Cortical and axonal excitability studies were undertaken on 26 ALS patients, with motor responses recorded over the APB, FDI and ADM muscles. Results were compared to 21 controls. Short interval intracortical inhibition (SICI), a biomarker of cortical excitability, was significantly reduced across the range of intrinsic hand muscles (APBSICI ALS 0.3±2.0%, APBSICI controls 16.0±1.9%, P<0.0001; FDISICI ALS 2.7±1.7%, FDI SICI controls 14.8±1.9%, P<0.0001; ADMSICI ALS 2.6±1.5%, ADM SICI controls 9.7±2.2%, P<0.001), although the reduction was most prominent when recorded over APB/FDI. Changes in SICI were accompanied by a significant increase in motor evoked potential amplitude and reduction of cortical silent period duration, all indicative of cortical hyperexcitability, and these were most prominent from the APB/FDI. At a peripheral level, a significant increase in strength-duration time constant and reduction in depolarising threshold electrotonus were evident in ALS, although these changes did not follow a split-hand distribution. Cortical dysfunction contributed to development of the split-hand in ALS, thereby implying an importance of cortical hyperexcitability in ALS pathogenesis.

Does Sporadic Amyotrophic Lateral Sclerosis Spread via Axonal Connectivities?

“…The concept that the disease process can be primarily influenced by the cerebral cortex is corroborated by the clinical findings reported for split-hand syndrome and split-leg phenomenon [48][49][50][51][52][53][54]. Clinical sALS phenotypes that eventually allow for alternative interpretations, e. g., flail-arm or flail-leg syndrome [45][46][47]55], still require neuropathological confirmation [56,57].…”

Spinal excitability changes do not influence the mechanisms of split‐hand syndrome in amyotrophic lateral sclerosis

“…The pathophysiological mechanism of this phenomenon in ALS is uncertain. A cortical‐based process related to a larger representation of the thenar muscles has been proposed . Menon et al .…”

“…A cortical-based process related to a larger representation of the thenar muscles has been proposed. 2 Menon et al 2 reported that short interval intracortical inhibition, a biomarker of cortical excitability, was significantly reduced in the abductor pollicis brevis (APB), first dorsal interosseous (FDI), and ADM muscles in patients with ALS, although the reduction was most pronounced when recorded over APB/FDI muscles. Moreover, in a study that evaluated the cortical/peripheral stimulation evoked response (motor evoked potential/compound muscle action potential [CMAP]) ratios, Weber at al.…”

Persistent alterations in active and passive electrical membrane properties of regenerated nerve fibers of man and mice

“…It is recognized that excitability of different nerves is heterogeneous, as suggested by the 'split hand' syndrome in amyotrophic lateral sclerosis (Eisen & Kuwabara, 2012), although reflecting a primarily cortical dysfunction (Menon et al, 2014). This indicates that intrinsic functional differences of motor axons in the ulnar and median nerves could influence their response during pathological situations.…”