Amyotrophic lateral sclerosis (ALS), a fatal disease causing progressive loss of motor neurons, still has no effective treatment. We developed a phenotypic screen to repurpose existing drugs using ALS motor neuron survival as readout. Motor neurons were generated from induced pluripotent stem cells (iPSCs) derived from an ALS patient with a mutation in superoxide dismutase 1 (SOD1). Results of the screen showed that more than half of the hits targeted the Src/c-Abl signaling pathway. Src/c-Abl inhibitors increased survival of ALS iPSC-derived motor neurons in vitro. Knockdown of Src or c-Abl with small interfering RNAs (siRNAs) also rescued ALS motor neuron degeneration. One of the hits, bosutinib, boosted autophagy, reduced the amount of misfolded mutant SOD1 protein, and attenuated altered expression of mitochondrial genes. Bosutinib also increased survival in vitro of ALS iPSC-derived motor neurons from patients with sporadic ALS or other forms of familial ALS caused by mutations in TAR DNA binding protein (TDP-43) or repeat expansions in C9orf72. Furthermore, bosutinib treatment modestly extended survival of a mouse model of ALS with an SOD1 mutation, suggesting that Src/c-Abl may be a potentially useful target for developing new drugs to treat ALS.

Writer's cramp, or focal hand dystonia, is characterized by involuntary coactivation of antagonist or unnecessary muscles while writing or performing other tasks. Although the mechanism underlying this muscle overactivation is unknown, recent studies of changes in cerebral blood flow during writing have demonstrated a reduction in the activation of the primary motor cortex (MC) and hyperactivity of parts of the frontal non-primary motor areas. Therefore, any measures that decrease the activities of non-primary motor areas such as the premotor cortex (PMC) and the supplementary motor area (SMA) might improve dystonic symptoms. To explore this possibility, we studied nine patients with writer's cramp and seven age-matched control subjects, using subthreshold low-frequency (0.2 Hz) repetitive transcranial magnetic stimulation (rTMS), which exerts an inhibitory action on the cortex. Previous studies have demonstrated shortened cortical silent periods in dystonia, suggesting deficient cortical inhibition in the MC. We compared the silent periods and computer-assisted ratings of handwriting before and after rTMS applied to the MC, SMA or PMC. We also used the sham coil for control runs. Stimulation of the PMC but not the MC significantly improved the rating of handwriting (mean tracking error from the target, P = 0.004; pen pressure, P = 0.01) and prolonged the silent period (P = 0.02) in the patient group. rTMS over the other sites or using a sham coil in the patient group or trials in the control group revealed no physiological or clinical changes. This increased susceptibility of the PMC in dystonia suggests that the lack of inhibition in the MC is secondary to the hyperactivity of PMC neurons. Inhibition of the PMC using rTMS could provide a therapeutic measure of writer's cramp.

One characteristic of focal dystonia is the sensory trick, by which sensory input to a certain area of the body can reduce abnormal contractions in muscles nearby. This suggests that adjusting the link between sensory input and movement allows motor commands to be issued more effectively from the brain. To explore this sensorimotor link, we studied the attenuation (gating) of somatosensory evoked potentials (SEPs) before and during hand movements in patients with writer's cramp. For premovement gating, 10 patients and 11 age-matched normal subjects were given a warning sound followed 1s later by an electric stimulus to the right median nerve at the wrist. The latter served both as a reaction signal to start a finger extension task and as the input to evoke SEPs over the scalp. Because reaction times always exceeded 70 ms, short-latency SEPs thus obtained were unaffected by the afferents activated by the movement. The amplitudes of frontal N30 components were significantly decreased over the frontal leads compared with SEPs elicited at rest (P < 0.002) in the normal group, whereas significant gating was found not for N30 but for frontal P22 (P = 0.002) in the patient group. For midmovement gating studies, SEPs to the right median nerve stimulation were recorded in 16 patients and 12 age-matched normal subjects at rest, and during active and passive finger extension–flexion movements. In contrast to the premovement SEPs, the frontal N30 was equally gated during active and passive movements both in the patient (P ≤ 0.002) and the normal group (P ≤ 0.003). These findings indicate that in writer's cramp the sensitivity of sensory input channels from the hand is wrongly set by the central command to move. Perhaps the sensory trick, by supplying additional input not usually present during unobstructed movement, is a manoeuvre to correct this imbalance. Dystonia may result not only from abnormalities in the central motor command but also from disturbed central processing of sensory input.

Dystonia is a disorder of motor programmes controlling semiautomatic movements or postures, with clinical features such as sensory trick, which suggests sensorimotor mismatch as the basis. Dystonia was originally classified as a basal ganglia disease. It is now regarded as a ‘network’ disorder including the cerebellum, but the exact pathogenesis being unknown. Rare autopsy studies have found pathology both in the striatum and the cerebellum, and functional disorganisation was reported in the somatosensory cortex in patients. Recent animal studies showed physiologically tight disynaptic connections between the cerebellum and the striatum. We review clinical evidence in light of this new functional interaction between the cerebellum and basal ganglia, and put forward a hypothesis that dystonia is a basal ganglia disorder that can be induced by aberrant afferent inputs from the cerebellum.

Lower limb spasticity in post-stroke patients can impair ambulation and reduces activities of daily living (ADL) performance of patients. Botulinum toxin type A (BoNTA) has been shown effective for upper limb spasticity. This study assesses the treatment of lower limb spasticity in a large placebo-controlled clinical trial. In this multicenter, randomized, double-blind, parallel-group, placebo-controlled study, we evaluate the efficacy and safety of one-time injections of botulinum toxin type A (BoNTA) in Japanese patients with post-stroke lower limb spasticity. One hundred twenty patients with lower limb spasticity were randomized to a single treatment with BoNTA 300 U or placebo. The tone of the ankle flexor was assessed at baseline and through 12 weeks using the Modified Ashworth Scale (MAS). Gait pattern and speed of gait were also assessed. The primary endpoint was area under the curve (AUC) of the change from baseline in the MAS ankle score. Significant improvement in spasticity with BoNTA 300 U was demonstrated by a mean difference in the AUC of the change from baseline in the MAS ankle score between the BoNTA and placebo groups (−3.428; 95% CIs, −5.841 to −1.016; p = 0.006; t test). A significantly greater decrease from baseline in the MAS ankle score was noted at weeks 4, 6 and 8 in the BoNTA group compared to the placebo group (p < 0.001). Significant improvement in the Clinicians Global Impression was noted by the investigator at weeks 4, 6 and 8 (p = 0.016–0.048, Wilcoxon test), but not by the patient or physical/occupational therapist. Assessments of gait pattern using the Physician’s Rating Scale and speed of gait revealed no significant treatment differences but showed a tendency towards improvement with BoNTA. No marked difference was noted in the frequency of treatment-related adverse events between BoNTA and placebo groups. This was the first large-scale trial to indicate that BoNTA significantly reduced spasticity in lower limb muscles.