Hereditary Spastic Paraplegia Startling Acoustic Stimulus Central Motor Conduction Time Visual Reaction Time Primary Lateral Sclerosis
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The striking paradox of pure autosomal dominant hereditary spastic paraplegia (AD HSP), in contrast to capsular stroke or primary lateral sclerosis, for example, is that despite extensive corticospinal tract (CST) degeneration and prominent lower limb spasticity, leg weakness is not a prominent early feature of the disease. Therefore, other descending motor pathways presumably compensate for CST degeneration, though, until the recent article by Nonnekes et al.  in the Journal of Neurology, this assumption had remained unproven. Using startling acoustic stimuli (SAS), they showed that the reticulospinal tract (RST) is not only functioning in patients with HSP, but that it compensates for lower limb deficits of postural control caused by CST degeneration.
In most patients with pure AD HSP, electrophysiological evidence of CST disease is limited to the lumbosacral cord . However, some AD HSP genotypes (e.g., SPG4) are associated with a more severe phenotype and have motor-evoked potential (MEP) abnormalities in the upper limbs [3, 4, 5], consistent with post-mortem evidence of CST degeneration at all levels, from the medulla to the lumbo-sacral cord .
We tested MEPs (see Supplementary Methods) in two patients (father and son) with SPG31 AD HSP (REEP1 exon 5 c.337C > T/p.Arg113X ). In patient 2 (age 42; disease duration 37 years) MEPs were ‘typical’ of pure AD HSP , with prolonged central motor conduction times (CMCTs) in the lower limbs (CMCT 22.2 ms) and normal CMCTs in the upper limbs. However, in patient 1 (age 68; disease duration 64 years) CMCTs were significantly prolonged in the upper limbs (Fig. 1).
Given the absence of clinical upper limb weakness in patient 1, we measured EMG onset latencies in a Start-React paradigm to see whether the RST might be compensating for the CST deficit in the upper limbs [9, 10, 11] (Supplementary Methods), as illustrated in Fig. 2a. Experiments had the relevant institutional ethical approval and complied with the Declaration of Helsinki, and were performed in both patients and 11 controls, aged 56–82 years. Traditionally, the effects of SAS on the visual reaction time (VRT), and the visual start-react time (VSRT), are normalized, thus:
The normal ∆VRT is ~50 % , and a ∆VRT of less than 50 % is indicative of disease affecting the RST. However, because we were interested in measuring any change in the gain of the RST output, accessed via auditory pathways, we have used a ratio that incorporates the auditory reaction time (ART) following a low-intensity sound, as follows:
where ∆TSR is the shortening effect of a SAS on the visual reaction time and ∆TAR measures the shortening of reaction time provided by a non-startling auditory stimulus, which presumably does not activate RST pathways. The results of this analysis are shown in Fig. 2c, d. Patient 2, who had no evidence of cervical CST disease, had normal ∆TSR/∆TAR ratios. However, patient 1, who had MEP evidence of cervical CST disease, had significantly increased ratios, but only when measured from biceps brachii EMG, despite normal ARTs and VRTs (Supplementary Results/Fig. 2). This result supports the notion that the RST mitigates the effects of disease within the cervical CST. The RST appears to compensate by increasing its output gain by a factor of around 1.5. Although the RST does project to both proximal and distal upper limb muscles , the effects of SAS are only seen in distal muscles in some tasks , possibly explaining why we detected differences only in the biceps muscle. These observations suggest that therapeutic interventions aimed at increasing the gain of RST outputs could improve recovery from neurological disorders characterized by CST dysfunction.
This research was funded by the Wellcome Trust, the Academy of Medical Sciences, and National Institute for Health Research.
Conflicts of interest
The authors declare that they have no conflict of interest.
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