To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

Short-interval intracortical inhibition (SICI), intracortical facilitation (ICF) and short-interval intracortical facilitation (SICF)were assessed in the cortical motor area of the first dorsal interosseous muscle (FDI) of 16 healthy subjects. Paired-pulse TMS was delivered to the left hemisphere at the following interstimulus intervals (ISIs): 2 and 3 ms for SICI, 10 and 15 ms for ICF and 1-5 ms for SICF. Motor-evoked potentials were recorded from the resting and active right FDI. The effects exerted on SICI and ICF by four intensities (60-90% of active motor threshold, AMT) of the conditioning stimulus (S1) and by three levels of muscle contraction (10%, 25%, 50% of maximal voluntary contraction, MVC) were evaluated. The effects exerted on SICF were evaluated with two intensities (90% and 70% of AMT) of the test stimulus (S2) and with the same levels of muscle contraction. Results showed that: (i) during 10% MVC, maximum SICI was observed with S1 = 70% AMT; (ii) the amount of SICI obtained with S1 = 70% AMT was the same at rest as during 10% MVC, but decreased at higher contraction levels; (iii) ICF was observed only at rest with S1 = 90% AMT; (iv) SICF was facilitated at 10% and 25% MVC, but not at 50% MVC. We conclude that during muscle activation, intracortical excitability reflects a balance between activation of SICI and SICF systems. Part of the reduction in SICI during contraction is due to superimposed recruitment of SICF. Low intensity (70% AMT) conditioning stimuli can test SICI independently of effects on SICF at low contraction levels.

Interhemispheric interactions between the primary motor cortices (M1) have been described with a variety of TMS methods. Here we give a detailed description of the interhemispheric interactions of a period of theta burst simulation (TBS), a rapid method of producing long lasting after-effects on the excitability of the stimulated M1. A total of 18 right handed healthy subjects participated. In most experiments, continuous and intermittent TBS (cTBS and iTBS) were delivered over the right M1 using a coil orientated to induce antero-posterior followed by postero-anterior (AP-PA) currents in the brain. The intensity of stimulation was 80% of active motor threshold (AMT), and a total of 600 pulses were applied. The effects on the amplitude of motor evoked potentials (MEPs), short interval intracortical inhibition (SICI) and intracortical facilitation (ICF) were evaluated in the left and right M1 before and at three different times after TBS. We also tested long-interval intracortical inhibition (LICI) in right M1 and interhemispheric inhibition (IHI) from right to left M1. Finally, to explore the effect of different polarities of cTBS over dominant and non-dominant hemisphere we delivered AP-PA and postero-anterior followed by antero-posterior (PA-AP) cTBS over either right or left M1 and tested MEPs in both hemispheres. In the stimulated hemisphere, cTBS reduced MEPs and SICI whereas iTBS increased MEPs and SICI. In the non-stimulated hemisphere cTBS increased MEPs and reduced SICI, while iTBS reduced MEPs and increased SICI. There were no effects on ICF, LICI or IHI. Although both AP-PA cTBS and PA-AP cTBS reduced MEPs in the stimulated M1, the former increased MEPs from non-stimulated M1 whereas the latter did not. There was no difference in the effect of cTBS on the dominant or non-dominant hemisphere.