The Effect of Repetitive Transcranial Magnetic Stimulation on Motor Symptoms in Hereditary Spastic Paraplegia.

Background: Hereditary spastic paraplegia (HSP) is a heterogeneous group of inherited disorders affecting predominantly the motor cortex and pyramidal tract, which results in slowly progressing gait disorders, as well as spasticity and weakness of lower extremities. Repetitive transcranial magnetic stimulation (rTMS) has been previously investigated as a therapeutic tool for similar motor deficits in a number of neurologic conditions. The aim of this randomized, controlled trial was to investigate the therapeutic potential of rTMS in various forms of HSP, including pure and complicated forms, as well as adrenomyeloneuropathy. Methods: We recruited 15 patients (five women and 10 men; mean age 43.7 ± 10.6 years) with the mentioned forms of HSP. The intervention included five sessions of bilateral 10 Hz rTMS over primary motor areas of the muscles of lower extremities and five sessions of similar sham stimulation. Results: One patient dropped out due to seizure, and 14 patients completed the study protocol. After real stimulation, the strength of the proximal and distal muscles of lower extremities increased, and the spasticity of the proximal muscles decreased. Change in spasticity was still present during follow-up assessment. No effect was observed regarding gait velocity. No changes were seen after sham stimulation. A post hoc analysis revealed an inverse relation between motor threshold and the change of the strength after active rTMS. Conclusions: rTMS may have potential in improving weakness and spasticity of lower extremities in HSP, especially of proximal muscles whose motor areas are located more superficially. This trial is registered with Clinicaltrials.gov NCT03627416.

Understanding the structure details when drying hydrate crystals of pharmaceuticals - interpretations from diffuse scattering and inter-modulation satellites of a partially dehydrated crystal.

Simplified models for the crystal lattice of the sesquihydrate form of the hemi-sulfate salt of (5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazol[4,5b]pyridin-1-yl)-1-piperidine carboxylate (BMS-927711, C28H29F2N6O3(+)) are used to calculate diffuse diffraction features in order to develop a mechanistic understanding of the dehydration process with respect to disruption of the lattice, since a Bragg model cannot be established. The model demonstrates that what we observe when the water leaves the crystal is partial transformation from the parent form to a child form (a new form, less hydrated and structurally related to the parent). Yet this `dried' structure is not a pure phase. It consists of semi-random layers of both child, parent and an interfacial layer which has a modulated structure that represents a transitory phase. Understanding the fact that a single `dried' crystal can have the disordered layer structure described as well as understanding mechanistic relationships between the phases involved can have implications in understanding the effect of common large scale bulk drying procedures. During the development of BMS-927711, difficulties did arise during characterization of the dried bulk when using only routine solid-state analysis. The material is now better understood from this diffraction study. The diffraction experiments also reveal intermodulation satellites, which upon interpretation yield even more structural information about the crystal transformation. The model suggests the mechanism of transformation is laminar in which layers of the crystal are driven to approach a stable B-centered supercell phase of lower water content.